Moderating influences on parents' fatalistic beliefs about cancer and their association with sun safety behaviors among children of melanoma survivors: Implications for treatment.

The purpose of this study is to examine the association between parents' fatalism about melanoma and their children's sun protection, and the potential moderating role of parent-child communication. In this observational study of N = 69 melanoma-surviving parents of children ages 8-17, parents reported on their own melanoma fatalism, as well as their children's sun safety behaviors and parent-child discussion about sun safety. Parent gender, family history of melanoma, and frequency of parent-child discussions moderated the relationship between parents' fatalism and children's sun safety behaviors. Among mothers and parents with a family history of melanoma, high fatalism was associated with lower child sunscreen use, especially when discussions were less frequent. Melanoma surviving parents' fatalistic beliefs about cancer indirectly influence their children's health behavior and are a risk factor for unsafe sun behavior. Attending to parent gender, family history, and their communications about protective behaviors as co-factors of this risk could inform future intervention targeting.

ARF6-dependent endocytic trafficking of the Interferon-γ receptor drives adaptive immune resistance in cancer.

Adaptive immune resistance (AIR) is a protective process used by cancer to escape elimination by CD8+ T cells. Inhibition of immune checkpoints PD-1 and CTLA-4 specifically target Interferon-gamma (IFNγ)-driven AIR. AIR begins at the plasma membrane where tumor cell-intrinsic cytokine signaling is initiated. Thus, plasma membrane remodeling by endomembrane trafficking could regulate AIR. Herein we report that the trafficking protein ADP-Ribosylation Factor 6 (ARF6) is critical for IFNγ-driven AIR. ARF6 prevents transport of the receptor to the lysosome, augmenting IFNγR expression, tumor intrinsic IFNγ signaling and downstream expression of immunosuppressive genes. In murine melanoma, loss of ARF6 causes resistance to immune checkpoint blockade (ICB). Likewise, low expression of ARF6 in patient tumors correlates with inferior outcomes with ICB. Our data provide new mechanistic insights into tumor immune escape, defined by ARF6-dependent AIR, and support that ARF6-dependent endomembrane trafficking of the IFNγ receptor influences outcomes of ICB.

The Family Lifestyles, Actions and Risk Education (FLARE) study: Protocol for a randomized controlled trial of a sun protection intervention for children of melanoma survivors.

BACKGROUND: Children of parents who had melanoma are more likely to develop skin cancer themselves owing to shared familial risks. The prevention of sunburns and promotion of sun-protective behaviors are essential to control cancer among these children. The Family Lifestyles, Actions and Risk Education (FLARE) intervention will be delivered as part of a randomized controlled trial to support parent-child collaboration to improve sun safety outcomes among children of melanoma survivors. METHODS: FLARE is a two-arm randomized controlled trial design that will recruit dyads comprised of a parent who is a melanoma survivor and their child (aged 8-17 years). Dyads will be randomized to receive FLARE or standard skin cancer prevention education, which both entail 3 telehealth sessions with an interventionist. FLARE is guided by Social-Cognitive and Protection Motivation theories to target child sun protection behaviors through parent and child perceived risk for melanoma, problem-solving skills, and development of a family skin protection action plan to promote positive modeling of sun protection behaviors. At multiple assessments through one-year post-baseline, parents and children complete surveys to assess frequency of reported child sunburns, child sun protection behaviors and melanin-induced surface skin color change, and potential mediators of intervention effects (e.g., parent-child modeling). CONCLUSION: The FLARE trial addresses the need for melanoma preventive interventions for children with familial risk for the disease. If efficacious, FLARE could help to mitigate familial risk for melanoma among these children by teaching practices which, if enacted, decrease sunburn occurrence and improve children's use of well-established sun protection strategies.

Electrical Impedance Dermography Differentiates Squamous Cell Carcinoma In Situ from Inflamed Seborrheic Keratoses.

