Germline cancer susceptibility in individuals with melanoma.

BACKGROUND: Prior studies have estimated a small number of individuals with melanoma (2%-2.5%) have germline cancer predisposition, yet a recent twin study suggested melanoma has the highest hereditability among cancers. OBJECTIVE: To determine the incidence of hereditary melanoma and characterize the spectrum of cancer predisposition genes that may increase the risk of melanoma. METHODS: Four hundred individuals with melanoma and personal or family history of cancers underwent germline testing of >80 cancer predisposition genes. Comparative analysis of germline data was performed on 3 additional oncologic and dermatologic data sets. RESULTS: Germline pathogenic/likely pathogenic (P/LP) variants were identified in 15.3% (61) individuals with melanoma. Most variants (41, 67%) involved genes considered unrelated to melanoma (BLM, BRIP1, CHEK2, MLH1, MSH2, PMS2, RAD51C). A third (20, 33%) were in genes previously associated with familial melanoma (BAP1, BRCA2, CDKN2A, MITF, TP53). Nearly half (30, 46.9%) of P/LP variants were in homologous repair deficiency genes. Validation cohorts demonstrated P/LP rates of 10.6% from an unselected oncologic cohort, 15.8% from a selected commercial testing cohort, and 14.5% from a highly selected dermatologic study. LIMITATIONS: Cohorts with varying degrees of selection, some retrospective. CONCLUSION: Germline predisposition in individuals with melanoma is common, with clinically actionable findings diagnosed in 10.6% to 15.8%.

Plain language summary of the CheckMate 76K study results: nivolumab given after stage 2B/2C melanoma is removed by surgery.

WHAT IS THIS SUMMARY ABOUT?: In this article, we summarize results from the ongoing phase 3 CheckMate 76K clinical study published online in Nature Medicine in October 2023. The study goal was to learn whether nivolumab works as an adjuvant therapy (that is, helps to keep cancer from coming back when it is given after surgery) for stage 2 melanoma (skin cancer) that has not spread to other parts of the body. Nivolumab is an immunotherapy that activates a person's immune system so it can destroy cancer cells. In melanoma, staging describes the severity of the cancer. Melanoma staging ranges from 0 (very thin and confined to the upper layer of the skin) to 4 (spread to distant parts of the body), with earlier stages removed by surgery. The people in this study had stage 2 melanoma that had not spread to the lymph nodes or other organs in the body. HOW WAS THE STUDY DESIGNED?: People 12 years and older with stage 2 melanoma that had not spread and had been removed by surgery were included in CheckMate 76K. People were randomly assigned to receive either nivolumab (526 patients) or placebo (264 patients). A placebo resembles the test medicine but does not contain any active medicines. The researchers assessed whether people who received nivolumab lived longer without their cancer returning and/or spreading to other parts of their bodies (compared with placebo) and if nivolumab was well tolerated. WHAT WERE THE RESULTS?: Researchers found that people who received nivolumab were 58% less likely to have their cancer return and 53% less likely of having their cancer spread to distant parts of their body, compared with placebo. These reductions in risk with nivolumab were seen in different subgroups of people with a range of characteristics, and regardless of how deep the melanoma had gone into the skin. People taking nivolumab had more side effects than those taking placebo, but most were mild to moderate and manageable. WHAT DO THE RESULTS MEAN?: Results from CheckMate 76K support the benefit of using nivolumab as a treatment option for people with stage 2 melanoma post-surgery.

Best practices in surgical and nonsurgical management of head and neck Merkel cell carcinoma: An update.

Merkel cell carcinoma (MCC) is a rare, highly aggressive cutaneous neuroendocrine carcinoma. Controversy exists regarding optimal management of MCC as high-quality randomized studies and clinical trials are limited, and physicians are bound to interpret highly heterogeneous, retrospective literature in their clinical practice. Furthermore, the rising incidence and notably poor prognosis of MCC urges the establishment of best practices for optimal management of the primary tumor and its metastases. Herein, we summarized the relevant evidence and provided an algorithm for decision-making in MCC management based on the latest 2021 National Comprehensive Cancer Network guidelines. Additionally, we report current active MCC clinical trials in the United States. The initial management of MCC is dependent upon the pathology of the primary tumor and presence of metastatic disease. Patients with no clinical evidence of regional lymph node involvement generally require sentinel node biopsy (SLNB) while clinically node-positive patients should undergo fine needle aspiration (FNA) or core biopsy and full imaging workup. If SLNB or FNA/core biopsy are positive, a multidisciplinary team should be assembled to discuss if additional node dissection or adjuvant therapy is necessary. Wide local excision is optimal for primary tumor management and SLNB remains the preferred staging and predictive tool in MCC. The management of MCC has progressively improved in the last decade, particularly due to the establishment of immunotherapy as a new treatment option in advanced MCC. Ongoing trials and prospective studies are needed to further establish the best practices for MCC management.

