Professor of Dermatology


  • A retrospective analysis of diagnostic testing in a large North American cohort of patients with epidermolysis bullosa. Journal of the American Academy of Dermatology Phillips, G. S., Huang, A., Augsburger, B. D., Kaplan, L., Peoples, K., Bruckner, A. L., Khuu, P., Tang, J. Y., Lara-Corrales, I., Pope, E., Wiss, K., Levin, L. E., Morel, K. D., Hook, K. P., Paller, A. S., Eichenfield, L. F., McCuaig, C. C., Powell, J., Castelo-Soccio, L., Levy, M. L., Price, H. N., Schachner, L. A., Browning, J. C., Jahnke, M., Shwayder, T., Bayliss, S., Lucky, A. W., Glick, S. A. 2021


    BACKGROUND: Accurate diagnosis of epidermolysis bullosa (EB) has significant implications for prognosis, management, and genetic counseling.OBJECTIVE: To describe diagnostic testing patterns and assess diagnostic concordance of transmission electron microscopy (TEM), immunofluorescence mapping (IFM), and genetic analysis for EB.METHODS: A retrospective cohort of patients enrolled in the Epidermolysis Bullosa Clinical Characterization and Outcomes Database from January 1, 2004 to July 8, 2019 was included. Tests concluding the same EB type (EB simplex [EBS], junctional EB [JEB], dominant dystrophic EB [DDEB], recessive dystrophic EB [RDEB]) were considered concordant, different EB types discordant, and non-specific/non-definitive results equivocal.RESULTS: A total of 970 diagnostic tests were conducted from 1984 to 2018 in 771 patients. Genetic analyses were performed chronologically later than IFM or TEM (p<.001). The likelihood of undergoing genetic analysis was greater for JEB and RDEB, and the same for DDEB as compared to EBS. TEM results in 163 patients were equivocal (55%), concordant (42%), and discordant (3%). IFM results in 185 patients were equivocal (54%), concordant (42%), and discordant (4%).LIMITATIONS: Retrospective design.CONCLUSION: Diagnostic testing has shifted in favor of genetic analysis. TEM and IFM frequently offer equivocal findings when compared to the specificity afforded by genetic analysis.

    View details for DOI 10.1016/j.jaad.2021.09.065

    View details for PubMedID 34634382

  • Patient-reported outcomes and quality of life in dominant dystrophic epidermolysis bullosa: A global cross-sectional survey. Pediatric dermatology Fulchand, S., Harris, N., Li, S., Barriga, M., Gorell, E., De Souza, M., Murrell, D., Marinkovich, P., Krishna Yenamandra, V., Tang, J. Y. 2021


    INTRODUCTION: Dystrophic epidermolysis bullosa is a debilitating skin condition, without curative treatment. Previous research has focused on the recessive variant, which is known to cause severe disease. Limited work focusing on the clinical manifestations and outcomes of dominant dystrophic epidermolysis bullosa is found (DDEB).METHODS: Analysis of an online survey of 42 DDEB patients.RESULTS: Self-reported severity of disease did not correlate with size of the wound or number of dressing changes, but did correlate with severity of pain reported in the last 12months (3.4 mild vs 6.8 severe disease, P=0.0002). Patients with severe DDEB also reported more severe internal disease symptoms, such as difficulty swallowing (62.5%, P=0.01) and greater analgesic use during dressing changes (4.4% mild vs 81.3% severe, P=<0.001).DISCUSSION: Patient perception of disease severity in DDEB appears to be most impacted by pain, presence of chronic open wounds, difficulty swallowing, difficulty walking, and anal strictures. As research on DDEB increases, future studies focused on these symptoms might be the most impactful for DDEB patients. However, distinguishing DDEB from other subtypes remains a challenge.

    View details for DOI 10.1111/pde.14802

    View details for PubMedID 34515355

  • Cannabinoid use and effects in patients with epidermolysis bullosa: an international cross-sectional survey study. Orphanet journal of rare diseases Schrader, N. H., Gorell, E. S., Stewart, R. E., Duipmans, J. C., Harris, N., Perez, V. A., Tang, J. Y., Wolff, A. P., Bolling, M. C. 2021; 16 (1): 377


