Assessment of Mammalian Target of Rapamycin Pathway Activation in Basal Cell Carcinoma as a New Therapeutic Approach.

ABSTRACT: Targeting the mammalian target of rapamycin (mTOR) pathway represents a potentially novel approach to treat basal cell carcinoma (BCC), but activation of this pathway has not been well described in human BCCs. The purpose of this study was to assess whether mTOR pathway activation occurs in BCCs (both sporadic and syndromic) and report a case of a patient with Gorlin syndrome (GS) whose clinically suspicious BCCs responded to mTOR inhibition through topical sirolimus treatment. After Stanford Institutional Review Board Approval, archived BCCs from patients with GS (n = 25), sporadic BCCs (n = 35), and control tissues were subjected to immunohistochemical analysis for the activation of mTOR pathway, and immunohistochemical staining intensity was evaluated by a dermatopathologist. BCCs (compared with normal skin) had elevated levels of eIF4EBP1 (Padjusted = 0.0336), which is downstream of mTOR. a serine/threonine kinase Phospho-(AKT), which interacts with mTOR, was also significantly elevated (perinuclear: Padjusted < 0.0001; cytoplasmic: Padjusted = 0.0021). When off-label topical 1% sirolimus was used on a pediatric patient with GS, we noted reduction of new BCC development and decreased size of existing neoplasms clinically suspicious for BCCs. This treatment was well tolerated after 2 years of continuous use, with no other treatments needed during this period. Topical sirolimus is a promising therapeutic candidate against both sporadic and GS-associated BCC. Multicenter, prospective studies are needed to understand the efficacy and safety of topical mTOR inhibitors in BCC treatment, and ascertain whether the immunohistochemical markers downstream of mTOR could have predictive value in identifying BCCs most likely to respond to topical mTOR inhibitors, such as sirolimus.

Pachyonychia Congenita: A Research Agenda Leading to New Therapeutic Approaches.

Pachyonychia congenita (PC) is a dominantly inherited genetic disorder of cornification. PC stands out among other genodermatoses because despite its rarity, it has been the focus of a very large number of pioneering translational research efforts over the past 2 decades, mostly driven by a patient support organization, the Pachyonychia Congenita Project. These efforts have laid the ground for innovative strategies that may broadly impact approaches to the management of other inherited cutaneous and noncutaneous diseases. This article outlines current avenues of research in PC, expected outcomes, and potential hurdles.

Assessment of Hormonal Contraceptive Utilization and Associated Odds of Hypercoagulopathy in Patients with Venous Malformations Using a National Claims Database.

BACKGROUND: Vascular anomalies that exhibit a slow velocity of blood flow, specifically venous malformations (VM), are associated with hypercoagulability. There is limited literature on the utilization of hormonal contraceptives (HCs) and the development of clotting events in female individuals diagnosed with VM. OBJECTIVE: We aimed to characterize HC utilization and associated odds of hypercoagulopathy in patients with VM of child-bearing age. METHODS: Using a national administrative claims database, we identified female patients with VM aged 15-49 years and a control population, matched for age and length of insurance enrollment, from 2016 to 2021. Multivariable logistic regression was used to estimate the odds of hypercoagulation events associated with HC use. RESULTS: Two hundred and sixty-seven (47.2%) patients with VM and 1284 (45.4%) control patients utilized HCs during the study period. Oral contraceptives were the most common HC for patients with and without VM (73.8% and 76.9% of those taking HCs, respectively), and estrogen-containing combination HCs (70.4% in patients with VM and 75.9% in controls) were more prevalent than progestin-only HCs in both populations. Despite a heightened baseline odds of hypercoagulopathy in patients with VM relative to patients without VM (odds ratio = 12.54; 95% confidence interval 7.73-20.3), HC use was not associated with an increased odds of hypercoagulation in the VM subpopulation (odds ratio = 0.82; 95% confidence interval 0.46-1.46). In contrast, tobacco use (odds ratio = 2.12; 95% confidence interval 1.09-4.12) and a history of coagulopathy (odds ratio = 3.92; 95% confidence interval 1.48-10.36) were predictive of thromboembolic events in the VM cohort. CONCLUSIONS: These findings suggest that patients with VM may safely use HCs with careful consideration of other risk factors for thromboses.

Evidence-Based Clinical Practice Guidelines for Laser-Assisted Drug Delivery.

