Publications by authors named "Kavita Y Sarin"

86 Publications

Treatment of Cutaneous Squamous Cell Carcinoma With the Topical Histone Deacetylase Inhibitor Remetinostat.

JAMA Dermatol 2021 Nov 17. Epub 2021 Nov 17.

Department of Dermatology, Stanford University, Stanford, California.

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http://dx.doi.org/10.1001/jamadermatol.2021.4549DOI Listing
November 2021

Characterization of comorbidity heterogeneity among 13,667 patients with hidradenitis suppurativa.

JCI Insight 2021 Nov 8;6(21). Epub 2021 Nov 8.

Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disorder characterized by recurrent abscesses in the groin and flexural areas. HS is associated with a wide range of comorbidities that complicate the disease course. Although these comorbidities have been well described, it remains unclear how these comorbidities coassociate and whether comorbidity profiles affect disease trajectory. In addition, it is unknown how comorbidity associations are modulated by race and sex. In this comprehensive analysis of 77 million patients in a large US population-based cohort, we examined coassociation patterns among HS comorbidities and identified clinically relevant phenotypic subtypes within HS. We demonstrated that these subtypes not only differed among races, but also influenced clinical outcomes as measured by HS-related emergency department visits and cellulitis. Taken together, our findings provide key insights that elucidate the unique disease trajectories experienced by patients with HS and equip clinicians with a framework for risk stratification and improved targeted care in HS.
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http://dx.doi.org/10.1172/jci.insight.151872DOI Listing
November 2021

Transcriptomic Repositioning Analysis Identifies mTOR Inhibitor as Potential Therapy for Epidermolysis Bullosa Simplex.

J Invest Dermatol 2021 Sep 15. Epub 2021 Sep 15.

Department of Dermatology, Stanford Medicine, Stanford University, Redwood City, California, USA. Electronic address:

Expression-based systematic drug repositioning has been explored to predict novel treatments for a number of skin disorders. In this study, we utilize this approach to identify, to our knowledge, previously unreported therapies for epidermolysis bullosa simplex (EBS). RNA sequencing analysis was performed on skin biopsies of acute blisters (<1 week old) (n = 9) and nonblistered epidermis (n = 11) obtained from 11 patients with EBS. Transcriptomic analysis of blistered epidermis in patients with EBS revealed a set of 1,276 genes dysregulated in EBS blisters. The IL-6, IL-8, and IL-10 pathways were upregulated in the epidermis from EBS. Consistent with this, predicted upstream regulators included TNF-α, IL-1β, IL-2, IL-6, phosphatidylinositol 3-kinase, and mTOR. The 1,276 gene EBS blister signature was integrated with molecular signatures from cell lines treated with 2,423 drugs using the Connectivity Map CLUE platform. The mTOR inhibitors and phosphatidylinositol 3-kinase inhibitors most opposed the EBS signature. To determine whether mTOR inhibitors could be used clinically in EBS, we conducted an independent pilot study of two patients with EBS treated with topical sirolimus for painful plantar keratoderma due to chronic blistering. Both individuals experienced marked clinical improvement and a notable reduction of keratoderma. In summary, a computational drug repositioning analysis successfully identified, to our knowledge, previously unreported targets in the treatment of EBS.
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http://dx.doi.org/10.1016/j.jid.2021.07.170DOI Listing
September 2021

Hidradenitis suppurativa in patients of color is associated with increased disease severity and healthcare utilization: A retrospective analysis of 2 U.S. cohorts.

JAAD Int 2021 Jun 14;3:42-52. Epub 2021 Mar 14.

Department of Dermatology, Stanford University, Stanford, California.

Background: Hidradenitis suppurativa (HS) is known to disproportionately affect patients of color; however, there is a paucity of evidence on how its disease profile varies between races and ethnic groups.

Objective: Explore potential race-dependent differences in the disease profile of HS.

Methods: A retrospective analysis was conducted on HS patients at Stanford Hospital and Clinics. Data were compared in terms of demographics, disease severity, and healthcare utilization between races in adults identified to have at least 2 encounters coded for HS. Validation was conducted using Optum's de-identified Clinformatics Data Mart Database of national insurance claims.