    BACKGROUND: Epidermolysis bullosa (EB) patient anecdotes and case reports indicate that cannabinoid-based medicines (CBMs) may alleviate pain and pruritus and improve wound healing. CBM use has not been characterized in the EB patient population.OBJECTIVES: To evaluate CBM use among EB patients, including CBM types, effects on symptoms (e.g., pain and pruritus), disease process (e.g., blistering, wounds, and inflammation), well-being (e.g., sleep, appetite) and concomitant medications.METHODS: English-speaking EB patients or caregivers completed an online international, anonymous, cross-sectional survey regarding CBM use. Respondents reported the types of CBMs, subsequent effects including perceived EB symptom alteration, changes in medication use, and side effects.RESULTS: Seventy-one EB patients from five continents reported using or having used CBMs to treat their EB. Missing question responses ranged between 0 (0%) and 33 (46%). Most used more than one CBM preparation (mean: 2.4±1.5) and route of administration (mean: 2.1±1.1). Topical and ingested were the most common routes. Pain and pruritus were reported retrospectively to decrease by 3 points (scale: 0-10; p<0.001 for both) after CBM use. Most reported that CBM use improved their overall EB symptoms (95%), pain (94%), pruritus (91%) and wound healing (81%). Most participants (79%) reported decreased use of pain medications. The most common side-effect was dry mouth (44%).CONCLUSIONS: CBMs improve the perception of pain, pruritus, wound healing, and well-being in EB patients and reduced concomitant medication use. Nevertheless, a direct relation between the use of CBMs and reduction of the above-mentioned symptoms cannot be proven by these data. Therefore, future controlled studies using pharmaceutically standardised CBM preparations in EB are warranted to delineate the risks and benefits of CBMs.

    View details for DOI 10.1186/s13023-021-02010-0

    View details for PubMedID 34488820

  • 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., Li, S., Marinkovich, P. M., Tang, J. Y. 2021; 85 (2): 468-469
  • Measurement of skin adhesion in recessive dystrophic epidermolysis bullosa patients JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Nazaroff, J., Manoukian, M., Barriga, M., Lane, A., Marinkovich, M., Tang, J. Y. 2021; 85 (2): 491-492
  • A systematic literature review of the disease burden in patients with recessive dystrophic epidermolysis bullosa. Orphanet journal of rare diseases Tang, J. Y., Marinkovich, M. P., Lucas, E., Gorell, E., Chiou, A., Lu, Y., Gillon, J., Patel, D., Rudin, D. 2021; 16 (1): 175


    BACKGROUND/OBJECTIVE: Recessive dystrophic epidermolysis bullosa (RDEB) is a genetic collagen disorder characterized by skin fragility leading to blistering, wounds, and scarring. There are currently no approved curative therapies. The objective of this manuscript is to provide a comprehensive literature review of the disease burden caused by RDEB.METHODS: A systematic literature review was conducted in MEDLINE and Embase in accordance with PRISMA guidelines. Observational and interventional studies on the economic, clinical, or humanistic burden of RDEB were included.RESULTS: Sixty-five studies were included in the review. Patients had considerable wound burden, with 60% reporting wounds covering more than 30% of their body. Increases in pain and itch were seen with larger wound size. Chronic wounds were larger and more painful than recurrent wounds. Commonly reported symptoms and complications included lesions and blistering, anemia, nail dystrophy and loss, milia, infections, musculoskeletal contractures, strictures or stenoses, constipation, malnutrition/nutritional problems, pseudosyndactyly, ocular manifestations, and dental caries. Many patients underwent esophageal dilation (29-74%; median dilations, 2-6) and gastrostomy tube placement (8-58%). In the severely affected population, risk of squamous cell carcinoma (SCC) was 76% and mortality from SCC reached 84% by age 40. Patients with RDEB experienced worsened quality of life (QOL), decreased functioning and social activities, and increased pain and itch when compared to other EB subtypes, other skin diseases, and the general population. Families of patients reported experiencing high rates of burden including financial burden (50-54%) and negative impact on private life (79%). Direct medical costs were high, though reported in few studies; annual payer-borne total medical costs in Ireland were

  • Clinical characteristics associated with increased wound size in patients with recessive dystrophic epidermolysis bullosa. Pediatric dermatology Solis, D. C., Gorell, E. S., Teng, C., Barriga, M., Nazaroff, J., Li, S., Subica, A., Lu, Y., Marinkovich, M. P., Tang, J. Y. 2021


    As more therapeutic clinical trials focus on treatment of individual wounds in patients with recessive dystrophic epidermolysis bullosa, it has become crucial to understand the baseline clinical characteristics of these wounds. To investigate these features, we administered an RDEB-specific wound survey. Forty participants reported on location, size, pain, infection frequency, wound type, and duration of 189 wounds; a subset of 22 participants reported on pruritus in 63 wounds. Increased wound size was significantly associated with increased pain, increased pruritus, longer wound duration, increased infection frequency, and patients with mutations resulting in truncated type VII collagen.

