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Especialidades médicas y/o especialidades quirúrgicas

Dermatology

Trabajo y educación

Educación

Stanford University Hospital & Clinics - Dermatology Department, Stanford, CA, 2003

Primeros años de residencia

Santa Clara Valley Medical Center, San Jose, CA, 2004

Últimos años de residencia

Stanford University Hospital & Clinics - Dermatology Department, Stanford, CA, 2007

Subespecialidad

UCSF Dept of Epidemiology and Biostatistics, San Francisco, CA, 2008

Certificado(s) de especialidad

Dermatology, American Board of Dermatology

Todo Publicaciones

Patient Reported Outcomes and Quality of Life in Recessive Dystrophic Epidermolysis Bullosa: A Global Cross-sectional Survey. Journal of the American Academy of Dermatology Eng, V. A., Solis, D. C., Gorell, E. S., Choi, S., Nazaroff, J., Li, S., de Souza, M. P., Murrell, D. F., Marinkovich, M. P., Tang, J. Y. 2020

Abstract

A spectrum of skin disease severity exists in patients with recessive dystrophic epidermolysis bullosa (RDEB).To characterize the patient reported outcomes and quality of life (QOL) in RDEB patients.A cross-sectional study of RDEB patients surveyed through the global EBCare Registry. Patient reported outcomes included skin disease severity, wound characteristics, pain, itch, extra-cutaneous symptoms, and medications. QOL was measured using the validated Quality of Life in Epidermolysis Bullosa (QOLEB) instrument.85 RDEB patients reported on 1,226 wounds (937 recurrent wounds and 289 chronic open wounds). Overall skin disease severity was self-reported as mild (26%, 22/83), moderate (48%, 40/83), or severe (25%, 21/83). Worsening skin disease severity was significantly associated with larger wounds, increased opiate use, anemia, gastrostomy tube use, infections, osteoporosis, and squamous cell carcinoma. Larger wound size was associated with worse quality of life scores.All data were self-reported from an online EB patient registry.This study shows a significant correlation between larger wound size with worsening skin disease severity and quality of life in RDEB participants. Worsening skin disease severity significantly correlated with key clinical manifestations. These results demonstrate that RDEB patients are able to self-report their skin disease severity and wounds.

View details for DOI 10.1016/j.jaad.2020.03.028

View details for PubMedID 32199895

Phase 1/2a clinical trial of gene-corrected autologous cell therapy for recessive dystrophic epidermolysis bullosa. JCI insight Eichstadt, S., Barriga, M., Ponakala, A., Teng, C., Nguyen, N. T., Siprashvili, Z., Nazaroff, J., Gorell, E. S., Chiou, A. S., Taylor, L., Khuu, P., Keene, D. R., Rieger, K., Khosla, R. K., Furukawa, L. K., Lorenz, H. P., Marinkovich, M. P., Tang, J. Y. 2019; 4 (19)

Abstract

BACKGROUNDRecessive dystrophic epidermolysis bullosa (RDEB) patients have mutations in the COL7A1 gene and thus lack functional type VII collagen (C7) protein; they have marked skin fragility and blistering. This single-center phase 1/2a open-label study evaluated the long-term efficacy, safety, and patient-reported outcomes in RDEB patients treated with gene-corrected autologous cell therapy.METHODSAutologous keratinocytes were isolated from participant skin biopsies. Epidermal sheets were prepared from cells transduced with a retrovirus carrying the full-length human COL7A1 gene. These gene-corrected autologous epidermal sheets measured 5 * 7 cm (35 cm2) and were transplanted onto 6 wound sites in each of 7 adult participants (n = 42 sites total) from 2013 to 2017. Participants were followed for 2 to 5 years.RESULTSNo participants experienced any serious related adverse events. Wound healing of 50% or greater by Investigator Global Assessment was present in 95% (36 of 38) of treated wounds versus 0% (0 of 6) of untreated control wounds at 6 months (P < 0.0001). At year 1, 68% (26 of 38) of treated wounds had 50% or greater healing compared with 17% (1 of 6) of control wounds (P = 0.025). At year 2, 71% (27 of 38) of treated wounds had 50% or greater healing compared with 17% (1 of 6) of control wounds (P = 0.019).CONCLUSIONC7 expression persisted up to 2 years after treatment in 2 participants. Treated wounds with 50% or greater healing demonstrated improvement in patient-reported pain, itch, and wound durability. This study provides additional data to support the clinically meaningful benefit of treating chronic RDEB wounds with ex vivo, C7 gene-corrected autologous cell therapy. This approach was safe and promoted wound healing that was associated with improved patient-reported outcomes.TRIAL REGISTRATIONClinicaltrials.gov identifier: NCT01263379.FUNDINGEpidermolysis Bullosa Research Partnership, Epidermolysis Bullosa Medical Research Foundation, NIH R01 AR055914, Office of Research and Development at the Palo Alto Veteran's Affairs Medical Center, and the Dermatology Foundation.

View details for DOI 10.1172/jci.insight.130554

View details for PubMedID 31578311

Phase 2 Trial of a Neurokinin-1 Receptor Antagonist for the Treatment of Chronic Itch in Epidermolysis Bullosa Patients: A Randomized Clinical Trial. Journal of the American Academy of Dermatology Chiou, A. S., Choi, S., Barriga, M., Dutt-Singkh, Y., Solis, D. C., Nazaroff, J., Bailey-Healy, I., Li, S., Shu, K., Joing, M., Kwon, P., Tang, J. Y. 2019

Abstract

BACKGROUND: Chronic pruritus causes major morbidity in epidermolysis bullosa (EB). The substance P-neurokinin 1 receptor (SP-NK1) pathway is a promising target for treating EB-related pruritus.OBJECTIVE: To evaluate the safety and efficacy of oral NK1 receptor antagonist serlopitant in treating moderate-severe pruritus in EB.METHODS: 14 patients were randomized to serlopitant or placebo for 8 weeks, followed by a 4-week washout and optional open-label extension. The primary endpoint was change in itch as measured by a numeric rating scale (NRS). Secondary endpoints were change in: (1) itch during dressing changes and (2) wound size.RESULTS: We observed greater itch reduction with serlopitant, equivalent to a 0.64-point comparative reduction on the 11-point NRS by week 8, though this failed to meet statistical significance (p=0.11). More serlopitant patients achieved 3-point reduction compared to placebo (43% vs. 14%, p=0.35). In post hoc analysis excluding one subject with a concurrent seborrheic dermatitis flare, serlopitant achieved significantly greater median itch reduction from baseline by week 4 (-2 points vs. 0, p=0.01). We observed no statistically significant differences in secondary endpoints. Serlopitant was well-tolerated.LIMITATIONS: Small sample size due to disease rarity CONCLUSION: The potential itch reduction with serlopitant observed in this trial will be pursued by a larger powered trial (NCT03836001).

View details for DOI 10.1016/j.jaad.2019.09.014

View details for PubMedID 31541747

Frequent basal cell cancer development is a clinical marker for inherited cancer susceptibility JCI INSIGHT Cho, H. G., Kuo, K. Y., Li, S., Bailey, I., Aasi, S., Chang, A. S., Oro, A. E., Tang, J. Y., Sarin, K. Y. 2018; 3 (15)

Abstract

Innate DNA repair mechanisms play a critical role in protecting skin keratinocytes from UV mutagenesis and skin cancer development. We hypothesized that individuals who develop frequent skin cancers may harbor germline defects in DNA repair genes and have increased predisposition to internal malignancies. We enrolled 61 patients with unusually frequent basal cell carcinoma (BCC) development, seen at Stanford Hospital and Clinics from January 2005 until December 2015, for germline analysis of 29 DNA repair genes. In parallel, a case-control retrospective review was performed to interrogate the association of malignancies with frequent BCC development in a large US medical insurance claims database (Truven), which included 13,264 individuals with 6 or more BCCs from 2007 to 2011. 19.7% of the frequent BCC cohort harbored pathogenic mutations in DNA repair genes: APC, BARD1, BRCA1, BRCA2, CDH1, CHEK2, MLH1, MSH2, MSH6, MUTYH, NBN, and PALB2. Individuals with 6 or more BCCs had an increased risk of other malignancies, with a 3.5-fold increase in the frequent BCC cohort and a 3.2-fold increase in the Truven database. Individuals who developed frequent BCCs have an increased prevalence of germline mutations in DNA repair genes and increased malignancy risk. Our data implicate frequent BCC development as an external marker of inherited cancer risk.

View details for DOI 10.1172/jci.insight.122744

View details for Web of Science ID 000441201300022

View details for PubMedID 30089731

Distinguishing malignant from benign microscopic skin lesions using desorption electrospray ionization mass spectrometry imaging. Proceedings of the National Academy of Sciences of the United States of America Margulis, K., Chiou, A. S., Aasi, S. Z., Tibshirani, R. J., Tang, J. Y., Zare, R. N. 2018

Abstract

Detection of microscopic skin lesions presents a considerable challenge in diagnosing early-stage malignancies as well as in residual tumor interrogation after surgical intervention. In this study, we established the capability of desorption electrospray ionization mass spectrometry imaging (DESI-MSI) to distinguish between micrometer-sized tumor aggregates of basal cell carcinoma (BCC), a common skin cancer, and normal human skin. We analyzed 86 human specimens collected during Mohs micrographic surgery for BCC to cross-examine spatial distributions of numerous lipids and metabolites in BCC aggregates versus adjacent skin. Statistical analysis using the least absolute shrinkage and selection operation (Lasso) was employed to categorize each 200-m-diameter picture element (pixel) of investigated skin tissue map as BCC or normal. Lasso identified 24 molecular ion signals, which are significant for pixel classification. These ion signals included lipids observed at m/z 200-1,200 and Krebs cycle metabolites observed at m/z < 200. Based on these features, Lasso yielded an overall 94.1% diagnostic accuracy pixel by pixel of the skin map compared with histopathological evaluation. We suggest that DESI-MSI/Lasso analysis can be employed as a complementary technique for delineation of microscopic skin tumors.

View details for PubMedID 29866838

Genomic Stability in Syndromic Basal Cell Carcinoma. The Journal of investigative dermatology Chiang, A., Jaju, P. D., Batra, P., Rezaee, M., Epstein, E. H., Tang, J. Y., Sarin, K. Y. 2017

Abstract

Basal cell cancers (BCCs) are characterized by up-regulation of Hedgehog pathway through loss of Patched1 or activation of Smoothened, and smoothened-inhibitors such as vismodegib are effective therapies for advanced BCCs. Although most BCCs are sporadic, rare individuals with Basal Cell Nevus Syndrome (BCNS) harbor germline defects in Patched1 and develop up to hundreds of tumors that are histopathologically indistinguishable from sporadic BCCs. Interestingly, BCNS-BCCs are more responsive to Smoothened-inhibitors than sporadic BCCs, with minimal development of resistance. Given differences in clinical course and therapy response, we sought to characterize BCCs in the setting of BCNS. We found that BCNS individuals with low-tumor burden demonstrated significantly fewer UV signature somatic mutations and lower overall somatic mutational load compared to BCNS individuals with high-burden, supporting a role of UV exposure in driving BCC development in BCNS individuals. However, compared with sporadic BCCs, BCNS-BCCs have a significantly lower mutational load, lower proportion of ultraviolet mutagenesis, increased genomic stability, and harbor fewer functionally resistant Smoothened mutations at baseline, explaining why BCNS-BCCs lack intrinsic resistance to Smoothened-inhibitors. BCNS-BCCs appear to have reduced mutator phenotype as compared with sporadic BCCs, which may contribute to their relatively more indolent clinical course and responsiveness to therapy.

View details for PubMedID 29111235

Inhibition of the hedgehog pathway in patients with basal-cell nevus syndrome: final results from the multicentre, randomised, double-blind, placebo-controlled, phase 2 trial LANCET ONCOLOGY Tang, J. Y., Ally, M. S., Chanana, A. M., Mackay-Wiggan, J. M., Aszterbaum, M., Lindgren, J. A., Ulerio, G., Rezaee, M. R., Gildengorin, G., Marji, J., Clark, C., Bickers, D. R., Epstein, E. H. 2016; 17 (12): 1720-1731

Abstract

Aberrant hedgehog signalling underlies the development of basal-cell carcinomas. We previously reported the interim analysis of a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial in patients with the basal-cell nevus (Gorlin) syndrome indicating that the smoothened inhibitor vismodegib reduces basal-cell carcinoma tumour burden and prevents new basal-cell carcinoma growth in patients with basal-cell nevus syndrome. We report the final results of this 36 month trial.In our multicentre, randomised, double-blind, placebo-controlled, phase 2 trial we enrolled patients aged 35-75 years with basal-cell nevus syndrome with at least ten surgically eligible basal-cell carcinomas at the Children's Hospital Oakland, Columbia University outpatient dermatology clinic (NY, USA) and a private practice outpatient dermatology office in Newport Beach (CA, USA). Patients were assigned to vismodegib or placebo (2:1) according to a randomisation sequence generated by computer code. The primary endpoint of the trial of 41 patients was to compare the effect of oral vismodegib (150 mg/day) versus placebo on the incidence of new surgically eligible basal-cell carcinomas after 3 months of treatment. In the subsequent, open-label phase (n=37) patients continued vismodegib at two sites for as long as month 36 (n=25) and at the third site were monitored up to month 36 (n=12). Additional endpoints for this phase were: whether continuous versus interrupted dosing differentially affected tumour burden; time to reach various levels of reduction in tumour burden; reduction in tumour size in patients who took less than 50% of the expected number of vismodegib tablets; reduction in the number of surgical excisions required per year before, during, and after treatment; and the effect of vismodegib on hedgehog target gene expression. We monitored patients at visits every 3 months for up to 36 months. The primary endpoint was analysed on a modified intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT00957229.Between Sept 22, 2009, and Jan 24, 2011, 41 patients were monitored for a median of 36 months (IQR 36-36). Patients treated with vismodegib (n=26) had a mean reduced rate of new surgically eligible basal-cell carcinomas compared with patients randomly assigned to placebo (n=15; two [SD 012] new surgically eligible basal-cell carcinomas per patient per year vs 34 [132] new surgically eligible basal-cell carcinomas per patient per year, p<00001). In the 11 patients initially assigned to placebo, mean cross over to vismodegib reduced the development of new surgically eligible basal-cell carcinomas compared with placebo (04 [SD 02] new surgically eligible basal-cell carcinomas per patient per year vs 300 [78] new surgically eligible basal-cell carcinomas per patient per year, p<00001). Only three (17%) of 18 patients tolerated vismodegib continuously for the full 36 months. Fewer new surgically eligible basal-cell carcinomas developed in patients receiving vismodegib continuously than in those who interrupted dosing (mean 06 [072] new surgically eligible basal-cell carcinomas per patient per year vs 17 [18] new surgically eligible basal-cell carcinomas per patient per year, p<00001). Treatment-related grade 3-4 adverse events included weight loss of 20% or more (n=6) and muscle cramps (n=2). Two patients died during the course of the trial, one each from laryngeal and metastatic prostate cancer, deemed probably unrelated to drug.Vismodegib reduces basal-cell carcinoma tumour burden in patients with basal-cell nevus syndrome. Adverse events associated with vismodegib frequently led to interruption of treatment, which is followed by basal-cell carcinoma recurrence.Genentech investigator-initiated trial funding, Clinical and Translational Science Award from the National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Cancer Institute, Damon Runyon Cancer Research Foundation Clinical Investigator Award, Swim across America Foundation, and Michael J Rainen Family Foundation.

View details for DOI 10.1016/S1470-2045(16)30566-6

View details for Web of Science ID 000389537700040

View details for PubMedID 27838224

Safety and Wound Outcomes Following Genetically Corrected Autologous Epidermal Grafts in Patients With Recessive Dystrophic Epidermolysis Bullosa. JAMA Siprashvili, Z., Nguyen, N. T., Gorell, E. S., Loutit, K., Khuu, P., Furukawa, L. K., Lorenz, H. P., Leung, T. H., Keene, D. R., Rieger, K. E., Khavari, P., Lane, A. T., Tang, J. Y., Marinkovich, M. P. 2016; 316 (17): 1808-1817

Abstract

Recessive dystrophic epidermolysis bullosa (RDEB) is a devastating, often fatal, inherited blistering disorder caused by mutations in the COL7A1 gene encoding type VII collagen. Support and palliation are the only current therapies.To evaluate the safety and wound outcomes following genetically corrected autologous epidermal grafts in patients with RDEB.Single-center phase 1 clinical trial conducted in the United States of 4 patients with severe RDEB with a measured area of wounds suitable for grafting of at least 100 cm2. Patients with undetectable type VII collagen keratinocyte expression were excluded.Autologous keratinocytes isolated from biopsy samples collected from 4 patients with RDEB were transduced with good manufacturing practice-grade retrovirus carrying full-length human COL7A1 and assembled into epidermal sheet grafts. Type VII collagen gene-corrected grafts (approximately 35 cm2) were transplanted onto 6 wounds in each of the patients (n=24 grafts).The primary safety outcomes were recombination competent retrovirus, cancer, and autoimmune reaction. Molecular correction was assessed as type VII collagen expression measured by immunofluorescence and immunoelectron microscopy. Wound healing was assessed using serial photographs taken at 3, 6, and 12 months after grafting.The 4 patients (mean age, 23 years [range, 18-32 years]) were all male with an estimated body surface area affected with RDEB of 4% to 30%. All 24 grafts were well tolerated without serious adverse events. Type VII collagen expression at the dermal-epidermal junction was demonstrated on the graft sites by immunofluorescence microscopy in 9 of 10 biopsy samples (90%) at 3 months, in 8 of 12 samples (66%) at 6 months, and in 5 of 12 samples (42%) at 12 months, including correct type VII collagen localization to anchoring fibrils. Wounds with recombinant type VII collagen graft sites displayed 75% or greater healing at 3 months (21 intact graft sites of 24 wound sites; 87%), 6 months (16/24; 67%), and 12 months (12/24; 50%) compared with baseline wound sites.In this preliminary study of 4 patients with RDEB, there was wound healing in some type VII collagen gene-corrected grafts, but the response was variable among patients and among grafted sites and generally declined over 1 year. Long-term follow-up is necessary for these patients, and controlled trials are needed with a broader range of patients to better understand the potential long-term efficacy of genetically corrected autologous epidermal grafts.clinicaltrials.gov Identifier: NCT01263379.

View details for DOI 10.1001/jama.2016.15588

View details for PubMedID 27802546

Smoothened variants explain the majority of drug resistance in Basal cell carcinoma. Cancer cell Atwood, S. X., Sarin, K. Y., Whitson, R. J., Li, J. R., Kim, G., Rezaee, M., Ally, M. S., Kim, J., Yao, C., Chang, A. L., Oro, A. E., Tang, J. Y. 2015; 27 (3): 342-353

Abstract

Advanced basal cell carcinomas (BCCs) frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms. Here we identify SMO mutations in 50% (22 of 44) of resistant BCCs and show that these mutations maintain Hedgehog signaling in the presence of SMO inhibitors. Alterations include four ligand binding pocket mutations defining sites of inhibitor binding and four variants conferring constitutive activity and inhibitor resistance, illuminating pivotal residues that ensure receptor autoinhibition. In the presence of a SMO inhibitor, tumor cells containing either class of SMO mutants effectively outcompete cells containing the wild-type SMO. Finally, we show that both classes of SMO variants respond toaPKC-/ or GLI2 inhibitors that operate downstream of SMO, setting the stage for the clinical use of GLI antagonists.

View details for DOI 10.1016/j.ccell.2015.02.002

View details for PubMedID 25759020

Inhibiting the Hedgehog Pathway in Patients with the Basal-Cell Nevus Syndrome NEW ENGLAND JOURNAL OF MEDICINE Tang, J. Y., Mackay-Wiggan, J. M., Aszterbaum, M., Yauch, R. L., Lindgren, J., Chang, K., Coppola, C., Chanana, A. M., Marji, J., Bickers, D. R., Epstein, E. H. 2012; 366 (23): 2180-2188

Abstract

Dysregulated hedgehog signaling is the pivotal molecular abnormality underlying basal-cell carcinomas. Vismodegib is a new orally administered hedgehog-pathway inhibitor that produces objective responses in locally advanced and metastatic basal-cell carcinomas.We tested the anti-basal-cell carcinoma efficacy of vismodegib in a randomized, double-blind, placebo-controlled trial in patients with the basal-cell nevus syndrome at three clinical centers from September 2009 through January 2011. The primary end point was reduction in the incidence of new basal-cell carcinomas that were eligible for surgical resection (surgically eligible) with vismodegib versus placebo after 3 months; secondary end points included reduction in the size of existing basal-cell carcinomas.In 41 patients followed for a mean of 8 months (range, 1 to 15) after enrollment, the per-patient rate of new surgically eligible basal-cell carcinomas was lower with vismodegib than with placebo (2 vs. 29 cases per group per year, P<0.001), as was the size (percent change from baseline in the sum of the longest diameter) of existing clinically significant basal-cell carcinomas (-65% vs. -11%, P=0.003). In some patients, all basal-cell carcinomas clinically regressed. No tumors progressed during treatment with vismodegib. Patients receiving vismodegib routinely had grade 1 or 2 adverse events of loss of taste, muscle cramps, hair loss, and weight loss. Overall, 54% of patients (14 of 26) receiving vismodegib discontinued drug treatment owing to adverse events. At 1 month, vismodegib use had reduced the hedgehog target-gene expression by basal-cell carcinoma by 90% (P<0.001) and diminished tumor-cell proliferation, but apoptosis was not affected. No residual basal-cell carcinoma was detectable in 83% of biopsy samples taken from sites of clinically regressed basal-cell carcinomas.Vismodegib reduces the basal-cell carcinoma tumor burden and blocks growth of new basal-cell carcinomas in patients with the basal-cell nevus syndrome. The adverse events associated with treatment led to discontinuation in over half of treated patients. (Funded by Genentech and others; ClinicalTrials.gov number, NCT00957229.).