Results: Our cohorts consisted of 939 HS patients seen at Stanford and 13,885 HS patients taken from the national dataset. Black and Hispanic patients had greater healthcare utilization compared to White patients. In addition, Hispanic patients at our institution also had significantly increased disease severity compared to their White counterparts (  = .009). Hispanic patients entered tertiary care at an earlier age (Stanford mean: 30.8 years for Hispanics vs 38.7 for Whites;  < .001), while Black patients entered later (Stanford mean: 39.6 years).

Limitations: These cohorts may not be representative of the entire HS patient population.

Conclusion: Our findings suggest that patients of color may have greater healthcare utilization and disease severity compared to other groups.
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http://dx.doi.org/10.1016/j.jdin.2021.01.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362278PMC
June 2021

Phase II Open-Label, Single-Arm Trial to Investigate the Efficacy and Safety of Topical Remetinostat Gel in Patients with Basal Cell Carcinoma.

Clin Cancer Res 2021 Sep 6;27(17):4717-4725. Epub 2021 Aug 6.

Department of Dermatology, Stanford Medicine Outpatient Center, Stanford University, Redwood City, California.

Purpose: The mainstay of treatment for basal cell carcinoma (BCC) is surgical excision, which can result in significant associated morbidity, particularly for patients with recurrent tumors. We previously conducted a drug repositioning screen using molecular data from human BCCs and identified histone deacetylase (HDAC) inhibitors as a potential treatment for BCC. Here we conduct the first proof-of-principle study of a topical pan-HDAC inhibitor, remetinostat, in human BCC.

Patients And Methods: We conducted a phase II, open-label, single-arm, single-institution trial of a topical HDAC inhibitor. Participants with at least one BCC were recruited. All participants applied 1% remetinostat gel three times daily for 6 weeks, with measurements of tumor diameter conducted at baseline and week 8. Surgical excision of the remaining tumor was conducted at the end of the study and microscopic evaluation was performed.

Results: Thirty-three per-protocol tumors from 25 participants were included in the analysis. The overall response rate, defined as the proportion of tumors achieving more than 30% decrease in the longest diameter from baseline to week 8, was 69.7% [90% confidence interval (CI), 54%-82.5%]. On pathologic examination, 54.8% of tumors demonstrated complete resolution. Pharmacodynamic analysis demonstrated similar levels of acetylated histone H3 in skin tissue before and after treatment, however, phosphorylation was increased. No systemic adverse events were reported.

Conclusions: The HDAC inhibitor remetinostat is a well-tolerated and effective topical treatment for reducing BCC disease burden in a clinically significant manner. This provides in-human validation of HDAC inhibitors as a therapy for BCC.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416931PMC
September 2021

Review of the Molecular Genetics of Basal Cell Carcinoma; Inherited Susceptibility, Somatic Mutations, and Targeted Therapeutics.

Cancers (Basel) 2021 Jul 31;13(15). Epub 2021 Jul 31.

Department of Dermatology, Stanford University School of Medcine, Stanford, CA 94305, USA.

Basal cell carcinoma (BCC) is a significant public health concern, with more than 3 million cases occurring each year in the United States, and with an increasing incidence. The molecular basis of BCC is complex, involving an interplay of inherited genetic susceptibility, including single nucleotide polymorphisms and genetic syndromes, and sporadic somatic mutations, often induced by carcinogenic exposure to UV radiation. This review outlines the currently known germline and somatic mutations implicated in the pathogenesis of BCC, including the key molecular pathways affected by these mutations, which drive oncogenesis. With advances in next generation sequencing and our understanding of the molecular genetics of BCC, established and emerging targeted therapeutics are offering new avenues for the non-surgical treatment of BCC. These agents, including Hedgehog pathway inhibitors, immune modulators, and histone deacetylase inhibitors, will also be discussed.
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http://dx.doi.org/10.3390/cancers13153870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345475PMC
July 2021

Status and Recommendations for Incorporating Biomarkers for Cutaneous Neurofibromas Into Clinical Research.

Neurology 2021 08 6;97(7 Suppl 1):S42-S49. Epub 2021 Jul 6.

