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Background Obesity is a risk factor for colorectal cancer and possibly the formation of precancerous, colorectal polyps . Bariatric surgery is very effective for long-term weight loss; however, it is not known whether bariatric surgery decreases the risk of subsequent colonic neoplasia. We hypothesized that bariatric surgery would decrease the risk of developing colorectal lesions (new cancer and precancerous polyps). Methods We reviewed all patients (n = 3,676) who underwent bariatric surgery (gastric bypass, sleeve gastrectomy, or gastric banding) at the University of Virginia (Charlottesville, VA) 1985–2015. Obese, nonoperative patients (n = 46,873) from an institutional data repository were included as controls. Cases and controls were propensity score matched 1:1 by demographics, comorbidities, body mass index, and socioeconomic factors. The matched cohort was compared by univariate analysis and conditional logistic regression. Results A total of 4,462 patients (2,231 per group) with a median follow-up of 7.8 years were well-matched with no statistically significant baseline differences in initial body mass index (48 vs 49 kg/m2), sex, and age in addition to other comorbidities (all P > .05). The operative cohort had more weight loss (55.5% vs –1.4% decrease in excess body mass index, P .05). After risk adjustment, bariatric surgery was independently associated with a decrease in new colorectal lesions (OR 0.62, 95% CI 0.42–0.91, P = .016). Conclusion Bariatric surgery was associated with lesser, risk-adjusted incidence of new colorectal lesions in this large population of propensity matched patients undergoing bariatric surgery compared with a control group not undergoing bariatric surgery. These results suggest the benefits of bariatric surgery may extend beyond weight loss and mitigation of comorbidities.

The incidence of melanoma continues to increase even as advances in immunotherapy have led to survival benefits in advanced stages. Vaccines are capable of inducing strong, antitumor immune responses with limited toxicity. Some vaccines have demonstrated clinical benefit in clinical trials alone; however, others have not despite inducing strong immune responses. Recent advancements have improved vaccine design, and combining vaccines with other immunotherapies offers promise. This review highlights the underlying principles of vaccine development, common components of vaccines, and the remaining challenges and future directions of vaccine therapy in melanoma.

Melanoma brain metastasis (MBM) frequently occurs in patients with advanced melanoma, yet our understanding of the underlying salient biology is rudimentary. Here, we performed single-cell/nucleus RNA-seq in 22 treatment-naïve MBM and 10 extracranial melanoma metastases (ECM), and matched spatial single-cell transcriptomics and T cell receptor (TCR)-seq. Cancer cells from MBM were more chromosomally unstable, adopted a neuronal-like cell state, and enriched for spatially variably expressed metabolic pathways. Key observations were validated in independent patient cohorts, patient-derived MBM/ECM xenograft models, RNA/ATAC-seq, proteomics, and multiplexed imaging. Integrated spatial analyses revealed distinct geography of putative cancer immune evasion, and evidence for more abundant intra-tumoral B to plasma cell differentiation in lymphoid aggregates in MBM. MBM harbored larger fractions of monocyte-derived macrophages and dysfunctional TOX(+)CD8(+) T cells with distinct expression of immune checkpoints. This work provides comprehensive insights into MBM biology and serves as a foundational resource for further discovery and therapeutic exploration.

BACKGROUND: Identifying factors that impact progression of surgery trainees into academic versus non-academic practices may permit tailoring residency experiences to promote academic careers in institutions charged with the training of future surgeon scientists. The aim of this study was to identify factors associated with progression of surgery trainees into academic versus non-academic practice. METHODS: A survey was distributed to 135 surgeons graduating from the University of Virginia residency program from 1964–2016, a single academic institution. Questions addressed practice type, research productivity, work/life balance, mentorship, and overall sentiment toward research and academic surgery. A 5-point Likert scale measured career satisfaction and influence of factors in practice setting choice. RESULTS: Of the 135 surveys that were electronically distributed, 69 participants responded (response rate: 51%). Of the 54 with known current practice types, 34 (63%) were academic and 20 (37%) non-academic. Academic surgeons reported more publications by the conclusion of surgery training (56% vs 25% with >10 publications, P = .02). More academic surgeons reported > $100,000 in student debt at graduation (44% vs 25%, P < .05). Factors encouraging an academic career were similar for both types of surgeons, including involvement in education of trainees and access to mentorship. Both groups were discouraged from an academic practice by requirements of grant-writing and funding responsibilities. Surgeons in academic practice were more likely to recommend surgery as a career to a current medical student (100% vs 70%, P = .001). CONCLUSION: This knowledge may help to tailor training experiences to promote academic careers. By supporting funding mechanisms and grant-writing programs, while encouraging mentorship and productive research experiences, current surgical trainees may be more enthusiastic about a career in academic practice.