Importance: Laser-assisted drug delivery (LADD) is used for various medical and cosmetic applications. However, there is insufficient evidence-based guidance to assist clinicians performing LADD. Objective: To develop recommendations for the safe and effective use of LADD. Evidence Review: A systematic literature review of Cochrane Central Register of Controlled Trials, Embase, and MEDLINE was conducted in December 2019 to identify publications reporting research on LADD. A multidisciplinary panel was convened to draft recommendations informed by the systematic review; they were refined through 2 rounds of Delphi survey, 2 consensus meetings, and iterative review by all panelists until unanimous consensus was achieved. Findings: Of the 48 published studies of ablative fractional LADD that met inclusion criteria, 4 were cosmetic studies; 21, oncologic; and 23, medical (not cosmetic/oncologic), and 6 publications of nonablative fractional LADD were included at the request of the expert panel, producing a total of 54 studies. Thirty-four studies (63.0%) were deemed to have low risk of bias, 17 studies (31.5%) had moderate risk, and 3 (5.5%) had serious risk. The key findings that informed the guidelines developed by the expert panel were as follows: LADD is safe in adults and adolescents (≥12 years) with all Fitzpatrick skin types and in patients with immunosuppression; it is an effective treatment for actinic keratosis, cutaneous squamous cell carcinoma in situ, actinic cheilitis, hypertrophic scars, and keloids; it is useful for epidermal and dermal analgesia; drug delivery may be increased through the application of heat, pressure, or occlusion, or by using an aqueous drug solution; laser settings should be selected to ensure that channel diameter is greater than the delivered molecule; antibiotic prophylaxis is not recommended, except with impaired wound healing; antiviral prophylaxis is recommended when treating the face and genitalia; and antifungal prophylaxis is not recommended. The guideline's 15 recommendations address 5 areas of LADD use: (I) indications and contraindications; (II) parameters to report; (III) optimization of drug delivery; (IV) safety considerations; and (V) prophylaxis for bacterial, viral, and fungal infections. Conclusions and Relevance: This systematic review and Delphi consensus approach culminated in an evidence-based clinical practice guideline for safe and effective use of LADD in a variety of applications. Future research will further improve our understanding of this novel treatment technique.

A global, cross-sectional survey of patient-reported outcomes, disease burden, and quality of life in epidermolysis bullosa simplex.

BACKGROUND: Epidermolysis bullosa simplex (EBS) comprises a group of rare, blistering genodermatoses. Prior work has been limited by small sample sizes, and much remains unexplored about the disease burden and health-related quality of life (QOL) of patients with EBS. The aim of this study was to characterize the most common patient-reported clinical manifestations and the health-related impact of QOL in EBS, and to examine differences in disease burden by age. METHODS: Patients with a diagnosis of epidermolysis bullosa (EB) or their caregivers completed a one-time online survey administered by EBCare, an international online EB registry. Survey data from respondents self-reporting a diagnosis of EBS were analyzed for clinical and wound manifestations, medication use, and QOL (using Quality of Life in Epidermolysis Bullosa [QOLEB] scores). Differences across age groups were assessed using Kruskal-Wallis and Fisher's exact tests. RESULTS: There were 214 survey respondents with EBS. The mean age was 32.8 years (standard deviation = 19.2). Many respondents reported blisters (93%), recurrent wounds (89%), pain (74%), chronic wounds (59%), itch (55%), and difficulty walking (44%). Mean QOLEB score was 14.7 (standard deviation = 7.5) indicating a "moderate" impact on QOL, and 12% of respondents required regular use of opiates. Findings were consistent in subgroup analyses restricted to respondents with diagnostic confirmation via genetic testing or skin biopsy (n = 63 of 214). Age-stratified analyses revealed differences in disease burden: younger respondents were more likely to self-report severe disease (24% vs. 19% vs. 5% for respondents aged 0-9 vs. 10-17 vs. 18 + , p = 0.001), failure to thrive (9% vs. 15% vs. 3%, p = 0.02), and use of gastrostomy tubes (15% vs. 12% vs. 1%, p < 0.001) and topical antibiotics (67% vs. 69% vs. 34%, p < 0.001), while older respondents were more likely to be overweight or obese (6% vs. 0% vs. 51%, p < 0.001) and have difficulty walking (24% vs. 46% vs. 48%, p = 0.04). CONCLUSIONS: In the largest international cross-sectional survey of EBS patients conducted, respondents reported extensive disease burden including significant wounding, pain, itch, difficulty walking, and impact on QOL. Age stratified disease manifestations. These findings suggest significant unmet need, and treatment and counseling for EBS patients should consider age-specific differences.

