Inconsistent Associations Between Risk Factor Profiles and Adjuvant Radiation Therapy (ART) Treatment in Patients with Cutaneous Squamous Cell Carcinoma and Utility of the 40-Gene Expression Profile to Refine ART Guidance.

INTRODUCTION: National Comprehensive Cancer Network (NCCN) recommendations for adjuvant radiation therapy (ART) use are similar for High Risk and Very High Risk cutaneous squamous cell carcinoma (cSCC) with negative post-surgical margins. Although studies report reductions in disease progression following ART treatment, ART use is likely inconsistent when guided by available risk factors. This study evaluated the association of ART with clinical risk factors in ART-treated and untreated patients and showed the clinical utility of the 40-gene expression profile (40-GEP) for guiding ART. METHODS: A multicenter study of 954 patients was conducted with institutional review board (IRB) approval. The 40-GEP test was performed using primary tumor tissue from patients with either a minimum of 3 years of follow-up or a documented regional or distant metastasis. Unsupervised hierarchical cluster analysis identified patterns of clinical risk factors for ART-treated patients, then identified untreated patients with matching risk factor profiles. Results were cross-referenced to 40-GEP test results to determine utility of the test to guide ART. RESULTS: Analysis demonstrated inconsistent implementation of ART for eligible patients. Cluster analysis identified four patient profiles based on clusters of risk factors and, notably, matching profiles in ART-treated and untreated patients. Further, the analysis identified patients who received but could have deferred ART on the basis of 40-GEP test result and biologically low risk of metastasis, and untreated patients who likely would have benefitted from ART on the basis of their 40-GEP test result. CONCLUSIONS: ART guidance is not determined by the presence of specific clinicopathologic factors, with treated and untreated patients sharing the same risk factor profiles. cSCC risk determination based on NCCN recommendations for clinical factor assessment results in inconsistent use of ART. Including tumor biology-based prognostic information from the 40-GEP refines risk and identifies patients who are most appropriate and likely to benefit from ART, and those that can consider deferring ART.

Integrating the 40-Gene Expression Profile (40-GEP) Test Improves Metastatic Risk-Stratification Within Clinically Relevant Subgroups of High-Risk Cutaneous Squamous Cell Carcinoma (cSCC) Patients.

INTRODUCTION: The validated 40-gene expression profile (40-GEP) test independently stratifies risk of regional or distant metastasis for cutaneous squamous cell carcinoma (cSCC) tumors with high-risk clinicopathologic features. This study evaluated the stratification of risk by the 40-GEP test in a large cohort of tumors with one or more high-risk factors and in clinically relevant subgroups, including tumors within National Comprehensive Cancer Network (NCCN) high- and very-high-risk groups, lower-stage BWH T1 and T2a tumors, and patients > 65 years old. METHODS: This multicenter (n = 58) performance study of the 40-GEP included 897 patients. Kaplan-Meier analyses were performed to assess risk stratification profiles for 40-GEP Class 1 (low), Class 2A (higher) and Class 2B (highest) risk groups, while nested Cox regression models were used to compare risk prediction of clinicopathologic risk classification systems versus risk classification systems in combination with 40-GEP. RESULTS: Patients classified as 40-GEP Class 1, Class 2A, or Class 2B had significantly different metastatic risk profiles (p < 0.0001). Integrating 40-GEP results into models with individual clinicopathologic risk factors or risk classification systems (Brigham and Women's Hospital, American Joint Committee on Cancer Staging Manual, 8th Edition) and NCCN demonstrated significant improvement in accuracy for prediction of metastatic events (ANOVA for model deviance, p < 0.0001 for all models). CONCLUSION: The 40-GEP test demonstrates accurate, independent, clinically actionable stratification of metastatic risk and improves predictive accuracy when integrated into risk classification systems. The improved accuracy of risk assessment when including tumor biology via the 40-GEP test ensures more risk-aligned, personalized patient management decisions.

Expert Consensus on the Use of Prognostic Gene Expression Profiling Tests for the Management of Cutaneous Melanoma: Consensus from the Skin Cancer Prevention Working Group.