Perspectives in Melanoma: meeting report from the Melanoma Bridge (December 1st-3rd, 2022-Naples, Italy).

Outcomes for patients with melanoma have improved over the past decade with the clinical development and approval of immunotherapies targeting immune checkpoint receptors such as programmed death-1 (PD-1), programmed death ligand 1 (PD-L1) or cytotoxic T lymphocyte antigen-4 (CTLA-4). Combinations of these checkpoint therapies with other agents are now being explored to improve outcomes and enhance benefit-risk profiles of treatment. Alternative inhibitory receptors have been identified that may be targeted for anti-tumor immune therapy, such as lymphocyte-activation gene-3 (LAG-3), as have several potential target oncogenes for molecularly targeted therapy, such as tyrosine kinase inhibitors. Unfortunately, many patients still progress and acquire resistance to immunotherapy and molecularly targeted therapies. To bypass resistance, combination treatment with immunotherapies and single or multiple TKIs have been shown to improve prognosis compared to monotherapy. The number of new combinations treatment under development for melanoma provides options for the number of patients to achieve a therapeutic benefit. Many diagnostic and prognostic assays have begun to show clinical applicability providing additional tools to optimize and individualize treatments. However, the question on the optimal algorithm of first- and later-line therapies and the search for biomarkers to guide these decisions are still under investigation. This year, the Melanoma Bridge Congress (Dec 1st-3rd, 2022, Naples, Italy) addressed the latest advances in melanoma research, focusing on themes of paramount importance for melanoma prevention, diagnosis and treatment. This included sessions dedicated to systems biology on immunotherapy, immunogenicity and gene expression profiling, biomarkers, and combination treatment strategies.

Prophylactic Lymphaticovenous Anastomosis Performed with Lymphadenectomy is Oncologically Safe for Melanoma.

BACKGROUND: A major concern of lymphaticovenous anastomosis (LVA), which has not been studied, is increased risk of metastasis. Melanoma patients with macrometastatic lymph node disease represent a high-risk group for recurrence and metastasis. On the basis of a literature review, this present study is the first to evaluate the impact of prophylactic LVA on cancer survival and recurrence. METHODS: This was a comparison study of patients with cutaneous melanoma who underwent therapeutic lymphadenectomy alone (comparison group) or combined with prophylactic LVA (LVA group) between 2014 and 2020. A single surgeon performed all cancer resections, therapeutic lymphadenectomies, and LVA. Exclusion criteria included non-melanoma skin cancers, stage IV cancers before lymphadenectomy, microscopic lymphatic disease (i.e., positive sentinel node biopsy was the sole indication for lymph node dissection), or follow-up time less than 12 months unless the patient died earlier owing to melanoma-related complications. RESULTS: This study included 23 patients in the LVA group and 22 consecutive patients in the comparison group. The two groups were similar in age, sex, and cancer stages. The comparison group had longer follow-up times (median 67.62 versus 29.73 months in the LVA group; p < 0.01). Average size of largest metastatic lymph node was 45.91 ± 35.03 mm and 44.54 ± 23.32 mm in the LVA and comparison groups, respectively (p = 0.99). There were no differences in OS, DMFS, and RFS times after more than 2 years of follow-up since the index surgery. CONCLUSION: Prophylactic LVA performed for macrometastatic melanoma is not a strong risk factor for relapse and metastasis. LEVEL OF EVIDENCE: II Therapeutic.

Development of a Risk Prediction Model for Complications Following Forehead Flaps for Nasal and Periorbital Reconstruction.