From the Department of Genetics (D.W., B.K.), University of Alabama at Birmingham; Department of Pathology (A.S.-R.), Massachusetts General Hospital, Harvard Medical School, Boston; Department of Nephrology (S.A.), Wyoming Medical Center, Casper; National Institute of Arthritis and Musculoskeletal and Skin Diseases (D.P.), NIH, Bethesda, MD; Department of Neurology (J.B.), Johns Hopkins University School of Medicine, Baltimore, MD; and Department of Dermatology (K.Y.S.), Stanford University Medical Center, Redwood City, CA.

Objective: To summarize existing biomarker data for cutaneous neurofibroma (cNF) and to inform the incorporation of biomarkers into clinical trial design for cNFs.

Methods: The cNF working group, a subgroup of the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) consortium, was formed to review and inform clinical trial design for cNFs. Between June 2018 and February 2020, the cNF working group performed a review of existing data on genetic biomarkers for cNFs in the setting of neurofibromatosis type 1. We also reviewed criteria for successful biomarker application in the clinic. The group then held a series of meetings to develop a consensus report.

Results: Our systematic literature review of existing data revealed a lack of validated biomarkers for cNFs. In our report, we summarize the existing signaling, genomic, transcriptomic, histopathologic, and proteomic data relevant to cNF. Finally, we make recommendations for incorporating exploratory aims for predictive biomarkers into clinical trials through biobanking samples.

Conclusion: These recommendations are intended to provide both researchers and clinicians with best practices for clinical trial design to aid in the identification of clinically validated biomarkers for cNF.
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http://dx.doi.org/10.1212/WNL.0000000000012426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8594001PMC
August 2021

Dermatology Advances Into an Era of Precision Medicine.

JAMA Dermatol 2021 Jul;157(7):770-772

Department of Dermatology, Stanford University School of Medicine, Stanford, California.

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http://dx.doi.org/10.1001/jamadermatol.2021.0024DOI Listing
July 2021

Prevalence of potentially allergenic ingredients in products labeled for eczema care.

J Am Acad Dermatol 2021 May 29. Epub 2021 May 29.

Department of Dermatology, Stanford University School of Medicine, Redwood City, California. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2021.05.038DOI Listing
May 2021

Loss-of-Function Variants in the Tumor-Suppressor Gene Confer Increased Cancer Risk.

Cancer Res 2021 04 18;81(8):1954-1964. Epub 2021 Feb 18.

deCODE Genetics/Amgen, Reykjavik, Iceland.

The success of genome-wide association studies (GWAS) in identifying common, low-penetrance variant-cancer associations for the past decade is undisputed. However, discovering additional high-penetrance cancer mutations in unknown cancer predisposing genes requires detection of variant-cancer association of ultra-rare coding variants. Consequently, large-scale next-generation sequence data with associated phenotype information are needed. Here, we used genotype data on 166,281 Icelanders, of which, 49,708 were whole-genome sequenced and 408,595 individuals from the UK Biobank, of which, 41,147 were whole-exome sequenced, to test for association between loss-of-function burden in autosomal genes and basal cell carcinoma (BCC), the most common cancer in Caucasians. A total of 25,205 BCC cases and 683,058 controls were tested. Rare germline loss-of-function variants in conferred substantial risks of BCC (OR, 8.0; = 1.9 × 10), with a quarter of carriers getting BCC before age 70 and over half in their lifetime. Furthermore, common variants at the locus were associated with BCC, suggesting as a new, high-impact BCC predisposition gene. A follow-up investigation of 24 cancers and three benign tumor types showed that loss-of-function variants are associated with high risk of cervical cancer (OR, 12.7, = 1.6 × 10) and low age at diagnosis. Our findings, using power-increasing methods with high-quality rare variant genotypes, highlight future prospects for new discoveries on carcinogenesis. SIGNIFICANCE: This study identifies the tumor-suppressor gene as a high-impact BCC predisposition gene and indicates that inactivation of by germline sequence variants may also lead to increased risk of cervical cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3065DOI Listing
April 2021

Patient Crowdfunding for the Treatment of Cutaneous Malignancies.

Dermatol Surg 2021 07;47(7):1012-1013

Department of Dermatology, Stanford University School of Medicine, Stanford, California.

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http://dx.doi.org/10.1097/DSS.0000000000002866DOI Listing
July 2021

AP-1 and TGFß cooperativity drives non-canonical Hedgehog signaling in resistant basal cell carcinoma.

