Clinical challenges in interpreting multiple pathogenic mutations in single patients.

BACKGROUND: In the past two decades, genetic testing for cancer risk assessment has entered mainstream clinical practice due to the availability of low-cost panels of multiple cancer-associated genes. However, the clinical value of multiple-gene panels for cancer susceptibility is not well established, especially in cases where panel testing identifies more than one pathogenic variant. The risk for specific malignancies as a result of a mutated gene is complex and likely influenced by superimposed modifier variants and/or environmental effects. Recent data suggests that the combination of multiple pathogenic variants may be fewer than reported by chance, suggesting that some mutation combinations may be detrimental. Management of patients with "incidentally" discovered mutations can be particularly challenging, especially when established guidelines call for radical procedures (e.g. total gastrectomy in CDH1) in patients and families without a classic clinical history concerning for that cancer predisposition syndrome. CASE PRESENTATION: We present two cases, one of an individual and one of a family, with multiple pathogenic mutations detected by multi-gene panel testing to highlight challenges practitioners face in counseling patients about pathogenic variants and determining preventive and therapeutic interventions. CONCLUSIONS: Ongoing investigation is needed to improve our understanding of inherited susceptibility to disease in general and cancer predisposition syndromes, as this information has the potential to lead to the development of more precise and patient-specific counseling and surveillance strategies. The real-world adoption of new or improved technologies into clinical practice frequently requires medical decision-making in the absence of established understanding of gene-gene interactions. In the meantime, practitioners must be prepared to apply a rationale based on currently available knowledge to clinical decision-making. Current practice is evolving to rely heavily on clinical concordance with personal and family history in making specific therapeutic decisions.

Perioperative management of pyoderma gangrenosum.

Pyoderma gangrenosum (PG) classically presents with an acute inflammatory stage, characterized by rapid evolution of painful ulcerations. The pathergy associated with PG lesions complicates disease management. Although PG is commonly treated with immunosuppression, some patients have refractory noninflammatory ulcers. In this subpopulation, there are case reports of successful surgical treatment. However, there is no consensus on optimal perioperative treatment for patients with PG undergoing surgery of any kind, PG related or otherwise. Therefore, we conducted a comprehensive literature review describing perioperative management practices and risk factors that may predict response to surgical intervention. We identified 126 cases of surgical intervention in patients with active PG; among these, only 16.7% experienced postoperative disease progression. No perioperative treatments or clinical risk factors were identified as statistically significant predictors of disease recurrence. Although limited by case series design and publication bias, this study is a valuable means of hypothesis generation for this rare condition.

Human papillomavirus-associated cutaneous disease burden in human immunodeficiency virus (HIV)-positive patients: the role of human papillomavirus vaccination and a review of the literature.

Human papillomavirus (HPV) infection is related to the development of cutaneous squamous cell carcinoma, oropharyngeal carcinoma, and anogenital malignancies. Patients infected with human immunodeficiency virus (HIV) have impaired cell-mediated immunity, placing them at risk for more prolonged infection with a greater likelihood of disease expression. This presents important implications for screening and treatment of HPV in the HIV patient population. The use of prophylactic vaccines directed against HPV has been a promising clinical development, though the immunogenicity of these vaccines in the immunocompromised host and in patients with previously established HPV infections has not been well established. In this review, we describe the pathogenesis and epidemiology of HPV-related cutaneous malignancies in patients with HIV. We outline the current guidelines and recent advances in the field of HPV vaccination. It is our hope that increasing awareness of the HPV-related HIV comorbidities will lead to developments in preventative medicine capable of reducing the burden of these diseases. We recognize the importance of prevention as a primary defense against disease and hope that this article organizes and disseminates recent findings in the field of HPV-associated comorbidities in the HIV population.

Biopsies for skin cancer detection: Dispelling the myths.

This review debunks 5 myths and provides the information you need to perform rapid, high-quality biopsies to detect skin cancers at their earliest stages.