View details for Web of Science ID 000304863400007

View details for PubMedID 22670904

View details for PubMedCentralID PMC4362529

Gene Therapy for Epidermolysis Bullosa JOURNAL OF INVESTIGATIVE DERMATOLOGY Marinkovich, M., Tang, J. Y. 2019; 139 (6): 122126
Prevalence and penetrance of breast cancer-associated mutations identified by multiple-gene sequencing in the Women's Health Initiative. Kurian, A. W., Hughes, E., Bernhisel, R., Larson, K., Caswell-Jin, J., Shadyab, A. H., Ochs-Balcom, H., Pan, K., Qi, L., Reding, K., Hartman, A., Lancaster, J. M., Tang, J. Y., Stefanick, M. L. AMER SOC CLINICAL ONCOLOGY. 2019
Assessment of the Timing of Milestone Clinical Events in Patients With Epidermolysis Bullosa From North America JAMA DERMATOLOGY Feinstein, J. A., Jambal, P., Peoples, K., Lucky, A. W., Phuong Khuu, Tang, J. Y., Lara-Corrales, I., Pope, E., Wiss, K., Hook, K. P., Levin, L. E., Morel, K. D., Paller, A. S., McCuaig, C. C., Powell, J., Eichenfield, L. F., Price, H., Levy, M. L., Schachner, L. A., Browning, J. C., Bayliss, S., Jahnke, M., Shwayder, T., Glick, S. A., Bruckner, A. L. 2019; 155 (2): 196203
From Clinical Phenotype to Genotypic Modelling: Incidence and Prevalence of Recessive Dystrophic Epidermolysis Bullosa (RDEB) CLINICAL COSMETIC AND INVESTIGATIONAL DERMATOLOGY Eichstadt, S., Tang, J. Y., Solis, D. C., Siprashvili, Z., Marinkovich, M., Whitehead, N., Schu, M., Fang, F., Erickson, S. W., Ritchey, M. E., Colao, M., Spratt, K., Shaygan, A., Ahn, M. J., Sarin, K. Y. 2019; 12: 93342
Genetic mutations underlying phenotypic plasticity in basosquamous carcinoma Journal of Investigative Dermatology Chiang, A., Tan, C. Z., Kuonen, F., Hodgkinson, L. M., Chiang, F., Cho, R. J., South, A. P., Tang, J. Y., Chang, A. L., Rieger, K. E., Oro, A. E., Sarin, K. Y. 2019
Topical Itraconazole for the Treatment of Basal Cell Carcinoma in Patients With Basal Cell Nevus Syndrome or High-Frequency Basal Cell Carcinomas: A Phase 2, Open-Label, Placebo-Controlled Trial. JAMA dermatology Sohn, G. K., Kwon, G. P., Bailey-Healy, I., Mirza, A., Sarin, K., Oro, A., Tang, J. Y. 2019

View details for DOI 10.1001/jamadermatol.2019.1541

View details for PubMedID 31339515

From Clinical Phenotype to Genotypic Modelling: Incidence and Prevalence of Recessive Dystrophic Epidermolysis Bullosa (RDEB). Clinical, cosmetic and investigational dermatology Eichstadt, S., Tang, J. Y., Solis, D. C., Siprashvili, Z., Marinkovich, M. P., Whitehead, N., Schu, M., Fang, F., Erickson, S. W., Ritchey, M. E., Colao, M., Spratt, K., Shaygan, A., Ahn, M. J., Sarin, K. Y. 2019; 12: 93342

Abstract

Recessive dystrophic epidermolysis bullosa (RDEB) is an inherited genetic disorder characterized by recurrent and chronic open wounds with significant morbidity, impaired quality of life, and early mortality. RDEB patients demonstrate reduction or structural alteration type VII collagen (C7) owing to mutations in the gene COL7A1, the main component of anchoring fibrils (AF) necessary to maintain epidermal-dermal cohesion. While over 700 alterations in COL7A1 have been reported to cause dystrophic epidermolysis bullosa (DEB), which may be inherited in an autosomal dominant (DDEB) or autosomal recessive pattern (RDEB), the incidence and prevalence of RDEB is not well defined. To date, the widely estimated incidence (0.2-6.65 per million births) and prevalence (3.5-20.4 per million people) of RDEB has been primarily characterized by limited analyses of clinical databases or registries.Using a genetic modelling approach, we use whole exome and genome sequencing data to estimate the allele frequency of pathogenic variants. Through the ClinVar and NCBI database of human genome variants and phenotypes, DEB Register, and analyzing premature COL7A1 termination variants we built a model to predict the pathogenicity of previously unclassified variants. We applied the model to publicly available sequences from the Exome Aggregation Consortium (ExAC) and Genome Aggregation Database (gnomAD) and identified variants which were classified as pathogenic for RDEB from which we estimate disease incidence and prevalence.Genetic modelling applied to the whole exome and genome sequencing data resulted in the identification of predicted RDEB pathogenic alleles, from which our estimate of the incidence of RDEB is 95 per million live births, 30 times the 3.05 per million live birth incidence estimated by the National Epidermolysis Bullosa Registry (NEBR). Using a simulation approach, we estimate a mean of approximately 3,850 patients in the US who may benefit from COL7A1-mediated treatments in the US.We conclude that genetic allele frequency estimation may enhance the underdiagnosis of rare genetic diseases generally, and RDEB specifically, which may improve incidence and prevalence estimates of patients who may benefit from treatment.

View details for DOI 10.2147/CCID.S232547

View details for PubMedID 31920360

View details for PubMedCentralID PMC6935313

Assessment of the Timing of Milestone Clinical Events in Patients With Epidermolysis Bullosa From North America. JAMA dermatology Feinstein, J. A., Jambal, P., Peoples, K., Lucky, A. W., Khuu, P., Tang, J. Y., Lara-Corrales, I., Pope, E., Wiss, K., Hook, K. P., Levin, L. E., Morel, K. D., Paller, A. S., McCuaig, C. C., Powell, J., Eichenfield, L. F., Price, H., Levy, M. L., Schachner, L. A., Browning, J. C., Bayliss, S., Jahnke, M., Shwayder, T., Glick, S. A., Bruckner, A. L. 2018

Abstract

Importance: Children with epidermolysis bullosa (EB) comprise a rare population with high morbidity and mortality. An improved understanding of the clinical trajectory of patients with EB, including age at time of clinical diagnosis and major clinical events, is needed to refine best practices and improve quality of life and clinical outcomes for patients with EB.Objectives: To describe demographics, clinical characteristics, milestone diagnostic and clinical events (such as initial esophageal dilation), and outcomes in patients with EB using the Epidermolysis Bullosa Clinical Characterization and Outcomes Database and to determine what characteristics may be associated with overall EB severity and/or disease progression.Design, Setting, and Participants: This cohort study included data on patients with EB who were enrolled in the Epidermolysis Bullosa Clinical Characterization and Outcomes Database from January 1, 2011, to June 30, 2017; 17 participating EB centers in the United States and Canada contributed data to this study.Exposures: Type of EB, including recessive dystrophic epidermolysis bullosa (RDEB), junctional epidermolysis bullosa (JEB), dominant dystrophic epidermolysis bullosa (DDEB), and epidermolysis bullosa simplex (EBS).Main Outcomes and Measures: Demographic information, clinical characteristics (including age at onset of signs of EB and subsequent clinical diagnosis), types of diagnostic testing performed, and milestone clinical events for patients with RDEB.Results: Of 644 enrolled patients from 17 sites included in this study, 323 were male (50.2%), with a mean (SD) age of 14.4 (11.7) years; 283 (43.9%) had RDEB, 194 (30.1%) had EBS, 104 (16.2%) had DDEB, and 63 (9.8%) had JEB. Signs of disease were present at birth in 202 patients with RDEB (71.4%), 39 with JEB (61.9%), 60 with DDEB (57.7%), and 74 with EBS (38.1%). For those with signs of disease at birth, a clinical diagnosis was made at the time of birth in 135 patients with RDEB (67.0%), 31 with DDEB (52.6%), 35 with EBS, (47.3%) and 18 with JEB (46.2%). Patients with JEB had the highest rate of any confirmatory testing (51 of 63 [81.0%]), followed by RDEB (218 of 283 [77.0%]), DDEB (71 of 104 [68.3%]), and EBS (100 of 194 [51.5%]). For all types of EB, both electron microscopy and immunofluorescence microscopy were performed at younger ages than genetic analysis. Among 283 patients with RDEB, 157 (55.5%) had esophageal dilation, 104 (36.7%) had gastrostomy tube placement, 62 (21.9%) had hand surgery, 18 (6.4%) developed squamous cell carcinoma, and 19 (6.7%) died.Conclusions and Relevance: The findings suggest that diagnostic testing for EB is more common for patients with severe phenotypes. Earlier diagnostic testing may enable improved characterizations of patients so that appropriate counseling and clinical care may be offered, especially pertaining to milestone events for those with RDEB.

View details for PubMedID 30586139

Screening Clinical Cell Products for Replication Competent Retrovirus: The National Gene Vector Biorepository Experience MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT Cornetta, K., Duffy, L., Feldman, S. A., Mackall, C. L., Davila, M. L., Curran, K. J., Junghans, R. P., Tang, J., Kochenderfer, J. N., O'Cearbhaill, R., Archer, G., Kiem, H., Shah, N. N., Delbrook, C., Kaplan, R., Brentjens, R. J., Riviere, I., Sadelain, M., Rosenberg, S. A. 2018; 10: 37178

Abstract

Replication-competent retrovirus (RCR) is a safety concern for individuals treated with retroviral gene therapy. RCR detection assays are used to detect RCR in manufactured vector, transduced cell products infused into research subjects, and in theresearch subjects after treatment. In this study, we reviewed286 control (n= 4) and transduced cell products (n= 282) screened for RCR in the National Gene Vector Biorepository. The transduced cell samples were submitted from 14 clinical trials. All vector products were previously shown to be negative for RCR prior to use in cell transduction. After transduction, all 282 transduced cell products were negative for RCR. In addition, 241 of the clinical trial participants were also screened for RCR by analyzing peripheral blood at least 1month after infusion, all of which were also negative for evidence of RCR infection. The majority of vector products used in the clinical trials were generated in the PG13 packaging cell line. The findings suggest that screening of the retroviral vector product generated in PG13 cell line may be sufficient and that further screening of transduced cells does not provide added value.

View details for PubMedID 30211249

Melanoma risk prediction using a multilocus genetic risk score in the Women's Health Initiative cohort JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Cho, H. G., Ransohoff, K. J., Yang, L., Hedlin, H., Assimes, T., Han, J., Stefanick, M., Tang, J. Y., Sarin, K. Y. 2018; 79 (1): 36-+
Association of 25-hydroxyvitamin D levels and cutaneous melanoma: A nested case-control study of the Women's Health Initiative Observation Study. Journal of the American Academy of Dermatology Kwon, G. P., Gamba, C. S., Stefanick, M. L., Swetter, S. M., Li, S., Shi, R. Z., Clarke, C. A., Feldman, D., Millen, A. E., Messina, C., Shikany, J. M., Manson, J. E., Chlebowski, R. T., Tang, J. Y. 2018; 79 (1): 14547

View details for PubMedID 29908819

Risk of Melanoma With Phosphodiesterase Type 5 Inhibitor Use Among Patients With Erectile Dysfunction, Pulmonary Hypertension, and Lower Urinary Tract Symptoms. The journal of sexual medicine Shkolyar, E., Li, S., Tang, J., Eisenberg, M. L. 2018

Abstract

BACKGROUND: Phosphodiesterase type 5 inhibitors (PDE5is), a treatment for erectile dysfunction, pulmonary hypertension (pHTN), and lower urinary tract symptoms (LUTS), have been implicated in melanoma development.AIM: We sought to determine the association between PDE5i use and melanoma development among patients with erectile dysfunction, pHTN, and LUTS.METHODS: This was a retrospective cohort study of subjects contained within the Truven Health MarketScan claims database, which provides information on insurance claims in the United States for privately insured individuals, from 2007-2015. Individuals taking PDE5i were identified through pharmacy claims. A comparison group of men diagnosed with conditions for which PDE5i are prescribed was assembled.OUTCOMES: Cox proportional hazard models were used to estimate the hazard ratio (HR) (95% CI) of incident melanoma, basal cell carcinoma, and squamous cell carcinoma.RESULTS: Of 610,881 subjects prescribed PDE5i, 636 developed melanoma (0.10%). The control group had 8,711 diagnoses of melanoma. There was an association between increased PDE5i tablet use and melanoma (HR1.05, 95% CI 1.05-1.09). This association was also present between PDE5i use and basal cell carcinoma (HR 1.04, 95% CI 1.02-1.07) and squamous cell carcinoma (HR 1.04, 95% CI 1.01-1.07). In patients with pHTN and LUTS prescribed PDE5is, there was no relationship between exposure and melanoma incidence (HR 0.74, 95% CI 0.48-1.13; and HR 1.03, 95% CI 0.97-1.10, respectively).CLINICAL IMPLICATIONS: There is little evidence for a clinically relevant association between PDE5i use and melanoma incidence.STRENGTHS & LIMITATIONS: Our current work represents the largest study to date evaluating the relationship between PDE5i use and melanoma risk, and the first to examine all current indications of PDE5i use among men and women. Limitations include a patient population limited to commercially insured individuals, unknown patient medication compliance, and lack of information on patient skin type, lifestyle, and sun-exposure habits.CONCLUSION: There is a slight association between higher-volume PDE5i use and development of melanoma, basal cell carcinoma, and squamous cell carcinoma. This association among all skin cancers implies that confounding may account for the observed association. Shkolyar E, Li S, Tang J, etal. Risk of Melanoma With Phosphodiesterase Type 5 Inhibitor Use Among Patients With Erectile Dysfunction, Pulmonary Hypertension, and Lower Urinary Tract Symptoms. J Sex Med 2018;XX:XXX-XXX.

View details for PubMedID 29884444

Serlopitant for the treatment of chronic pruritus: Results of a randomized, multicenter, placebo-controlled phase 2 clinical trial JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Yosipovitch, G., Stander, S., Kerby, M. B., Larrick, J. W., Perlman, A. J., Schnipper, E. F., Zhang, X., Tang, J. Y., Luger, T., Steinhoff, M. 2018; 78 (5): 882-+

Abstract

The substance P/neurokinin 1 receptor pathway is critical in chronic pruritus; anecdotal evidence suggests that antagonism of this pathway can reduce chronic itch.To assess the safety and efficacy of the substance P/neurokinin 1 receptor antagonist serlopitant in treating chronic pruritus.Eligible patients with severe chronic pruritus who were refractory to antihistamines or topical steroids were randomized to serlopitant, 0.25, 1, or 5mg, or to placebo, administered once daily for 6weeks as monotherapy or with midpotency steroids and emollients. The primary efficacy end point was percentage change in visual analog scale pruritus score from baseline.Serlopitant treatment resulted in a dose-dependent decrease in pruritus. The mean percentage decreases from baseline visual analog scale pruritus scores were statistically significantly larger with the 1-and 5-mg doses of serlopitant (P=.022 and P=.013, respectively) than with placebo at week 6. No significant safety or tolerability differences were detected among the groups.The sample size was insufficient for subgroup analyses of the efficacy of serlopitant for chronic pruritus on the basis of underlying conditions.Serlopitant, 1mg and 5mg daily, was associated with a statistically significant reduction in chronic pruritus and was well tolerated (NCT01951274).

View details for PubMedID 29462657

Melanoma risk prediction using a multilocus genetic risk score in the Women's Health Initiative cohort. Journal of the American Academy of Dermatology Cho, H. G., Ransohoff, K. J., Yang, L., Hedlin, H., Assimes, T., Han, J., Stefanick, M., Tang, J. Y., Sarin, K. Y. 2018

Abstract

BACKGROUND: Single-nucleotide polymorphisms (SNPs) associated with melanoma have been identified though genome-wide association studies. However, the combined impact of these SNPs on melanoma development remains unclear, particularly in postmenopausal women who carry a lower melanoma risk.OBJECTIVE: We examine the contribution of a combined polygenic risk score on melanoma development in postmenopausal women.METHODS: Genetic risk scores were calculated using 21 genome-wide association study-significant SNPs. Their combined effect on melanoma development was evaluated in 19,102 postmenopausal white women in the clinical trial and observational study arms of the Women's Health Initiative dataset.RESULTS: Compared to the tertile of weighted genetic risk score with the lowest genetic risk, the women in the tertile with the highest genetic risk were 1.9 times more likely to develop melanoma (95% confidence interval 1.50-2.42). The incremental change in c-index from adding genetic risk scores to age were 0.075 (95% confidence interval 0.041-0.109) for incident melanoma.LIMITATIONS: Limitations include a lack of information on nevi count, Fitzpatrick skin type, family history of melanoma, and potential reporting and selection bias in the Women's Health Initiative cohort.CONCLUSION: Higher genetic risk is associated with increased melanoma prevalence and incidence in postmenopausal women, but current genetic information may have a limited role in risk prediction when phenotypic information is available.

View details for PubMedID 29499294

Natural history of lesions suspicious for basal cell carcinoma in older adults in Ikaria, Greece. The British journal of dermatology Wehner, M. R., Dalma, N., Landefeld, C., Pare-Anastasiadou, A., Koutelidas, I., Chren, M. M., Aji, N., Teng, C. E., Koenig, B. A., Tang, J., Covinsky, K., Linos, E. 2018

Abstract

BCC is a disease of ageing, with the majority occurring in people 65 years or older.1,2 Incidence is rising especially among those over 80 years of age.3 Most of these skin cancers are not dangerous: typically, they grow slowly and rarely metastasize or affect quality of life.4 The time-lag to benefit of treatment of asymptomatic BCC has not been estimated. Currently, the standard of care is to biopsy and treat most BCCs;5 as a result, many older patients get frequent procedures. This article is protected by copyright. All rights reserved.

View details for DOI 10.1111/bjd.16730

View details for PubMedID 29741766

Neuronal delivery of Hedgehog directs spatial patterning of taste organ regeneration. Proceedings of the National Academy of Sciences of the United States of America Lu, W. J., Mann, R. K., Nguyen, A., Bi, T., Silverstein, M., Tang, J. Y., Chen, X., Beachy, P. A. 2018; 115 (2): E200E209

Abstract

How organs maintain and restore functional integrity during ordinary tissue turnover or following injury represents a central biological problem. The maintenance of taste sensory organs in the tongue was shown 140 years ago to depend on innervation from distant ganglion neurons, but the underlying mechanism has remained unknown. Here, we show that Sonic hedgehog (Shh), which encodes a secreted protein signal, is expressed in these sensory neurons, and that experimental ablation of neuronal Shh expression causes loss of taste receptor cells (TRCs). TRCs are also lost upon pharmacologic blockade of Hedgehog pathway response, accounting for the loss of taste sensation experienced by cancer patients undergoing Hedgehog inhibitor treatment. We find that TRC regeneration following such pharmacologic ablation requires neuronal expression of Shh and can be substantially enhanced by pharmacologic activation of Hedgehog response. Such pharmacologic enhancement of Hedgehog response, however, results in additional TRC formation at many ectopic sites, unlike the site-restricted regeneration specified by the projection pattern of Shh-expressing neurons. Stable regeneration of TRCs thus requires neuronal Shh, illustrating the principle that neuronal delivery of cues such as the Shh signal can pattern distant cellular responses to assure functional integrity during tissue maintenance and regeneration.

View details for PubMedID 29279401

View details for PubMedCentralID PMC5777079

Noncanonical hedgehog pathway activation through SRF-MKL1 promotes drug resistance in basal cell carcinomas. Nature medicine Whitson, R. J., Lee, A., Urman, N. M., Mirza, A., Yao, C. Y., Brown, A. S., Li, J. R., Shankar, G., Fry, M. A., Atwood, S. X., Lee, E. Y., Hollmig, S. T., Aasi, S. Z., Sarin, K. Y., Scott, M. P., Epstein, E. H., Tang, J. Y., Oro, A. E. 2018; 24 (3): 27181

Abstract

Hedgehog pathway-dependent cancers can escape Smoothened (SMO) inhibition through mutations in genes encoding canonical hedgehog pathway components; however, around 50% of drug-resistant basal cell carcinomas (BCCs) lack additional variants of these genes. Here we use multidimensional genomics analysis of human and mouse drug-resistant BCCs to identify a noncanonical hedgehog activation pathway driven by the transcription factor serum response factor (SRF). Active SRF along with its coactivator megakaryoblastic leukemia 1 (MKL1) binds DNA near hedgehog target genes and forms a previously unknown protein complex with the hedgehog transcription factor glioma-associated oncogene family zinc finger-1 (GLI1), causing amplification of GLI1 transcriptional activity. We show that cytoskeletal activation through Rho and the formin family member Diaphanous (mDia) is required for SRF-MKL-driven GLI1 activation and for tumor cell viability. Remarkably, nuclear MKL1 staining served as a biomarker in tumors from mice and human subjects to predict tumor responsiveness to MKL inhibitors, highlighting the therapeutic potential of targeting this pathway. Thus, our study illuminates, for the first time, cytoskeletal-activation-driven transcription as a personalized therapeutic target for combatting drug-resistant malignancies.

View details for PubMedID 29400712

View details for PubMedCentralID PMC5839965

Azathioprine and risk of multiple keratinocyte cancers. Journal of the American Academy of Dermatology Cho, H. G., Kuo, K. Y., Xiao, K., Batra, P., Li, S., Tang, J. Y., Sarin, K. Y. 2018; 78 (1): 2728.e1

View details for PubMedID 28989107

Validity and Accuracy of a Mobile Phone Application for the Assessment of Wounds in Recessive Dystrophic Epidermolysis Bullosa. Journal of the American Academy of Dermatology Nazaroff, J., Solis, D., Barriga, M., Dutt-Singkh, Y., Shufeng, L., Marinkovich, M. P., Tang, J. Y. 2017

View details for PubMedID 29146128

Statin use and non-melanoma skin cancer risk: a meta-analysis of randomized controlled trials and observational studies ONCOTARGET Yang, K., Marley, A., Tang, H., Song, Y., Tang, J. Y., Han, J. 2017; 8 (43): 7541117

Abstract

Existing evidence of the association between statin use and non-melanoma skin cancer (NMSC) risk has been inconsistent.To maximize statistical power to synthesize prospective evidence on this relationship.PubMed, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials, and ClinicalTrial.gov were systematically searched up to December 11, 2016. A random-effects meta-analysis was conducted to calculate summary estimates.Our meta-analysis of 14 randomized controlled trials (RCTs) including 63,157 subjects showed no significant association between statin use and NMSC risk (RR = 1.09, 95%CI = 0.85-1.39). However, meta-analysis of four observational studies including 1,528,215 participants showed significantly increased risk of NMSC among statin users compared to non-users (RR = 1.11, 95%CI = 1.02-1.22). Furthermore, ever using lipophilic statins (RR = 1.14, 95%CI = 1.04-1.24) or lower-potency statins (RR = 1.14, 95%CI = 1.03-1.26), as well as usage of any statin longer than one year (RR = 1.14, 95%CI = 1.09-1.18) were significantly associated with increased NMSC risk based on observational studies.Evidence from observational studies supported an association between statin use and increased NMSC risk. This finding should be interpreted with caution due to modest number of included studies, possible between-study heterogeneity and inherent limitations of observational studies.

View details for PubMedID 29088876

Diagnostic Distinction of Malignant Melanoma and Benign Nevi by a Gene Expression Signature and Correlation to Clinical Outcomes CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Ko, J. S., Matharoo-Ball, B., Billings, S., Thomson, B. J., Tang, J. Y., Sarin, K. Y., Cai, E., Kim, J., Rock, C., Kimbrell, H. Z., Flake, D. D., Warf, M., Nelson, J., Davis, T., Miller, C., Rushton, K., Hartman, A., Wenstrup, R. J., Clarke, L. E. 2017; 26 (7): 110713

Abstract

Background: Histopathologic examination alone can be inadequate for diagnosis of certain melanocytic neoplasms. Recently, a 23-gene expression signature was clinically validated as an ancillary diagnostic test to differentiate benign nevi from melanoma. The current study assessed the performance of this test in an independent cohort of melanocytic lesions against clinically proven outcomes.Methods: Archival tissue from primary cutaneous melanomas and melanocytic nevi was obtained from four independent institutions and tested with the gene signature. Cases were selected according to pre-defined clinical outcome measures. Malignant lesions were defined as stage I-III primary cutaneous melanomas that produced distant metastases (metastatic to sites other than proximal sentinel lymph node(s)) following diagnosis of the primary lesion. Melanomas that were metastatic at the time of diagnosis, all re-excisions, and lesions with <10% tumor volume were excluded. Benign lesions were defined as cutaneous melanocytic lesions with no adverse long-term events reported.Results: Of 239 submitted samples, 182 met inclusion criteria and produced a valid gene expression result. This included 99 primary cutaneous melanomas with proven distant metastases and 83 melanocytic nevi. Median time to melanoma metastasis was 18 months. Median follow-up time for nevi was 74.9 months. The gene expression score differentiated melanoma from nevi with a sensitivity of 93.8% and a specificity of 96.2%.Conclusions: The results of gene expression testing closely correlate with long-term clinical outcomes of patients with melanocytic neoplasms.Impact: Collectively, this provides strong evidence that the gene signature adds valuable adjunctive information to aid in the accurate diagnosis of melanoma. Cancer Epidemiol Biomarkers Prev; 26(7); 1107-13. 2017 AACR.