β-catenin (βcat) is an important downstream effector in the Wnt signaling pathway and plays important roles in the development and progression of many cancers including melanoma. βcat expression is regulated by GSK-3β-mediated phosphorylation at positions 33, 37 and 41. In normal cells, phosphorylation at these sites triggers proteasomal degradation, which prevents accumulation of free cytoplasmic βcat. In cancer cells, stabilized β-catenin translocates into the nucleus, where it associates with TCF/Lef proteins to activate transcription of genes that promote tumorigenesis and metastasis, including PD-L1. It has been suggested that nuclear phospho-βcat (pβcat) staining may be diagnostically useful in differentiating primary from metastatic melanoma. Also, a pβcat peptide (residues 30–39, with only S33 phosphorylated) is naturally presented by melanoma cells as a T-cell target. We evaluated expression of pS33-βcat in primary and metastatic melanomas by immunohistochemistry and found its expression varied widely but was most commonly cytoplasmic. Nuclear staining was identified in only 18% of metastatic melanomas. Staining with antibodies to pS33-βcat and pS33/37/T41-βcat was most intense in mitotic melanoma cells; however, pS33-βcat intensity was not significantly associated with AJCC stage, tumor location, BRAF mutation status, or immune infiltrates. Yet, PD-L1 and PD-L2 expression by tumor cells were significantly higher in tumors with high pS33-βcat expression. The low rate of nuclear pS33-βcat expression suggests that pS33-βcat may have limited utility for identifying metastatic melanomas. However, high expression in dividing cells and strong associations with PD-L1 and PD-L2 expression may inform future personalized therapies for tumors with high pS33-βcat expression.

There are compelling arguments for designing cancer vaccines specifically to induce CD4+ helper T cell responses. Recent studies highlight the crucial role of proliferating, activated effector memory Th1 CD4+ T cells in effective antitumor immunity and reveal that CD4+ T cells induce more durable immune-mediated tumor control than CD8+ T cells. CD4+ T cells promote antitumor immunity by numerous mechanisms including enhancing antigen presentation, co- stimulation, T cell homing, T cell activation, and effector function. These effects are mediated at sites of T cell priming and at the tumor microenvironment. Several cancer vaccine approaches induce durable CD4+ T cell responses and have promising clinical activity. Future work should further optimize vaccine adjuvants and combination therapies incorporating helper peptide vaccines.

Background Funding toward surgical research through the National Institutes of Health has decreased relative to other medical specialties. This study was initiated to characterize features of academically successful surgeon-scientists and departments of surgery. We hypothesized that there may be decreases in young investigators obtaining independent National Institutes of Health awards and that successful academic departments of surgery may be depending increasingly on PhD faculty. Methods The National Institutes of Health RePORTER database was queried for grants awarded to departments of surgery during fiscal years 2003 and 2013. Grant summaries were categorized by research methodology. Training of the principal investigator and academic position were determined through the RePORTER database and publicly available academic biographies. Institutions were ranked by number of grants funded. Results Between 2003 and 2013, total surgery grants awarded decreased by 19%. The number of National Institutes of Health-funded, clinically active surgeons (MDs) decreased 11%, while funded PhDs increased 9%; however, clinically active junior faculty have comprised an increasing proportion of funded MDs (from 20–38%). Shifts in research topics include an increasing proportion of investigators engaged in outcomes research. Among institutions ranking in the top 20 for surgical research in both 2003 and 2013 ( N = 15), the ratio of MDs to PhDs was 2:1 in both fiscal years. Among institutions falling out of the top 20, this ratio was less than 1:1. Conclusion There has been an expansion of outcomes-based surgical research. The most consistently successful institutions are those that actively cultivate MD researchers. Encouragingly, the number of young, independently funded surgeon-scientists in America appears to be increasing.