BACKGROUND: Forehead flaps are a workhorse for nasal reconstruction, but complications occur in up to 30% of patients and risk factors are not well characterized. This study aimed to identify risk factors for complications, and provide clinicians a method to stratify patient risk to facilitate shared decision-making. MATERIALS AND METHODS: This retrospective study included patients who underwent forehead flaps between 2007 and 2020. Demographic and treatment characteristics were abstracted, in addition to clinical outcomes data. Multivariable regression was conducted, with step-wise variable elimination to determine inclusion in the final model. From the final regression, a risk-stratification scheme was developed. RESULTS: One hundred ninety-seven patients underwent forehead flap reconstruction, with a mean age of 68.5 years. Mean follow-up time was 42 months. There were 50 (25.4%) patients who developed a complication, including impaired nasal function (18.8%), flap congestion (5.1%), infection (2.5%), poor donor site healing (2.5%) wound dehiscence (2.0%), and flap congestion (1.5%). On univariate analysis, female sex, immunosuppression, prior radiotherapy, and larger resection area were associated with complications ( P <0.05). On multivariable analysis, female sex [odds ratio (OR): 3.89, P <0.001], hypoalbuminemia (OR: 3.70, P =0.01), and prior wide local excision (OR: 3.62, P =0.04) were predictors of complications. A clinical calculator was developed incorporating these risk factors, with a C-statistic of 0.85, indicating strong predictive value. CONCLUSIONS: We conducted the most comprehensive review of risk factors for the development of complications after forehead flap reconstruction. From this analysis, a novel, implementable, risk-stratification scheme was developed to equip surgeons with the ability to provide individualized risk assessment to patients and address preoperative comorbidities to optimize outcomes.

Immune status does not independently influence cutaneous squamous cell carcinoma metastasis and death when stratified by tumor stage: A dual-center retrospective cohort analysis of primary N0 disease.

BACKGROUND: Although immunocompromised patients have a higher risk of developing cutaneous squamous cell carcinomas, it is unknown whether immune status is an independent risk factor for poor outcomes. OBJECTIVE: To compare cutaneous squamous cell carcinoma outcomes in immunocompromised and immunocompetent patients when controlling for T-stage. METHODS: We performed a retrospective cohort study at 2 tertiary care centers, examining 989 primary tumors from 814 immunocompromised patients (solid organ transplant: 259 [31.7%], chronic lymphocytic leukemia: 113 [13.9%]) and 6608 tumors from 4198 immunocompetent patients. Our primary outcome was the composite of disease-specific death or tumor metastasis ("poor outcomes"). RESULTS: Immunocompromised patients had 50% more high T-stage tumors (ie, Brigham and Women's Hospital stage T2b and T3), than immunocompetent patients (3.3% vs 4.9%, respectively; P < .001). Significant predictors of poor outcomes included tumor stage (sub hazards ratio [SHR], 14.8 for high T-stage tumors; 95% confidence interval [CI], 8.0-27.6; P < .001) and male sex (SHR, 2.3; 95% CI, 1.4-3.8; P = .002). Immune status was not a significant predictor (SHR, 1.04; 95% CI, 0.69-1.6; P = .85). LIMITATIONS: This study is retrospective. CONCLUSION: Although immunocompromised patients had 50% more high T-stage tumors than immunocompetent patients, immunocompromised patients had a similar chance of metastasis and disease-specific death when adjusting for T-stage in our cohort of primary tumors.

Optimizing treatment approaches for patients with cutaneous melanoma by integrating clinical and pathologic features with the 31-gene expression profile test.

BACKGROUND: Many patients with low-stage cutaneous melanoma will experience tumor recurrence, metastasis, or death, and many higher staged patients will not. OBJECTIVE: To develop an algorithm by integrating the 31-gene expression profile test with clinicopathologic data for an optimized, personalized risk of recurrence (integrated 31 risk of recurrence [i31-ROR]) or death and use i31-ROR in conjunction with a previously validated algorithm for precise sentinel lymph node positivity risk estimates (i31-SLNB) for optimized treatment plan decisions. METHODS: Cox regression models for ROR were developed (n = 1581) and independently validated (n = 523) on a cohort with stage I-III melanoma. Using National Comprehensive Cancer Network cut points, i31-ROR performance was evaluated using the midpoint survival rates between patients with stage IIA and stage IIB disease as a risk threshold. RESULTS: Patients with a low-risk i31-ROR result had significantly higher 5-year recurrence-free survival (91% vs 45%, P < .001), distant metastasis-free survival (95% vs 53%, P < .001), and melanoma-specific survival (98% vs 73%, P < .001) than patients with a high-risk i31-ROR result. A combined i31-SLNB/ROR analysis identified 44% of patients who could forego sentinel lymph node biopsy while maintaining high survival rates (>98%) or were restratified as being at a higher or lower risk of recurrence or death. LIMITATIONS: Multicenter, retrospective study. CONCLUSION: Integrating clinicopathologic features with the 31-GEP optimizes patient risk stratification compared to clinicopathologic features alone.