Gorlin Syndrome: Assessing Genotype-Phenotype Correlations and Analysis of Early Clinical Characteristics as Risk Factors for Disease Severity.

PURPOSE: Gorlin syndrome (GS) is a rare genetic disorder characterized by lifetime risk of basal cell carcinomas (BCCs), skeletal anomalies (SAs), and other extracutaneous neoplasms. There is great variation in disease severity, and a genotype-phenotype correlation has not been well established. Here, we investigate whether patients' clinical characteristics predict disease severity to inform clinical decision making. METHODS: Data of 248 patients with GS were collected between 2014 and 2021 from three institutions. Multivariable regression analyses were performed to investigate whether clinical characteristics predicted disease burden. Genotype-phenotype correlations were investigated in 40 patients. RESULTS: Patients with SAs had a mean increase of 120 lifetime BCCs (95% CI, 27.1 to 213) relative to patients without SAs. Those with ≥ 2 SAs had 2.45 increased odds (95% CI, 1.01 to 5.91) of advanced or metastatic BCCs. Moreover, the presence of multiple SAs was associated with 5.00 increased odds of having a keratocystic odontogenic tumor (95% CI, 2.22 to 11.3) and 2.79 increased odds of an ovarian fibroma (95% CI, 1.05 to 7.40). Genotype-phenotype analyses showed that missense/in-frame mutations were more likely to be hereditary compared with severe deleterious mutation types (100% v 27%; P = .004). In addition, heat map visualization illustrated that those with more deleterious variants, like large deletions, trended toward increased burden of SAs and BCCs per year. CONCLUSION: GS patients with SAs may be at greater risk for developing more numerous and severe BCCs and other neoplastic growths including keratocystic odontogenic tumors and ovarian fibromas. Current clinical guidelines suggest yearly follow-up in individuals with GS. Since SAs are usually recognized at the time of diagnosis, our results suggest that more vigilant lifetime multidisciplinary surveillance should be considered for these patients starting in childhood.

Spitz nevus with EHBP1-ALK fusion and distinctive membranous localization of ALK.

ALK rearrangements define a histopathologically distinctive yet diverse subset of Spitz tumors characterized by fusiform to epithelioid melanocytes with frequent fascicular growth and ALK overexpression. Molecularly, these tumors are characterized by fusions between ALK and a variety of gene partners, most commonly TPM3 and DCTN1. We describe an unusual case of a Spitz nevus occurring in a 13-year-old female that manifested ALK immunopositivity with cell membrane localization. The proliferation was polypoid and composed of elongated nests of epithelioid melanocytes with enlarged nuclei, prominent nucleoli, and abundant cytoplasm without significant atypia and lacking mitotic figures. The nevus exhibited strong and diffuse expression of p16. Targeted next-generation RNA sequencing revealed an in-frame EHBP1-ALK fusion, which has been reported only once in the literature. EHBP1 encodes an adaptor protein with plasma membrane targeting potential. Together, these findings suggest that the 5' ALK fusion partner in Spitz tumors may dictate the subcellular localization of the ALK chimeric oncoprotein. In summary, this case highlights a rare ALK fusion associated with a distinct immunohistochemical staining pattern and further expands the spectrum of ALK-rearranged melanocytic tumors.

Next-generation sequencing confirms T-cell clonality in a subset of pediatric pityriasis lichenoides.

BACKGROUND: Pityriasis lichenoides (PL) is a papulosquamous disease that affects both adults and children. Previous studies have shown a subset of this entity to have clonal T-cell populations via PCR-based assays. In this study, we sought to implement next-generation sequencing (NGS) as a more sensitive and specific test to examine for T-cell clonality within the pediatric population. METHODS: We identified 18 biopsy specimens from 12 pediatric patients with clinical and histopathologic findings compatible with PL. Patient demographics, clinical features, management, and histopathologic findings were reviewed. All specimens were analyzed for clonality with NGS of T-cell receptor beta (TRB) and gamma (TRG) genes. RESULTS: Of the 12 patients, 9 (75%) had complete resolution of lesions at the time of data collection (mean follow-up 31 months). The remaining three patients significantly improved with methotrexate (with or without acitretin). Interestingly, 7 of 12 patients (58%) and 9 of 17 biopsy specimens (53%) showed evidence of T-cell clonality. Two patients showed matching TRB clones from different anatomic sites. CONCLUSIONS: T-cell clonality is a common finding in PL, probably representing a "reactive clonality" rather than a true lymphoproliferative disorder. Clonality alone cannot be used as a means to distinguish PL from lymphomatoid papulosis or cutaneous lymphoma.