View details for PubMedID 28377414

Correlates of multiple basal cell carcinoma in a retrospective cohort study: Sex, histologic subtypes, and anatomic distribution. Journal of the American Academy of Dermatology Kuo, K. Y., Batra, P., Cho, H. G., Li, S., Chahal, H. S., Rieger, K. E., Tang, J. Y., Sarin, K. Y. 2017

View details for DOI 10.1016/j.jaad.2017.02.047

View details for PubMedID 28392289

Two-stage genome-wide association study identifies a novel susceptibility locus associated with melanoma. Oncotarget Ransohoff, K. J., Wu, W., Cho, H. G., Chahal, H. C., Lin, Y., Dai, H., Amos, C. I., Lee, J. E., Tang, J. Y., Hinds, D. A., Han, J., Wei, Q., Sarin, K. Y. 2017

Abstract

Genome-wide association studies have identified 21 susceptibility loci associated with melanoma. These loci implicate genes affecting pigmentation, nevus count, telomere maintenance, and DNA repair in melanoma risk. Here, we report the results of a two-stage genome-wide association study of melanoma. The stage 1 discovery phase consisted of 4,842 self-reported melanoma cases and 286,565 controls of European ancestry from the 23andMe research cohort and the stage 2 replication phase consisted of 1,804 melanoma cases and 1,026 controls from the University of Texas M.D. Anderson Cancer Center. We performed a combined meta-analysis totaling 6,628 melanoma cases and 287,591 controls. Our study replicates 20 of 21 previously known melanoma-loci and confirms the association of the telomerase reverse transcriptase, TERT, with melanoma susceptibility at genome-wide significance. In addition, we uncover a novel polymorphism, rs187843643 (OR = 1.96; 95% CI = [1.54, 2.48]; P = 3.53 x 10-8), associated with melanoma. The SNP rs187842643 lies within a noncoding RNA 177kb downstream of BASP1 (brain associated protein-1). We find that BASP1 expression is suppressed in melanoma as compared with benign nevi, providing additional evidence for a putative role in melanoma pathogenesis.

View details for DOI 10.18632/oncotarget.15230

View details for PubMedID 28212542

View details for PubMedCentralID PMC5392271

Association between genetic variation within vitamin D receptor-DNA binding sites and risk of basal cell carcinoma. International journal of cancer Lin, Y., Chahal, H. S., Wu, W., Cho, H. G., Ransohoff, K. J., Dai, H., Tang, J. Y., Sarin, K. Y., Han, J. 2017

Abstract

An increasing number of studies have reported a protective association between vitamin D and cancer risk. The vitamin D endocrine system regulates transcriptional programs involved in inflammation, cell growth and differentiation through the binding of vitamin D receptor (VDR) to specific VDR elements. However, limited attention has been given to the role of variation within VDR binding sites in the development of basal cell carcinoma (BCC). Across 2,776 previously identified VDR binding sites, we identified 2,540 independent single-nucleotide polymorphisms (SNPs) and examined their associations with BCC risk in a genome-wide association meta-analysis totaling 17,187 BCC cases and 287,054 controls from two data sets. After multiple testing corrections, we identified two SNPs at new loci (rs16917546 at 10q21.1: odds ratio (OR)=1.06, p=3.16 10(-7) and rs79824801 at 12q13.3: OR=1.10, p=1.88 10(-5) ) for the first time as independently related to BCC risk in meta-analysis; and both SNPs were nominally significant in two data sets. In addition, the SNP rs3769823 within VDR binding site at a previously reported BCC susceptibility locus (2q33.1, rs13014235) also exhibited a significant association (OR=1.12, p=3.99 10(-18) ). A mutually adjusted model suggested that rs3769823 explained the signal in this region. Our findings support the hypothesis that inherited common variation in VDR binding sites affects the development of BCC.

View details for DOI 10.1002/ijc.30634

View details for PubMedID 28177523

Risk Factors for Basal Cell Carcinoma Among Patients With Basal Cell Nevus Syndrome Development of a Basal Cell Nevus Syndrome Patient Registry JAMA DERMATOLOGY Solis, D. C., Kwon, G. P., Ransohoff, K. J., Li, S., Chahal, H. S., Ally, M. S., Peters, M. A., Schmitt-Burr, K., Lindgren, J., Bailey-Healy, I., Teng, J. M., Epstein, E. H., Tang, J. Y. 2017; 153 (2): 189-192

Abstract

Patients with basal cell nevus syndrome (BCNS) have a greater risk of developing numerous basal cell carcinomas (BCCs). Risk factors influencing the wide variation in tumor burden are poorly understood.To describe the burden of BCCs in patients with BCNS in the United States and identify potential risk factors for BCCs.Prospective clinical registry with data collected from September 2014 to March 2016. Participants were recruited from a mailing list of patients with BCNS at Children's Hospital Oakland Research Institute and Basal Cell Carcinoma Nevus Syndrome Life Support Network. Patients of all ages with a diagnosis of BCNS were eligible for enrollment. Participants completed a clinical questionnaire on their disease characteristics and risk factors.Number of BCCs in the past 2 years and over lifetime (disease burden), risk factors for BCCs.A consecutive sample of the first 141 participants was included (34% [100 of 297] response rate from paper survey, 23% [41 of 179] from online survey; 85 [60%] female; mean age at start of study, 53 [range, 8-83] years; 131 [93%] white). In the previous 2 years, participants reported a mean of 25 BCCs (median, 11; range, 0-250). Over their lifetime, participants reported a mean of 257 BCCs (median, 160; range, 0-2200). Univariate analysis identified age (odds ratio [OR], 1.05; 95% CI, 1.03-1.07; P<.001), number of sunburns (OR, 1.05; 95% CI, 1.00-1.10; P=.047), and history of radiation exposure (OR, 2.26; 95% CI, 1.02-5.03; P=.046) as potential risk factors for lifetime BCC severity. On multivariate analysis, only age (OR, 1.04; 95% CI, 1.02-1.07; P<.001) and number of sunburns (OR, 1.06; 95% CI, 1.00-1.11; P=.04) were statistically significant. In our adjusted models, BCC burden increased by 4% per year of age and by 6% per number of sunburns.Patients with BCNS have a high burden of BCCs. Age and number of sunburns were significantly associated with the severity of lifetime BCC. Further interventions to prevent and treat BCCs in patients with BCNS are needed.

View details for DOI 10.1001/jamadermatol.2016.4347

View details for Web of Science ID 000395670800017

Factors influencing and modifying the decision to pursue genetic testing for skin cancer risk. Journal of the American Academy of Dermatology Fogel, A. L., Jaju, P. D., Li, S., Halpern-Felsher, B., Tang, J. Y., Sarin, K. Y. 2017

Abstract

Across cancers, the decision to pursue genetic testing is influenced more by subjective than objective factors. However, skin cancer, which is more prevalent, visual, and multifactorial than many other malignancies, may offer different motivations for pursuing such testing.The primary objective was to determine factors influencing the decision to receive genetic testing for skin cancer risk. A secondary objective was to assess the impact of priming with health questions on the decision to receive testing.We distributed anonymous online surveys through ResearchMatch.org to assess participant health, demographics, motivations, and interest in pursuing genetic testing for skin cancer risk. Two surveys with identical questions but different question ordering were used to assess the secondary objective.We received 3783 responses (64% response rate), and 85.8% desired testing. Subjective factors, including curiosity, perceptions of skin cancer, and anxiety, were the most statistically significant determinants of the decision to pursue testing (P<.001), followed by history of sun exposure (odds ratio 1.85, P<.01) and history of skin cancer (odds ratio 0.5, P=.01). Age and family history of skin cancer did not influence this decision. Participants increasingly chose testing if first queried about health behaviors (P<.0001).The decision to pursue hypothetical testing may differ from in-clinic decision-making. Self-selected, online participants may differ from the general population. Surveys may be subject to response bias.The decision to pursue genetic testing for skin cancer is primarily determined by subjective factors, such as anxiety and curiosity. Health factors, including skin cancer history, also influenced decision-making. Priming with consideration of objective health factors can increase the desire to pursue testing.

View details for DOI 10.1016/j.jaad.2016.11.050

View details for PubMedID 28087134

Height, height-related SNPs, and risk of non-melanoma skin cancer BRITISH JOURNAL OF CANCER Li, X., Liang, L., Feng, Y., De Vivo, I., Giovannucci, E., Tang, J. Y., Han, J. 2017; 116 (1): 13440

Abstract

Adult height has been associated with risk of several site-specific cancers, including melanoma. However, less attention has been given to non-melanoma skin cancer (NMSC).We prospectively examined the risk of squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) in relation to adult height in the Nurses' Health Study (NHS, n=117863) and the Health Professionals Follow-up Study (HPFS, n=51111). We also investigated the relationships between height-related genetic markers and risk of BCC and SCC in the genetic data sets of the NHS and HPFS (3898 BCC cases, and 8530 BCC controls; 527 SCC cases, and 8962 SCC controls).After controlling for potential confounding factors, the hazard ratios were 1.09 (95% CI: 1.02, 1.15) and 1.10 (95% CI: 1.07, 1.13) for the associations between every 10cm increase in height and risk of SCC and BCC respectively. None of the 687 height-related single-nucleotide polymorphisms (SNPs) was significantly associated with the risk of SCC or BCC, nor were the genetic scores combining independent height-related loci.Our data from two large cohorts provide further evidence that height is associated with an increased risk of NMSC. More studies on height-related genetic loci and early-life exposures may help clarify the underlying mechanisms.

View details for PubMedID 27846199

View details for PubMedCentralID PMC5220142

Combined inhibition of atypical PKC and histone deacetylase 1 is cooperative in basal cell carcinoma treatment. JCI insight Mirza, A. N., Fry, M. A., Urman, N. M., Atwood, S. X., Roffey, J., Ott, G. R., Chen, B., Lee, A., Brown, A. S., Aasi, S. Z., Hollmig, T., Ator, M. A., Dorsey, B. D., Ruggeri, B. R., Zificsak, C. A., Sirota, M., Tang, J. Y., Butte, A., Epstein, E., Sarin, K. Y., Oro, A. E. 2017; 2 (21)

Abstract

Advanced basal cell carcinomas (BCCs) circumvent Smoothened (SMO) inhibition by activating GLI transcription factors to sustain the high levels of Hedgehog (HH) signaling required for their survival. Unfortunately, there is a lack of efficacious therapies. We performed a gene expression-based drug repositioning screen in silico and identified the FDA-approved histone deacetylase (HDAC) inhibitor, vorinostat, as a top therapeutic candidate. We show that vorinostat only inhibits proliferation of BCC cells in vitro and BCC allografts in vivo at high dose, limiting its usefulness as a monotherapy. We leveraged this in silico approach to identify drug combinations that increase the therapeutic window of vorinostat and identified atypical PKC / (aPKC) as a HDAC costimulator of HH signaling. We found that aPKC promotes GLI1-HDAC1 association in vitro, linking two positive feedback loops. Combination targeting of HDAC1 and aPKC robustly inhibited GLI1, lowering drug doses needed in vitro, in vivo, and ex vivo in patient-derived BCC explants. We identified a bioavailable and selective small-molecule aPKC inhibitor, bringing the pharmacological blockade of aPKC and HDAC1 into the realm of clinical possibility. Our findings provide a compelling rationale and candidate drugs for combined targeting of HDAC1 and aPKC in HH-dependent cancers.

View details for PubMedID 29093271

Tumor-Derived Suppressor of Fused Mutations Reveal Hedgehog Pathway Interactions PLOS ONE Urman, N. M., Mirza, A., Atwood, S. X., Whitson, R. J., Sarin, K. Y., Tang, J. Y., Oro, A. E. 2016; 11 (12)

Abstract

The Hedgehog pathway is a potent regulator of cellular growth and plays a central role in the development of many cancers including basal cell carcinoma (BCC). The majority of BCCs arise from mutations in the Patched receptor resulting in constitutive activation of the Hedgehog pathway. Secondary driver mutations promote BCC oncogenesis and occur frequently due to the high mutational burden resulting from sun exposure of the skin. Here, we uncover novel secondary mutations in Suppressor of Fused (SUFU), the major negative regulator of the Hedgehog pathway. SUFU normally binds to a Hedgehog transcriptional activator, GLI1, in order to prevent it from initiating transcription of Hedgehog target genes. We sequenced tumor-normal pairs from patients with early sporadic BCCs. This resulted in the discovery of nine mutations in SUFU, which were functionally investigated to determine whether they help drive BCC formation. Our results show that four of the SUFU mutations inappropriately activate the Hedgehog pathway, suggesting they may act as driver mutations for BCC development. Indeed, all four of the loss of function SUFU variants were found to disrupt its binding to GLI, leading to constitutive pathway activation. Our results from functional characterization of these mutations shed light on SUFU's role in Hedgehog signaling, tumor progression, and highlight a way in which BCCs can arise.

View details for DOI 10.1371/journal.pone.0168031

View details for Web of Science ID 000391222000030

View details for PubMedID 28030567

View details for PubMedCentralID PMC5193403

Protective Effects of Statins in Cancer: Should They Be Prescribed for High-Risk Patients? Current atherosclerosis reports Wang, A., Wakelee, H. A., Aragaki, A. K., Tang, J. Y., Kurian, A. W., Manson, J. E., Stefanick, M. L. 2016; 18 (12): 72-?

Abstract

Statins are one of the most widely prescribed drug classes in the USA. This review aims to summarize recent research on the relationship between statin use and cancer outcomes, in the context of clinical guidelines for statin use in patients with cancer or who are at high risk for cancer.A growing body of research has investigated the relationship between statins and cancer with mixed results. Cancer incidence has been more extensively studied than cancer survival, though results are inconsistent as some large meta-analyses have not found an association, while other studies have reported improved cancer outcomes with the use of statins. Additionally, two large studies reported increased all-cancer survival with statin use. Studies on specific cancer types in relation to cancer use have also been mixed, though the most promising results appear to be found in gastrointestinal cancers. Few studies have reported an increased risk of cancer incidence or decreased survival with statin use, though this type of association has been more commonly reported for cutaneous cancers. The overall literature on statins in relation to cancer incidence and survival is mixed, and additional research is warranted before any changes in clinical guidelines can be recommended. Future research areas include randomized controlled trials, studies on specific cancer types in relation to statin use, studies on populations without clinical indication for statins, elucidation of underlying biological mechanisms, and investigation of different statin types. However, studies seem to suggest that statins may be protective and are not likely to be harmful in the setting of cancer, suggesting that cancer patients who already take statins should not have this medication discontinued.

View details for PubMedID 27796821

A genome-wide analysis of gene-caffeine consumption interaction on basal cell carcinoma CARCINOGENESIS Li, X., Cornelis, M. C., Liang, L., Song, F., De Vivo, I., Giovannucci, E., Tang, J. Y., Han, J. 2016; 37 (12): 113843

Abstract

Animal models have suggested that oral or topical administration of caffeine could inhibit ultraviolet-induced carcinogenesis via the ataxia telangiectasia and rad3 (ATR)-related apoptosis. Previous epidemiological studies have demonstrated that increased caffeine consumption is associated with reduced risk of basal cell carcinoma (BCC). To identify common genetic markers that may modify this association, we tested gene-caffeine intake interaction on BCC risk in a genome-wide analysis. We included 3383 BCC cases and 8528 controls of European ancestry from the Nurses' Health Study and Health Professionals Follow-up Study. Single nucleotide polymorphism (SNP) rs142310826 near the NEIL3 gene showed a genome-wide significant interaction with caffeine consumption (P = 1.78 10-8 for interaction) on BCC risk. There was no gender difference for this interaction (P = 0.64 for heterogeneity). NEIL3, a gene belonging to the base excision DNA repair pathway, encodes a DNA glycosylase that recognizes and removes lesions produced by oxidative stress. In addition, we identified several loci with P value for interaction <5 10-7 in gender-specific analyses (P for heterogeneity between genders < 0.001) including those mapping to the genes LRRTM4, ATF3 and DCLRE1C in women and POTEA in men. Finally, we tested the associations between caffeine consumption-related SNPs reported by previous genome-wide association studies and risk of BCC, both individually and jointly, but found no significant association. In sum, we identified a DNA repair gene that could be involved in caffeine-mediated skin tumor inhibition. Further studies are warranted to confirm these findings.

View details for PubMedID 27797824

View details for PubMedCentralID PMC5137266

Nanoelectroablation therapy for murine basal cell carcinoma (vol 424, pg 446, 2012) BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS Nuccitelli, R., Tran, K., Athos, B., Kreis, M., Nuccitelli, P., Chang, K. S., Epstein, E. H., Tang, J. Y. 2016; 480 (2): 288

View details for PubMedID 27793303

View details for PubMedCentralID PMC5555211

Classification of basal cell carcinoma in human skin using machine learning and quantitative features captured by polarization sensitive optical coherence tomography. Biomedical optics express Marvdashti, T., Duan, L., Aasi, S. Z., Tang, J. Y., Ellerbee Bowden, A. K. 2016; 7 (9): 3721-3735

Abstract

We report the first fully automated detection of basal cell carcinoma (BCC), the most commonly occurring type of skin cancer, in human skin using polarization-sensitive optical coherence tomography (PS-OCT). Our proposed automated procedure entails building a machine-learning based classifier by extracting image features from the two complementary image contrasts offered by PS-OCT, intensity and phase retardation (PR), and selecting a subset of features that yields a classifier with the highest accuracy. Our classifier achieved 95.4% sensitivity and specificity, validated by leave-one-patient-out cross validation (LOPOCV), in detecting BCC in human skin samples collected from 42 patients. Moreover, we show the superiority of our classifier over the best possible classifier based on features extracted from intensity-only data, which demonstrates the significance of PR data in detecting BCC.

View details for PubMedID 27699133

Pre-diagnostic leukocyte mitochondrial DNA copy number and skin cancer risk CARCINOGENESIS Meng, S., De Vivo, I., Liang, L., Giovannucci, E., Tang, J. Y., Han, J. 2016; 37 (9): 897903

Abstract

No previous study has examined the association between mitochondrial DNA copy number (mtCN) and skin cancer risk prospectively. We examined the associations between peripheral blood leukocytes mtCN level and the risks of skin cancers in a case-control study nested within the Nurses' Health Study of non-Hispanic White women, including 272 melanoma cases and 293 controls, 508 squamous cell carcinoma (SCC) cases and 550 controls, and 515 basal cell carcinoma (BCC) cases and 536 controls. Relative mtCN in peripheral blood leukocytes was measured by quantitative PCR-based assay. Unconditional logistic regression models were used to examine the associations between mtCN and skin cancer risks. Compared with those with high mtCN, the risk for melanoma was 1.06 [95% confidence interval (CI) = 0.70-1.62] in the median group and 1.19 (95% CI = 0.78-1.81) for the low group. There was suggestive evidence that increased risk for melanoma was apparent among low constitutional susceptibility group [odds ratio (OR)low versus high = 1.80, 95% CI = 0.95-3.39, P for trend = 0.07, P for interaction = 0.06]. The increased risk of melanoma was also apparent among high cumulative UV exposure group (ORlow versus high = 3.40, 95% CI = 1.46-7.92, P for trend = 0.004, P for interaction = 0.01). For non-melanoma skin cancers, compared with high-mtCN group, low-mtCN group had an increased risk for SCC (OR = 1.26, 95% CI = 0.93-1.71) and BCC (OR = 1.35; 95% CI = 1.00-1.82). Because some of the associations were marginally significant, the results only provided suggestive evidence. Further studies are warranted to replicate these findings and better understand the underlying mechanisms.

View details for PubMedID 27381830

View details for PubMedCentralID PMC5008249

Statin use and all-cancer survival: prospective results from the Women's Health Initiative BRITISH JOURNAL OF CANCER Wang, A., Aragaki, A. K., Tang, J. Y., Kurian, A. W., Manson, J. E., Chlebowski, R. T., Simon, M., Desai, P., Wassertheil-Smoller, S., Liu, S., Kritchevsky, S., Wakelee, H. A., Stefanick, M. L. 2016; 115 (1): 129-135

Abstract

This study aims to investigate the association between statin use and all-cancer survival in a prospective cohort of postmenopausal women, using data from the Women's Health Initiative Observational Study (WHI-OS) and Clinical Trial (WHI-CT).The WHI study enrolled women aged 50-79 years from 1993 to 1998 at 40 US clinical centres. Among 146326 participants with median 14.6 follow-up years, 23067 incident cancers and 3152 cancer deaths were observed. Multivariable-adjusted Cox proportional hazards models were used to investigate the relationship between statin use and cancer survival.Compared with never-users, current statin use was associated with significantly lower risk of cancer death (hazard ratio (HR), 0.78; 95% confidence interval (CI), 0.71-0.86, P<0.001) and all-cause mortality (HR, 0.80; 95% CI, 0.74-0.88). Use of other lipid-lowering medications was also associated with increased cancer survival (P-interaction (int)=0.57). The lower risk of cancer death was not dependent on statin potency (P-int=0.22), lipophilicity/hydrophilicity (P-int=0.43), type (P-int=0.34) or duration (P-int=0.33). However, past statin users were not at lower risk of cancer death compared with never-users (HR, 1.06; 95% CI, 0.85-1.33); in addition, statin use was not associated with a reduction of overall cancer incidence despite its effect on survival (HR, 0.96; 95% CI, 0.92-1.001).In a cohort of postmenopausal women, regular use of statins or other lipid-lowering medications was associated with decreased cancer death, regardless of the type, duration, or potency of statin medications used.British Journal of Cancer advance online publication, 9 June 2016; doi:10.1038/bjc.2016.149 www.bjcancer.com.

View details for DOI 10.1038/bjc.2016.149

View details for PubMedID 27280630

Pathway analysis of expression-related SNPs on genome-wide association study of basal cell carcinoma ONCOTARGET Li, X., Liang, L., De Vivo, I., Tang, J. Y., Han, J. 2016; 7 (24): 3688595

Abstract

Genome-wide association studies (GWASs) have primarily focused on the association between individual genetic markers and risk of disease. We applied a novel approach that integrates skin expression-related single-nucleotide polymorphisms (eSNPs) and pathway analysis for GWAS of basal cell carcinoma (BCC) to identify potential novel biological pathways. We evaluated the associations between 70,932 skin eSNPs and risk of BCC among 2,323 cases and 7,275 controls of European ancestry, and then assigned them to the pathways defined by KEGG, GO, and BioCarta databases. Three KEGG pathways (colorectal cancer, actin cytoskeleton, and BCC), two GO pathways (cellular component disassembly in apoptosis, and nucleus organization), and four BioCarta pathways (Ras signaling, T cell receptor signaling, natural killer cell-mediated cytotoxicity, and links between Pyk2 and Map Kinases) showed significant association with BCC risk with p-value<0.05 and FDR<0.2. These pathways also ranked at top in sensitivity analyses. Two positive controls in KEGG, the hedgehog pathway and the BCC pathway, showed significant association with BCC risk in both main and sensitivity analyses. Our results indicate that SNPs that are undetectable by conventional GWASs are significantly associated with BCC when tested as pathways. Biological studies of these gene groups suggest their potential roles in the etiology of BCC.