BACKGROUND: Prognostic assessment of cutaneous melanoma relies on historical, clinicopathological, and phenotypic risk factors according to American Joint Committee on Cancer(AJCC) and National Comprehensive Cancer Network (NCCN) guidelines but may not account for a patient's individual additional genetic risk factors. OBJECTIVE: To review the available literature regarding commercially available gene expression profile (GEP) tests and their use in the management of cutaneous melanoma. METHODS: A literature search was conducted for original, English-language studies or meta-analyses published between 2010 and 2021 on commercially available GEP tests in cutaneous melanoma prognosis, clinical decision-making regarding sentinel lymph node biopsy, and real-world efficacy. After the literature review, the Skin Cancer Prevention Working Group, an expert panel of dermatologists with specialized training in melanoma and non-melanoma skin cancer diagnosis and management, utilized a modified Delphi technique to develop consensus statements regarding prognostic gene expression profile tests. Statements were only adopted with a supermajority vote of > 80%. RESULTS: The initial search identified 1064 studies/meta-analyses that met the search criteria. Of these, we included 21 original articles and meta-analyses that studied the 31-GEP test (DecisionDx-Melanoma; Castle Biosciences, Inc.), five original articles that studied the 11-GEP test (Melagenix; NeraCare GmbH), and four original articles that studied the 8-GEP test with clinicopathological factors (Merlin; 8-GEP + CP; SkylineDx B.V.) in this review. Six statements received supermajority approval and were adopted by the panel. CONCLUSION: GEP tests provide additional, reproducible information for dermatologists to consider within the larger framework of the eighth edition of the AJCC and NCCN cutaneous melanoma guidelines when counseling regarding prognosis and when considering a sentinel lymph node biopsy.

Integrating gene expression profiling into NCCN high-risk cutaneous squamous cell carcinoma management recommendations: impact on patient management.

Objective: To integrate gene expression profiling into the management of high-risk cutaneous squamous cell carcinoma (cSCC) within the National Comprehensive Cancer Network (NCCN) guidelines to improve risk-aligned management recommendations.Methods: A cohort of 300 NCCN-defined high-risk cSCC patients, along with the American Joint Committee on Cancer (AJCC) T stage, Brigham and Women's Hospital (BWH) T stage, and known patient outcomes were analyzed. Risk classifications using a validated 40-gene expression profile (40-GEP) test and T stage were applied to NCCN patient management guidelines. Risk-directed patient management recommendations within the NCCN guidelines framework were aligned based on risk for metastasis.Results: Of the 300 NCCN high-risk cSCC patients, 159 (53.0%) were 40-GEP Class 1 and AJCC T1-T2, and 173 (57.7%) were Class 1 and BWH T1-2a, indicating low risk for metastasis and, thereby, suggesting low management intensity. The 40-GEP integration suggested high intensity management for only 24 (8.0%) patients (all Class 2B), and moderate intensity management for the remainder of the cohort.Conclusions: The 40-GEP test can be integrated within existing NCCN guideline recommendations for managing cSCC patients to help refine risk-directed management decisions. Integration of the 40-GEP test would allow >50% of this NCCN-defined high-risk cohort to be managed with the lowest intensity recommendations within the broad NCCN guidelines. High intensity management was deemed risk-appropriate for a small subpopulation (8.0%). This study demonstrates that the 40-GEP test, in combination with T stage, has clinical utility to impact patient management decisions in NCCN high-risk cSCC for improving risk-aligned management within the NCCN guidelines framework.

The role of vitamins and supplements on skin appearance.

Skin appearance is affected by intrinsic factors (eg, aging) and extrinsic factors (eg, UV light). A myriad of treatments has been created to combat the phenotypic effects of these forces, including vitamins and supplements. This article reviews these therapies with a focus on carotenoids; vitamins C, E, and D; as well as collagen, ceramides, and mixed supplements.

Nonsurgical hair restoration treatment.