There are no currently available low-cost, noninvasive methods for discerning the depth of squamous cell carcinoma (SCC) invasion or distinguishing SCC from its benign mimics, such as inflamed seborrheic keratosis (SK). We studied 35 subjects with subsequently confirmed SCC or SK. Subjects underwent electrical impedance dermography measurements at six frequencies to assess the electrical properties of the lesion. Averaged greatest intrasession reproducibility values were 0.630 for invasive SCC at 128 kHz, 0.444 for SCC in situ at 16 kHz, and 0.460 for SK at 128 kHz. Electrical impedance dermography modeling revealed significant differences between SCC and inflamed SK in normal skin (P < 0.001) and also between invasive SCC and SCC in situ (P < 0.001), invasive SCC and inflamed SK (P < 0.001), and SCC in situ and inflamed SK (P < 0.001). A diagnostic algorithm classified SCC in situ from inflamed SK with an accuracy of 0.958, a sensitivity of 94.6%, and a specificity of 96.9%; it also classified SCC in situ from normal skin with an accuracy of 0.796, a sensitivity of 90.2%, and a specificity of 51.2%. This study provides preliminary data and a methodology that can be used in future studies to further advance the value of electrical impedance dermography and inform biopsy decision making in patients with lesions suspicious of SCC.

Three pathologic criteria for reproducible diagnosis of colonic sessile serrated lesion versus hyperplastic polyp.

Colonic SSLs are thought to predispose to ∼30% of colonic adenocarcinomas. This increased risk, compared to benign HPs, makes their distinction vitally important. However, no gold standard exists to differentiate them, and wide observer variability is reported. To better distinguish these polyps, we investigated 94 serrated polyps (53 SSLs and 41 HPs) using an easy-to-apply pathologic scoring system that combines, for the first time, three established distinguishing features: polyp morphology, location, and size. As an additional novel approach, polyp size was assessed by serrated biopsy number compared to endoscopic size. RNA expression profiling served as an additional biomarker. The considerable morphologic overlap across serrated polyps was quantitated for the first time. Interobserver variability was assessed by 8 expert gastrointestinal pathologists. By ROC analysis, polyp size by biopsy number performed best, followed by polyp location and morphology (areas under the curves [AUCs] = 85.9%, 81.2%, and 65.9%, respectively). Optimal discrimination combined all 3 features (AUC = 92.9%). For polyp size, the biopsy number proved superior to endoscopic size (AUC = 85.9% versus 55.2%, P = .001). Interobserver variability analysis yielded the highest reported Fleiss and Kappa statistics (0.879) and percent agreement (96.8%), showing great promise toward improved diagnosis. The proposed 3-criteria pathologic system, combining size by biopsy number, location, and morphology, yields an improved, easy-to-use, and highly reproducible diagnostic approach for differentiating SSLs and HPs.

Feasibility of personalized circulating tumor DNA detection in stage II and III melanoma.

The objective of this study was to evaluate the feasibility of developing personalized, tumor-informed assays for patients with high-risk resectable melanoma and examine circulating tumor DNA (ctDNA) levels in relation to clinical status. Pilot prospective study of clinical stage IIB/C and resectable stage III melanoma patients. Tumor tissue was used to design bespoke somatic assays for interrogating ctDNA in patients' plasma using a multiplex PCR (mPCR) next-generation sequencing (NGS)-based approach. Plasma samples for ctDNA analysis were collected pre-/post-surgery and during surveillance. Out of 28 patients (mean 65 years, 50% male), 13 (46%) had detectable ctDNA prior to definitive surgery and 96% (27/28) tested ctDNA-negative within 4 weeks post-surgery. Pre-surgical detection of ctDNA was significantly associated with the later-stage ( P  = 0.02) and clinically evident stage III disease ( P  = 0.007). Twenty patients continue in surveillance with serial ctDNA testing every 3-6 months. With a median follow-up of 443 days, six out of 20 (30%) patients developed detectable ctDNA levels during surveillance. All six of these patients recurred with a mean time to recurrence of 280 days. Detection of ctDNA in surveillance preceded the diagnosis of clinical recurrence in three patients, was detected concurrent with clinical recurrence in two patients and followed clinical recurrence in one patient. One additional patient developed brain metastases without detection of ctDNA during surveillance but had positive pre-surgical ctDNA. Our results demonstrate the feasibility of obtaining a personalized, tumor-informed mPCR NGS-based ctDNA assay for patients with melanoma, particularly in resectable stage III disease.