View details for PubMedID 27367190

Impact of residential UV exposure in childhood versus adulthood on skin cancer risk in Caucasian, postmenopausal women in the Women's Health Initiative CANCER CAUSES & CONTROL Ransohoff, K. J., Ally, M. S., Stefanick, M. L., Keiser, E., Spaunhurst, K., Kapphahn, K., Pagoto, S., Messina, C., Hedlin, H., Manson, J. E., Tang, J. Y. 2016; 27 (6): 817-823

Abstract

Sun exposure is a major risk factor for skin cancer; however, the relative contribution of ultraviolet (UV) exposure during childhood versus adulthood on skin cancer risk remains unclear.Our goal was to determine the impact of residential UV, measured by AVerage daily total GLObal solar radiation (AVGLO), exposure during childhood (birth, 15years) versus adulthood (35, 50years, and present) on incident non-melanoma skin cancer (NMSC) and malignant melanoma (MM) in postmenopausal women.Women were followed with yearly surveys throughout the duration of their participation in the Women's Health Initiative Observational study, a multicenter study from 1993 to 2005. A total of 56,557 women had data on all observations and were included in the baseline characteristics. The main exposure, residential UV (as measured by AVGLO), was measured by geographic residence during childhood and adulthood. Outcome was risk of incident NMSC and MM.Over 11.9years (median follow-up), there were 9,195 (16.3%) cases of NMSC and 518 (0.92%) cases of MM. Compared with the reference group (women with low childhood and low adulthood UV), women with low childhood and high adulthood UV had a 21% increased risk of NMSC (odds ratio 1.21, 95% confidence interval 1.12, 1.31). Women with high childhood and high adulthood UV had a 19% increased risk of NMSC (odds ratio 1.19, 95% confidence interval 1.11, 1.27). Surprisingly, women with high childhood UV and low adulthood UV did not have a significant increase in NMSC risk compared with the reference group (odds ratio 1.08, 95% confidence interval 0.91, 1.28) in multivariable models. Residential UV exposure in childhood or adulthood was not associated with increased melanoma risk.This study reveals an increase in NMSC risk associated with adulthood residential UV exposure, with no effect for childhood UV exposure.

View details for DOI 10.1007/s10552-016-0730-9

View details for Web of Science ID 000376619500011

View details for PubMedID 27153844

Posaconazole, a Second-Generation Triazole Antifungal Drug, Inhibits the Hedgehog Signaling Pathway and Progression of Basal Cell Carcinoma MOLECULAR CANCER THERAPEUTICS Chen, B., Vinh Trang, V., Lee, A., Williams, N. S., Wilson, A. N., Epstein, E. H., Tang, J. Y., Kim, J. 2016; 15 (5): 866-876

Abstract

Deregulation of Hedgehog (Hh) pathway signaling has been associated with the pathogenesis of various malignancies, including basal cell carcinomas (BCC). Inhibitors of the Hh pathway currently available or under clinical investigation all bind and antagonize Smoothened (SMO), inducing a marked but transient clinical response. Tumor regrowth and therapy failure were attributed to mutations in the binding site of these small-molecule SMO antagonists. The antifungal itraconazole was demonstrated to be a potent SMO antagonist with a distinct mechanism of action from that of current SMO inhibitors. However, itraconazole represents a suboptimal therapeutic option due to its numerous drug-drug interactions. Here, we show that posaconazole, a second-generation triazole antifungal with minimal drug-drug interactions and a favorable side-effect profile, is also a potent inhibitor of the Hh pathway that functions at the level of SMO. We demonstrate that posaconazole inhibits the Hh pathway by a mechanism distinct from that of cyclopamine and other cyclopamine-competitive SMO antagonists but, similar to itraconazole, has robust activity against drug-resistant SMO mutants and inhibits the growth of Hh-dependent BCC in vivo Our results suggest that posaconazole, alone or in combination with other Hh pathway antagonists, may be readily tested in clinical studies for the treatment of Hh-dependent cancers. Mol Cancer Ther; 15(5); 866-76. 2016 AACR.

View details for DOI 10.1158/1535-7163.MCT-15-0729-T

View details for PubMedID 26823493

Management of common vismodegib (VISMO)-related adverse events in patients with locally advanced basal cell carcinoma (laBCC): RegiSONIC Disease Registry Study Lacouture, M. E., Guillen, J., Kudchadkar, R., Rogers, G., Olencki, T., Tang, J., Yoo, S., Dawson, K., Mun, Y., Sekulic, A. MOSBY-ELSEVIER. 2016: AB200
Preliminary effectiveness and safety in the first 88 patients with newly diagnosed locally advanced basal cell carcinoma treated with vismodegib in the RegiSONIC Disease Registry study Lacouture, M. E., Tang, J. Y., Rogers, G., Olencki, T., Kudchadkar, R. R., Yoo, S., Guillen, J., Mun, Y., Dawson, K., Sekulic, A. MOSBY-ELSEVIER. 2016: AB202
Effects of Combined Treatment With Arsenic Trioxide and Itraconazole in Patients With Refractory Metastatic Basal Cell Carcinoma. JAMA dermatology Ally, M. S., Ransohoff, K., Sarin, K., Atwood, S. X., Rezaee, M., Bailey-Healy, I., Kim, J., Beachy, P. A., Chang, A. L., Oro, A., Tang, J. Y., Colevas, A. D. 2016; 152 (4): 452-456

Abstract

Tumor resistance is an emerging problem for Smoothened (SMO) inhibitor-treated metastatic basal cell carcinoma (BCC). Arsenic trioxide and itraconazole antagonize the hedgehog (HH) pathway at sites distinct from those treated by SMO inhibitors.To determine whether administration of intravenous arsenic trioxide and oral itraconazole in patients with metastatic BCC is associated with a reduction in GLI1 messenger RNA expression in tumor and/or normal skin biopsy samples.Five men with metastatic BCC who experienced relapse after SMO inhibitor treatment underwent intravenous arsenic trioxide treatment for 5 days, every 28 days, and oral itraconazole treatment on days 6 to 28. Data were collected from April 10 to November 14, 2013. Follow-up was completed on October 3, 2015, and data were analyzed from June 5 to October 6, 2015.The primary outcome was the change in messenger RNA levels of the GLI family zinc finger 1 (GLI1) gene (HH-pathway target gene) in biopsy specimens of normal skin or BCC before and after treatment. Secondary objectives were evaluation of tumor response and tolerability.Of the 5 patients (mean [SD] age, 52 [9] years; age range, 43-62 years), 3 completed 3 cycles of treatment and 2 discontinued treatment early owing to disease progression or adverse events. Adverse effects included grade 2 transaminitis and grade 4 leukopenia with a grade 3 infection. Overall, arsenic trioxide and itraconazole reduced GLI1 messenger RNA levels by 75% from baseline (P<.001). The best overall response after 3 treatment cycles was stable disease in 3 patients.Targeting the HH pathway with sequential arsenic trioxide and itraconazole treatment is a feasible treatment for metastatic BCC. Although some patients experienced stable disease for 3 months, none had tumor shrinkage, which may be owing to transient GLI1 suppression with sequential dosing. Continuous dosing may be required to fully inhibit the HH pathway and achieve clinical response.

View details for DOI 10.1001/jamadermatol.2015.5473

View details for PubMedID 26765315

Familial skin cancer syndromes Increased melanoma risk JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Ransohoff, K. J., Jaju, P. D., Tang, J. Y., Carbone, M., Leachman, S., Sarin, K. Y. 2016; 74 (3): 423-434

Abstract

Phenotypic traits, such as red hair and freckling, increase melanoma risk by 2- to 3-fold. In addition, approximately 10% of melanomas are caused by inherited germline mutations that increase melanoma risk from 4- to >1000-fold. This review highlights the key genes responsible for inherited melanoma, with an emphasis on when a patient should undergo genetic testing. Many genetic syndromes associated with increased melanoma risk are also associated with an increased risk of other cancers. Identification of these high-risk patients is essential for preventive behavior reinforcement, genetic counseling, and ensuring other required cancer screenings.

View details for DOI 10.1016/j.jaad.2015.09.070

View details for PubMedID 26892652

Familial skin cancer syndromes Increased risk of nonmelanotic skin cancers and extracutaneous tumors JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Jaju, P. D., Ransohoff, K. J., Tang, J. Y., Sarin, K. Y. 2016; 74 (3): 437-451

Abstract

Nonmelanoma skin cancers (NMSCs) represent the most common malignancies worldwide, with reported incidence rising each year. Both cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), as well as other NMSCs, represent complex diseases with a combination of environmental and genetic risk factors. In general, hereditary cancer syndromes that increase the risk of NMSC fall under several broad categories: those associated with immunodeficiencies, those that affect skin pigmentation, and those that perturb key molecular pathways involved in the pathogenesis of NMSCs. Many of the syndromes are also associated with extracutaneous manifestations, including internal malignancies; therefore, most require a multidisciplinary management approach with a medical geneticist. Finally, dermatologists play a critical role in the diagnosis and management of these conditions, because cutaneous findings are often the presenting manifestations of disease.

View details for DOI 10.1016/j.jaad.2015.08.073

View details for Web of Science ID 000370372300008

View details for PubMedID 26892653

Relation of statin use with non-melanoma skin cancer: prospective results from the Women's Health Initiative. British journal of cancer Wang, A., Stefanick, M. L., Kapphahn, K., Hedlin, H., Desai, M., Manson, J. A., Strickler, H., Martin, L., Wactawski-Wende, J., Simon, M., Tang, J. Y. 2016; 114 (3): 314-320

Abstract

The relationship between statin use and non-melanoma skin cancer (NMSC) is unclear with conflicting findings in literature. Data from the Women's Health Initiative (WHI) Observational Study and WHI Clinical Trial were used to investigate the prospective relationship between statin use and NMSC in non-Hispanic white (NHW) postmenopausal women.The WHI study enrolled women aged 50-79 years at 40 US centres. Among 133541 NHW participants, 118357 with no cancer history at baseline and complete medication/covariate data comprised the analytic cohort. The association of statin use (baseline, overall as a time-varying variable, duration, type, potency, lipophilicity) and NMSC incidence was determined using random-effects logistic regression models.Over a mean of 10.5 years of follow-up, we identified 11555 NMSC cases. Compared with participants with no statin use, use of any statin at baseline was associated with significantly increased NMSC incidence (adjusted odds ratio (ORadj) 1.21; 95% confidence interval (CI): 1.07-1.35)). In particular, lovastatin (OR 1.52; 95% CI: 1.08-2.16), simvastatin (OR 1.38; 95% CI: 1.12-1.69), and lipophilic statins (OR 1.39; 95% CI: 1.18-1.64) were associated with higher NMSC risk. Low and high, but not medium, potency statins were associated with higher NMSC risk. No significant effect modification of the statin-NMSC relationship was found for age, BMI, smoking, solar irradiation, vitamin D use, and skin cancer history.Use of statins, particularly lipophilic statins, was associated with increased NMSC risk in postmenopausal white women in the WHI cohort. The lack of duration-effect relationship points to possible residual confounding. Additional prospective research should further investigate this relationship.

View details for DOI 10.1038/bjc.2015.376

View details for PubMedID 26742009

View details for PubMedCentralID PMC4742576

Genome-wide association study identifies novel susceptibility loci for cutaneous squamous cell carcinoma. Nature communications Chahal, H. S., Lin, Y., Ransohoff, K. J., Hinds, D. A., Wu, W., Dai, H., Qureshi, A. A., Li, W., Kraft, P., Tang, J. Y., Han, J., Sarin, K. Y. 2016; 7: 12048-?

Abstract

Cutaneous squamous cell carcinoma represents the second most common cutaneous malignancy, affecting 7-11% of Caucasians in the United States. The genetic determinants of susceptibility to cutaneous squamous cell carcinoma remain largely unknown. Here we report the results of a two-stage genome-wide association study of cutaneous squamous cell carcinoma, totalling 7,404 cases and 292,076 controls. Eleven loci reached genome-wide significance (P<5 10(-8)) including seven previously confirmed pigmentation-related loci: MC1R, ASIP, TYR, SLC45A2, OCA2, IRF4 and BNC2. We identify an additional four susceptibility loci: 11q23.3 CADM1, a metastasis suppressor gene involved in modifying tumour interaction with cell-mediated immunity; 2p22.3; 7p21.1 AHR, the dioxin receptor involved in anti-apoptotic pathways and melanoma progression; and 9q34.3 SEC16A, a putative oncogene with roles in secretion and cellular proliferation. These susceptibility loci provide deeper insight into the pathogenesis of squamous cell carcinoma.

View details for DOI 10.1038/ncomms12048

View details for PubMedID 27424798

View details for PubMedCentralID PMC4960294

Effects of combined treatment with arsenic trioxide and itraconazole in patients with refractory metastatic basal cell carcinoma JAMA Dermatology Sarin, K. Y., Ally, M. S., Ransohoff, K. J., Atwood, S. X., Rezaee, M. 2016: 15

Abstract

Tumor resistance is an emerging problem for Smoothened (SMO) inhibitor-treated metastatic basal cell carcinoma (BCC). Arsenic trioxide and itraconazole antagonize the hedgehog (HH) pathway at sites distinct from those treated by SMO inhibitors.To determine whether administration of intravenous arsenic trioxide and oral itraconazole in patients with metastatic BCC is associated with a reduction in GLI1 messenger RNA expression in tumor and/or normal skin biopsy samples.Five men with metastatic BCC who experienced relapse after SMO inhibitor treatment underwent intravenous arsenic trioxide treatment for 5 days, every 28 days, and oral itraconazole treatment on days 6 to 28. Data were collected from April 10 to November 14, 2013. Follow-up was completed on October 3, 2015, and data were analyzed from June 5 to October 6, 2015.The primary outcome was the change in messenger RNA levels of the GLI family zinc finger 1 (GLI1) gene (HH-pathway target gene) in biopsy specimens of normal skin or BCC before and after treatment. Secondary objectives were evaluation of tumor response and tolerability.Of the 5 patients (mean [SD] age, 52 [9] years; age range, 43-62 years), 3 completed 3 cycles of treatment and 2 discontinued treatment early owing to disease progression or adverse events. Adverse effects included grade 2 transaminitis and grade 4 leukopenia with a grade 3 infection. Overall, arsenic trioxide and itraconazole reduced GLI1 messenger RNA levels by 75% from baseline (P<.001). The best overall response after 3 treatment cycles was stable disease in 3 patients.Targeting the HH pathway with sequential arsenic trioxide and itraconazole treatment is a feasible treatment for metastatic BCC. Although some patients experienced stable disease for 3 months, none had tumor shrinkage, which may be owing to transient GLI1 suppression with sequential dosing. Continuous dosing may be required to fully inhibit the HH pathway and achieve clinical response.

View details for DOI 10.1001/jamadermatol.2015.5473

Genome-wide association study identifies 14 novel risk alleles associated with basal cell carcinoma. Nature communications Chahal, H. S., Wu, W., Ransohoff, K. J., Yang, L., Hedlin, H., Desai, M., Lin, Y., Dai, H., Qureshi, A. A., Li, W., Kraft, P., Hinds, D. A., Tang, J. Y., Han, J., Sarin, K. Y. 2016; 7: 12510-?

Abstract

Basal cell carcinoma (BCC) is the most common cancer worldwide with an annual incidence of 2.8 million cases in the United States alone. Previous studies have demonstrated an association between 21 distinct genetic loci and BCC risk. Here, we report the results of a two-stage genome-wide association study of BCC, totalling 17,187 cases and 287,054 controls. We confirm 17 previously reported loci and identify 14 new susceptibility loci reaching genome-wide significance (P<5 10(-8), logistic regression). These newly associated SNPs lie within predicted keratinocyte regulatory elements and in expression quantitative trait loci; furthermore, we identify candidate genes and non-coding RNAs involved in telomere maintenance, immune regulation and tumour progression, providing deeper insight into the pathogenesis of BCC.

View details for DOI 10.1038/ncomms12510

View details for PubMedID 27539887

View details for PubMedCentralID PMC4992160

Mutations in the Kinetochore Gene KNSTRN in Basal Cell Carcinoma. journal of investigative dermatology Jaju, P. D., Nguyen, C. B., Mah, A. M., Atwood, S. X., Li, J., Zia, A., Chang, A. L., Oro, A. E., Tang, J. Y., Lee, C. S., Sarin, K. Y. 2015; 135 (12): 3197-3200

View details for DOI 10.1038/jid.2015.339

View details for PubMedID 26348826

Effect of Calcium Channel Blockade on Vismodegib-Induced Muscle Cramps. JAMA dermatology Ally, M. S., Tang, J. Y., Lindgren, J., Acosta-Raphael, M., Rezaee, M., Chanana, A. M., Epstein, E. H. 2015; 151 (10): 1132-1134

View details for DOI 10.1001/jamadermatol.2015.1937

View details for PubMedID 26200175

Squamous Change in Basal-Cell Carcinoma with Drug Resistance. New England journal of medicine Ransohoff, K. J., Tang, J. Y., Sarin, K. Y. 2015; 373 (11): 1079-1082

View details for DOI 10.1056/NEJMc1504261

View details for PubMedID 26352826

Smoothened Inhibitors in Sonic Hedgehog Subgroup Medulloblastoma. Journal of clinical oncology Ransohoff, K. J., Sarin, K. Y., Tang, J. Y. 2015; 33 (24): 2692-2694

View details for DOI 10.1200/JCO.2015.62.2225

View details for PubMedID 26195713

Rolling the Genetic Dice: Neutral and Deleterious Smoothened Mutations in Drug-Resistant Basal Cell Carcinoma. journal of investigative dermatology Atwood, S. X., Sarin, K. Y., Li, J. R., Yao, C. Y., Urman, N. M., Chang, A. L., Tang, J. Y., Oro, A. E. 2015; 135 (8): 2138-2141

View details for DOI 10.1038/jid.2015.115

View details for PubMedID 25801792

Pilot study on the bioactivity of vitamin d in the skin after oral supplementation. Cancer prevention research Curiel-Lewandrowski, C., Tang, J. Y., Einspahr, J. G., Bermudez, Y., Hsu, C. H., Rezaee, M., Lee, A. H., Tangrea, J., Parnes, H. L., Alberts, D. S., Chow, H. S. 2015; 8 (6): 563-569

Abstract

Laboratory studies suggest that vitamin D (VD) supplementation inhibits skin carcinogenesis. However, epidemiologic studies report mixed findings in the association between circulating VD levels and skin cancer risk. We conducted a clinical study to determine whether oral cholecalciferol supplementation would exert direct bioactivity in human skin through modulation of the VD receptor (VDR). We enrolled 25 individuals with serum 25-hydroxyvitamin-D levels <30 ng/mL and with skin photodamage to take 50,000 IU of cholecalciferol biweekly for 8 to 9 weeks. Then, we obtained baseline and end-of-study skin biopsies from photodamaged (PD) and photoprotected (PP) skin, and from benign nevi (BN) and tested for mRNA expression of VDR and cytochrome P450-24 (CYP24), and markers of keratinocytic differentiation. High-dose cholecalciferol supplementation significantly elevated circulating levels of 25-hydroxyvitamin-D (P < 0.0001) and 1,25-dihydroxyvitamin-D (P < 0.0001). VDR expression in PD- and PP-skin showed minimum changes after supplementation. CYP24 expression in PD- and PP-skin was increased after supplementation by 186%, P = 0.08, and 134%, P = 0.07, respectively. In BNs from 11 participants, a trend for higher VDR and CYP24 expression was observed (average of 20%, P = 0.08, and 544%, P = 0.09, respectively). Caspase-14 expression at the basal layer in PD skin samples was the only epidermal differentiation marker that was significantly increased (49%, P < 0.0001). High-dose cholecalciferol supplementation raised serum VD metabolite levels concurrently with CYP24 mRNA and caspase-14 levels in the skin. Our findings of significant variability in the range of VDR and CYP24 expression across study samples represent an important consideration in studies evaluating the role of VD as a skin cancer chemopreventive agent.

View details for DOI 10.1158/1940-6207.CAPR-14-0280

View details for PubMedID 25835512

Determination of locally advanced basal cell carcinoma (BCC) in the first 285 patients enrolled in the RegiSONIC disease registry study. Yoo, S. S., Tang, J. Y., Rogers, G. S., Olencki, T., Lacouture, M. E., Kudchadkar, R., Guillen, J., Mun, Y., Dawson, K., Sekulic, A. AMER SOC CLINICAL ONCOLOGY. 2015
Genomic analysis of smoothened inhibitor resistance in Basal cell carcinoma. Cancer cell Sharpe, H. J., Pau, G., Dijkgraaf, G. J., Basset-Seguin, N., Modrusan, Z., Januario, T., Tsui, V., Durham, A. B., Dlugosz, A. A., Haverty, P. M., Bourgon, R., Tang, J. Y., Sarin, K. Y., Dirix, L., Fisher, D. C., Rudin, C. M., Sofen, H., Migden, M. R., Yauch, R. L., de Sauvage, F. J. 2015; 27 (3): 327-341

Abstract

Smoothened (SMO) inhibitors are under clinical investigation for the treatment of several cancers. Vismodegib is approved for the treatment of locally advanced and metastatic basal cell carcinoma (BCC). Most BCCpatients experience significant clinical benefit on vismodegib, but some develop resistance. Genomic analysis of tumor biopsies revealed that vismodegib resistance is associated with Hedgehog (Hh) pathway reactivation, predominantly through mutation of the drug target SMO and to a lesser extent through concurrent copy number changes in SUFU and GLI2. SMO mutations either directly impaired drug binding or activated SMO to varying levels. Furthermore, we found evidence for intra-tumor heterogeneity, suggesting that a combination of therapies targeting components at multiple levels of the Hh pathway is required to overcome resistance.

View details for DOI 10.1016/j.ccell.2015.02.001

View details for PubMedID 25759019

Detection of Non-Melanoma Skin Cancer by in vivo Fluorescence Imaging with Fluorocoxib A. Neoplasia Ra, H., Gonzlez-Gonzlez, E., Uddin, M. J., King, B. L., Lee, A., Ali-Khan, I., Marnett, L. J., Tang, J. Y., Contag, C. H. 2015; 17 (2): 201-207

Abstract

Non-melanoma skin cancer (NMSC) is the most common form of cancer in the US and its incidence is increasing. The current standard of care is visual inspection by physicians and/or dermatologists, followed by skin biopsy and pathologic confirmation. We have investigated the use of in vivo fluorescence imaging using fluorocoxib A as a molecular probe for early detection and assessment of skin tumors in mouse models of NMSC. Fluorocoxib A targets the cyclooxygenase-2 (COX-2) enzyme that is preferentially expressed by inflamed and tumor tissue, and therefore has potential to be an effective broadly active molecular biomarker for cancer detection. We tested the sensitivity of fluorocoxib A in a BCC allograft SCID hairless mouse model using a wide-field fluorescence imaging system. Subcutaneous allografts comprised of 1000 BCC cells were detectable above background. These BCC allograft mice were imaged over time and a linear correlation (R(2) = 0.8) between tumor volume and fluorocoxib A signal levels was observed. We also tested fluorocoxib A in a genetically engineered spontaneous BCC mouse model (Ptch1(+/-) K14-Cre-ER2 p53(fl/fl)), where sequential imaging of the same animals over time demonstrated that early, microscopic lesions (100 m size) developed into visible macroscopic tumor masses over 11 to 17 days. Overall, for macroscopic tumors, the sensitivity was 88% and the specificity was 100%. For microscopic tumors, the sensitivity was 85% and specificity was 56%. These results demonstrate the potential of fluorocoxib A as an in vivo imaging agent for early detection, margin delineation and guided biopsies of NMSCs.