Patterned hair loss is common and can negatively impact quality of life. Patients often seek nonsurgical treatment options as a first-line measure to avoid undue risks and expense associated with surgery. This article discusses these noninvasive treatment options, with a focus on minoxidil, finasteride, dutasteride, spironolactone, low-level laser therapy (LLLT), platelet-rich plasma (PRP), microneedling, and oral supplements.

Level of Evidence Review for a Gene Expression Profile Test for Cutaneous Melanoma.

BACKGROUND: The advent of molecular medicine may allow for individualized cancer prognostication, which should enable better clinical management and, hopefully, improve patient outcomes. A 31-gene expression profile (31-GEP) test is currently available for patients diagnosed with cutaneous melanoma; this test helps inform patients' individual treatment plans, especially when combined with traditional biomarkers. OBJECTIVE: The objective of this study was to review the current literature and establish the level of evidence for a cutaneous melanoma 31-GEP test. METHODS: A review of seven development and validation studies for the 31-GEP test was conducted. The respective strengths and weaknesses of each study were applied to the level of evidence criteria from major organizations that publish guidelines for melanoma management: American Joint Committee on Cancer, National Comprehensive Cancer Network, and American Academy of Dermatology. RESULTS: Evaluating each study led to classifying the 31-GEP test as level I/II, I-IIIB, and IIA according to American Joint Committee on Cancer, National Comprehensive Cancer Network, and American Academy of Dermatology criteria, respectively. This stands in contrast to the official unrated status conferred by the American Joint Committee on Cancer and National Comprehensive Cancer Network and the II/IIIC rating designated by the American Academy of Dermatology. CONCLUSIONS: Differences between the authors' findings and official published ratings may be attributed to chronological issues, as many of the studies were not yet published when the aforementioned organizations conducted their reviews. There was also difficulty in applying the National Comprehensive Cancer Network criteria to this prognostic test, as their guidelines were intended for evaluation of predictive markers. Nevertheless, based upon the most current data available, integration of the 31-GEP test into clinical practice may be warranted in certain clinical situations.

The role of diet in preventing photoaging and treating common skin conditions.

As interest in complementary and alternative medicine has grown, the relationship between diet and skin health has become an active area of research. Various supplements, plant derivatives, and antioxidants have gained attention as possible tools to prevent signs of aging and improve skin conditions. As such, knowledge of clinical trial data is important to counsel patients appropriately on risks and benefits of these complementary treatments and lifestyle modifications. Herein, we review the role of diet and supplements in preventing photoaging and treating common skin conditions.

Dose-response effect of human equivalent radiation in the mandible.

BACKGROUND: Despite widespread use of adjuvant irradiation for head and neck cancer, the extent of damage to the underlying bone is not fully understood but is associated with pathologic fractures, nonunion, and osteoradionecrosis. The authors' laboratory previously demonstrated that radiation significantly impedes new bone formation in the murine mandible. We hypothesize that the detrimental effects of human equivalent radiation on the murine mandible results in a dose-dependent degradation in traditional micro-computed tomography (micro-CT) metrics. METHODS: Fifteen male Sprague-Dawley rats were randomized into 3 radiation dosage groups: low (5.91 Gy), middle (7 Gy), and high (8.89 Gy), delivered in 5 daily fractions. These dosages approximated 75%, 100%, and 150%, respectively, of the biologically equivalent dose that the human mandible receives during radiation treatment. Hemimandibles were harvested 56 days after radiation and scanned using micro-CT. Bone mineral density, tissue mineral density, and bone volume fraction were measured along with microdensitometry measurements. RESULTS: Animals demonstrated dose-dependent adverse effects of mucositis, alopecia, weight loss, and mandibular atrophy with increasing radiation. Traditional micro-CT parameters were not sensitive enough to demonstrate statistically significant differences between the radiated groups; however, microdensitometry analysis showed clear differences between radiated groups and statistically significant changes between radiated and nonradiated groups. CONCLUSIONS: The authors report dose-dependent and clinically significant adverse effects of fractionated human equivalent radiation to the murine mandible. The authors further report the limited capacity of traditional micro-CT metrics to adequately capture key changes in bone composition and present microdensitometric histogram analysis to demonstrate significant radiation-induced changes in mineralization patterns.