Prospective Pilot Study of 18F-Fluoroestradiol PET/CT in Patients With Invasive Lobular Carcinomas.

BACKGROUND. PET/CT with 18F-fluoroestradiol (FES) (FDA-approved in 2020) depicts tissues expressing estrogen receptor (ER). Invasive lobular carcinoma (ILC) is commonly ER positive. OBJECTIVE. The primary aim of this study was to assess the frequency with which sites of histologically proven ILC have abnormal uptake on FES PET/CT. METHODS. This prospective single-center pilot study, conducted from December 2020 to August 2021, enrolled patients with histologically confirmed ILC to undergo FES PET/CT; patients optionally underwent FDG PET/CT. Two nuclear radiologists assessed FES PET/CT and FDG PET/CT studies for abnormal uptake corresponding to known ILC sites at enrollment and for additional sites of abnormal uptake, resolving differences by consensus. The primary endpoint was percentage of known ILC sites showing abnormal FES uptake. The alternative to the null hypothesis was that more than 60% of sites would have abnormal FES uptake, exceeding the percentage of ILC with abnormal FDG uptake described in prior literature. A sample size of 24 biopsied lesions was preselected to provide 81% power for the alternative hypothesis (one-sided α = .10). Findings on FES PET/CT and FDG PET/CT were summarized for additional secondary endpoints. RESULTS. The final analysis included 17 patients (mean age, 59.1 ± 13.2 years) with 25 sites of histologically confirmed ILC at enrollment (22 breast lesions, two axillary lymph nodes, one distant metastasis). FES PET/CT showed abnormal uptake in 22 of 25 (88%) lesions, sufficient to reject the null hypothesis (p = .002). Thirteen patients underwent FDG PET/CT. Four of 23 (17%) sites of histologically confirmed ILC, including additional sites detected and confirmed after enrollment, were identified with FES PET/CT only, and 1 of 23 (4%) was identified only with FDG PET/CT (p = .18). FES PET/CT depicted additional lesions not detected with standard-of-care evaluation in 4 of 17 (24%) patients (two contralateral breast cancers and two metastatic axillary lymph nodes, all with subsequent histologic confirmation). Use of FES PET/CT resulted in changes in clinical stage with respect to standard-of-care evaluation in 3 of 17 (18%) patients. CONCLUSION. The primary endpoint of the trial was met. The frequency of abnormal FES uptake among sites of histologically known ILC was found to be to be significantly greater than 60%. CLINICAL IMPACT. This pilot study shows a potential role of FES PET/CT in evaluation of patients with ILC. TRIAL REGISTRATION. ClinicalTrials.gov NCT04252859.

Multianalyte Serum Biomarker Panel for Early Detection of Pancreatic Adenocarcinoma.

PURPOSE: We determined whether a large, multianalyte panel of circulating biomarkers can improve detection of early-stage pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS: We defined a biologically relevant subspace of blood analytes on the basis of previous identification in premalignant lesions or early-stage PDAC and evaluated each in pilot studies. The 31 analytes that met minimum diagnostic accuracy were measured in serum of 837 subjects (461 healthy, 194 benign pancreatic disease, and 182 early-stage PDAC). We used machine learning to develop classification algorithms using the relationship between subjects on the basis of their changes across the predictors. Model performance was subsequently evaluated in an independent validation data set from 186 additional subjects. RESULTS: A classification model was trained on 669 subjects (358 healthy, 159 benign, and 152 early-stage PDAC). Model evaluation on a hold-out test set of 168 subjects (103 healthy, 35 benign, and 30 early-stage PDAC) yielded an area under the receiver operating characteristic curve (AUC) of 0.920 for classification of PDAC from non-PDAC (benign and healthy controls) and an AUC of 0.944 for PDAC versus healthy controls. The algorithm was then validated in 146 subsequent cases presenting with pancreatic disease (73 benign pancreatic disease and 73 early- and late-stage PDAC cases) and 40 healthy control subjects. The validation set yielded an AUC of 0.919 for classification of PDAC from non-PDAC and an AUC of 0.925 for PDAC versus healthy controls. CONCLUSION: Individually weak serum biomarkers can be combined into a strong classification algorithm to develop a blood test to identify patients who may benefit from further testing.