BETA PRIME: Phase I study of AdAPT-001 as monotherapy and combined with a checkpoint inhibitor in superficially accessible, treatment-refractory solid tumors.

AdAPT-001 is an investigational therapy consisting of a replicative type 5 adenovirus armed with a TGF-ß receptor-immunoglobulin Fc fusion trap, designed to neutralize isoforms 1 and 3 of the profibrotic and immunosuppressive cytokine, TGF-ß. In preclinical studies with an immunocompetent mouse model, AdAPT-001 eradicated directly treated 'cold' tumors as well as distant untreated tumors, and, from its induction of systemic CD8+ T cell-mediated antitumor immunity, protected the mice from rechallenge with tumor cells. AdAPT-001 also sensitized resistant tumors to checkpoint blockade. This manuscript describes the rationale and design of the first-in-human phase I, dose-escalation and dose-expansion study of AdAPT-001 alone and in combination with a checkpoint inhibitor in adults with treatment-refractory superficially accessible solid tumors.

The purpose of this study is to find out more about the experimental oncolytic virus called AdAPT-001 that has been designed to selectively eliminate cancer cells. The virus is also designed to make a particular protein called a TGF-ß trap, which neutralizes TGF-ß, an overproduced chemical in cancer cells that puts the immune system into a comatose state. This article discusses a clinical trial called BETA PRIME for patients with no other standard treatment options. The trial will explore different doses of AdAPT-001 both alone and in combination with an approved checkpoint inhibitor or another immunotherapy, which blocks the 'off' signal on immune cells, to determine the safest and best dose. Clinical Trial Registration: NCT04673942 (ClinicalTrials.gov).

Youngest Composite Full-Face Transplant: A Model for Vascularized Composite Allograft in Younger Populations.

BACKGROUND: The field of face transplantation continues to evolve, with more complex defects being addressed, and, at the same time, increased outcome expectations. Given our unique long-term experience in this field, we consented one of the youngest patients to undergo a full-face transplant. METHODS: An 18-year-old woman presented with complete destruction of her central face and craniofacial structures. She had coexisting major injuries, including pituitary gland, visual axis, and motor control. After extensive rehabilitation and reconstruction techniques, the patient underwent face transplant on May 4, 2017, at the age of 21 years. RESULTS: The total operative time for the recipient was 26 hours. There were no major perioperative complications. Since transplant, the patient has undergone 3 revision surgeries. She is near completely independent from a daily life activity standpoint. She has had 1 episode of rejection above grade II that was successfully treated with a short-term increased in immunosuppression. CONCLUSIONS: Contrary to data in solid organ transplantation where youth is associated with increased risk of rejection, our current algorithm in immunosuppression, combined with this patient's compliance, has led to only 1 rejection episode beyond grade II. This successful transplant can serve as a model for future vascularized composite transplants in younger populations.

Ten-Year Institutional Experience to Predict Risk of Calvarial Bone Flap Loss Using Long-Term Outcome Data.

BACKGROUND: Calvarial bone flap (CBF) loss is a common complication following craniotomy and subsequent skull reconstruction can be challenging. Defining predictors of CBF failure not only improves patient outcomes but reduces the need for complex reconstruction often requiring plastic surgery consultation. As CBF failure can occur many years following craniotomy, this study aimed to determine risk factors of CBF loss using long-term follow-up. MATERIALS AND METHODS: This retrospective study included patients who underwent craniotomy with CBF reinsertion between 2003 and 2013 at a tertiary academic institution. Patients were included if demographics, comorbidities, and long-term outcomes were available. Multivariable logistic regression modeled the odds of CBF failure, defined as permanent removal for bone flap-related issues. The median follow-up was 6.9 years (interquartile range: 1.8-10.8 y). RESULTS: There were 222 patients who met inclusion criteria and underwent craniotomy with CBF reinsertion, primarily for tumor resection or intracranial pressure relief. CBF failure occurred in 76 (34.2%) patients. Up to 4 CBF reinsertions were performed in both failure and nonfailure groups. The risks of CBF loss increased with each additional CBF elevation by 17-fold ( P <0.001), male sex by 3-fold ( P =0.005), and tumor etiology by 3-fold ( P =0.033) ( C -index=0.942). CONCLUSIONS: Each CBF reinsertion dramatically increases the risk of CBF loss. This finding may optimize patient selection and surgical planning. Early multidisciplinary discussions between plastic surgeons and neurosurgeons may avoid multiple CBF elevations and prevent the adverse sequela of high-risk calvarial reconstruction efforts.