    View details for DOI 10.1111/pde.14576

    View details for PubMedID 33749033

  • Direct-to-Consumer Genetic Risk Scoring for Melanoma Improves Adherence to Sun-Protective Behaviors Among Increased-Risk Groups: Results from a Prospective U.S. Cohort Study. Journal of the American Academy of Dermatology Hu, X. n., Kilgour, J. M., Fogel, A. L., Jia, J. L., Jaju, P. D., Tang, J. Y., Sarin, K. Y. 2021

    View details for DOI 10.1016/j.jaad.2021.01.042

    View details for PubMedID 33476728

  • Financial burden of epidermolysis bullosa on patients in the United States. Pediatric dermatology Gorell, E. S., Wolstencroft, P. W., de Souza, M. P., Murrell, D. F., Linos, E., Tang, J. Y. 2020


    Individuals with epidermolysis bullosa (EB), a group of genodermatoses with skin fragility, often require specialized and expensive bandaging. We analyzed the results from an online survey of 249 EB patients and caregivers living in the United States to investigate the financial impact of EB. Of respondents with severe EB subtypes (recessive dystrophic and junctional), 73% reported a major or moderate financial impact and 26% spent greater than

  • Multidisciplinary Care of Epidermolysis Bullosa during the COVID-19 Pandemic - Consensus: Recommendations by an International Panel of Experts. Journal of the American Academy of Dermatology Murrell, D. F., Lucky, A. W., Salas-Alanis, J. C., Woodley, D. T., Palisson, F., Natsuga, K., Nikolic, M., Ramirez-Quizon, M., Paller, A. S., Lara-Corrales, I., Barzegar, M. A., Sprecher, E., Has, C., Laimer, M., Bruckner, A. L., Bilgic, A., Nanda, A., Purvis, D., Hovnanian, A., Murat-Susic, S., Bauer, J., Kern, J. S., Bodemer, C., Martin, L. K., Mellerio, J., Kowaleski, C., Robertson, S. J., Bruckner-Tuderman, L., Pope, E., Marinkovich, M. P., Tang, J. Y., Su, J., Uitto, J., Eichenfield, L. F., Teng, J., Aan Koh, M. J., Lee, S. E., Khuu, P., Rishel, H. I., Sommerlund, M., Wiss, K., Hsu, C., Chiu, T. W., Martinez, A. E. 2020

    View details for DOI 10.1016/j.jaad.2020.06.1023

    View details for PubMedID 32682031

  • The association between cigarette smoking, cancer screening, and cancer stage: a prospective study of the women's health initiative observational cohort. BMJ open Eng, V. A., David, S. P., Li, S. n., Ally, M. S., Stefanick, M. n., Tang, J. Y. 2020; 10 (8): e037945


    To assess the dose-dependent relationship between smoking history and cancer screening rates or staging of cancer diagnoses.Prospective, population-based cohort study.Questionnaire responses from the Women's Health Initiative (WHI) Observational Study.89 058 postmenopausal women.Logistic regression models were used to assess the odds of obtaining breast, cervical, and colorectal cancer screening as stratified by smoking status. The odds of late-stage cancer diagnoses among patients with adequate vs inadequate screening as stratified by smoking status were also calculated.Of the 89 058 women who participated, 52.8% were never smokers, 40.8% were former smokers, and 6.37% were current smokers. Over an average of 8.8 years of follow-up, current smokers had lower odds of obtaining breast (OR 0.55; 95% CI 0.51 to 0.59), cervical (OR 0.53; 95% CI 0.47 to 0.59), and colorectal cancer (OR 0.71; 95% CI 0.66 to 0.76) screening compared with never smokers. Former smokers were more likely than never smokers to receive regular screening services. Failure to adhere to screening guidelines resulted in diagnoses at higher cancer stages among current smokers for breast cancer (OR 2.78; 95% CI 1.64 to 4.70) and colorectal cancer (OR 2.26; 95% CI 1.01 to 5.05).Active smoking is strongly associated with decreased use of cancer screening services and more advanced cancer stage at the time of diagnosis. Clinicians should emphasise the promotion of both smoking cessation and cancer screening for this high-risk group.

    View details for DOI 10.1136/bmjopen-2020-037945

    View details for PubMedID 32796021

  • Induced Remission of Metastatic Squamous Cell Carcinoma with an Immune Checkpoint Inhibitor in a Patient with Recessive Dystrophic Epidermolysis Bullosa. Case reports in oncology Khaddour, K. n., Gorell, E. S., Dehdashti, F. n., Tang, J. Y., Ansstas, G. n. 2020; 13 (2): 911–15


    Recessive dystrophic epidermolysis bullosa (RDEB) is a genodermatosis that leads to skin fragility and chronic wound formation. Patients with RDEB are at risk for cutaneous squamous cell carcinoma (SCC) which is a major cause of morbidity and mortality in these patients. No standard of care exists for the treatment of SCC in this patient population and therapy is based on anecdotal reports and expert opinion. We report a 32-year-old man with RDEB with previously localized SCC who later developed metastatic SCC. He was started on cemiplimab (an immune checkpoint inhibitor) 350 mg IV every 3 weeks. An objective radiological response was noted within 3 cycles. On 14 months follow-up, there was a durable response to treatment clinically and on imaging, without immune-related adverse events. To our knowledge, this is the first case report describing safe administration of immune checkpoint inhibitors in a patient with RDEB with objective and durable response of metastatic SCC. Larger case series and controlled clinical trials are needed to further investigate these medications in the RDEB population, given their high burden of aggressive and often lethal SCC.