Phase I Trial of Combination Therapy With Avelumab and Cabozantinib in Patients With Newly Diagnosed Metastatic Clear Cell Renal Cell Carcinoma.

BACKGROUND: Combination immunotherapy is now considered the standard first-line therapy for patients with metastatic clear cell renal cell carcinoma (mccRCC) after multiple clinical trials demonstrated improved overall survival compared with single-agent tyrosine kinase inhibitors. Cabozantinib modulates critical components of the immune system, such as decreasing regulatory T cells and increasing T-effector cell populations, and is approved for the treatment of mRCC. Avelumab is a human IgG1 monoclonal antibody that binds to programmed death-ligand 1 protein and inhibits the interaction with PD-1. This phase I trial assessed the safety and clinical activity of avelumab and cabozantinib combination therapy in mccRCC. METHODS: This study was a phase I, 3+3 dose escalation clinical trial. The primary endpoint was the safety and identification of the recommended phase II dose (RP2D). Secondary endpoints included objective response rate (ORR) and radiographic progression-free survival (rPFS). There were 3 dose cohorts: cabozantinib 20, 40, and 60 mg/day, each combined with avelumab (10 mg/kg intravenously every 2 weeks). An additional 3 patients were included in the final dose cohort as a confirmation of the RP2D. No dose modifications were allowed for avelumab, but dose delays were permitted. Both dose reductions and holds were allowed for cabozantinib. Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, was used to determine ORR, and treatment beyond progression was allowed. RESULTS: Twelve patients with newly diagnosed mccRCC were enrolled from July 2018 until March 2020. Three patients were enrolled in the 20 and 40 mg cohorts each, and 6 were enrolled in the 60 mg cohort. The International Metastatic RCC Database Consortium (IMDC) risk categories for these patients were: 4 patients (favorable risk), 6 patients (intermediate risk), and 2 patients (poor risk). No dose-limiting toxicities (DLTs) were observed in any cohort. Six patients developed serious adverse events related to study treatment after the DLT window period. Immune-related adverse events (iRAEs) were reported in 11 patients; fatigue and diarrhea were the most common (each with n = 4, 33.3%), followed by maculopapular rash and hand-foot syndrome (each with n = 3, 25%). Dose reductions were required in 5 of 6 patients in the cabozantinib 60 mg cohort after the DLT period. One patient discontinued avelumab due to irAE (nephritis), while none discontinued cabozantinib due to toxicity. The ORR was 50%, with one complete response (CR) and 5 partial responses (PR). The disease control rate (CR + PR + stable disease) was noted in 92% of the patients. Radiological PFS survival rate at 6 and 12 months was reported in 67.7% and 33.5% of patients, respectively. CONCLUSION: Combination therapy with avelumab and cabozantinib is safe and showed preliminary clinical activity in mccRCC. Even though the DLT was not met in any of the 3 cohorts, the recommended RP2D dose for the combination is cabozantinib 40 mg/day due to a high incidence of grade 2 toxicity for cabozantinib 60 mg/day after the DLT period. (ClinicalTrials.gov Identifier: NCT03200587).

Improving Bone Health in Patients with Metastatic Prostate Cancer with the Use of Algorithm-Based Clinical Practice Tool.