Maxillary and Mandibular Healing After Facial Allotransplantation.

INTRODUCTION: Facial transplantation has emerged as a viable option in treating devastating facial injuries.Despite the high healing rate of Le Fort III and bilateral sagittal split osteotomies (BSSO) in nontransplant patients, few studies have reported assessment of maxillary and mandibular healing in face transplant patients compared with nontransplant patients. The aim of this study was to examine differences in bone healing in our patients. PATIENTS AND METHODS: A retrospective chart review was conducted of facial allotransplantation patients at the Cleveland Clinic from December 2008 to inception. Demographics such as age, date of birth, and sex were recorded. Additional variables included procedures, revisions, reoperations, medications, and bone stability and healing. Computed tomography (CT) images assessed the alignment of skeletal components, bony union quality, and stability of fixation. RESULTS: Three patients were included: 2 had Le Fort III segment transplantation, and 1 had transplantation of both a Le Fort III segment and mandibular BSSO. The Le Fort III segment in all patients exhibited mobility and fibrous union at the Le Fort III osteotomy on CT. In contrast, the BSSO healed uneventfully after transplantation and revision surgery, with bony union confirmed by both CT and histology of the fixation area between the donor and recipient mandible bilaterally. No patients with midfacial fibrous union required revision of the nonunion as they were clinically asymptomatic. CONCLUSION: Le Fort osteotomy demonstrates inferior healing in facial transplantation compared with the nontransplant population. In contrast, the successful healing in the mandible is likely owing to the high density of rich cancellous bone.

Mixed Reality and 3D Printed Models for Planning and Execution of Face Transplantation.

OBJECTIVE: The aim of this study was to evaluate a novel holographic craniofacial surgical planning application and its implementation throughout the planning and operative stages of facial transplantation by performing a critical analysis of comparative utility, cost, and limitations of MR and 3D printing. SUMMARY OF BACKGROUND DATA: Face transplantation is a highly complex form of craniofacial reconstruction requiring significant planning, knowledge of patient-specific spatial relationships, and time-sensitive decision making. Computer-aided 3D modeling has improved efficiency and outcomes of complex craniofacial reconstruction by enabling virtual surgical planning and 3D printed model generation. MR technology can enhance surgical planning, improve visualization, and allow manipulation of virtual craniofacial biomodels within the operative field. METHODS: Accounting for the time-sensitive nature of face transplantation, a unique, highly coordinated workflow for image acquisition and processing was designed to facilitate rapid holographic rendering and 3D printing. During recent face transplantation, both holographic and 3D printed models were utilized, and the time and cost of fabrication were compared. RESULTS: Holographic models required less time and cost for fabrication. They provided both comprehensive visualization of 3D spatial relationships and novel means to perform VSP and virtual face transplantation by interacting with and manipulating patient-specific, anatomic holograms. CONCLUSION: Time efficiency, low-cost biomodel production, provision of unlimited preoperative surgical rehearsal, and potential for intraoperative surgical guidance makes holographic VSP and MR highly promising technology for use in complex craniofacial surgery.

NCCN Guidelines® Insights: Melanoma: Cutaneous, Version 2.2021.

Over the past few years, the NCCN Guidelines for Melanoma: Cutaneous have been expanded to include pathways for treatment of microscopic satellitosis (added in v2.2020), and the following Principles sections: Molecular Testing (added in v2.2019), Systemic Therapy Considerations (added in v2.2020), and Brain Metastases Management (added in v3.2020). The v1.2021 update included additional modifications of these sections and notable revisions to Principles of: Pathology, Surgical Margins for Wide Excision of Primary Melanoma, Sentinel Lymph Node Biopsy, Completion/Therapeutic Lymph Node Dissection, and Radiation Therapy. These NCCN Guidelines Insights discuss the important changes to pathology and surgery recommendations, as well as additions to systemic therapy options for patients with advanced disease.