View details for DOI 10.1016/j.neo.2014.12.009

View details for PubMedID 25748239

Smoking behavior and association of melanoma and nonmelanoma skin cancer in the Women's Health Initiative JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Henderson, M. T., Kubo, J. T., Desai, M., David, S. P., Tindle, H., Sinha, A. A., Hou, L., Messina, C., Saquib, N., Stefanick, M. L., Tang, J. Y. 2015; 72 (1): 190-191

View details for DOI 10.1016/j.jaad.2014.09.024

View details for Web of Science ID 000346404500053

View details for PubMedID 25497923

Towards automated detection of basal cell carcinoma from polarization sensitive optical coherence tomography images of human skin Marvdashti, T., Duan, L., Ransohoff, K. J., Aasi, S. Z., Tang, J. Y., Ellerbee, A. K., IEEE IEEE. 2015
Non-melanoma skin cancer and NSAID use in women with a history of skin cancer in the Women's Health Initiative PREVENTIVE MEDICINE Wysong, A., Ally, M. S., Gamba, C. S., Desai, M., Swetter, S. M., Seiffert-Sinha, K., Sinha, A. A., Stefanick, M. L., Tang, J. Y. 2014; 69: 8-12

Abstract

Evidence for the effect of non-steroidal anti-inflammatory drugs (NSAIDs) on non-melanoma skin cancer (NMSC) risk is inconsistent. We prospectively examined whether regular, inconsistent, or no/low-use of NSAIDs is associated with lower NMSC risk among 54,728 postmenopausal Caucasian women in the Women's Health Initiative Observational Study enrolled between 1993 and 1998.Logistic regression models were used to assess odds of NMSC after adjusting for skin type, sun exposure history and indication for NSAID use.There were 7652 incident cases of NMSC (median follow-up: 6.9years). There was no association between regular NSAID-use and NMSC risk relative to no/low-users. However, in a subgroup analysis of 5325 women with a history of skin cancer (incident NMSC: 1897), odds of NMSC were lower among regular NSAID users whether <5years (OR 0.82, 95% CI: 0.70-0.95) or 5years (OR 0.82, 95% CI: 0.69-0.98) of use compared to no/low-users. Inconsistent NSAID use and acetaminophen use were not associated with NMSC risk.Overall, NSAID use was not associated with NMSC risk. However, in women with a history of skin cancer, regular NSAID use was associated with 18% lower odds of NMSC. Future studies on potential chemopreventative effects of NSAIDs should focus on subjects with prior history of NMSC.

View details for DOI 10.1016/j.ypmed.2014.08.024

View details for Web of Science ID 000346221600003

Vitamin D levels and menopause-related symptoms. Menopause (New York, N.Y.) LeBlanc, E. S., Desai, M., Perrin, N., Wactawski-Wende, J., Manson, J. E., Cauley, J. A., Michael, Y. L., Tang, J., Womack, C., Song, Y., Johnson, K. C., O'Sullivan, M. J., Woods, N., Stefanick, M. L. 2014; 21 (11): 1197-1203

Abstract

This study aims to determine whether vitamin D levels are associated with menopause-related symptoms in older women.A randomly selected subset of 1,407 women, among 26,104 potentially eligible participants of the Women's Health Initiative Calcium and Vitamin D trial of postmenopausal women aged 51 to 80 years, had 25-hydroxyvitamin D [25(OH)D] levels measured at the Women's Health Initiative Calcium and Vitamin D trial baseline visit. Information about menopause-related symptoms at baseline was obtained by questionnaire and included overall number of symptoms and composite measures of sleep disturbance, emotional well-being, and energy/fatigue, as well as individual symptoms. After exclusions for missing data, 530 women (mean [SD] age, 66.2 [6.8] y) were included in these analyses.Borderline significant associations between 25(OH)D levels and total number of menopausal symptoms were observed (with P values ranging from 0.05 to 0.06 for fully adjusted models); however, the effect was clinically insignificant and disappeared with correction for multiple testing. No associations between 25(OH)D levels and composite measures of sleep disturbance, emotional well-being, or energy/fatigue were observed (P's > 0.10 for fully adjusted models).There is no evidence for a clinically important association between serum 25(OH)D levels and menopause-related symptoms in postmenopausal women.

View details for DOI 10.1097/GME.0000000000000238

View details for PubMedID 24736200

An investigator-initiated open-label clinical trial of vismodegib as a neoadjuvant to surgery for high-risk basal cell carcinoma. Journal of the American Academy of Dermatology Ally, M. S., Aasi, S., Wysong, A., Teng, C., Anderson, E., Bailey-Healy, I., Oro, A., Kim, J., Chang, A. L., Tang, J. Y. 2014; 71 (5): 904-911 e1

Abstract

Vismodegib is an oral hedgehog-pathway inhibitor approved for advanced basal cell carcinoma (BCC). Although most BCCs are amenable to surgery, excision of large tumors in aesthetically sensitive sites may compromise function or cosmesis.We sought to evaluate the reduction in BCC surgical defect area after 3 to 6 months of neoadjuvant vismodegib.This was an open-label, single-arm intervention trial with a primary outcome of change in target-tumor surgical defect area pre- and post-vismodegib (150 mg/d). Secondary outcomes were change in tumor area and tolerability.Eleven of 15 enrolled patients, aged 39 to 100 years, completed the trial. Thirteen target tumors were excised after a mean of 42 months of vismodegib. In all, 29% (4 of 14 patients) could not complete more than 3 months because of vismodegib-related side effects. The mean baseline target-tumor diameter was 3.2 cm, and 10 of 13 tumors occurred on the face. Overall, vismodegib reduced the surgical defect area by 27% (95% confidence interval -45.7% to -7.9%; P=.006) from baseline. Vismodegib was not effective in patients who received less than 3 months. Over a mean follow-up of 11.5 (range 4-21) months for all tumors, only 1 tumor recurred at 17 months post-Mohs micrographic surgery.Short follow-up time and no placebo control are limitations.Neoadjuvant vismodegib appears to reduce surgical defect area when taken for 3 months or longer for nonrecurrent BCCs in functionally sensitive locations. Further studies with larger sample sizes and long-term follow-up are warranted.

View details for DOI 10.1016/j.jaad.2014.05.020

View details for PubMedID 24929884

Dermatologic applications of direct-to-consumer genomic analysis. Journal of the American Academy of Dermatology Fogel, A. L., Azizi, N., Tang, J., Sarin, K. Y. 2014; 71 (5): 993-995

View details for DOI 10.1016/j.jaad.2014.04.066

View details for PubMedID 25437956

Non-steroidal anti-inflammatory drugs and cancer risk in women: Results from the Women's Health Initiative INTERNATIONAL JOURNAL OF CANCER Brasky, T. M., Liu, J., White, E., Peters, U., Potter, J. D., Walter, R. B., Baik, C. S., Lane, D. S., Manson, J. E., Vitolins, M. Z., Allison, M. A., Tang, J. Y., Wactawski-Wende, J. 2014; 135 (8): 1869-1883

Abstract

The use of non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with reduced risks of cancers at several sites in some studies; however, we recently reported no association between their use and total cancer risk in women in a prospective study. Here we examine the association between NSAIDs and total and site-specific cancer incidence in the large, prospective Women's Health Initiative (WHI). Women (129,013) were recruited to participate in the WHI at 40 US clinical centers from 1993 to 1998 and followed prospectively. After 9.7 years of follow-up, 12,998 incident, first primary, invasive cancers were diagnosed. NSAID use was systematically collected at study visits. We used Cox proportional hazards regression models to estimate multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI) for associations between NSAIDs use and total and site-specific cancer risk. Relative to non-use, consistent use (i.e., use at baseline and year 3 of follow-up) of any NSAID was not associated with total cancer risk (HR 1.00, 95% CI: 0.94-1.06). Results for individual NSAIDs were similar to the aggregate measure. In site-specific analyses, NSAIDs were associated with reduced risks of colorectal cancer, ovarian cancer, and melanoma. Our study confirms a chemopreventive benefit for colorectal cancer in women and gives preliminary evidence for a reduction of the risk of some rarer cancers. NSAIDs' benefit on cancer risk was therefore limited to specific sites and not evident when total cancer risk was examined. This information may be of importance when NSAIDs are considered as chemopreventive agents.

View details for DOI 10.1002/ijc.28823

View details for Web of Science ID 000340524100014

View details for PubMedID 24599876

Automated identification of basal cell carcinoma by polarization-sensitive optical coherence tomography BIOMEDICAL OPTICS EXPRESS Duan, L., Marvdashti, T., Lee, A., Tang, J. Y., Ellerbee, A. K. 2014; 5 (10): 3717-3729

Abstract

We report an automated classifier to detect the presence of basal cell carcinoma in images of mouse skin tissue samples acquired by polarization-sensitive optical coherence tomography (PS-OCT). The sensitivity and specificity of the classifier based on combined information of the scattering intensity and birefringence properties of the samples are significantly higher than when intensity or birefringence information are used alone. The combined information offers a sensitivity of 94.4% and specificity of 92.5%, compared to 78.2% and 82.2% for intensity-only information and 85.5% and 87.9% for birefringence-only information. These results demonstrate that analysis of the combination of complementary optical information obtained by PS-OCT has great potential for accurate skin cancer diagnosis.

View details for DOI 10.1364/BOE.5.003717

View details for Web of Science ID 000343135200036

View details for PubMedCentralID PMC4206336

Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition. Nature medicine Tang, Y., Gholamin, S., Schubert, S., Willardson, M. I., Lee, A., Bandopadhayay, P., Bergthold, G., Masoud, S., Nguyen, B., Vue, N., Balansay, B., Yu, F., Oh, S., Woo, P., Chen, S., Ponnuswami, A., Monje, M., Atwood, S. X., Whitson, R. J., Mitra, S., Cheshier, S. H., Qi, J., Beroukhim, R., Tang, J. Y., Wechsler-Reya, R., Oro, A. E., Link, B. A., Bradner, J. E., Cho, Y. 2014; 20 (7): 732-740

Abstract

Hedgehog signaling drives oncogenesis in several cancers, and strategies targeting this pathway have been developed, most notably through inhibition of Smoothened (SMO). However, resistance to Smoothened inhibitors occurs by genetic changes of Smoothened or other downstream Hedgehog components. Here we overcome these resistance mechanisms by modulating GLI transcription through inhibition of bromo and extra C-terminal (BET) bromodomain proteins. We show that BRD4 and other BET bromodomain proteins regulate GLI transcription downstream of SMO and suppressor of fused (SUFU), and chromatin immunoprecipitation studies reveal that BRD4 directly occupies GLI1 and GLI2 promoters, with a substantial decrease in engagement of these sites after treatment with JQ1, a small-molecule inhibitor targeting BRD4. Globally, genes associated with medulloblastoma-specific GLI1 binding sites are downregulated in response to JQ1 treatment, supporting direct regulation of GLI activity by BRD4. Notably, patient- and GEMM (genetically engineered mouse model)-derived Hedgehog-driven tumors (basal cell carcinoma, medulloblastoma and atypical teratoid rhabdoid tumor) respond to JQ1 even when harboring genetic lesions rendering them resistant to Smoothened antagonists. Altogether, our results reveal BET proteins as critical regulators of Hedgehog pathway transcriptional output and nominate BET bromodomain inhibitors as a strategy for treating Hedgehog-driven tumors with emerged or a priori resistance to Smoothened antagonists.

View details for DOI 10.1038/nm.3613

View details for PubMedID 24973920

OVERCOMING ACQUIRED AND A PRIORI RESISTANCE TO SMO ANTAGONISTS THROUGH EPIGENETIC REGULATION OF HEDGEHOG PATHWAY TRANSCRIPTIONAL OUTPUT Tang, Y., Schubert, S., Brian Nguyen, Masoud, S., Gholamin, S., Lee, A., Willardson, M., Bandopadhayay, P., Bergthold, G., Atwood, S., Whitson, R., Cheshier, S., Qi, J., Beroukhim, R., Tang, J., Wechsler-Reya, R., Oro, A., Link, B., Bradner, J., Cho, Y. OXFORD UNIV PRESS INC. 2014: 8182
Lack of efficacy with 1064-nm neodymium:yttrium-aluminum-garnet laser for thetreatment of onychomycosis: A randomized, controlled trial. Journal of the American Academy of Dermatology Hollmig, S. T., Rahman, Z., Henderson, M. T., Rotatori, R. M., Gladstone, H., Tang, J. Y. 2014; 70 (5): 911-917

Abstract

Laser therapies have been Food and Drug Administration approved for temporary nail plate clearance; however, there is minimal evidence of their long-term efficacy.We sought to evaluate the clinical and mycological clearance of toenails treated with 1064-nm neodymium:yttrium-aluminum-garnet laser versus no treatment.This was a randomized, controlled, single-center trial comparing 2 treatments with 1064-nm neodymium:yttrium-aluminum-garnet laser (fluence of 5 J/cm(2), rate of 6 Hz) spaced 2 weeks apart versus no treatment in 27 patients (N= 125 affected nails) with clinical and mycological diagnosis of onychomycosis. At 3 months, patients were assessed with mycological cultures and proximal nail plate measurements. Patients treated with laser were also assessed with proximal nail plate measurements at 12 months.At 3 months, 33% of patients treated with laser achieved a negative mycological culture compared with 20% of the control group (P= .49), and had more proximal nail plate clearance compared with control subjects (0.44 vs 0.15 mm, P= .18), which was not statistically significant. At 12 months, there was no difference in nail plate clearance between laser versus control subjects (0.24 vs 0.15 mm, P= .59).Our study was limited by the small sample size and number of treatments.There was no significant mycological culture or clinical nail plate clearance with 1064-nmneodymium:yttrium-aluminum-garnet laser compared with control.

View details for DOI 10.1016/j.jaad.2013.12.024

View details for PubMedID 24641985

The use of vismodegib to shrink keratocystic odontogenic tumors in patients with Basal cell nevus syndrome. JAMA dermatology Ally, M. S., Tang, J. Y., Joseph, T., Thompson, B., Lindgren, J., Raphael, M. A., Ulerio, G., Chanana, A. M., Mackay-Wiggan, J. M., Bickers, D. R., Epstein, E. H. 2014; 150 (5): 542-545

Abstract

Keratocystic odontogenic tumors (KCOTs) of the jaw affect more than 65% of patients with basal cell nevus syndrome (BCNS). Surgery frequently causes facial disfigurement and is not always curative. Most BCNS-related and some sporadic KCOTs have malignant activation of the Hedgehog signaling pathway.We examined the effect of vismodegib (an oral Hedgehog pathway inhibitor) on KCOT size in patients with BCNS enrolled in a clinical trial testing vismodegib for basal cell carcinoma prevention (NCT00957229), using pretreatment and posttreatment magnetic resonance imaging. Four men and 2 women had pretreatment KCOTs (mean longest diameter, 2.0 cm; range, 0.7-3.3 cm), occurring primarily in the mandible. Patients were treated with vismodegib, 150 mg/d, for a mean (SD) of 18.0 (4.8) months (range, 11-24 months). Four patients experienced a size reduction and 2 had no change. Vismodegib reduced the mean longest diameter of KCOTs in all patients by 1.0 cm (95% CI, 0.03-1.94; P=.02) or 50% from baseline. We observed no enlargement of existing KCOTs or new KCOT development.Vismodegib shrinks some KCOTs in patients with BCNS and may offer an alternative to surgical therapy. These effects were maintained for at least 9 months after drug cessation in 1 patient. Further studies assessing long-term efficacy and optimal maintenance regimens should be performed.

View details for DOI 10.1001/jamadermatol.2013.7444

View details for PubMedID 24623282

View details for PubMedCentralID PMC4024084

Network geometry shows evidence sequestration for medical vs. surgical practices: treatments for basal cell carcinoma. Journal of clinical epidemiology Kim, D. D., Tang, J. Y., Ioannidis, J. P. 2014; 67 (4): 391-400

Abstract

Basal cell carcinoma (BCC) is the most common cancer with 2 million treatments per year with little evidence-based guidelines for treatment. There are three classes of interventions (surgical, destructive, and topical) for BCC, and this study aimed to determine whether there are preferences or avoidances in comparisons of different types of treatments for BCC in randomized controlled trials (RCTs).PubMed, Cochrane Central Registry of Clinical Trials, and ClinicalTrials.Gov were used to identify eligible published and registered ongoing RCTs.Fifty-five trials (42 published and 13 registered trials) were identified. Only one unpublished registered trial compared a topical vs. a surgical intervention, and only one trial compared a topical vs. a destructive intervention. Conversely, 44 of the 55 trials compared interventions within the same treatment class and 9 of 55 trials compared surgical vs. destructive interventions. In most trials, selection of same-class comparators was not necessitated by the type of BCC lesions (nonaggressive superficial or nodular vs. aggressive, infiltrative, morpheic BCCs, P=0.155) or their location (face vs. nonfacial, P=0.137).This is the first time that an evaluation of network geometry is applied to address issues of comparisons between different families of interventions that belong to different specialties and practices (medical vs. surgical). Previous evaluations of homophily have addressed different families of interventions, in which all interventions are medical (drugs) and performed in the same health-care settings. The noncommunicating bodies of evidence between medical and surgical interventions that we document highlight a problem of unnecessary sequestration of the evidence and the corresponding health-care practices.

View details for DOI 10.1016/j.jclinepi.2013.10.015

View details for PubMedID 24491794

Open-Label, Exploratory Phase II Trial of Oral Itraconazole for the Treatment of Basal Cell Carcinoma. Journal of clinical oncology Kim, D. J., Kim, J., Spaunhurst, K., Montoya, J., Khodosh, R., Chandra, K., Fu, T., Gilliam, A., Molgo, M., Beachy, P. A., Tang, J. Y. 2014; 32 (8): 745-751

Abstract

Itraconazole, a US Food and Drug Administration-approved antifungal drug, inhibits the Hedgehog (HH) signaling pathway, a crucial driver of basal cell carcinoma (BCC) tumorigenesis, and reduces BCC growth in mice. We assessed the effect of itraconazole on the HH pathway and on tumor size in human BCC tumors.Patients with one BCC tumor > 4 mm in diameter were enrolled onto two cohorts to receive oral itraconazole 200 mg twice per day for 1 month (cohort A) or 100 mg twice per day for an average of 2.3 months (cohort B). The primary end point was change in biomarkers: Ki67 tumor proliferation and HH activity (GLI1 mRNA). Secondary end points included change in tumor size in a subset of patients with multiple tumors.A total of 29 patients were enrolled, of whom 19 were treated with itraconazole. Itraconazole treatment was associated with two adverse events (grade 2 fatigue and grade 4 congestive heart failure). Itraconazole reduced cell proliferation by 45% (P = .04), HH pathway activity by 65% (P = .03), and reduced tumor area by 24% (95% CI, 18.2% to 30.0%). Of eight patients with multiple nonbiopsied tumors, four achieved partial response, and four had stable disease. Tumors from untreated control patients and from those previously treated with vismodegib showed no significant changes in proliferation or tumor size.Itraconazole has anti-BCC activity in humans. These results provide the basis for larger trials of longer duration to measure the clinical efficacy of itraconazole, especially relative to other HH pathway inhibitors.

View details for DOI 10.1200/JCO.2013.49.9525

View details for PubMedID 24493717

Tazarotene: randomized, double-blind, vehicle-controlled, and open-label concurrent trials for Basal cell carcinoma prevention and therapy in patients with Basal cell nevus syndrome. Cancer prevention research Tang, J. Y., Chiou, A. S., Mackay-Wiggan, J. M., Aszterbaum, M., Chanana, A. M., Lee, W., Lindgren, J. A., Raphael, M. A., Thompson, B. J., Bickers, D. R., Epstein, E. H. 2014; 7 (3): 292-299

Abstract

Sporadic human basal cell carcinomas (BCC) are generally well managed with current surgical modalities. However, in the subset of high-risk patients predisposed to developing large numbers of BCCs, there is an unmet need for effective, low-morbidity chemoprevention. This population includes fair-skinned patients with extensive sun exposure and those with genodermatoses such as the basal cell nevus (Gorlin) syndrome (BCNS). Tazarotene (Tazorac, Allergan) is a topical retinoid with relative specificity for RAR- and RAR- receptors. We previously demonstrated tazarotene's robust anti-BCC efficacy in Ptch1(+/-) mice, a murine equivalent of BCNS, and others have found it to have some efficacy against sporadic human BCCs. We report here results of a randomized, double-blind, vehicle-controlled study in patients with BCNS evaluating the efficacy of topically applied tazarotene for BCC chemoprevention (N = 34 subjects), along with an open-label trial evaluating tazarotene's efficacy for chemotherapy of BCC lesions (N = 36 subjects) for a maximum follow-up period of 3 years. We found that only 6% of patients had a chemopreventive response and that only 6% of treated BCC target lesions were clinically cured. Our studies provide no evidence for either chemopreventive or chemotherapeutic effect of tazarotene against BCCs in patients with BCNS.

View details for DOI 10.1158/1940-6207.CAPR-13-0305

View details for PubMedID 24441673

View details for PubMedCentralID PMC4323274

Alcohol consumption and risk of melanoma and non-melanoma skin cancer in the Women's Health Initiative CANCER CAUSES & CONTROL Kubo, J. T., Henderson, M. T., Desai, M., Wactawski-Wende, J., Stefanick, M. L., Tang, J. Y. 2014; 25 (1): 1-10

Abstract

The relationship between alcohol consumption and preference of alcohol type with hazard of melanoma (MM) and risk of non-melanoma skin cancer (NMSC) was examined in the Women's Health Initiative (WHI) Observational Study (OS).A prospective cohort of 59,575 White postmenopausal women in the WHI OS (mean age 63.6) was analyzed. Cox proportional hazards models and logistic regression techniques were used to assess the hazard and risk of physician-adjudicated MM and self-reported NMSC, respectively, after adjusting for potential confounders including measures of sun exposure and skin type.Over 10.2 mean years of follow-up, 532 MM cases and 9,593 NMSC cases occurred. A significant relationship between amount of alcohol consumed and both MM and NMSC was observed, with those who consume 7+ drinks per week having a higher hazard of MM (HR 1.64 (1.09, 2.49), p global=0.0013) and higher risk of NMSC (OR 1.23 (1.11, 1.36), p global<0.0001) compared to non-drinkers. Lifetime alcohol consumption was also positively associated with hazard of MM (p=0.0011) and risk of NMSC (p<0.0001). Further, compared to non-drinkers, a preference for either white wine or liquor was associated with an increased hazard of MM (HR 1.52 (1.02, 2.27) for white wine; HR 1.65 (1.07, 2.55) for liquor) and risk of NMSC (OR 1.16 (1.05, 1.28) for white wine; OR 1.26 (1.13, 1.41) for liquor).Higher current alcohol consumption, higher lifetime alcohol consumption, and a preference for white wine or liquor were associated with increased hazard of MM and risk of NMSC.

View details for DOI 10.1007/s10552-013-0280-3

View details for Web of Science ID 000329351700001

View details for PubMedID 24173533

Epigenetic targeting of hedgehog pathway transcriptional output. Neuro-oncology Cho, Y. J., Tang, Y., Schubert, S., Willardson, M., Bandopadhayay, P., Bergthold, G., Nguyen, B., Masoud, S., Vue, N., Balansay, B., Gholamin, S., Cheshier, S. H., Atwood, S. X., Whitson, R. J., Lee, A., Tang, J. Y., Qi, J., Beroukhim, R., Wechsler-Reya, R., Oro, A. E., Link, B., Bradner, J. E., Cho, Y. J. 2014; 16 Suppl 3: iii25

Abstract

(blind field)We used ligand and genetic activation of the Hedgehog pathway to study the effects of BET bromodomain inhibition on Hedgehog pathway transcriptional output. Furthermore, we studied the in vitro and in vivo efficacy of BET bromodomain inhibitors using tumor cells generated from genetically engineered mouse (GEM) and patient derived xenograft models of Hedgehog driven tumors, including a panel of tumors resistant to the current FDA-approved Smoothened antagonists.We show that knockdown of BRD4 or treatment with the BET bromodomain inhibitor, JQ1, dramatically inhibits transcription of GLI1, GLI2 and other Hedgehog target genes upon ligand-mediated or genetic activation of the Hedgehog pathway. We confirm the inhibitory effect of JQ1 occurs downstream of SMO and SUFU and verify by chromatin immunoprecipitation that BRD4 directly occupies the GLI1 and GLI2 promoters with a substantial decrease in the engagement of these genomic sites upon treatment with JQ1. We observe a corresponding downregulation of genes associated with medulloblastoma-specific GLI1 binding sites upon exposure to JQ1, confirming the direct regulation of GLI1 by BET bromodomain proteins. Finally, in patient- and GEM-derived cells of Hedgehog-driven cancer (basal cell carcinoma, medulloblastoma and atypical teratoid/rhabdoid tumor), we show that JQ1 decreases Hh pathway output and proliferation, even in cells resistant to Smoothened inhibitors.These results expand the role of BET bromodomain inhibitors to targeting Hedgehog-driven cancers and highlight a strategy that overcomes the limitation of Hedgehog pathway inhibitors currently in clinical use.Pediatrics.