Background: The bone health of patients with locally advanced and metastatic prostate cancer is at risk from treatment-related bone density loss and skeletal-related events from metastatic disease in bones. Evidence-based guidelines recommend using denosumab or zoledronic acid at bone metastasis-indicated dosages in the setting of castration-resistant prostate cancer with bone metastases and at the osteoporosis-indicated dosages in the hormone-sensitive setting in patients with a significant risk of fragility fracture. For the concerns of jaw osteonecrosis, a dental evaluation is recommended before starting bone-modifying agents. The literature review suggests a limited evidence-based practice for bone health with prostate cancer in the real world. Both under-treatment and inappropriate dosing of bone remodeling therapies place additional risks to bone health. An incomplete dental work up before starting bone-modifying agents increases the risk of jaw osteonecrosis. Methods: We created an algorithm-based clinical practice tool to minimize the deviation from evidence-based guidelines at our center and provide appropriate bone health care to our patients by ensuring indication-appropriate dosing and dental screening rates. This order set was incorporated into the electronic medical record system for ordering a bone remodeling agent for prostate cancer. The tool prompts the clinicians to follow the appropriate algorithm in a stepwise manner to ensure a pretreatment dental evaluation and use of the correct dosage of drugs. Results: We analyzed the data from Sept 2019 to April 2022 following the incorporation of this tool. 0/35 (0%) patients were placed on inappropriate bone modifying agent dosing, and dental health was addressed in every patient before initiating treatment. We compared the change in the practice of prescribing and noted a significant difference in the clinician's practice while prescribing denosumab/zoledronic acid before and after implementation of this tool [incorrect dosing: 24/41 vs. 0/35 (p < 0.00001)]; and an improvement in pretreatment dental checkup before and after implementation of the tool was noted to be [missed dental evaluation:12/41 vs. 0/35 (p < 0.00001)]. Conclusion: We found that incorporating an evidence-based algorithm in the order set while prescribing bone remodeling agents significantly improved our institutional clinical practice of indication-appropriate dosing and dental screening rates, and facilitated high-quality, evidence-based care to our patients with prostate cancer.

Comprehensive evaluation and efficient classification of BRCA1 RING domain missense substitutions.

BRCA1 is a high-risk susceptibility gene for breast and ovarian cancer. Pathogenic protein-truncating variants are scattered across the open reading frame, but all known missense substitutions that are pathogenic because of missense dysfunction are located in either the amino-terminal RING domain or the carboxy-terminal BRCT domain. Heterodimerization of the BRCA1 and BARD1 RING domains is a molecularly defined obligate activity. Hence, we tested every BRCA1 RING domain missense substitution that can be created by a single nucleotide change for heterodimerization with BARD1 in a mammalian two-hybrid assay. Downstream of the laboratory assay, we addressed three additional challenges: assay calibration, validation thereof, and integration of the calibrated results with other available data, such as computational evidence and patient/population observational data to achieve clinically applicable classification. Overall, we found that 15%-20% of BRCA1 RING domain missense substitutions are pathogenic. Using a Bayesian point system for data integration and variant classification, we achieved clinical classification of 89% of observed missense substitutions. Moreover, among missense substitutions not present in the human observational data used here, we find an additional 45 with concordant computational and functional assay evidence in favor of pathogenicity plus 223 with concordant evidence in favor of benignity; these are particularly likely to be classified as likely pathogenic and likely benign, respectively, once human observational data become available.

A Randomized Double-blind Placebo-controlled Trial of Oral Aspirin for Protection of Melanocytic Nevi Against UV-induced DNA Damage.

DNA damage plays a role in ultraviolet (UV)-induced melanoma. We previously showed that aspirin (ASA) can suppress prostaglandin-E2 (PGE2) and protect melanocytes from UV-induced DNA damage in mice, and suggested that taking ASA before acute sun exposure may reduce melanoma risk. We conducted a prospective randomized placebo-controlled trial to determine if orally administered ASA could suppress PGE2 in plasma and nevi and protect nevi from UV-induced DNA damage. After obtaining plasma and determining the minimal erythemal dose (MED) in 95 subjects at increased risk for melanoma, they were randomized to receive a daily dose of placebo, 81 mg ASA, or 325 mg ASA, in double-blind fashion for one month. After this intervention, one nevus was irradiated (dose = 1 or 2 MED) using a solar simulator. One day later, MED was re-determined, a second plasma sample was obtained, and the UV-irradiated nevus and an unirradiated nevus were removed. ASA metabolites were detected in the second plasma sample in subjects in the ASA arms. There were no significant differences in the pre- and post-intervention MED between those patients receiving ASA and placebo. Significantly reduced PGE2 levels were detected in plasma (second vs. first samples) and in nevi (both unirradiated and UV-treated) in subjects receiving ASA compared to placebo. Comparing UV-treated nevi from the ASA and placebo cohorts, however, did not reveal significant reductions in CD3-cell infiltration or 8-oxoguanine and cyclobutane pyrimidine dimers. Thus ASA did not effectively protect nevi from solar-simulated UV-induced inflammation and DNA damage under the conditions examined. PREVENTION RELEVANCE: Despite promising rationale, ASA at conventional dosing was not able to protect nevi against UV-induced DNA damage under the conditions examined.See related Spotlight, p. 71.