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

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-1ß, 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.

Eruptive nevi in a patient with constitutional mismatch repair deficiency (CMMRD).

Biallelic mutations in the DNA mismatch repair genes MLH1, MSH2, MSH6, or PMS2 result in one of the most aggressive genetic cancer conditions, constitutional mismatch repair syndrome (CMMRD). We present a case of a 10-year-old boy with biallelic MSH6 mutation and systemic lupus erythematosus with eruptive melanocytic nevi after receiving chemotherapy for mediastinal T-cell lymphoblastic lymphoma.

Dermatologic toxicities of targeted antineoplastic agents and immune checkpoint inhibitor therapy in pediatric patients: A systematic review.

Cutaneous adverse events (cAEs) from targeted antineoplastic agents and immune checkpoint inhibitors are common in children with cancer and may lead to dose reduction or cessation of critical oncologic treatment. Timely diagnosis and proper management of cAEs in pediatric oncology patients is essential to optimize ongoing cancer-directed therapy and improve quality of life. This systematic review of published studies summarizes dermatologic toxicities to targeted anticancer treatments and immune checkpoint inhibitors.

Genotype‒Structurotype‒Phenotype Correlations in Patients with Pachyonychia Congenita.

Pachyonychia congenita (PC) is a genetic disorder of keratin that presents with nail dystrophy, painful palmoplantar keratoderma, and other clinical manifestations. We investigated the genotype‒structurotype‒phenotype correlations seen with mutations in keratin genes (keratin [K]6A, K6B, K6C, K16, K17) and utilized protein structure modeling of high-frequency mutations to examine the functional importance of keratin structural domains in PC pathogenesis. Participants of the International PC Research Registry underwent genetic testing and completed a standardized survey on their symptoms. Our results support previous reports associating oral leukokeratosis with K6A mutations and cutaneous cysts, follicular hyperkeratosis, and natal teeth with K17 mutations. Painful keratoderma was prominent with K6A and K16 mutations. Nail involvement was most common in patients with K6A mutation and least common in those with K6C mutation. Across keratin subtypes, patients with coil 2B mutations had the greatest impairment in ambulation, and patients with coil 1A mutations reported more emotional issues. Molecular modeling demonstrated that hotspot missense mutations in PC largely disrupted hydrophobic interactions or surface charge. The former may destabilize keratin dimers/tetramers, whereas the latter likely interferes with higher-order keratin filament formation. Understanding the pathologic alterations in keratin structure improves our knowledge of how PC genotype correlates with clinical phenotype, advancing insight into disease pathogenesis and therapeutic development.

Imatinib as a potentially effective therapeutic alternative in corticosteroid-resistant eosinophilic fasciitis.

Eosinophilic fasciitis (EF) is a rare condition in children that is typically treated with systemic corticosteroids. We present the case of a 9-year-old boy with biopsy-proven EF, refractory to systemic corticosteroids and methotrexate. The tyrosine kinase inhibitor imatinib was added as adjuvant therapy, leading to improvement in joint function and skin laxity. Our case is the first to suggest the anti-fibrotic properties of imatinib may benefit EF patients.

Atypical presentations of congenital hemangiomas: Extending the clinical phenotype.

BACKGROUND/OBJECTIVES: Congenital hemangiomas (CH) are a group of benign vascular tumors that are present at birth and exhibit variable involution during infancy. Congenital hemangiomas that do not involute are typically solitary patch or plaque-type tumors that grow proportionally with somatic growth. We report a case series of 9 patients with persistent CH, which exhibited uncommon features including segmental involvement, recurrent or severe pain, or growth via volumetric increase in size or apparent increased extent of anatomic involvement over time. METHODS: Via retrospective chart review, we included patients with persistent CH and atypical presentations. Available data regarding clinical characteristics, natural history, histopathology, imaging, and genetic tests were collected. RESULTS: Data on 9 patients were collected, including 7 noninvoluting CH and 2 partially involuting CH. Three of the 9 cases had segmental distribution, 6 had apparent growth or clinical evolution, and 4 were symptomatic with pain. One also had marked localized intravascular coagulopathy. CONCLUSIONS: Ongoing or recurrent pain and large extent of anatomic involvement can be features of CH, albeit uncommon ones, and can pose both diagnostic and management challenges. Tissue genomic studies can offer a novel tool for CH diagnosis.