Successful Treatment of Life-Threatening COVID-19 Infection in a Face Transplant Recipient.

ABSTRACT: Recent literature suggests that severe COVID-19 is associated with an exaggerated immune response during viral infection, resulting in cytokine storm. Although elevated plasma interleukin 6 (IL-6) has been reported in severe COVID-19 infections, and treatment with anti-IL-6 (tocilizumab) has demonstrated promising outcomes both domestically and abroad, reports remain limited and therapeutic regimens vary considerably. Furthermore, research pertaining to transplant recipients, COVID-19 infection, and anti-IL-6 therapy remains underdeveloped. Herein, we report the successful treatment of the only reported facial vascularized composite allograft (VCA) recipient who contracted severe COVID-19 and the first reported VCA recipient with COVID-19 infection that received anti-IL-6 immunotherapy resulting in an excellent recovery despite his multiple preexisting and COVID-19-related comorbidities-adult respiratory distress syndrome, acute renal failure requiring hemodialysis, and concomitant sepsis due to extensive drug-resistant bacterial pneumonia upon presentation. To date, he has not demonstrated any anti-IL-6 drug-related adverse effects. This preliminary report also suggests that our immunosuppressed VCA patients can indeed demonstrate a robust cytokine response during COVID-19 infection and may also respond favorably to emerging anticytokine immune therapies. We hope that our experience proves helpful to other centers that might encounter critically ill VCA recipients in the ongoing COVID-19 pandemic and in the years to follow.

Tocilizumab therapy in 5 solid and composite tissue transplant recipients with early ARDS due to SARS-CoV-2.

There are emerging data depicting the clinical presentation of coronavirus disease 19 (COVID-19) in solid organ transplant recipients but negligible data-driven guidance on clinical management. A biphasic course has been described in some infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), beginning with a flu-like illness followed by an intense inflammatory response characterized by elevated c-reactive protein (CRP), interleukin 6 (IL-6), and acute respiratory distress syndrome (ARDS) associated with high mortality. The exuberant and possibly dysregulated immune response has prompted interest in therapeutic agents that target the cytokines involved, particularly IL-6. Tocilizumab is an IL-6 receptor antagonist with a record of use for a variety of rheumatologic conditions and cytokine release syndrome due to chimeric antigen receptor T-cell therapy but experience in solid organ and composite tissue transplant recipients (SOT/CTTRs) with SARS-CoV-2-related ARDS has not been previously reported in detail. We present the clinical course of 5 SOT/CTTRs with SARS-CoV-2-related ARDS that received tocilizumab with favorable short-term outcomes in 4. Responses were characterized by reductions in CRP, discontinuation of vasopressors, improved oxygenation and respiratory mechanics, and variable duration of ventilator support. Four bacterial infections occurred within 2 weeks of tocilizumab administration. We discuss safety concerns and the need for randomized comparative trials to delineate tocilizumab's clinical utility in this population.

NCCN Guidelines Insights: Uveal Melanoma, Version 1.2019.

The NCCN Guidelines for Uveal Melanoma include recommendations for staging, treatment, and follow-up of patients diagnosed with uveal melanoma of the choroid or ciliary body. In addition, because distinguishing between uveal melanoma and benign uveal nevi is in some cases difficult, these guidelines also contain recommendations for workup of patients with suspicious pigmented uveal lesions, to clarify the tests needed to distinguish between those who should have further workup and treatment for uveal melanoma versus those with uncertain diagnosis and low risk who should to be followed and later reevaluated. These NCCN Guidelines Insights describe recommendations for treatment of newly diagnosed nonmetastatic uveal melanoma in patients who have already undergone a complete workup.

Molecular risk prediction in cutaneous melanoma: A meta-analysis of the 31-gene expression profile prognostic test in 1,479 patients.