Correlation between FDG-PET uptake and survival in patients with primary brain tumors.

This study evaluates F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) semi-quantitative analysis as biomarker of tumor aggressiveness and predictor of survival in patients with primary brain tumors. Semi-quantitative analyses (SUVmax, SUVmean) were derived from FDG PET images in 78 patients with suspected recurrence of primary brain tumors based on MRI. SUVmax and the ratio of lesion SUVmax to the SUVmean of contralateral white matter (SUVmax/WM) were measured. A one-way Analysis of Variance (ANOVA), Kaplan-Meier analyses and the log rank test for evaluating statistical significance were utilized. There was statistical significance for time between FDG-PET and patient death. There was a significant difference with respect to FDG-PET time to death between patients with glioblastoma and patients with anaplastic oligodendroglioma, oligodendroglioma, and other histological subtypes. There is significant correlation with SUVmax/WM and patient survival following FDG-PET when a cut-point ratio of 1.90 is used. A 1.90 cut-point ratio of SUVmax/WM was associated with a difference in survival. GBM was associated with a significant difference in terms of reduced survival following FDG PET compared to most other histological sub-types. These results may inform current treatment and counseling strategies for patients with primary brain tumors.

A Phase 1 dose-escalation study of disulfiram and copper gluconate in patients with advanced solid tumors involving the liver using S-glutathionylation as a biomarker.

BACKGROUND: Disulfiram and metals inactivate key oncoproteins resulting in anti-neoplastic activity. The goal of this study was to determine the maximum tolerated dose of copper when administered with disulfiram in patients with advanced solid tumors and liver involvement. METHODS: Disulfiram 250 mg was administered daily in 28-day cycles. Four doses of copper gluconate were tested (2, 4, 6, and 8 mg of elemental copper) in a standard 3 + 3 dose escalation design. Patients were evaluated for dose limiting toxicities and response. Protein S-glutathionylation was evaluated as a pharmacodynamic marker. RESULTS: Twenty-one patients were enrolled and 16 patients were evaluable for dose limiting toxicities. Among the 21 patients, there was a median of 4 lines of prior chemotherapy. Five Grade 3 toxicities were observed (anorexia, elevated aspartate aminotransferase or AST, elevated alkaline phosphatase, fever, and fatigue). Response data was available for 15 patients. Four patients had stable disease with the longest duration of disease control being 116 days. The median duration of treatment for evaluable patients was 55 days (range 28-124). Reasons for discontinuation included functional decline, disease progression, and disease-associated death. Increased S-glutathionylation of serum proteins was observed with treatment. CONCLUSION: Disulfiram 250 mg daily with copper gluconate (8 mg of elemental copper) was well-tolerated in patients with solid tumors involving the liver and was not associated with dose limiting toxicities. While temporary disease stabilization was noted in some patients, no objective responses were observed. Treatment was associated with an increase in S-glutathionylation suggesting that this combination could exert a suppressive effect on cellular growth and protein function. TRIAL REGISTRATION: NCT00742911 , first posted 28/08/2008.

Aspirin Protects Melanocytes and Keratinocytes against UVB-Induced DNA Damage In Vivo.