Successful Medical Management of Life-threatening Hepatic Hemangioma in Neonates.

Hepatic hemangioma (HH) is a common asymptomatic, self-limiting benign vascular tumor of the liver in neonates. Although complicated HHs are rare, they have significant risks of morbidity and mortality, especially during the perinatal period. Because of the high risks of complications from surgical interventions, there is an unmet need for effective medical therapy. We report 2 neonates with life-threatening HH who were evaluated for a liver transplant before being treated successfully with combined medical therapy, which included sirolimus, corticosteroids, and propranolol.

RASA1-dependent cellular export of collagen IV controls blood and lymphatic vascular development.

Combined germline and somatic second hit inactivating mutations of the RASA1 gene, which encodes a negative regulator of the Ras signaling pathway, cause blood and lymphatic vascular lesions in the human autosomal dominant vascular disorder capillary malformation-arteriovenous malformation (CM-AVM). How RASA1 mutations in endothelial cells (EC) result in vascular lesions in CM-AVM is unknown. Here, using different murine models of RASA1-deficiency, we found that RASA1 was essential for the survival of EC during developmental angiogenesis in which primitive vascular plexuses are remodeled into hierarchical vascular networks. RASA1 was required for EC survival during developmental angiogenesis because it was necessary for export of collagen IV from EC and deposition in vascular basement membranes. In the absence of RASA1, dysregulated Ras mitogen-activated protein kinase (MAPK) signal transduction in EC resulted in impaired folding of collagen IV and its retention in the endoplasmic reticulum (ER) leading to EC death. Remarkably, the chemical chaperone, 4-phenylbutyric acid, and small molecule inhibitors of MAPK and 2-oxoglutarate dependent collagen IV modifying enzymes rescued ER retention of collagen IV and EC apoptosis and resulted in normal developmental angiogenesis. These findings have important implications with regards an understanding of the molecular pathogenesis of CM-AVM and possible means of treatment.

Successful treatment of spindle cell hemangiomas in a patient with Maffucci syndrome and review of literatures.

Maffucci syndrome is a rare genetic disease due to somatic mutation of IDH1 gene. Currently there is no medical treatment available for spindle cell hemangioma associated with this disorder. Here we report successful management of these hemangiomas using sirolimus in combination with surgery.

Extracutaneous manifestations in phacomatosis cesioflammea and cesiomarmorata: Case series and literature review.

Phacomatosis pigmentovascularis (PPV) comprises a family of rare conditions that feature vascular abnormalities and melanocytic lesions that can be solely cutaneous or multisystem in nature. Recently published work has demonstrated that both vascular and melanocytic abnormalities in PPV of the cesioflammea and cesiomarmorata subtypes can result from identical somatic mosaic activating mutations in the genes GNAQ and GNA11. Here, we present three new cases of PPV with features of the cesioflammea and/or cesiomarmorata subtypes and mosaic mutations in GNAQ or GNA11. To better understand the risk of potentially occult complications faced by such patients we additionally reviewed 176 cases published in the literature. We report the frequency of clinical findings, their patterns of co-occurrence as well as published recommendations for surveillance after diagnosis. Features assessed include: capillary malformation; dermal and ocular melanocytosis; glaucoma; limb asymmetry; venous malformations; and central nervous system (CNS) anomalies, such as ventriculomegaly and calcifications. We found that ocular findings are common in patients with phacomatosis cesioflammea and cesiomarmorata. Facial vascular involvement correlates with a higher risk of seizures (p = .0066). Our genetic results confirm the role of mosaic somatic mutations in GNAQ and GNA11 in phacomatosis cesioflammea and cesiomarmorata. Their clinical and molecular findings place these conditions on a clinical spectrum encompassing other GNAQ and GNA11 related disorders and inform recommendations for their management.