View details for DOI 10.1093/neuonc/nou208.9

View details for PubMedID 25165259

Eczema and sensitization to common allergens in the United States: a multiethnic, population-based study. Pediatric dermatology Fu, T., Keiser, E., Linos, E., Rotatori, R. M., Sainani, K., Lingala, B., Lane, A. T., Schneider, L., Tang, J. Y. 2014; 31 (1): 21-26

Abstract

The relationship between food and environmental allergens in contributing to eczema risk is unclear on a multiethnic population level. Our purpose was to determine whether sensitization to specific dietary and environmental allergens as measured according to higher specific immunoglobulin E (IgE) levels is associated with eczema risk in children. National Health and Nutrition Examination Survey participants ages 1 to 17 years were asked whether they had ever received a diagnosis of eczema from a physician (n = 538). Total and specific serum IgE levels for four dietary allergens (egg, cow's milk, peanut, and shrimp) and five environmental allergens (dust mite, cat, dog, Aspergillus, and Alternaria) were measured. Logistic regression was used to examine the association between eczema and IgE levels. In the United States, 10.4 million children (15.6%) have a history of eczema. Eczema was more common in black children (p < 0.001) and in children from families with higher income and education (p = 0.01). The median total IgE levels were higher in children with a history of eczema than in those without (66.4 vs 50.6 kU/L, p = 0.004). In multivariate analysis adjusted for age, race, sex, family income, household education, and physician-diagnosed asthma, eczema was significantly associated with sensitization to cat dander (odds ratio [OR] = 1.2, 95% confidence interval [CI] 1.05, 1.4, p = 0.009) and dog dander (OR = 1.5, 95% CI, 1.2, 1.7, p < 0.001). After correction for multiple comparisons, only sensitization to dog dander remained significant. U.S. children with eczema are most likely to be sensitized to dog dander. Future prospective studies should further explore this relationship.

View details for DOI 10.1111/pde.12237

View details for PubMedID 24283549

Quantifying Soft Tissue Loss in Facial Aging: A Study in Women Using Magnetic Resonance Imaging DERMATOLOGIC SURGERY Wysong, A., Joseph, T., Kim, D., Tang, J. Y., Gladstone, H. B. 2013; 39 (12): 1895-1902

Abstract

Facial aging involves changes in the facial skeleton and soft tissues. There is limited quantitative data on soft tissue aging of the face.Magnetic resonance imaging (MRI) was used to quantify and compare facial soft tissue loss over time.Two thousand thirty-seven MRI scans from 58 women divided into young, middle-aged, and older groups were screened. A blinded radiologist used MRI to measure the temporal, infraorbital, and medial and lateral cheek areas.The mean thickness of the subcutaneous tissue in the temporal area was 12.3, 8.4, and 8.9 mm in the young, middle-aged, and older groups, respectively (p < .001). A mean difference of 1.6 mm was seen between the young and middle-aged groups and 2.2 mm between the young and older group (p < .001) in the infraorbital area, 3.3 mm between the young and middle-aged groups and 3.2 mm between the young and older group in the medial cheeks (p < .001), and 2.4 mm between the young and middle-aged groups and 2.4 mm between the young and older group in the lateral cheeks (p = .01).Facial soft tissue undergoes significant deterioration over time, with the most dramatic changes between the ages of 30 and 60 in the temporal, infraorbital, and lateral and medial cheek areas. Soft tissue augmentation and volume correction in these areas may be an effective strategy for facial rejuvenation.

View details for DOI 10.1111/dsu.12362

View details for PubMedID 24238002

Lower Skin Cancer Risk in Women with Higher Body Mass Index: The Women's Health Initiative Observational Study. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Tang, J. Y., Henderson, M. T., Hernandez-Boussard, T., Kubo, J., Desai, M., Sims, S. T., Aroda, V., Thomas, F., McTiernan, A., Stefanick, M. L. 2013; 22 (12): 2412-2415

Abstract

The unclear relationship of obesity to incident melanoma and nonmelanoma skin cancer (NMSC) risks was evaluated in the large, geographically diverse longitudinal, prospective Women's Health Initiative (WHI) observational study. Risks of melanoma and NMSC in normal weight women were compared with risks in overweight [body mass index (BMI) = 25-29.0 kg/m(2)] and obese (BMI 30 kg/m(2)) women, using Cox proportional hazards models for melanoma and logistic regression for NMSC. Over a mean 9.4 years of follow-up, there were 386 melanoma and 9,870 NSMC cases. Risk of melanoma did not differ across weight categories (P = 0.86), whereas in fully adjusted models, NMSC risk was lower in overweight [OR, 0.93; 95% confidence interval (CI), 0.89-0.99] and obese (OR, 0.85; 95% CI, 0.80-0.91) women (P < 0.001). Excess body weight was not associated with melanoma risk in postmenopausal women but was inversely associated with NMSC risk, possibly due to lower sun exposure in overweight and obese women. This supports previous work demonstrating the relationship between excess body weight and skin cancer risk. Cancer Epidemiol Biomarkers Prev; 22(12); 2412-5. 2013 AACR.

View details for DOI 10.1158/1055-9965.EPI-13-0647

View details for PubMedID 24042260

Role of aspirin and non-aspirin NSAIDs in preventing melanoma. Future oncology Ally, M. S., Swetter, S. M., Tang, J. Y. 2013; 9 (11): 1671-1674

View details for DOI 10.2217/fon.13.112

View details for PubMedID 23731359

The BAF Complex Interacts with Pax6 in Adult Neural Progenitors to Establish a Neurogenic Cross-Regulatory Transcriptional Network CELL STEM CELL Ninkovic, J., Steiner-Mezzadri, A., Jawerka, M., Akinci, U., Messerdotti, G., Petricca, S., Fischer, J., von Holst, A., Beckers, J., Lie, C. D., Petrik, D., Miller, E., Tang, J., Wu, J., Lefebvre, V., Demmers, J., Eisch, A., Metzger, D., Crabtree, G., Irmler, M., Poot, R., Goetz, M. 2013; 13 (4): 403-418

Abstract

Numerous transcriptional regulators of neurogenesis have been identified in the developing and adult brain, but how neurogenic fate is programmed at the epigenetic level remains poorly defined. Here, we report that the transcription factor Pax6 directly interacts with the Brg1-containing BAF complex inadult neural progenitors. Deletion of either Brg1 or Pax6 in the subependymal zone (SEZ) causes theprogeny of adult neural stem cells to convert to the ependymal lineage within the SEZ while migrating neuroblasts convert to different glial lineages en route to or in the olfactory bulb (OB). Genome-wide analyses reveal that the majority of genes downregulated in the Brg1 null SEZ and OB contain Pax6 binding sites and are also downregulated inPax6 null SEZ and OB. Downstream of the Pax6-BAF complex, we find that Sox11, Nfib, and Pou3f4 form a transcriptional cross-regulatory network that drives neurogenesis and canconvert postnatal glia into neurons. Taken together, elements of our work identify a tripartite effector network activated by Pax6-BAF that programs neuronal fate.

View details for DOI 10.1016/j.stem.2013.07.002

View details for Web of Science ID 000329571100010

View details for PubMedID 23933087

Low-Fat Diet and Skin Cancer Risk: The Women's Health Initiative Randomized Controlled Dietary Modification Trial CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Gamba, C. S., Stefanick, M. L., Shikany, J. M., Larson, J., Linos, E., Sims, S. T., Marshall, J., Van Horn, L., Zeitouni, N., Tang, J. Y. 2013; 22 (9): 1509-1519

Abstract

Background: Large cohort studies have reported no relationship between dietary fat and nonmelanoma skin cancer (NMSC), although a low-fat diet intervention reduced NMSC risk in a small clinical trial. In animal studies, skin tumor development has been reduced by low-fat diet. We evaluated the effect of a low-fat dietary pattern on NMSC and melanoma in the Women's Health Initiative Dietary Modification trial. Methods: Postmenopausal women aged 50 to 79 years (N=48,835) were randomly assigned to the low-fat dietary pattern intervention (N=19,541) or comparison group (N=29,294). The intervention goals included decreasing fat intake to 20% of calories, increasing vegetable and fruit intake, and increasing grain intake. Self-reported incident NMSC (N=4,907) and physician-adjudicated incident melanoma (N=279) were ascertained every 6 months. Results: Over 8.1 years of follow-up, the low-fat diet intervention did not affect overall incidence of NMSC (hazard ratio [HR] 0.98, 95% confidence interval [CI]: 0.92-1.04) or melanoma (HR 1.04, 95% CI: 0.82-1.32). In subgroup analyses of melanoma risk, baseline fat intake interacted significantly with group assignment (Pinteraction=0.006). Among women with higher baseline fat intake, the dietary intervention significantly increased risk (HR 1.48; 95% CI: 1.06-2.07), whereas, among women with lower baseline fat intake, the intervention tended to reduce melanoma risk (HR 0.72, 95% CI: 0.50-1.02). Conclusions: In this large randomized trial, a low-fat dietary pattern did not affect overall incidence of NMSC or melanoma. Impact: A low-fat diet does not reduce incidence of NMSC, but an interaction between baseline fat intake and dietary intervention on melanoma risk warrants further investigation.

View details for DOI 10.1158/1055-9965.EPI-13-0341

View details for Web of Science ID 000324674500004

View details for PubMedID 23697610

Cutaneous human papillomavirus infection and Basal cell carcinoma of the skin. journal of investigative dermatology Ally, M. S., Tang, J. Y., Arron, S. T. 2013; 133 (6): 1456-1458

Abstract

Human papillomavirus (HPV) is ubiquitous in skin and has been associated with nonmelanoma skin cancer. Iannacone et al. investigate the role of HPV in basal cell carcinoma (BCC) by assessing the presence of HPV antibodies, HPV DNA in tumors, and the relationship between these two markers and BCC. In contrast to squamous cell carcinoma (SCC), there is no association between HPV and BCC.

View details for DOI 10.1038/jid.2013.46

View details for PubMedID 23673499

The use of aprepitant in brachioradial pruritus. JAMA dermatology (Chicago, Ill.) Ally, M. S., Gamba, C. S., Peng, D. H., Tang, J. Y. 2013; 149 (5): 627-628

View details for DOI 10.1001/jamadermatol.2013.170

View details for PubMedID 23677105

Vismodegib as an adjuvant to surgery for basal cell carcinomas International Investigative Dermatology Meeting ALLY, M. S., Aasi, S., Chang, A., Teng, C., Anderson, E. M., Bailey, I., Wysong, A., Kim, J., Tang, J. Y. NATURE PUBLISHING GROUP. 2013: S178S178
Lower serum vitamin D levels are associated with increased risk of eczema in US adults International Investigative Dermatology Meeting Fu, T., Gamba, C., IVE, H., Tang, J. Y. NATURE PUBLISHING GROUP. 2013: S93S93
Update on metastatic basal cell carcinoma: a summary of published cases from 1981 through 2011. JAMA dermatology Wysong, A., Aasi, S. Z., Tang, J. Y. 2013; 149 (5): 615-616

View details for DOI 10.1001/jamadermatol.2013.3064

View details for PubMedID 23677097

Aspirin is associated with lower melanoma risk among postmenopausal Caucasian women The Women's Health Initiative CANCER Gamba, C. A., Swetter, S. M., Stefanick, M. L., Kubo, J., Desai, M., Spaunhurst, K. M., Sinha, A. A., Asgari, M. M., Sturgeon, S., Tang, J. Y. 2013; 119 (8): 1562-1569

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with decreased risk of gastric, colorectal, and breast cancer. However, the impact of NSAIDs on the risk of melanoma has been inconsistent. The authors evaluated the association between NSAID use and cutaneous melanoma risk in the Women's Health Initiative (WHI) Observational Study (OS).At study entry, use of aspirin (acetylsalicylic acid [ASA]) and nonaspirin NSAIDs was assessed among 59,806 postmenopausal Caucasian women ages 50 to 79 years. Cox proportional hazards models were constructed after adjusting for participant skin type, sun exposure history, and medical indications for NSAID use among other confounders.During a median follow-up of 12 years, 548 incident melanomas were confirmed by medical review. Women who used ASA had a 21% lower risk of melanoma (hazard ratio, 0.79; 95% confidence interval, 0.63-0.98) relative to nonusers. Increased duration of ASA use (<1 year, 1-4 years, and 5 years) was associated with an 11% lower risk of melanoma for each categorical increase (Ptrend = .01), and women with 5 years of use had a 30% lower melanoma risk (hazard ratio, 0.70; 95% confidence interval, 0.55-0.94). In contrast, use of non-ASA NSAIDs and acetaminophen were not associated with melanoma risk.Postmenopausal women who used ASA had a significantly lower risk of melanoma, and longer duration of ASA use was associated with greater protection. Although this study was limited by the observational design and self-report of NSAID use, the findings suggest that ASA may have a chemopreventive effect against the development of melanoma and warrant further clinical investigation.

View details for DOI 10.1002/cncr.27817

View details for PubMedID 23483536

Nonmelanoma Skin Cancer Visits and Procedure Patterns in a Nationally Representative Sample: National Ambulatory Medical Care Survey 1995-2007 DERMATOLOGIC SURGERY Wysong, A., Linos, E., Hernandez-Boussard, T., Arron, S. T., Gladstone, H., Tang, J. Y. 2013; 39 (4): 596-602

Abstract

The rising incidence of nonmelanoma skin cancer (NMSC) is well documented, but data are limited on the number of visits and treatment patterns of NMSC in the outpatient setting.To evaluate practice and treatment patterns of NMSC in the United States over the last decade and to characterize differences according to sex, age, race, insurance type, and physician specialty.Adults with an International Classification of Diseases, Ninth Revision, diagnosis of NMSC were included in this cross-sectional survey study of the National Ambulatory Medical Care Survey between 1995 and 2007. Primary outcomes included population-adjusted NMSC visit rates and odds ratios of receiving a procedure for NMSC using logistic regression.Rates of NMSC visits increased between 1995 and 2007. The number of visits was significantly higher in men, particularly those aged 65 and older. Fifty-nine percent of NMSC visits were associated with a procedure, and the individuals associated with that visit were more likely to be male, to be seen by a dermatologist, and to have private-pay insurance.Nonmelanoma skin cancer visit rates increased from 1995 to 2007 and were higher in men than women. Visits to a dermatologist are more likely to be associated with a procedure for NMSC, and there may be discrepancies in treatment patterns based on insurance type and sex.

View details for DOI 10.1111/dsu.12092

View details for Web of Science ID 000317018200010

View details for PubMedID 23331766

GLI activation by atypical protein kinase C iota/lambda regulates the growth of basal cell carcinomas NATURE Atwood, S. X., Li, M., Lee, A., Tang, J. Y., Oro, A. E. 2013; 494 (7438): 484-488

Abstract

Growth of basal cell carcinomas (BCCs) requires high levels of hedgehog (HH) signalling through the transcription factor GLI. Although inhibitors of membrane protein smoothened (SMO) effectively suppress HH signalling, early tumour resistance illustrates the need for additional downstream targets for therapy. Here we identify atypical protein kinase C / (aPKC-/) as a novel GLI regulator in mammals. aPKC-/ and its polarity signalling partners co-localize at the centrosome and form a complex with missing-in-metastasis (MIM), a scaffolding protein that potentiates HH signalling. Genetic or pharmacological loss of aPKC-/ function blocks HH signalling and proliferation of BCC cells. Prkci is a HH target gene that forms a positive feedback loop with GLI and exists at increased levels in BCCs. Genome-wide transcriptional profiling shows that aPKC-/ and SMO control the expression of similar genes in tumour cells. aPKC-/ functions downstream of SMO to phosphorylate and activate GLI1, resulting in maximal DNA binding and transcriptional activation. Activated aPKC-/ is upregulated in SMO-inhibitor-resistant tumours and targeting aPKC-/ suppresses signalling and growth of resistant BCC cell lines. These results demonstrate that aPKC-/ is critical for HH-dependent processes and implicates aPKC-/ as a new, tumour-selective therapeutic target for the treatment of SMO-inhibitor-resistant cancers.

View details for DOI 10.1038/nature11889

View details for Web of Science ID 000315661500040

New Onset of Keratoacanthomas After Vismodegib Treatment for Locally Advanced Basal Cell Carcinomas: A Report of 2 Cases JAMA DERMATOLOGY Aasi, S., Silkiss, R., Tang, J. Y., Wysong, A., Liu, A., Epstein, E., Oro, A. E., Chang, A. L. 2013; 149 (2): 242-243
Factors affecting sunscreen use and sun avoidance in a US national sample of organ transplant recipients BRITISH JOURNAL OF DERMATOLOGY Mihalis, E. L., Wysong, A., Boscardin, W. J., Tang, J. Y., Chren, M. M., Arron, S. T. 2013; 168 (2): 346-353

Abstract

Organ transplant recipients have an increased risk of nonmelanoma skin cancers due to immunosuppressive therapy following transplantation. Use of sunscreen has been shown to reduce this risk.To identify patient and healthcare factors associated with sun-protective behaviours in organ transplant recipients after transplantation with the goal of increasing overall sunscreen use.This study utilized a cross-sectional, retrospective survey from a national sample of 198 organ transplant recipients in the U.S.A. from 2004 to 2008 with no prior diagnosis of skin cancer. The main outcome measures were sunscreen use and sun avoidance before and after transplantation. Frequency of sunscreen use and sun exposure was obtained by self-report on Likert scales ranging from never to always, and these responses were converted to a numerical scale from 0 to 4.Overall sunscreen use increased after transplantation (from a score of 14 to 21, P < 0001). Sex, Fitzpatrick skin type, receiving advice to avoid sun from a healthcare provider, and pretransplantation sunscreen use were significantly associated with frequency of post-transplantation sunscreen use in multivariate models. Pretransplantation sun exposure, advice to avoid sun and pretransplantation sunscreen use were significantly associated with sun avoidance post-transplantation.Both patient features and clinician advice are associated with sun-protective behaviours after organ transplantation. These results will help physicians target expanded sun-protection counselling to those patients most in need of such intervention.

View details for DOI 10.1111/j.1365-2133.2012.11213.x

View details for Web of Science ID 000314470600021

View details for PubMedID 22880814

Itraconazole and Arsenic Trioxide Inhibit Hedgehog Pathway Activation and Tumor Growth Associated with Acquired Resistance to Smoothened Antagonists CANCER CELL Kim, J., Aftab, B. T., Tang, J. Y., Kim, D., Lee, A. H., Rezaee, M., Kim, J., Chen, B., King, E. M., Borodovsky, A., Riggins, G. J., Epstein, E. H., Beachy, P. A., Rudin, C. M. 2013; 23 (1): 23-34

Abstract

Recognition of the multiple roles of Hedgehog signaling in cancer has prompted intensive efforts to develop targeted pathway inhibitors. Leading inhibitors in clinical development act by binding to a common site within Smoothened, a critical pathway component. Acquired Smoothened mutations, including SMO(D477G), confer resistance to these inhibitors. Here, we report that itraconazole and arsenic trioxide, two agents in clinical use that inhibit Hedgehog signaling by mechanisms distinct from that of current Smoothened antagonists, retain inhibitory activity in vitro in the context of all reported resistance-conferring Smoothened mutants and GLI2 overexpression. Itraconazole and arsenic trioxide, alone or in combination, inhibit the growth of medulloblastoma and basal cell carcinoma in vivo, and prolong survival of mice with intracranial drug-resistant SMO(D477G) medulloblastoma.

View details for DOI 10.1016/j.ccr.2012.11.017

View details for PubMedID 23291299

The Evolving Conception and Management Challenges of Malignant Fibrous Histiocytoma DERMATOLOGIC SURGERY Hollmig, S. T., Kirkland, E. B., Henderson, M. T., Tang, J. Y., Gladstone, H. B. 2012; 38 (12): 1922-1929

Abstract

Malignant fibrous histiocytoma (MFH) is a rare and aggressive tumor. Mohs micrographic surgery (MMS) has been reported as an effective treatment, although most cases were published before advances in cytopathologic techniques led to reclassification of many tumors.To evaluate a contemporary cohort of individuals with MFH and analyze management practices.We reviewed all cases of MFH diagnosed at our institution from January 1995 to December 2010, evaluating 839 records to identify 36 patients undergoing management of tumors of the head and neck.Seventeen of the total 36 patients (47%; mean age 67) experienced tumor recurrence, and 10 (28%) developed metastases. Seven of nine patients initially treated with MMS (78%), and 10 of 24 (42%) treated with WLE experienced recurrence (p=.06). Patients treated with MMS had smaller tissue defects after surgery. The mean contemporary recurrence rate of MFH treated with MMS is significantly higher (58.8%) than the cumulative recurrence rate reported before 2000 (7.4%) (p<.001).Our study is consistent with reports of MFH as an aggressive neoplasm and describes the largest population treated with MMS in 3 decades. The changing conception of MFH, along with a propensity for in-transit metastases, may explain higher contemporary recurrence rates.

View details for DOI 10.1111/j.1524-4725.2012.02538.x

View details for Web of Science ID 000312217900003

View details for PubMedID 22882717

Is Tanning Bed Exposure Associated With Aggressive Basal Cell Carcinoma? JOURNAL OF CLINICAL ONCOLOGY Gamba, C. A., Wysong, A., Million, L., Aasi, S., Kim, J., Tang, J. Y. 2012; 30 (32): E333-E336

View details for DOI 10.1200/JCO.2012.42.1008

View details for Web of Science ID 000310914800006

View details for PubMedID 23008324

Sunscreen use in NCAA collegiate athletes: Identifying targets for intervention and barriers to use PREVENTIVE MEDICINE Wysong, A., Gladstone, H., Kim, D., Lingala, B., Copeland, J., Tang, J. Y. 2012; 55 (5): 493-496

Abstract

Ultraviolet radiation is a known risk factor for skin cancer and photoaging. Athletes are at high-risk with frequent sun exposure during peak hours of ultraviolet radiation. The aim of this study was to identify attitudes, personal characteristics, and barriers associated with sunscreen use among a high-risk athlete population.A cross-sectional survey study conducted in 290 collegiate athletes from April 2010 to June 2011 at Duke and Stanford Universities.The average athlete spent 4h per day and 10 months per year training outdoors. While 96% agreed that sunscreen helps prevent skin cancer, over 50% never used sunscreen and 75% used sunscreen 3 or fewer days/week. Having a coach or athletic administrator discuss photoprotection was significantly associated with sunscreen use. Predictors of sunscreen use were female gender, sunburns in the last year, belief at risk for skin cancer, knowing someone with skin cancer, and being worried about wrinkles, sun burns, or skin cancer.Continued identification of characteristics and barriers to sunscreen use can lead to targeted interventions and education in this high-risk group of collegiate athletes with early and elevated total lifetime ultraviolet exposure.