UVR promotes skin cancer through multiple mechanisms, including induction of inflammation, oxidative stress, and DNA damage such as 8-oxoguanine and cyclobutane pyrimidine dimers. We investigated whether the anti-inflammatory activities of aspirin (acetylsalicylic acid [ASA]) could protect against UVB-induced DNA damage and skin carcinogenesis. ASA reduced UVB-induced 8-oxoguanine and cyclobutane pyrimidine dimers in Melan-A melanocytes and HaCaT keratinocytes. Skin from UVB-irradiated C57BL/6 mice receiving 0.4 mg ASA daily by gavage exhibited less inflammation, fewer sunburn cells, and reduced 8-oxoguanine lesions than skin from irradiated control animals. ASA similarly reduced UVB-induced sunburn cells, 8-oxoguanine, and cyclobutane pyrimidine dimer lesions in skin of melanoma-prone TN61R mice, and this was associated with decreased prostaglandin E2 in plasma and skin. These effects of ASA, however, did not delay melanoma onset in TN61R mice exposed to a single neonatal dose of UVB. In SKH1-E mice prone to squamous cell carcinoma, ASA reduced plasma and skin prostaglandin E2 levels and indices of UVB-induced DNA damage and delayed squamous cell carcinoma onset induced by chronic UVB. These results indicate that ASA can protect against UVB-induced inflammation in skin and reduce UVB-induced DNA damage in both melanocytes and keratinocytes. These effects translated into greater chemopreventive efficacy for UVB-induced squamous cell carcinoma than melanoma mouse models.

Low accuracy of self-reported family history of melanoma in high-risk patients.

Family history of melanoma is a major melanoma risk factor. However, self-reported family histories for some cancers, including melanoma, are commonly inaccurate. We used a unique database, the Utah Population Database (UPDB), as well as the Utah Cancer Registry to determine the accuracy of self-reported family history of melanoma in a large cohort of high-risk patients. Patient charts were reviewed and compared to records in the UPDB and the UCR to confirm personal and family history of melanoma in 1780 patients enrolled in a total body photography monitoring program. Self-reported family history of melanoma in first-degree relatives had an overall sensitivity of 71%, specificity of 79%, PPV of 31%, and NPV of 95%, with decreased accuracy (PPV) for second-degree relatives. A personal history of melanoma was the only factor significantly associated with accuracy in self-reported family history of melanoma. Patient age, sex, estimated nevus count, and number of prior personal melanomas were not significant predictors. Dermatologists should educate patients on the differences between melanomas, keratinocyte carcinomas, and pre-cancers. Confirming self-reported family history of melanoma may improve risk assessment for patients undergoing screening.

Fitting a naturally scaled point system to the ACMG/AMP variant classification guidelines.

Recently, we demonstrated that the qualitative American College of Medical Genetics and Genomics/Association for Medical Pathology (ACMG/AMP) guidelines for evaluation of Mendelian disease gene variants are fundamentally compatible with a quantitative Bayesian formulation. Here, we show that the underlying ACMG/AMP "strength of evidence categories" can be abstracted into a point system. These points are proportional to Log(odds), are additive, and produce a system that recapitulates the Bayesian formulation of the ACMG/AMP guidelines. The strengths of this system are its simplicity and that the connection between point values and odds of pathogenicity allows empirical calibration of the strength of evidence for individual data types. Weaknesses include that a narrow range of prior probabilities is locked in and that the Bayesian nature of the system is inapparent. We conclude that a points-based system has the practical attribute of user-friendliness and can be useful so long as the underlying Bayesian principles are acknowledged.

Multi-omics Analysis Reveals Adipose-tumor Crosstalk in Patients with Colorectal Cancer.