    View details for DOI 10.1159/000508933

    View details for PubMedID 32884539

    View details for PubMedCentralID PMC7443658

  • 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. n., Nazaroff, J. n., Li, S. n., de Souza, M. P., Murrell, D. F., Marinkovich, M. P., Tang, J. Y. 2020


    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

  • Gene Therapy for Epidermolysis Bullosa JOURNAL OF INVESTIGATIVE DERMATOLOGY Marinkovich, M., Tang, J. Y. 2019; 139 (6): 1221–26
  • 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): 196–203
  • 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: 933–42
  • From Clinical Phenotype to Genotypic Modelling: Incidence and Prevalence of Recessive Dystrophic Epidermolysis Bullosa (RDEB). Clinical, cosmetic and investigational dermatology Eichstadt, S. n., Tang, J. Y., Solis, D. C., Siprashvili, Z. n., Marinkovich, M. P., Whitehead, N. n., Schu, M. n., Fang, F. n., Erickson, S. W., Ritchey, M. E., Colao, M. n., Spratt, K. n., Shaygan, A. n., Ahn, M. J., Sarin, K. Y. 2019; 12: 933–42


    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

  • 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. n., Mirza, A. n., Sarin, K. n., Oro, A. n., Tang, J. Y. 2019

    View details for DOI 10.1001/jamadermatol.2019.1541

    View details for PubMedID 31339515

  • 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


    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: 371–78


    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 the research subjects after treatment. In this study, we reviewed 286 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 1 month 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

  • Measurement of Skin Adhesion in Recessive Dystrophic Epidermolysis Bullosa Patients. Journal of the American Academy of Dermatology Nazaroff, J., Manoukian, M., Barriga, M., Lane, A., Marinkovich, M. P., Tang, J. Y. 2018

    View details for PubMedID 30081112

  • 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): 145–47

    View details for PubMedID 29908819

  • 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-+
  • 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


    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-+


    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 5 mg, or to placebo, administered once daily for 6 weeks 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, 1 mg and 5 mg 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


    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. n., Landefeld, C. n., Pare-Anastasiadou, A. n., Koutelidas, I. n., Chren, M. M., Aji, N. n., Teng, C. E., Koenig, B. A., Tang, J. n., Covinsky, K. n., Linos, E. n. 2018


    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

  • 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. n., Chiou, A. S., Aasi, S. Z., Tibshirani, R. J., Tang, J. Y., Zare, R. N. 2018


    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-µm-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

  • 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. n., Bi, T. n., Silverstein, M. n., Tang, J. Y., Chen, X. n., Beachy, P. A. 2018; 115 (2): E200–E209


    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

  • Azathioprine and risk of multiple keratinocyte cancers. Journal of the American Academy of Dermatology Cho, H. G., Kuo, K. Y., Xiao, K. n., Batra, P. n., Li, S. n., Tang, J. Y., Sarin, K. Y. 2018; 78 (1): 27–28.e1

    View details for PubMedID 28989107

  • Noncanonical hedgehog pathway activation through SRF-MKL1 promotes drug resistance in basal cell carcinomas. Nature medicine Whitson, R. J., Lee, A. n., Urman, N. M., Mirza, A. n., Yao, C. Y., Brown, A. S., Li, J. R., Shankar, G. n., 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): 271–81


    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

  • 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): 75411–17


    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 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): 1107–13


    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


    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


    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


    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


    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 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): 134–40


    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=117 863) and the Health Professionals Follow-up Study (HPFS, n=51 111). 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 10 cm 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. n., Ott, G. R., Chen, B. n., Lee, A. n., Brown, A. S., Aasi, S. Z., Hollmig, T. n., Ator, M. A., Dorsey, B. D., Ruggeri, B. R., Zificsak, C. A., Sirota, M. n., Tang, J. Y., Butte, A. n., Epstein, E. n., Sarin, K. Y., Oro, A. E. 2017; 2 (21)


    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 Ɩ/ʎ (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

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


    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

  • 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)


    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-?


    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): 1138–43


    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


    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): 897–903


    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


    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 146 326 participants with median 14.6 follow-up years, 23 067 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

    View details for DOI 10.1038/bjc.2016.149

    View details for PubMedID 27280630