Nat Commun 2020 10 8;11(1):5079. Epub 2020 Oct 8.

Program in Epithelial Biology, Stanford University School of Medicine, 269 Campus Drive, Stanford, CA, 94305, USA.

Tumor heterogeneity and lack of knowledge about resistant cell states remain a barrier to targeted cancer therapies. Basal cell carcinomas (BCCs) depend on Hedgehog (Hh)/Gli signaling, but can develop mechanisms of Smoothened (SMO) inhibitor resistance. We previously identified a nuclear myocardin-related transcription factor (nMRTF) resistance pathway that amplifies noncanonical Gli1 activity, but characteristics and drivers of the nMRTF cell state remain unknown. Here, we use single cell RNA-sequencing of patient tumors to identify three prognostic surface markers (LYPD3, TACSTD2, and LY6D) which correlate with nMRTF and resistance to SMO inhibitors. The nMRTF cell state resembles transit-amplifying cells of the hair follicle matrix, with AP-1 and TGFß cooperativity driving nMRTF activation. JNK/AP-1 signaling commissions chromatin accessibility and Smad3 DNA binding leading to a transcriptional program of RhoGEFs that facilitate nMRTF activity. Importantly, small molecule AP-1 inhibitors selectively target LYPD3+/TACSTD2+/LY6D+ nMRTF human BCCs ex vivo, opening an avenue for improving combinatorial therapies.
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http://dx.doi.org/10.1038/s41467-020-18762-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546632PMC
October 2020

Phenotypic heterogeneity of neurofibromatosis type 1 in a large international registry.

JCI Insight 2020 08 20;5(16). Epub 2020 Aug 20.

Department of Dermatology, Stanford University School of Medicine, Redwood City, California, USA.

Neurofibromatosis type 1 (NF1) is a rare genetic disorder, characterized by the development of benign and malignant nerve tumors. Although all individuals with NF1 harbor genetic alterations in the same gene, the clinical manifestations of NF1 are extremely heterogeneous even among individuals who carry identical genetic defects. In order to deepen the understanding of phenotypic manifestations in NF1, we comprehensively characterized the prevalence of 18 phenotypic traits in 2051 adults with NF1 from the Children's Tumor Foundation's NF1 registry. We further investigated the coassociation of traits and found positive correlations between spinal neurofibromas and pain, spinal neurofibromas and scoliosis, spinal neurofibromas and optic gliomas, and optic gliomas and sphenoid wing dysplasia. Furthermore, with increasing numbers of cutaneous neurofibromas, the odds ratio of malignant peripheral nerve sheath tumor increased. Phenotypic clustering revealed 6 phenotypic patient cluster subtypes: mild, freckling predominant, neurofibroma predominant, skeletal predominant, late-onset neural severe, and early-onset neural severe, highlighting potential phenotypic subtypes within NF1. Together, our results support potential shared molecular pathogenesis for certain clinical manifestations and illustrate the utility of disease registries for understanding rare diseases.
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http://dx.doi.org/10.1172/jci.insight.136262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455126PMC
August 2020

A phase 2, double-blinded, placebo-controlled trial of toll-like receptor 7/8/9 antagonist, IMO-8400, in dermatomyositis.

J Am Acad Dermatol 2021 Apr 8;84(4):1160-1162. Epub 2020 Aug 8.

Department of Dermatology, Stanford University School of Medicine, Redwood City, California. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2020.07.122DOI Listing
April 2021

Prevalence and risk factors for high-frequency basal cell carcinoma in the United States.

J Am Acad Dermatol 2021 May 28;84(5):1493-1495. Epub 2020 Jul 28.

Stanford University School of Medicine, Department of Dermatology, Stanford, California. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2020.07.088DOI Listing
May 2021

Fitzpatrick phototype disparities in identification of cutaneous malignancies by Google Reverse Image.

J Am Acad Dermatol 2021 May 7;84(5):1415-1417. Epub 2020 May 7.

Department of Dermatology, Stanford University School of Medicine, Stanford, California. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2020.05.005DOI Listing
May 2021

Gamification improves melanoma visual identification among high school students: Results from a randomized study.