Background In recent years, investigators have asserted that the 3 + 3 design lacks flexibility, making its use in modern early-phase trial settings, such as combinations and/or biological agents, inefficient. More innovative approaches are required to address contemporary research questions, such as those posed in trials involving immunotherapies. Design We describe the implementation of an adaptive design for identifying an optimal treatment regimen, defined by low toxicity and high immune response, in an early-phase trial of a melanoma helper peptide vaccine plus novel adjuvant combinations. Results Operating characteristics demonstrate the ability of the method to effectively recommend optimal regimens in a high percentage of trials with reasonable sample sizes. Conclusions The proposed design is a practical, early-phase, adaptive method for use with combined immunotherapy regimens. This design can be applied more broadly to early-phase combination studies, as it was used in an ongoing study of two small molecule inhibitors in relapsed/refractory mantle cell lymphoma.

SUMMARY: We analyze the transcriptome of baseline and on-therapy tumor biopsies from 101 patients with advanced melanoma treated with nivolumab (anti-PD-1) alone or combined with ipilimumab (anti-CTLA-4). We find that T cell infiltration and interferon-γ (IFNγ) signaling signatures correspond most highly with clinical response to therapy, with a reciprocal decrease in cell cycle and WNT signaling pathways in responding biopsies. We model the interaction in 58 human cell lines, where IFNγ in vitro exposure leads to a conserved transcriptome response unless cells have IFNγ receptor alterations. This conserved IFNγ transcriptome response in melanoma cells serves to amplify the antitumor immune response. Therefore, the magnitude of the antitumor T cell response and the corresponding downstream IFNγ signaling are the main drivers of clinical response or resistance to immune checkpoint blockade therapy. ETOC BLURB: Analyzing the transcriptome of biopsies of patients during immune checkpoint blockade therapy, Grasso et al. show that the increase of T cell infiltration and the downstream IFNγ signaling drive clinical responses.

Cancer vaccines offer a low-toxicity approach to induce anticancer immune responses. They have shown promise for clinical benefit with one cancer vaccine approved in the United States for advanced prostate cancer. As other immune therapies are now clearly effective for treatment of advanced cancers of many histologies, there is renewed enthusiasm for optimizing cancer vaccines for use to prevent recurrence in early-stage cancers and/or to combine with other immune therapies for therapy of advanced cancers. Future advancements in vaccine therapy will involve the identification and selection of effective antigen formulations, optimization of adjuvants, dendritic cell (DC) activation, and combination therapies. In this summary we present the current practice, the broad collection of challenges, and the promising future directions of vaccine therapy for cancer.

Differentiating melanoma metastasis from benign cutaneous lesions currently requires biopsy or costly imaging, such as positron emission tomography scans. Melanoma metastases have been observed to be subjectively warmer than similarly appearing benign lesions. We hypothesized that infrared (IR) thermography would be sensitive and specific in differentiating palpable melanoma metastases from benign lesions.Seventy-four patients (36 females and 38 males) had 251 palpable lesions imaged for this pilot study. Diagnosis was determined using pathologic confirmation or clinical diagnosis. Lesions were divided into size strata for analysis: 0-5,5-15,15-30, and30 mm. Images were scored on a scale from -1 (colder than the surrounding tissue) to +3 (significantly hotter than the surrounding tissue). Sensitivity and specificity were calculated for each stratum. Logistical challenges were scored.IR imaging was able to determine the malignancy of small (0-5 mm) lesions with a sensitivity of 39% and specificity of 100%. For lesions5-15 mm, sensitivity was 58% and specificity 98%. For lesions15-30 mm, sensitivity was 95% and specificity 100%, and for lesions30 mm, sensitivity was 78% and specificity 89%. The positive predictive value was 88%-100% across all strata, and the negative predictive value was 95% for15-30 mm lesions and 80% for30 mm lesions.Malignant lesions15 mm were differentiated from benign lesions with excellent sensitivity and specificity. IR imaging was well tolerated and feasible in a clinic setting. This pilot study shows promise in the use of thermography for the diagnosis of malignant melanoma with further potential as a noninvasive tool to follow tumor responses to systemic therapies.