BACKGROUND: Multiple studies have reported on the accuracy of the prognostic 31-gene expression profile test for cutaneous melanoma. Consistency of the test results across studies has not been systematically evaluated. OBJECTIVE: To assess the robustness of the prognostic value of the 31-gene expression profile. METHODS: Raw data were obtained from studies identified from systematic review. A meta-analysis was performed to determine overall effect of the 31-gene expression profile. Clinical outcome metrics for the 31-gene expression profile were compared with American Joint Committee on Cancer staging. RESULTS: Three studies met inclusion criteria; data from a novel cohort of 211 patients were included (n = 1,479). Five-year recurrence-free and distant metastasis-free survival rates were 91.4% and 94.1% for Class 1A patients and 43.6% and 55.5% for Class 2B patients (P < .0001). Meta-analysis results showed that Class 2 was significantly associated with recurrence (hazard ratio 2.90; P < .0001) and distant metastasis (hazard ratio 2.75; P < .0001). The 31-gene expression profile identified American Joint Committee on Cancer stage I to III patient subsets with high likelihood for recurrence and distant metastasis. Sensitivity was 76% (95% confidence interval 71%-80%) and 76% (95% confidence interval 70%-82%) for each end point, respectively. When 31-gene expression profile and sentinel lymph node biopsy results were considered together, sensitivity and negative predictive value for distant metastasis-free survival were both improved. CONCLUSION: The 31-gene expression profile test consistently and accurately identifies melanoma patients at increased risk of metastasis, is independent of other clinicopathologic covariates, and augments current risk stratification by reclassifying patients for heightened surveillance who were previously designated as being at low risk.

Incidence and outcomes of cutaneous angiosarcoma: A SEER population-based study.

BACKGROUND: Cutaneous angiosarcoma (CAS) is a rare, malignant tumor of vascular mesenchymal origin accounting for less than 1% of all sarcomas. OBJECTIVE: To examine epidemiologic trends and outcomes in CAS. METHODS: In this retrospective, population-based study, patients with CAS were identified from the Surveillance Epidemiology and End Results database. Age, sex, and race-standardized incidence rates (IRs) were calculated. Survival was assessed with Kaplan-Meier curves and Cox proportional hazards models. RESULTS: Of 811 patients with CAS, 43% had a prior primary cancer. CAS IR for patients without prior primary cancers dropped from 5.88 per 100,000 in 1973 to 1984 to 2.87 per 100,000 in 2005 to 2014. In those with prior primary cancers, IR rose from 0.03 per 100,000 in 1973 to 1984 to 2.25 per 100,000 in 2005 to 2014. On multivariate analysis, patients older than 70 years of age had a higher risk of death compared with those younger than 50 years (hazard ratio, 2.16; 95% confidence interval 1.33-3.57; P = .002), and distant disease was associated with increased risk of death compared with localized disease (hazard ratio, 1.50; 95% confidence interval, 1.11-2.03; P = .008). Receipt of surgery and/or radiation therapy was not associated with survival. LIMITATIONS: Potential selection and miscoding bias, retrospective nature. CONCLUSION: CAS rates are rising among those with other prior primary cancers. Survival is not affected by current therapeutic strategies, highlighting the need for additional treatment options.

Targeted next generation sequencing (NGS) to classify melanocytic neoplasms.

This study piloted a pan-solid-tumor next generation sequence (NGS)-based laboratory developed test as a diagnostic aid in melanocytic tumors. 31 cases (4 "epithelioid" nevi, 5 blue nevi variants, 7 Spitz tumors [3 benign and 4 malignant] and 15 melanomas) were evaluated. All tumors [median diameter 7 mm (range 4-15 mm); median thickness 2.25 mm (range 0.25-12 mm)] yielded satisfactory results. The number of small nucleotide variants/tumor was significantly different between melanoma (median 18/tumor, range 4-71) and all other lesions (median 8/tumor, range 3-17) (P < 0.004) and malignant (median 16/tumor, range 4-71) vs benign lesions (median 7/tumor, range 3-14) (P = 0.01). BRAF, MET, NTRK1, and ROS fusions only occurred in benign Spitz tumors; EML4 fusion, BRAF, MAP2K1 and TERT mutations occurred in malignant Spitz tumors and/or melanoma. Amplifications and NRAS and NF1 mutations only occurred in melanoma. Most melanomas contained >1 pathogenic alteration. Developed NGS-based criteria correctly classified all malignant lesions in this series. 10/12 cases showed concordance with FISH; consensus diagnosis agreed with NGS classification in FISH-non-concordant cases. This pilot study suggests that NGS may be an effective diagnostic adjunct comparable to FISH, but further studies with larger numbers of cases are needed.