Pediatr Dermatol 2020 Jul 7;37(4):752-753. Epub 2020 Apr 7.

Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA.

Identification of melanoma or worrisome moles is often taught as an important part of routine skin checks. We sought to evaluate the efficacy of gamified education vs. traditional ABCDEs education on melanoma identification and self-confidence in identifying worrisome moles. We report that in our cohort (n = 271), participants randomized to the gamified intervention were more likely to correctly identify melanoma and non-melanoma skin lesions than those randomized to the ABCDE control cohort (74.2% vs 63.5% correct, P < .0001) and perceived confidence in self-identifying worrisome lesions was slightly higher in the gamified group than the traditional group, though the trend was not significant. These novel findings have significant implications on improved ways to educate young patients on the visual identification of melanoma and worrisome moles.
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http://dx.doi.org/10.1111/pde.14158DOI Listing
July 2020

Sexual and Gender Minority Curricula Within US Dermatology Residency Programs.

JAMA Dermatol 2020 05;156(5):593-594

Department of Dermatology, Stanford University School of Medicine, Stanford, California.

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http://dx.doi.org/10.1001/jamadermatol.2020.0113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081143PMC
May 2020

Ways to Improve Care for LGBT Patients in Dermatology Clinics.

Dermatol Clin 2020 Apr 27;38(2):269-276. Epub 2019 Nov 27.

Department of Dermatology, Stanford University School of Medicine, 455 Broadway Street, MC 8843, Redwood City, CA 94063, USA. Electronic address:

Lesbian, Gay, Bisexual, and Transgender (LGBT) patients face significant dermatologic health disparities. LGBT patients are often discriminated against, refused healthcare, or otherwise have negative healthcare experiences that may deter future utilization of professional care. While a number of factors may mitigate these negative experiences, the present article focuses on improving organizational and institutional drivers specific to individual dermatology clinics. Clinic workflow and operations, emerging technologies and EHRs, clinic culture, clinic environment and resource availability, and provider and staff education are all characteristics of healthcare clinics that can be improved to better facilitate high-quality dermatologic care for LGBT patients.
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http://dx.doi.org/10.1016/j.det.2019.10.012DOI Listing
April 2020

Genome-wide meta-analysis identifies eight new susceptibility loci for cutaneous squamous cell carcinoma.

Nat Commun 2020 02 10;11(1):820. Epub 2020 Feb 10.

Department of Epidemiology, Richard M. Fairbanks School of Public Health, Melvin & Bren Simon Cancer Center, Indiana University, 1050 Wishard Blvd, Indianapolis, IN, 46202, USA.

Cutaneous squamous cell carcinoma (SCC) is one of the most common cancers in the United States. Previous genome-wide association studies (GWAS) have identified 14 single nucleotide polymorphisms (SNPs) associated with cutaneous SCC. Here, we report the largest cutaneous SCC meta-analysis to date, representing six international cohorts and totaling 19,149 SCC cases and 680,049 controls. We discover eight novel loci associated with SCC, confirm all previously associated loci, and perform fine mapping of causal variants. The novel SNPs occur within skin-specific regulatory elements and implicate loci involved in cancer development, immune regulation, and keratinocyte differentiation in SCC susceptibility.
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http://dx.doi.org/10.1038/s41467-020-14594-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010741PMC
February 2020

Angular compounding for speckle reduction in optical coherence tomography using geometric image registration algorithm and digital focusing.

Sci Rep 2020 02 5;10(1):1893. Epub 2020 Feb 5.

Department of Structural Biology, Stanford University School of Medicine, Stanford, California, 94305, USA.

Optical coherence tomography (OCT) suffers from speckle noise due to the high spatial coherence of the utilized light source, leading to significant reductions in image quality and diagnostic capabilities. In the past, angular compounding techniques have been applied to suppress speckle noise. However, existing image registration methods usually guarantee pure angular compounding only within a relatively small field of view in the focal region, but produce spatial averaging in the other regions, resulting in resolution loss and image blur. This work develops an image registration model to correctly localize the real-space location of every pixel in an OCT image, for all depths. The registered images captured at different angles are fused into a speckle-reduced composite image. Digital focusing, based on the convolution of the complex OCT images and the conjugate of the point spread function (PSF), is studied to further enhance lateral resolution and contrast. As demonstrated by experiments, angular compounding with our improved image registration techniques and digital focusing, can effectively suppress speckle noise, enhance resolution and contrast, and reveal fine structures in ex-vivo imaged tissue.
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http://dx.doi.org/10.1038/s41598-020-58454-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002526PMC
February 2020

From Clinical Phenotype to Genotypic Modelling: Incidence and Prevalence of Recessive Dystrophic Epidermolysis Bullosa (RDEB).