Objective To develop a research productivity scoring program within an academic department of surgery that would help realign incentives to encourage and reward research. Although research is highly valued in the academic mission, financial incentives are generally aligned to reward clinical productivity. Methods A formula assigning points for publications and extramural grants was created and used to award a research incentive payment proportional to the research productivity score, beginning July 2007. Publication points reflect journal impact factor, author role, and manuscript type. Grant points reflect total funding and percentage of effort. Publication data were gathered from Web of Science/PubMed/Medline and grants data from the departmental grants office. An annual award is presented to the person with the greatest improvement. The research productivity score data after July 2007 were compared with control data for the 2 preceding years. A 33-question survey to 28 clinical faculty was conducted after the first year to measure satisfaction and solicit constructive feedback. Results The mean annual point scores increased from the preresearch productivity score to the postresearch productivity score academic years (2180 vs 3389, respectively, P = .08), with a significant change in the grant component score (272 vs 801, P = .03). Since research productivity score implementation, the operative case volumes increased 4.3% from 2006 to 2011. With a response rate of 89%, the survey indicated that 76% of the faculty wished to devote more time to research and 52% believed 1 or more research-related behaviors would change because of the research productivity score program. Conclusions An objective, transparent research incentive program, through both monetary incentives and recognition, can stimulate productivity and was well-received by faculty.

The mechanisms by which immune checkpoint blockade modulates tumor evolution during therapy are unclear. We assessed genomic changes in tumors from 68 patients with advanced melanoma, who progressed on ipilimumab or were ipilimumab-naive, before and after nivolumab initiation (CA209-038 study). Tumors were analyzed by whole-exome, transcriptome, and/or T cell receptor (TCR) sequencing. In responding patients, mutation and neoantigen load were reduced from baseline, and analysis of intratumoral heterogeneity during therapy demonstrated differential clonal evolution within tumors and putative selection against neoantigenic mutations on-therapy. Transcriptome analyses before and during nivolumab therapy revealed increases in distinct immune cell subsets, activation of specific transcriptional networks, and upregulation of immune checkpoint genes that were more pronounced in patients with response. Temporal changes in intratumoral TCR repertoire revealed expansion of T cell clones in the setting of neoantigen loss. Comprehensive genomic profiling data in this study provide insight into nivolumab's mechanism of action.

Melanoma progresses as a multistep process where the thickness of the lesion and depth of tumor invasion are the best prognostic indicators of clinical outcome. Degradation of the interstitial collagens in the extracellular matrix is an integral component of tumor invasion and metastasis, and much of this degradation is mediated by collagenase-1 (MMP-1), a member of the matrix metalloproteinase (MMP) family. MMP-1 levels increase during melanoma progression where they are associated with shorter disease-free survival. The Ras/Raf/MEK/ERK mitogen-activated protein kinase (MAPK) pathway is a major regulator of melanoma cell proliferation. Recently, BRAF has been identified as a common site of activating mutations, and, although many reports focus on its growth-promoting effects, this pathway has also been implicated in progression toward metastatic disease. In this study, we describe four melanoma cell lines that produce high levels of MMP-1 constitutively. In each cell line the Ras/Raf/MEK/ERK pathway is constitutively active and is the dominant pathway driving the production of MMP-1. Activation of this pathway arises due to either an activating mutation in BRAF (three cell lines) or autocrine fibroblast growth factor signaling (one cell line). Furthermore, blocking MEK/ERK activity inhibits melanoma cell proliferation and abrogates collagen degradation, thus decreasing their metastatic potential. Importantly, this inhibition of invasive behavior can occur in the absence of any detectable changes in cell proliferation and survival. Thus, constitutive activation of this MAPK pathway not only promotes the increased proliferation of melanoma cells but is also important for the acquisition of an invasive phenotype.

A recent article by Riviere et al. calls for more frequent practical implementation of innovative and efficient approaches in early-phase drug-combination studies. This letter describes our experience in using a novel combination method, one that is overlooked by Riviere et al., in several FDA-approved, ongoing studies at multiple institutions.

Adoptive immunotherapy with tumor-specific cytotoxic T lymphocytes (CTLs) can induce tumor regressions in animals and in human cancer patients. Antigens recognized by CTLs from cancer patients are being sought as possible immunogens, a number of which have been identified during the past year. The ultimate result may be the development of novel peptide-based immunotherapies and a new understanding of the T-cell response to human cancer.