View details for DOI 10.1016/j.ypmed.2012.08.020

View details for Web of Science ID 000311061100029

View details for PubMedID 22975268

Vitamin D in cutaneous carcinogenesis Part II JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Tang, J. Y., Fu, T., Lau, C., Oh, D. H., Bikle, D. D., Asgari, M. M. 2012; 67 (5)
Vitamin D in cutaneous carcinogenesis Part I JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Tang, J. Y., Fu, T., Lau, C., Oh, D. H., Bikle, D. D., Asgari, M. M. 2012; 67 (5)

Abstract

Skin cancer is the most common cancer in the United States. Exposure to ultraviolet radiation is a known risk factor for skin cancer but is also the principal means by which the body obtains vitamin D. Several studies have suggested that vitamin D plays a protective role in a variety of internal malignancies. With regard to skin cancer, epidemiologic and laboratory studies suggest that vitamin D and its metabolites may have a similar protective effect. These noncalcemic actions of vitamin D have called into question whether the current recommended intake of vitamin D is too low for optimal health and cancer prevention. Part I will review the role of vitamin D in the epidermis; part II will review the role of vitamin D in keratinocyte-derived tumors to help frame the discussion on the possible role of vitamin D in the prevention of skin cancer.

View details for DOI 10.1016/j.jaad.2012.05.044

View details for Web of Science ID 000310776600037

View details for PubMedID 23062903

Does a History of Eczema Predict a Future Basal Cell Carcinoma? JOURNAL OF INVESTIGATIVE DERMATOLOGY Gamba, C. A., Tang, J. Y. 2012; 132 (11): 2497-2499

Abstract

Dyer et al. (this issue) assess the risk of new basal cell carcinoma (BCC) in the Veterans Affairs topical tretinoin chemoprevention trial, which included individuals with a history of at least two prior keratinocyte carcinomas. In addition to known risk factors for a future BCC, such as number of prior BCCs, a history of eczema and lower education levels were also associated with greater risk.

View details for DOI 10.1038/jid.2012.323

View details for Web of Science ID 000309997200005

View details for PubMedID 23069907

Vismodegib in Advanced Basal-Cell Carcinoma Reply NEW ENGLAND JOURNAL OF MEDICINE Epstein, E. H., Tang, J. Y., Bickers, D. R. 2012; 367 (10): 97071
Nanoelectroablation therapy for murine basal cell carcinoma BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS Nuccitelli, R., Kevin Tran, K., Athos, B., Kreis, M., Nuccitelli, P., Chang, K. S., Epstein, E. H., Tang, J. Y. 2012; 424 (3): 446-450

Abstract

When skin tumors are exposed to non-thermal, low energy, nanosecond pulsed electric fields (nsPEF), apoptosis is initiated both in vitro and in vivo. This nanoelectroablation therapy has already been proven effective in treating subdermal murine allograft tumors. We wanted to determine if this therapy would be equally effective in the treatment of autochthonous BCC tumors in Ptch1(+/-)K14-Cre-ER p53 fl/fl mice. These tumors are similar to human BCCs in histology [2,20] and in response to drug therapy [19]. We have treated 27 BCCs across 8 mice with either 300 pulses of 300 ns duration or 2700 pulses of 100 ns duration, all at 30 kV/cm and 5-7 pulses per second. Every nsPEF-treated BCC began to shrink within a day after treatment and their initial mean volume of 36 5 (SEM) mm(3) shrunk by 76 3% over the ensuing two weeks. After four weeks, they were 99.8% ablated if the size of the treatment electrode matched the tumor size. If the tumor was larger than the 4mm wide electrode, multiple treatments were needed for complete ablation. Treated tumors were harvested for histological analysis at various times after treatment and exhibited apoptosis markers. Specifically, pyknosis of nuclei was evident as soon as 2 days after nsPEF treatment, and DNA fragmentation as detected via TUNEL staining was also evident post treatment. Nanoelectroablation is effective in triggering apoptosis and remission of radiation-induced BCCs with a single 6 min-long treatment of 2700 pulses.

View details for DOI 10.1016/j.bbrc.2012.06.129

View details for Web of Science ID 000307618800014

View details for PubMedID 22771794

View details for PubMedCentralID PMC3415467

Pachyonychia congenita patients with mutations in KRT6A have more extensive disease compared with patients who have mutations in KRT16 BRITISH JOURNAL OF DERMATOLOGY Spaunhurst, K. M., Hogendorf, A. M., Smith, F. J., Lingala, B., Schwartz, M. E., Cywinska-Bernas, A., Zeman, K. J., Tang, J. Y. 2012; 166 (4): 875-878

Abstract

Pachyonychia congenita (PC) is an autosomal dominant, very rare keratin disorder caused by mutations in any of at least four genes (KRT6A, KRT6B, KRT16 or KRT17), which can lead to hypertrophic nail dystrophy and palmoplantar keratoderma, among other manifestations. Classically, patients with mutations in KRT6A and KRT16 have been grouped to the PC-1 subtype (Jadassohn-Lewandowsky type) and KRT6B and KRT17 to PC-2 (Jackson-Lawler type).To describe clinical heterogeneity among patients with PC who have genetic mutations in KRT6A and KRT16.In 2004, the Pachyonychia Congenita Project established the International PC Research Registry (IPCRR) for patients with PC. All patients reporting here underwent genetic testing and responded to a standardized, validated survey about their PC symptoms. We report results from 89 patients with KRT6A mutations and 68 patients with KRT16 mutations.Patients with PC who have KRT6A and KRT16 mutations display distinct phenotypic differences. Patients with PC-K6a experience earlier onset, more extensive nail disease and more substantial disease outside palms and soles, as they reported a higher prevalence of oral leucokeratosis (P < 0001), cysts (P < 0001) and follicular hyperkeratosis (P < 0001) compared with their PC-K16 counterparts.Phenotypic differences between patients with KRT6A and KRT16 mutations support adoption of a new classification system based on the mutant gene (PC-6a, PC-16) rather than the PC-1 nomenclature.

View details for DOI 10.1111/j.1365-2133.2011.10745.x

View details for Web of Science ID 000302013100099

View details for PubMedID 22098151

Ulcers and stellate scars on bilateral ankles. Archives of dermatology Spaunhurst, K. M., Wysong, A., Kim, J., Tang, J. Y. 2012; 148 (3): 385-390

View details for DOI 10.1001/archdermatol.2011.2923

View details for PubMedID 22431781

Reliability and prevalence of digital image skin types in the United States: Results from National Health and Nutrition Examination Survey 2003-2004 JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Keiser, E., Linos, E., Kanzler, M., Lee, W., Sainani, K. L., Tang, J. Y. 2012; 66 (1): 163-165

View details for DOI 10.1016/j.jaad.2011.02.044

View details for Web of Science ID 000298712100031

View details for PubMedID 22177642

Sun protective behaviors and vitamin D levels in the US population: NHANES 2003-2006 CANCER CAUSES & CONTROL Linos, E., Keiser, E., Kanzler, M., Sainani, K. L., Lee, W., Vittinghoff, E., Chren, M., Tang, J. Y. 2012; 23 (1): 133-140

Abstract

Sun protection is recommended for skin cancer prevention, yet little is known about the role of sun protection on vitamin D levels. Our aim was to investigate the relationship between different types of sun protective behaviors and serum 25(OH)D levels in the general US population.Cross-sectional, nationally representative survey of 5,920 adults aged 18-60 years in the US National Health and Nutrition Examination Survey 2003-2006. We analyzed questionnaire responses on sun protective behaviors: staying in the shade, wearing long sleeves, wearing a hat, using sunscreen and SPF level. Analyses were adjusted for multiple confounders of 25(OH)D levels and stratified by race. Our primary outcome measures were serum 25(OH)D levels (ng/ml) measured by radioimmunoassay and vitamin D deficiency, defined as 25(OH)D levels <20 ng/ml.Staying in the shade and wearing long sleeves were significantly associated with lower 25(OH)D levels. Subjects who reported frequent use of shade on a sunny day had -3.5 ng/ml (p (trend) < 0.001) lower 25(OH)D levels compared to subjects who reported rare use. Subjects who reported frequent use of long sleeves had -2.2 ng/ml (p (trend) = 0.001) lower 25(OH)D levels. These associations were strongest for whites, and did not reach statistical significance among Hispanics or blacks. White participants who reported frequently staying in the shade or wearing long sleeves had double the odds of vitamin D deficiency compared with those who rarely did so. Neither wearing a hat nor using sunscreen was associated with low 25(OH)D levels or vitamin D deficiency.White individuals who protect themselves from the sun by seeking shade or wearing long sleeves may have lower 25(OH)D levels and be at risk for vitamin D deficiency. Frequent sunscreen use does not appear to be linked to vitamin D deficiency in this population.

View details for DOI 10.1007/s10552-011-9862-0

View details for PubMedID 22045154

Vitamin D in cutaneous carcinogenesis: part II. Journal of the American Academy of Dermatology Tang, J. Y., Fu, T., Lau, C., Oh, D. H., Bikle, D. D., Asgari, M. M. 2012; 67 (5): 817.e111; quiz 82728

Abstract

The role of vitamin D in health maintenance and disease prevention in fields ranging from bone metabolism to cancer is currently under intensive investigation. A number of epidemiologic studies have suggested that vitamin D may have a protective effect on cancer risk and cancer-associated mortality. With regard to skin cancer, epidemiologic and laboratory studies suggest that vitamin D and its metabolites may have a similar risk reducing effect. Potential mechanisms of action include inhibition of the hedgehog signaling pathway and upregulation of nucleotide excision repair enzymes. The key factor complicating the association between vitamin D and skin cancer is ultraviolet B radiation. The same spectrum of ultraviolet B radiation that catalyzes the production of vitamin D in the skin also causes DNA damage that can lead to epidermal malignancies. Part II of this continuing medical education article will summarize the literature on vitamin D and skin cancer to identify evidence-based optimal serum levels of vitamin D and to recommend ways of achieving those levels while minimizing the risk of skin cancer.

View details for PubMedID 23062904

Emerging Treatments and Signaling Pathway Inhibitors SEMINARS IN CUTANEOUS MEDICINE AND SURGERY Tang, J. Y., Marghoob, A. A. 2011; 30 (4): S14-S18

Abstract

A number of therapies that target components of the Hedgehog signaling pathway currently are in clinical trials. The specific molecules that seem most promising in basal cell carcinoma and a number of other cancers are those that target the Smoothened transmembrane protein. The pivotal phase II trials have been completed on the Smoothened inhibitor known as GDC-0449; five other agents (BMS-833923, LDE225, LEQ506, IPI926, and TAK-441) have also shown promise in animal studies and early clinical trials and have shown some efficacy in a variety of cancers that are affected by the Hedgehog signaling pathway.

View details for DOI 10.1016/j.sder.2011.11.002

View details for Web of Science ID 000298710300004

View details for PubMedID 22177102

Elucidating the Role of Molecular Signaling Pathways in the Tumorigenesis of Basal Cell Carcinoma SEMINARS IN CUTANEOUS MEDICINE AND SURGERY Tang, J. Y. 2011; 30 (4): S6-S9

Abstract

The Hedgehog signaling pathway has been identified as fundamentally important to normal embryonic development in living organisms ranging from fruit flies to mammals. Postdevelopmentally, it remains active in hair and skin cells. Abnormal activation of components of the Hedgehog pathway--specifically, resulting from mutations in the Patched 1 gene--is associated with the development of basal cell carcinoma, as well as several other cancers, including medulloblastoma. Patched 1 gene mutation has also been identified as the underlying mechanism in most cases of Gorlin syndrome (also known as basal cell nevus syndrome or nevoid basal cell carcinoma syndrome). Research that resulted in the current understanding of the Hedgehog signaling pathway, in turn, led to multiple lines of investigation to discover mechanisms for halting abnormal signaling, in the hope that agents could be developed that could beneficially stop this pathway. To date, several agents have been developed-and some are in clinical trials-that hold promise for improved nonsurgical treatments for patients with Gorlin syndrome and those with locally advanced/metastatic BCCs.

View details for DOI 10.1016/j.sder.2011.11.001

View details for Web of Science ID 000298710300002

View details for PubMedID 22177103

Correlates of low bone mass in children with generalized forms of epidermolysis bullosa JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Bruckner, A. L., Bedocs, L. A., Keiser, E., Tang, J. Y., Doernbrack, C., Arbuckle, H. A., Berman, S., Kent, K., Bachrach, L. K. 2011; 65 (5): 1001-1009

Abstract

Epidermolysis bullosa (EB) is a family of rare, heterogeneous, genetic disorders characterized by fragility of the skin and mucous membranes. Reduced bone mass and fractures have been recognized as complications of generalized forms of EB.We sought to describe the range and to estimate the prevalence of low bone mass in children with generalized EB, and to identify correlates of low bone mass in this population.This was a prospective, observational study of 24 patients with generalized EB. Each patient completed a history, physical examination, laboratory studies, bone age, and x-rays of the lumbar spine. Those aged 6 years and older underwent dual energy x-ray absorptiometry scans of the lumbar spine. Primary outcomes were areal bone mineral density (aBMD) based on chronologic age, bone age, and adjusted for height Z-score. Descriptive statistics were used to summarize results, and linear regression was used to determine factors associated with low aBMD.Mean lumbar spine aBMD Z-scores SD were: -2.6 1.4 for chronologic age, -1.7 1.3 for bone age, and -1.0 1.2 after adjusting for height Z-score. aBMD Z-scores were less than or equal to -2 in 64% for chronologic age, 50% for bone age, and 28% after adjusting for height Z-score. aBMD correlated with height Z-score, weight Z-score, extensive blistering, immobility, albumin, hemoglobin, iron, erythrocyte sedimentation rate, and c-reactive protein values.Small sample size was a limitation.Children with severe, generalized recessive dystrophic EB have low aBMD for age. Deficits in aBMD were reduced after adjusting for delayed skeletal maturation and small body size.

View details for DOI 10.1016/j.jaad.2010.08.028

View details for Web of Science ID 000296268000011

View details for PubMedID 21550693

Menopausal Hormone Therapy and Risks of Melanoma and Nonmelanoma Skin Cancers: Women's Health Initiative Randomized Trials JOURNAL OF THE NATIONAL CANCER INSTITUTE Tang, J. Y., Spaunhurst, K. M., Chlebowski, R. T., Wactawski-Wende, J., Keiser, E., Thomas, F., Anderson, M. L., Zeitouni, N. C., Larson, J. C., Stefanick, M. L. 2011; 103 (19): 1469-1475

Abstract

Case-control studies have reported that exogenous estrogen use is associated with increased risk of skin cancer. The effects of menopausal hormone therapy on incidence of nonmelanoma skin cancer and melanoma were evaluated in post hoc analyses of the Women's Health Initiative randomized placebo-controlled hormone therapy trials of combined estrogen plus progestin (E + P) and estrogen only (E-alone).Postmenopausal women aged 50-79 years were randomly assigned to conjugated equine estrogen (0.625 mg/d) plus medroxyprogesterone acetate (2.5 mg/d) or placebo in the E + P trial if they had an intact uterus (N = 16,608) or to conjugated equine estrogen alone or placebo in the E-alone trial if they had a hysterectomy (N = 10,739); the mean follow-up was 5.6 and 7.1 years, respectively. Incident nonmelanoma skin cancers (n = 980 [E + P trial]; n = 820 [E-alone trial]) and melanomas (n = 57 [E + P trial]; n =38 [E-alone trial]) were ascertained by self-report. Incident cases of cutaneous malignant melanoma were confirmed by physician review of medical records. Incidences of nonmelanoma skin cancer and melanoma were compared between the two randomization groups within each trial using hazard ratios (HRs), with corresponding 95% confidence intervals (CIs) and Wald statistic P values from Cox proportional hazards models. All statistical tests were two-sided.Rates of incident nonmelanoma skin cancer and melanoma were similar between the active hormone (combined analysis of E + P and E-alone) and placebo groups (nonmelanoma skin cancer: HR = 0.98, 95% CI = 0.89 to 1.07; melanoma: HR = 0.92, 95% CI = 0.61 to 1.37). Results were similar for the E + P and E-alone trials when analyzed individually.Menopausal hormone therapy did not affect overall incidence of nonmelanoma skin cancer or melanoma. These findings do not support a role of menopausal estrogen, with or without progestin, in the development of skin cancer in postmenopausal women.

View details for DOI 10.1093/jnci/djr333

View details for PubMedID 21878677

Subcutaneous Nodules in an Elderly Patient Necrobiotic xanthogranuloma ARCHIVES OF DERMATOLOGY Fu, T., Zwerner, J., Kim, J., Tang, J. 2011; 147 (10): 1215-1220

View details for Web of Science ID 000295944300022

View details for PubMedID 22006142

Calcium Plus Vitamin D Supplementation and the Risk of Nonmelanoma and Melanoma Skin Cancer: Post Hoc Analyses of the Women's Health Initiative Randomized Controlled Trial JOURNAL OF CLINICAL ONCOLOGY Tang, J. Y., Fu, T., Leblanc, E., Manson, J. E., Feldman, D., Linos, E., Vitolins, M. Z., Zeitouni, N. C., Larson, J., Stefanick, M. L. 2011; 29 (22): 3078-3084

Abstract

In light of inverse relationships reported in observational studies of vitamin D intake and serum 25-hydroxyvitamin D levels with risk of nonmelanoma skin cancer (NMSC) and melanoma, we evaluated the effects of vitamin D combined with calcium supplementation on skin cancer in a randomized placebo-controlled trial.Postmenopausal women age 50 to 79 years (N = 36,282) enrolled onto the Women's Health Initiative (WHI) calcium/vitamin D clinical trial were randomly assigned to receive 1,000 mg of elemental calcium plus 400 IU of vitamin D3 (CaD) daily or placebo for a mean follow-up period of 7.0 years. NMSC and melanoma skin cancers were ascertained by annual self-report; melanoma skin cancers underwent physician adjudication.Neither incident NMSC nor melanoma rates differed between treatment (hazard ratio [HR], 1.02; 95% CI, 0.95 to 1.07) and placebo groups (HR, 0.86; 95% CI, 0.64 to 1.16). In subgroup analyses, women with history of NMSC assigned to CaD had a reduced risk of melanoma versus those receiving placebo (HR, 0.43; 95% CI, 0.21 to 0.90; P(interaction) = .038), which was not observed in women without history of NMSC.Vitamin D supplementation at a relatively low dose plus calcium did not reduce the overall incidence of NMSC or melanoma. However, in women with history of NMSC, CaD supplementation reduced melanoma risk, suggesting a potential role for calcium and vitamin D supplements in this high-risk group. Results from this post hoc subgroup analysis should be interpreted with caution but warrant additional investigation.

View details for DOI 10.1200/JCO.2011.34.5967

View details for Web of Science ID 000293222200029

View details for PubMedID 21709199

View details for PubMedCentralID PMC3157967

Hat, shade, long sleeves, or sunscreen? Rethinking US sun protection messages based on their relative effectiveness CANCER CAUSES & CONTROL Linos, E., Keiser, E., Fu, T., Colditz, G., Chen, S., Tang, J. Y. 2011; 22 (7): 1067-1071

Abstract

Sun protection messages in the United States emphasize sunscreen use, although its efficacy in skin cancer prevention remains controversial.We used data from NHANES 2003-2006, restricted to adult whites (n = 3,052) to evaluate how Americans protect themselves from the sun. Participants completed questionnaires on the frequency with which they used sunscreen, wore a hat, long sleeves, or stayed in the shade, in addition to the number of sunburns in the past year.Although using sunscreen is the most common sun protective behavior (30%), frequent sunscreen use was not associated with fewer sunburns. However, the odds of multiple sunburns were significantly lower in individuals who frequently avoided the sun by seeking shade (OR = 0.70, p < 0.001) or wearing long sleeves (OR = 0.73, p = 0.01).Our findings suggest that shade and protective clothing may be more effective than sunscreen, as typically used by Americans.

View details for DOI 10.1007/s10552-011-9780-1

View details for PubMedID 21637987

Targeting Superficial or Nodular Basal Cell Carcinoma with Topically Formulated Small Molecule Inhibitor of Smoothened CLINICAL CANCER RESEARCH Tang, T., Tang, J. Y., Li, D., Reich, M., Callahan, C. A., Fu, L., Yauch, R. L., Wang, F., Kotkow, K., Chang, K. S., Shpall, E., Wu, A., Rubin, L. L., Marsters, J. C., Epstein, E. H., Caro, I., de Sauvage, F. J. 2011; 17 (10): 3378-3387

Abstract

Inappropriate activation of the Hedgehog (Hh) signaling pathway in skin is critical for the development of basal cell carcinomas (BCC). We have investigated the anti-BCC efficacy of topically-applied CUR61414, an inhibitor of the Hh signal transduction molecule Smoothened.In preclinical studies, we used a depilatory model to evaluate the ability of topical formulations of CUR61414 to repress Hh responsive cells found at the base of hair follicles in normal skin. We also tested the in vivo effects of topical CUR61414 on murine BCCs developed in Ptch1 (+/-) K14-CreER2 p53 fl/fl mice. In a phase I clinical study, we evaluated the safety, tolerability, and efficacy of a multidose regimen of CUR61414 (0.09%, 0.35%, 1.1%, and 3.1%) applied topically to human superficial or nodular BCCs for up to 28 days.In mice, topical CUR61414 significantly inhibited skin Hh signaling, blocked the induction of hair follicle anagen, and shrank existing BCCs. However, we observed no clinical activity of this formulation in human superficial or nodular BCCs in a phase I clinical study.Our data highlight some of the challenges of translating preclinical experience into successful human results for a topical anticancer agent.

View details for DOI 10.1158/1078-0432.CCR-10-3370

View details for Web of Science ID 000290610000030

View details for PubMedID 21558397

View details for PubMedCentralID PMC3113453

Genotype-Phenotype Correlations among Pachyonychia Congenita Patients with K16 Mutations JOURNAL OF INVESTIGATIVE DERMATOLOGY Fu, T., Leachman, S. A., Wilson, N. J., Smith, F. J., Schwartz, M. E., Tang, J. Y. 2011; 131 (5): 1025-1028

Abstract

Pachyonychia congenita (PC) is a rare, autosomal dominant keratin disorder caused by mutations in four genes (KRT6A, KRT6B, KRT16, or KRT17). The International PC Research Registry is a database with information on patients' symptoms as well as genotypes. We sought to describe the heterogeneity of clinical symptoms and to investigate possible genotype-phenotype correlations in patients with two types of K16 mutations, p.Asn125 and p.Arg127, causing the PC-16 subtype of PC. We found that clinical symptoms depended on the type of amino-acid substitution. Patients with p.Asn125Asp and p.Arg127Pro mutations exhibited more severe disease than patients carrying p.Asn125Ser and p.Arg127Cys mutations in terms of age of onset of symptoms, extent of nail involvement, and impact on daily quality of life. We speculate that amino-acid substitutions causing larger, more disruptive changes to the K16 protein structure, such as a change in amino-acid charge in the p.Asn125Asp mutation or a bulky proline substitution in the p.Arg127Pro mutation, may also lead to more severe disease phenotypes. The variation in phenotypes seen with different substitutions at the same mutation site suggests a genotype-phenotype correlation. Knowledge of the exact gene defect is likely to assist in predicting disease prognosis and clinical management.