Clin Cosmet Investig Dermatol 2019 24;12:933-942. Epub 2019 Dec 24.

Stanford University School of Medicine, Department of Dermatology, Redwood City, CA 94063, USA.

Background: 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 , the main component of anchoring fibrils (AF) necessary to maintain epidermal-dermal cohesion. While over 700 alterations in 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.

Methods: 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.

Results: 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 -mediated treatments in the US.

Conclusion: 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.
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http://dx.doi.org/10.2147/CCID.S232547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935313PMC
December 2019

Comparing online engagement and academic impact of dermatology research: An Altmetric Attention Score and PlumX Metrics analysis.

J Am Acad Dermatol 2020 08 11;83(2):648-650. Epub 2019 Dec 11.

Department of Dermatology, Stanford University School of Medicine, Stanford, California. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2019.12.003DOI Listing
August 2020

Assessment of readability and content of patient-initiated google search results for epidermolysis bullosa.

Pediatr Dermatol 2019 Nov 29;36(6):1004-1006. Epub 2019 Aug 29.

Department of Dermatology, Stanford University School of Medicine, Stanford, California.

Epidermolysis bullosa describes a group of conditions commonly characterized by fragile skin and blistering of the mucosal membranes. Due to the complex and rare nature of the disease, we sought to evaluate the quality and readability of epidermolysis bullosa information available online. Analysis of the top 50 search results on Google demonstrated that information by non-dermatologists was of a lower reading level and more accessible when compared to information by dermatologists, even though dermatologist written information was more likely to be useful and medically comprehensive. There is an increasing need for dermatologists to provide useful and medically comprehensive EB information that is accessible to patients and patient families.
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http://dx.doi.org/10.1111/pde.13975DOI Listing
November 2019

Hyperhidrosis affects quality of life in hidradenitis suppurativa: A prospective analysis.

J Am Acad Dermatol 2020 03 23;82(3):753-754. Epub 2019 Aug 23.

Department of Dermatology, Stanford University School of Medicine, Stanford, California. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2019.08.046DOI Listing
March 2020

Clonal replacement of tumor-specific T cells following PD-1 blockade.

Nat Med 2019 08 29;25(8):1251-1259. Epub 2019 Jul 29.

Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA.

Immunotherapies that block inhibitory checkpoint receptors on T cells have transformed the clinical care of patients with cancer. However, whether the T cell response to checkpoint blockade relies on reinvigoration of pre-existing tumor-infiltrating lymphocytes or on recruitment of novel T cells remains unclear. Here we performed paired single-cell RNA and T cell receptor sequencing on 79,046 cells from site-matched tumors from patients with basal or squamous cell carcinoma before and after anti-PD-1 therapy. Tracking T cell receptor clones and transcriptional phenotypes revealed coupling of tumor recognition, clonal expansion and T cell dysfunction marked by clonal expansion of CD8CD39 T cells, which co-expressed markers of chronic T cell activation and exhaustion. However, the expansion of T cell clones did not derive from pre-existing tumor-infiltrating T lymphocytes; instead, the expanded clones consisted of novel clonotypes that had not previously been observed in the same tumor. Clonal replacement of T cells was preferentially observed in exhausted CD8 T cells and evident in patients with basal or squamous cell carcinoma. These results demonstrate that pre-existing tumor-specific T cells may have limited reinvigoration capacity, and that the T cell response to checkpoint blockade derives from a distinct repertoire of T cell clones that may have just recently entered the tumor.
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http://dx.doi.org/10.1038/s41591-019-0522-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689255PMC
August 2019

Response to Shih et al.

J Invest Dermatol 2019 11 19;139(11):2385-2386. Epub 2019 Jul 19.