Obesity and obesity-driven cancer rates are continuing to rise worldwide. We hypothesize that adipocyte-colonocyte interactions are a key driver of obesity-associated cancers. To understand the clinical relevance of visceral adipose tissue in advancing tumor growth, we analyzed paired tumor-adjacent visceral adipose, normal mucosa, and colorectal tumor tissues as well as presurgery blood samples from patients with sporadic colorectal cancer. We report that high peroxisome proliferator-activated receptor gamma (PPARG) visceral adipose tissue expression is associated with glycoprotein VI (GPVI) signaling-the major signaling receptor for collagen-as well as fibrosis and adipogenesis pathway signaling in colorectal tumors. These associations were supported by correlations between PPARG visceral adipose tissue expression and circulating levels of plasma 4-hydroxyproline and serum intercellular adhesion molecule 1 (ICAM1), as well as gene set enrichment analysis and joint gene-metabolite pathway results integration that yielded significant enrichment of genes defining epithelial-to-mesenchymal transition-as in fibrosis and metastasis-and genes involved in glycolytic metabolism, confirmed this association. We also reveal that elevated prostaglandin-endoperoxide synthase 2 (PTGS2) colorectal tumor expression is associated with a fibrotic signature in adipose-tumor crosstalk via GPVI signaling and dendritic cell maturation in visceral adipose tissue. Systemic metabolite and biomarker profiling confirmed that high PTGS2 expression in colorectal tumors is significantly associated with higher concentrations of serum amyloid A and glycine, and lower concentrations of sphingomyelin, in patients with colorectal cancer. This multi-omics study suggests that adipose-tumor crosstalk in patients with colorectal cancer is a critical microenvironment interaction that could be therapeutically targeted.See related spotlight by Colacino et al., p. 803.

Two integrated and highly predictive functional analysis-based procedures for the classification of MSH6 variants in Lynch syndrome.

PURPOSE: Variants in the DNA mismatch repair (MMR) gene MSH6, identified in individuals suspected of Lynch syndrome, are difficult to classify owing to the low cancer penetrance of defects in that gene. This not only obfuscates personalized health care but also the development of a rapid and reliable classification procedure that does not require clinical data. METHODS: The complete in vitro MMR activity (CIMRA) assay was calibrated against clinically classified MSH6 variants and, employing Bayes' rule, integrated with computational predictions of pathogenicity. To enable the validation of this two-component classification procedure we have employed a genetic screen to generate a large set of inactivating Msh6 variants, as proxies for pathogenic variants. RESULTS: The genetic screen-derived variants established that the two-component classification procedure displays high sensitivities and specificities. Moreover, these inactivating variants enabled the direct reclassification of human variants of uncertain significance (VUS) as (likely) pathogenic. CONCLUSION: The two-component classification procedure and the genetic screens provide complementary approaches to rapidly and cost-effectively classify the large majority of human MSH6 variants. The approach followed here provides a template for the classification of variants in other disease-predisposing genes, facilitating the translation of personalized genomics into personalized health care.

Improved melanoma outcomes and survival in patients monitored by total body photography: A natural experiment.

Total body photography (TBP) facilitates early melanoma detection, but long-term outcomes have not been well studied. Our objectives were to examine melanoma diagnoses, role of TBP-associated follow-up visits, and survival in patients monitored by TBP. A total of 1955 patients meeting inclusion criteria received TBP from 2004-2013 at a single academic center. We compared the melanoma diagnoses and overall survival of 1253 patients with any follow-up visits (median, three visits; range, 1-18) and 702 patients with no follow-up visits. Use of TBP photographs influenced decision to biopsy 66 of 121 (54.5%) melanomas diagnosed after TBP. Lower invasive melanoma Breslow depth was significantly associated with having one or more follow-up visit (median, 0.83 vs 0.33 mm; P = .002) and photographic review (median, 0.31 vs 0.48 mm; P = 0.02). In multivariable analyses, greater overall survival was significantly associated with having one or more follow-up visit after TBP (hazard ratio [HR], 0.36; 95% confidence interval [CI], 0.14-0.91; P < 0.032) and having more than 100 nevi (HR, 0.37; 95% CI, 0.22-0.64; P = 0.004). Worse overall survival was significantly associated with increasing age (HR per year, 1.06; 95% CI, 1.04-1.08; P < 0.001) and male sex (HR, 2.65; 95% CI, 1.48-4.73; P = 0.001). Thus, monitoring by TBP was associated with subsequent melanoma diagnoses of lower stage and depth and greater overall survival.