View details for DOI 10.1038/jid.2010.373

View details for Web of Science ID 000289789900009

View details for PubMedID 21160496

Vitamin D3 Inhibits Hedgehog Signaling and Proliferation in Murine Basal Cell Carcinomas CANCER PREVENTION RESEARCH Tang, J. Y., Xiao, T. Z., Oda, Y., Chang, K. S., Shpall, E., Wu, A., So, P., Hebert, J., Bikle, D., Epstein, E. H. 2011; 4 (5): 744-751

Abstract

Constitutive Hedgehog (HH) signaling underlies several human tumors, including basal cell carcinoma (BCC). Recently, Bijlsma and colleagues reported a new biologic function for vitamin D3 in suppressing HH signaling in an in vitro model system. On the basis of that work, we have assessed effects of vitamin D3 on HH signaling and proliferation of murine BCCs in vitro and in vivo. We find that indeed in BCC cells, vitamin D3 blocks both proliferation and HH signaling as assessed by mRNA expression of the HH target gene Gli1. These effects of vitamin D3 on Gli1 expression and on BCC cell proliferation are comparable to the effects of cyclopamine, a known inhibitor of the HH pathway. These results are specific for vitamin D3, because the precursor 7-dehydrocholesterol and the downstream products 25-hydroxy vitamin D3 [25(OH)D] and 1,25-dihydroxy vitamin D3 [1,25(OH)(2)D] are considerably less effective in reducing either Gli1 mRNA or cellular proliferation. Moreover, these effects seem to be independent of the vitamin D receptor (VDR) because short hairpin RNA knockdown of VDR does not abrogate the anti-HH effects of D3 despite reducing expression of the VDR target gene 24-hydroxylase. Finally, topical vitamin D3 treatment of existing murine BCC tumors significantly decreases Gli1 and Ki67 staining. Thus, topical vitamin D3 acting via its HH inhibiting effect may hold promise as an effective anti-BCC agent.

View details for DOI 10.1158/1940-6207.CAPR-10-0285

View details for PubMedID 21436386

An investigator-initiated, phase II randomized, double-blind, placebo controlled trial of GDC-0449 for prevention of BCCs in basal cell nevus syndrome (BCNS) patients.gg Tang, J. Y., Mackay-Wiggan, J. M., Aszterbaum, M., Lindgren, J., Chang, K., Coppola, C., Campbell, A., Chanana, A., Marji, J., Callahan, C., Yauch, R., Bickers, D. R., Epstein, E. H. AMER ASSOC CANCER RESEARCH. 2011
Association of facial skin aging and vitamin D levels in middle-aged white women CANCER CAUSES & CONTROL Chang, A. L., Fu, T., Amir, O., Tang, J. Y. 2010; 21 (12): 2315-2316

Abstract

To investigate the relationship between UV-induced skin photodamage and 25(OH) vitamin D levels, we performed a cross-sectional study in 45 female subjects aged >40. Menopausal status, smoking status, skin cancer history, oral supplement use, and season of blood draw were recorded and serum 25(OH)D measured. A single-blinded, dermatologist evaluated standardized digital facial images for overall photodamage, erythema/telangiectasias, hyperpigmentation, number of lentigines, and wrinkling. Adjusting for age and season of blood collection, women with lower photodamage scores were associated with a 5-fold increased odds of being vitamin D insufficient (OR 5.0, 95% CI: 1.1, 23). Low scores for specific photodamage parameters including erythema/telangiectasias, hyperpigmentation, and wrinkling were also significantly associated with vitamin D insufficiency. Our results suggest an association between skin aging and 25(OH)D levels.

View details for DOI 10.1007/s10552-010-9646-y

View details for Web of Science ID 000288609600041

View details for PubMedID 20882333

View details for PubMedCentralID PMC3042365

High Prevalence of Vitamin D Deficiency in Patients With Basal Cell Nevus Syndrome ARCHIVES OF DERMATOLOGY Tang, J. Y., Wu, A., Linos, E., Parimi, N., Lee, W., Aszterbaum, M., Asgari, M. M., Bickers, D. R., Epstein, E. H. 2010; 146 (10): 1105-1110

Abstract

To evaluate vitamin D status in patients with basal cell nevus syndrome (BCNS) who practice photoprotection because of their genetic predisposition to skin cancer and to determine risk factors for deficiency.Retrospective cohort study.Academic medical centers.Forty-one ambulatory patients with BCNS who participated in a 2-year chemoprevention clinical trial. Population-based controls (n = 360) were selected and matched by age, sex, Fitzpatrick skin type, and season/geography.Levels of 25-hydroxyvitamin D (25[OH]D) and vitamin D deficiency (defined as a 25[OH]D level of 20 ng/mL).Twenty-three patients with BCNS (56%) were vitamin D deficient. Patients with BCNS had mean 25(OH)D levels below those of the general population (-3 ng/mL; P = .02) and were 3 times more likely to be vitamin D deficient (56% vs 18%; P < .001). Levels of 25(OH)D were lower in patients who were overweight (-3.0 ng/mL; P = .04) and who had blood collected in the winter compared with the summer (-7.1 ng/mL; P < .001). Conclusion: Patients with BCNS may be at increased risk for vitamin D deficiency, depending on their adherence to photoprotection practices.

View details for Web of Science ID 000283087300007

View details for PubMedID 20956641

Novel investigational drugs for basal cell carcinoma EXPERT OPINION ON INVESTIGATIONAL DRUGS So, P., Tang, J. Y., Epstein, E. H. 2010; 19 (9): 1099-1112

Abstract

In the United States, the annual incidence of basal cell carcinoma (BCC) is close to 1 million. Ultraviolet radiation exposure is the main risk factor; however, the availability of ever more potent sunscreens and education have not prevented the rise in BCC incidence. Therefore, concerted effects to identify novel preventive and therapeutic strategies are necessary.This article summarizes our current understanding of the etiology and molecular mechanisms of BCC tumorigenesis and discusses the preclinical and clinical studies to identify agents with anti-BCC efficacy.The discovery that hyperactive Hh pathway signaling causes several cancers, including BCC, has spawned the development of many pharmacologic inhibitors of Hh signaling. Early clinical testing of the most advanced, GDC-0449, demonstrated impressive efficacy in patients with advanced BCC. Other promising anti-BCC chemopreventive strategies include drugs that are already FDA-approved for treating other diseases.Preclinical and clinical trials with pre-existing FDA-approved drugs suggest novel uses for BCC chemoprevention and treatment. Also, new chemical entities that inhibit the Hh pathway show promise, and in combination with other drugs may provide a nonsurgical cure for this most common cancer.

View details for DOI 10.1517/13543784.2010.504714

View details for Web of Science ID 000281968200007

View details for PubMedID 20662553

Association of Prediagnostic Serum Vitamin D Levels with the Development of Basal Cell Carcinoma JOURNAL OF INVESTIGATIVE DERMATOLOGY Asgari, M. M., Tang, J., Warton, M. E., Chren, M., Quesenberry, C. P., Bikle, D., Horst, R. L., Orentreich, N., Vogelman, J. H., Friedman, G. D. 2010; 130 (5): 1438-1443

Abstract

We investigated the association between serum 25-hydroxyvitamin D (25(OH)D) levels and basal cell carcinoma (BCC) risk in a nested case-control study at Kaiser Permanente Northern California (KPNC). A total of 220 case patients with BCC diagnosed after serum collection were matched to 220 control subjects. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using conditional logistic regression. Fully adjusted models included body mass index (BMI), smoking, education, sun-exposure variables, X-ray exposure, and personal history of cancer. For each measure of serum 25(OH)D (continuous, clinically relevant tertiles, quintiles), we found an increased risk of BCC in unadjusted models (OR=1.03, 95% CI 1.00-1.05, P<0.05; OR=3.98, 95% CI: 1.31-12.31, deficient vs. sufficient, test for trend P-value <0.01; OR=2.32, 95% CI: 1.20-4.50, 1st vs. 5th quintile, test for trend P-value 0.03). In fully adjusted models, the values attenuated slightly (OR=1.02, 95% CI 1.00-1.05, P<0.05; OR=3.61, 95% CI: 1.00-13.10, deficient vs. sufficient, t-trend P=0.03; OR=2.09 1st vs. 5th quintile, 95% CI: 0.95-4.58, t-trend P=0.11). Our findings suggest that higher prediagnostic serum 25(OH)D levels may be associated with increased risk of subsequent BCC. Further studies to evaluate the effect of sun exposure on BCC and serum 25(OH)D levels may be warranted.

View details for DOI 10.1038/jid.2009.402

View details for Web of Science ID 000276972300031

View details for PubMedID 20043012

View details for PubMedCentralID PMC2855394

Itraconazole, a Commonly Used Antifungal that Inhibits Hedgehog Pathway Activity and Cancer Growth CANCER CELL Kim, J., Tang, J. Y., Gong, R., Kim, J., Lee, J. J., Clemons, K. V., Chong, C. R., Chang, K. S., Fereshteh, M., Gardner, D., Reya, T., Liu, J. O., Epstein, E. H., Stevens, D. A., Beachy, P. A. 2010; 17 (4): 388-399

Abstract

In a screen of drugs previously tested in humans we identified itraconazole, a systemic antifungal, as a potent antagonist of the Hedgehog (Hh) signaling pathway that acts by a mechanism distinct from its inhibitory effect on fungal sterol biosynthesis. Systemically administered itraconazole, like other Hh pathway antagonists, can suppress Hh pathway activity and the growth of medulloblastoma in a mouse allograft model and does so at serum levels comparable to those in patients undergoing antifungal therapy. Mechanistically, itraconazole appears to act on the essential Hh pathway component Smoothened (SMO) by a mechanism distinct from that of cyclopamine and other known SMO antagonists, and prevents the ciliary accumulation of SMO normally caused by Hh stimulation.

View details for DOI 10.1016/j.ccr.2010.02.027

View details for PubMedID 20385363

Inverse association between serum 25(OH) vitamin D levels and non-melanoma skin cancer in elderly men CANCER CAUSES & CONTROL Tang, J. Y., Parimi, N., Wu, A., Boscardin, W. J., Shikany, J. M., Chren, M., Cummings, S. R., Epstein, E. H., Bauer, D. C. 2010; 21 (3): 387-391

Abstract

To determine the relationship between 25(OH) vitamin D levels and non-melanoma skin cancer (NMSC), we performed a nested case-control study in ambulatory, elderly men enrolled in the Osteoporotic Fractures in Men (MrOS) Study. Health habit and medical history, including self-reported history of NMSC were recorded and 25(OH)D levels were measured on serum collected at baseline from a random sample of Caucasian MrOS subjects. Mean age (73 +/- 5), BMI, daily vitamin D and calcium intake were similar in the men with (n = 178) and without NMSC (n = 930), but higher levels of 25(OH)D were associated with a decreased risk of having a history of NMSC (P(trend) = 0.04). Men in the highest quintile of 25(OH)D (>30 ng/mL) had 47% lower odds of NMSC (95% CI: 0.30-0.93, p = 0.026) compared to those in the lowest quintile. Our results suggest that a diagnosis of NMSC is not a surrogate for adequate 25(OH)D levels or increased UV exposure, and high 25(OH)D levels may be associated with a reduced risk of NMSC.

View details for DOI 10.1007/s10552-009-9470-4

View details for Web of Science ID 000275921300006

View details for PubMedID 19921445

View details for PubMedCentralID PMC2835729

Basal Cell Carcinoma Chemoprevention with Nonsteroidal Anti-inflammatory Drugs in Genetically Predisposed PTCH1(+/-) Humans and Mice CANCER PREVENTION RESEARCH Tang, J. Y., Aszterbaum, M., Athar, M., Barsanti, F., Cappola, C., Estevez, N., Hebert, J., Hwang, J., Khaimskiy, Y., Kim, A., Lu, Y., So, P., Tang, X., Kohn, M. A., McCulloch, C. E., Kopelovich, L., Bickers, D. R., Epstein, E. H. 2010; 3 (1): 25-34

Abstract

In vitro and epidemiologic studies favor the efficacy of nonsteroidal anti-inflammatory drugs (NSAID) in preventing skin squamous photocarcinogenesis, but there has been relatively little study of their efficacy in preventing the more common skin basal cell carcinoma (BCC) carcinogenesis. We first compared the relative anti-BCC effects of genetic deletion and NSAID pharmacologic inhibition of cyclooxygenase (COX) enzymes in the skin of Ptch1(+/-) mice. We then assessed the effects of celecoxib on the development of BCCs in a 3-year, double-blinded, randomized clinical trial in 60 (PTCH1(+/-)) patients with the basal cell nevus syndrome. In Ptch1(+/-) mice, genetic deletion of COX1 or COX2 robustly decreased (75%; P < 0.05) microscopic BCC tumor burden, but pharmacologic inhibition with celecoxib reduced microscopic BCCs less efficaciously (35%; P < 0.05). In the human trial, we detected a trend for oral celecoxib reducing BCC burden in all subjects (P = 0.069). Considering only the 60% of patients with less severe disease (<15 BCCs at study entry), celecoxib significantly reduced BCC number and burden: subjects receiving placebo had a 50% increase in BCC burden per year, whereas subjects in the celecoxib group had a 20% increase (P(difference) = 0.024). Oral celecoxib treatment inhibited BCC carcinogenesis in PTCH1(+/-) mice and had a significant anti-BCC effect in humans with less severe disease.

View details for DOI 10.1158/1940-6207.CAPR-09-0200

View details for Web of Science ID 000273295500006

View details for PubMedID 20051370

View details for PubMedCentralID PMC2894531

Statin use and risk of basal cell carcinoma JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Asgari, M. A., Tang, J., Epstein, E. H., Chren, M., Warton, E. M., Quesenberry, C. P., Go, A. S., Friedman, G. D. 2009; 61 (1): 66-72

Abstract

We examined the association between statin use and basal cell carcinoma (BCC) risk.We identified all members of a large integrated health care delivery system with a diagnosis of a histologically proven BCC in 1997. Subsequent BCCs were identified through 2006 from health plan electronic pathology records. Longitudinal exposure to statins and other lipid-lowering agents was determined from automated pharmacy records. We used extended Cox regression to examine the independent association between receipt of statin therapy (ever vs never, cumulative duration) and risk of subsequent BCC. To minimize confounding by indication, we conducted sensitivity analyses in the subset of individuals considered eligible for lipid-lowering therapy based on national guidelines.Among 12,123 members given a diagnosis of BCC who had no prior statin exposure, 6381 developed a subsequent BCC during follow-up. Neither "ever use of statins" (adjusted hazard ratio 1.02, 95% confidence interval: 0.92-1.12) or cumulative duration of statin (adjusted hazard ratio 1.02/year, 95% confidence interval: 0.99-1.11) was associated with subsequent BCC after adjustment for age, sex, and health care use. Risk estimates did not change appreciably when the analysis was limited to the subset of individuals who met eligibility criteria for initiating statin therapy. There was also no significant association between use of non-statin antilipemics and subsequent BCC (adjusted hazard ratio 1.10, 95% confidence interval: 0.76-1.58).No information was available for BCC risk factors, such as sun sensitivity and sun exposure.Among a large cohort of individuals with BCC, statin therapy was not significantly associated with risk of subsequent BCC.

View details for DOI 10.1016/j.jaad.2009.02.011

View details for Web of Science ID 000267325000010

View details for PubMedID 19464071

View details for PubMedCentralID PMC2700205

Novel Hedgehog pathway targets against basal cell carcinoma TOXICOLOGY AND APPLIED PHARMACOLOGY Tang, J. Y., So, P., Epstein, E. H. 2007; 224 (3): 257-264

Abstract

The Hedgehog signaling pathway plays a key role in directing growth and patterning during embryonic development and is required in vertebrates for the normal development of many structures, including the neural tube, axial skeleton, skin, and hair. Aberrant activation of the Hedgehog (Hh) pathway in adult tissue is associated with the development of basal cell carcinoma (BCC), medulloblastoma, and a subset of pancreatic, gastrointestinal, and other cancers. This review will provide an overview of what is known about the mechanisms by which activation of Hedgehog signaling leads to the development of BCCs and will review two recent papers suggesting that agents that modulate sterol levels might influence the Hh pathway. Thus, sterols may be a new therapeutic target for the treatment of BCCs, and readily available agents such as statins (HMG-CoA reductase inhibitors) or vitamin D might be helpful in reducing BCC incidence.

View details for DOI 10.1016/j.taap.2006.12.011

View details for Web of Science ID 000250639300008

View details for PubMedID 17276471

View details for PubMedCentralID PMC2719777

Xeroderma pigmentosum group C in an isolated region of Guatemala JOURNAL OF INVESTIGATIVE DERMATOLOGY Cleaver, J. E., Feeney, L., Tang, J. Y., Tuttle, P. 2007; 127 (2): 493-496

View details for DOI 10.1038/sj.jid.5700555

View details for Web of Science ID 000243732600037

View details for PubMedID 16990803

View details for PubMedCentralID PMC3031115

Toxicity from radiation therapy associated with abnormal transcriptional responses to DNA damage PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Rieger, K. E., Hong, W. J., Tusher, V. G., Tang, J., Tibshirani, R., Chu, G. 2004; 101 (17): 6635-6640

Abstract

Toxicity from radiation therapy is a grave problem for cancer patients. We hypothesized that some cases of toxicity are associated with abnormal transcriptional responses to radiation. We used microarrays to measure responses to ionizing and UV radiation in lymphoblastoid cells derived from 14 patients with acute radiation toxicity. The analysis used heterogeneity-associated transformation of the data to account for a clinical outcome arising from more than one underlying cause. To compute the risk of toxicity for each patient, we applied nearest shrunken centroids, a method that identifies and cross-validates predictive genes. Transcriptional responses in 24 genes predicted radiation toxicity in 9 of 14 patients with no false positives among 43 controls (P = 2.2 x 10(-7)). The responses of these nine patients displayed significant heterogeneity. Of the five patients with toxicity and normal responses, two were treated with protocols that proved to be highly toxic. These results may enable physicians to predict toxicity and tailor treatment for individual patients.

View details for DOI 10.1073/pnas.0307761101

View details for PubMedID 15096622

Interaction between UV-damaged DNA binding activity proteins and the c-Abl tyrosine kinase JOURNAL OF BIOLOGICAL CHEMISTRY Cong, F., Tang, J., Hwang, B. J., Vuong, B. Q., Chu, G., Goff, S. P. 2002; 277 (38): 34870-34878

Abstract

The c-Abl tyrosine kinase is activated by some forms of DNA damage, including ionizing radiation, but not UV radiation. The functions of this activation in the damage response pathways remain obscure. To identify potential targets of c-Abl kinase, we utilized the yeast two-hybrid system to screen a murine cDNA library. One c-Abl binding protein of particular interest was the large subunit (DDB1) of the heterodimeric complex with UV-damaged DNA binding activity (UV-DDB). This complex binds with high specificity to DNA damaged by UV, is absent in a subset of xeroderma pigmentosum group E cells, and is required for global genomic repair of UV-induced damage. The association of c-Abl with DDB1 required the kinase domain of c-Abl and preserved the interaction between DDB1 and the small subunit (DDB2) of the UV-DDB complex. Significantly, overexpression of c-Abl increased tyrosine phosphorylation of DDB2 and suppressed UV-DDB activity. Conversely, a dominant negative, kinase-deficient allele of c-Abl decreased tyrosine phosphorylation of DDB2 and dramatically stimulated UV-DDB activity. These results suggest that one role of c-Abl may be to negatively regulate UV-DDB activity by phosphorylation of DDB2.

View details for DOI 10.1074/jbc.M204416200

View details for Web of Science ID 000178117000029

View details for PubMedID 12107171

View details for PubMedCentralID PMC2894263

Xeroderma pigmentosum complementation group E and UV-damaged DNA-binding protein DNA REPAIR Tang, J., Chu, G. 2002; 1 (8): 601-616

Abstract

UV-damaged DNA-binding protein (UV-DDB) is composed of two subunits, DDB1 (p127) and DDB2 (p48). Mutations in the DDB2 gene inactivate UV-DDB in individuals from complementation group E of xeroderma pigmentosum (XP-E), an autosomal recessive disease characterized by sun sensitivity, severe risk for skin cancer and defective nucleotide excision repair. UV-DDB is also deficient in many rodent tissues, exposing a shortcoming in rodent models for cancer. In vitro, UV-DDB binds to cyclobutane pyrimidine dimers (CPDs), 6-4 photoproducts and other DNA lesions, stimulating the excision of CPDs, and to a lesser extent, of 6-4 photoproducts. In vivo, UV-DDB plays an important role in the p53-dependent response of mammalian cells to DNA damage. When cells are exposed to UV, the resulting accumulation of p53 activates DDB2 transcription, which leads to increased levels of UV-DDB. Binding of UV-DDB to CPDs targets these lesions for global genomic repair, suppressing mutations without affecting UV survival. Apparently, cells are able to survive with unrepaired CPDs because of the activity of bypass DNA polymerases. Finally, there is evidence that UV-DDB may have roles in the cell that are distinct from DNA repair.

View details for Web of Science ID 000178248700002

View details for PubMedID 12509284

Xeroderma pigmentosum p48 gene enhances global genomic repair and suppresses UV-induced mutagenesis MOLECULAR CELL Tang, J. Y., Hwang, B. J., Ford, J. M., Hanawalt, P. C., Chu, G. 2000; 5 (4): 737-744

Abstract

UV-damaged DNA-binding activity (UV-DDB) is deficient in some xeroderma pigmentosum group E individuals due to mutation of the p48 gene, but its role in DNA repair has been obscure. We found that UV-DDB is also deficient in cell lines and primary tissues from rodents. Transfection of p48 conferred UV-DDB to hamster cells, and enhanced removal of cyclobutane pyrimidine dimers (CPDs) from genomic DNA and from the nontranscribed strand of an expressed gene. Expression of p48 suppressed UV-induced mutations arising from the nontranscribed strand, but had no effect on cellular UV sensitivity. These results define the role of p48 in DNA repair, demonstrate the importance of CPDs in mutagenesis, and suggest how rodent models can be improved to better reflect cancer susceptibility in humans.

View details for PubMedID 10882109

INHIBITION OF LECITHIN-CHOLESTEROL ACYLTRANSFERASE AND MODIFICATION OF HDL APOLIPOPROTEINS BY ALDEHYDES ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY McCall, M., Tang, J. Y., Bielicki, J. K., Forte, T. M. 1995; 15 (10): 1599-1606

Abstract

Experimental evidence suggests that aldehydes generated as a consequence of lipid peroxidation may be involved in the pathogenesis of atherosclerosis. It is well documented that aldehydes modify LDL: however, less is known concerning the effects of aldehydes on other plasma and interstitial fluid components. In the present study, we investigated the effects of five physiologically relevant aldehydes (acetaldehyde, acrolein, hexanal, 4-hydroxynonenal [HNE], and malondialdehyde [MDA]) on two key constituents of the antiatherogenic reverse cholesterol transport pathway, lecithin-cholesterol acyltransferase (LCAT) and HDL. Human plasma was incubated for 3 hours at 37 degrees C with each one of the five aldehydes at concentrations ranging from 0.16 to 84 mmol/L. Dose-dependent decreases in LCAT activity were observed. The short-chain (acrolein) and long-chain (HNE) alpha,beta-unsaturated aldehydes were the most effective LCAT inhibitors. Micromolar concentrations of these unsaturated aldehydes resulted in significant reductions in plasma LCAT activity. The short- and longer-chain saturated aldehydes acetaldehyde and hexanal and the dialdehyde MDA were considerably less effective at inhibiting LCAT than were acrolein and HNE. In addition to inhibiting LCAT, aldehydes increased HDL electrophoretic mobility and cross-linked HDL apolipoproteins. Cross-linking of apolipoproteins A-I and A-II required higher aldehyde concentrations than inhibition of LCAT. The alpha,beta-unsaturated aldehydes acrolein and HNE were fourfold to eightfold more effective cross-linkers of apolipoproteins A-I and A-II than the other aldehydes studied. These data suggest that products of lipid peroxidation, especially unsaturated aldehydes, may interfere with normal HDL cholesterol transport by inhibiting LCAT and modifying HDL apolipoproteins.

View details for Web of Science ID A1995RZ86500010

View details for PubMedID 7583533