Department of Dermatology, Stanford University School of Medicine, Stanford, California, USA. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2019.06.139DOI Listing
November 2019

Genetic Mutations Underlying Phenotypic Plasticity in Basosquamous Carcinoma.

J Invest Dermatol 2019 11 15;139(11):2263-2271.e5. Epub 2019 Jun 15.

Department of Dermatology, Stanford University School of Medicine, Stanford, California, USA. Electronic address:

Basosquamous carcinoma (BSC) is an aggressive skin neoplasm with the features of both basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). While genetic drivers of BCC and SCC development have been extensively characterized, BSC has not been well studied, and it remains unclear whether these tumors originally derive from BCC or SCC. In addition, it is unknown which molecular pathways mediate the reprogramming of tumor keratinocytes toward basaloid or squamatized phenotypes. We sought to characterize the genomic alterations underlying sporadic BSC to elucidate the derivation of these mixed tumors. We identifed frequent Hedgehog (Hh) pathway mutations in BSCs, implicating Hh deregulation as the primary driving event in BSC. Principal component analysis of BCC and SCC driver genes further demonstrate the genetic similarity between BCC and BSC. In addition, 45% of the BSCs harbor recurrent mutations in the SWI/SNF complex gene, ARID1A, and evolutionary analysis revealed that ARID1A mutations occur after PTCH1 but before SCC driver mutations, indicating that ARID1A mutations may bestow plasticity enabling squamatization. Finally, we demonstrate mitogen-activated protein kinase pathway activation and the loss of Hh signaling associated with the squamatization of BSCs. Overall, these results support the genetic derivation of BSCs from BCCs and highlight potential factors involved in modulating tumor reprogramming between basaloid and squamatized phenotypes.
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http://dx.doi.org/10.1016/j.jid.2019.03.1163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839544PMC
November 2019

Early Detection of Adverse Drug Reactions in Social Health Networks: A Natural Language Processing Pipeline for Signal Detection.

JMIR Public Health Surveill 2019 Jun 3;5(2):e11264. Epub 2019 Jun 3.

Stanford Center for Biomedical Informatics Research, Stanford Department of Medicine, Stanford, CA, United States.

Background: Adverse drug reactions (ADRs) occur in nearly all patients on chemotherapy, causing morbidity and therapy disruptions. Detection of such ADRs is limited in clinical trials, which are underpowered to detect rare events. Early recognition of ADRs in the postmarketing phase could substantially reduce morbidity and decrease societal costs. Internet community health forums provide a mechanism for individuals to discuss real-time health concerns and can enable computational detection of ADRs.

Objective: The goal of this study is to identify cutaneous ADR signals in social health networks and compare the frequency and timing of these ADRs to clinical reports in the literature.

Methods: We present a natural language processing-based, ADR signal-generation pipeline based on patient posts on Internet social health networks. We identified user posts from the Inspire health forums related to two chemotherapy classes: erlotinib, an epidermal growth factor receptor inhibitor, and nivolumab and pembrolizumab, immune checkpoint inhibitors. We extracted mentions of ADRs from unstructured content of patient posts. We then performed population-level association analyses and time-to-detection analyses.

Results: Our system detected cutaneous ADRs from patient reports with high precision (0.90) and at frequencies comparable to those documented in the literature but an average of 7 months ahead of their literature reporting. Known ADRs were associated with higher proportional reporting ratios compared to negative controls, demonstrating the robustness of our analyses. Our named entity recognition system achieved a 0.738 microaveraged F-measure in detecting ADR entities, not limited to cutaneous ADRs, in health forum posts. Additionally, we discovered the novel ADR of hypohidrosis reported by 23 patients in erlotinib-related posts; this ADR was absent from 15 years of literature on this medication and we recently reported the finding in a clinical oncology journal.

Conclusions: Several hundred million patients report health concerns in social health networks, yet this information is markedly underutilized for pharmacosurveillance. We demonstrated the ability of a natural language processing-based signal-generation pipeline to accurately detect patient reports of ADRs months in advance of literature reporting and the robustness of statistical analyses to validate system detections. Our findings suggest the important contributions that social health network data can play in contributing to more comprehensive and timely pharmacovigilance.
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http://dx.doi.org/10.2196/11264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684218PMC
June 2019
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