Inducing trained immunity in pro-metastatic macrophages to control tumor metastasis.

Metastasis is the leading cause of cancer-related deaths and myeloid cells are critical in the metastatic microenvironment. Here, we explore the implications of reprogramming pre-metastatic niche myeloid cells by inducing trained immunity with whole beta-glucan particle (WGP). WGP-trained macrophages had increased responsiveness not only to lipopolysaccharide but also to tumor-derived factors. WGP in vivo treatment led to a trained immunity phenotype in lung interstitial macrophages, resulting in inhibition of tumor metastasis and survival prolongation in multiple mouse models of metastasis. WGP-induced trained immunity is mediated by the metabolite sphingosine-1-phosphate. Adoptive transfer of WGP-trained bone marrow-derived macrophages reduced tumor lung metastasis. Blockade of sphingosine-1-phosphate synthesis and mitochondrial fission abrogated WGP-induced trained immunity and its inhibition of lung metastases. WGP also induced trained immunity in human monocytes, resulting in antitumor activity. Our study identifies the metabolic sphingolipid-mitochondrial fission pathway for WGP-induced trained immunity and control over metastasis.

Melanoma Deaths by Thickness: Most Melanoma Deaths Are Not Attributable to Thin Melanomas.

INTRODUCTION: Previous population-based studies have reported that the majority of melanoma mortality is related to patients with thin (≤1 mm Breslow thickness) melanomas. The aim of the present study was to evaluate the relative proportion of melanoma-specific deaths across all stages of melanoma at diagnosis over the past 20 y in the United States. METHODS: A review of all cutaneous melanoma cases in the US Surveillance, Epidemiology, and End Results registry from 2004 to 2020 was performed. Breslow thickness was categorized as thin (≤1.0 mm), intermediate (>1-4 mm), or thick (>4 mm). All-cause deaths and melanoma-specific deaths were compared across tumor thickness and stage groups at diagnosis. Survival analysis was performed with nonmelanoma deaths considered as a competing risk to estimate the cumulative incidence of melanoma-specific death. RESULTS: Most melanoma deaths occurred in patients who initially presented with local disease (53%) compared to regional (36%) or distant (11%) disease (P < 0.001). However, most (66%) of the melanoma-specific deaths in patients who presented with localized disease were in those with intermediate or thick (i.e., Breslow thickness >1.0 mm) primary tumors compared to those with thin melanomas (34%). The cumulative incidence of melanoma-specific death at 10 y in patients with localized thin melanomas at the time of diagnosis was 2.6% (95% confidence intervals 2.5%-2.7%). CONCLUSIONS: The public health burden in terms of melanoma-specific mortality is related to patients with tumors >1 mm Breslow thickness, many of whom have regional and distant metastatic disease at the time of diagnosis, not patients with thin melanomas.

Interval Sentinel Lymph Nodes With the Use of Routine Lymphoscintigraphy in Extremity Melanoma.

INTRODUCTION: Lymphoscintigraphy (LS) helps identify drainage to interval (epitrochlear or popliteal) lymph node basins for extremity melanomas. This study evaluated how often routine LS evaluation identified an interval sentinel lymph node (SLN) and how often that node was found to have metastasis. METHODS: A single institution, retrospective study identified patients with an extremity melanoma who underwent routine LS and SLN biopsy over a 25-y period. Comparisons of factors associated with the identification of interval node drainage and tumor status were made. RESULTS: In 634 patients reviewed, 5.7% of patients drained to an interval SLN. Of those biopsied, 29.2% were positive for micrometastases. Among patients with biopsies of both the traditional and interval nodal basins, nearly 20% had positive interval nodes with negative SLNs in the traditional basin. Sex, age, thickness, ulceration, and the presence of mitotic figures were not predictive of identifying an interval node on LS, nor for having disease in an interval node. Anatomic location of the primary melanoma was the only identifiable risk factor, as no interval nodes were identified in melanomas of the thigh or upper arm (P ≤ 0.001). CONCLUSIONS: Distal extremity melanomas have a moderate risk of mapping to an interval SLN. Routine LS should be considered in these patients, especially as these may be the only tumor-positive nodes. However, primary extremity melanomas proximal to the epitrochlear or popliteal nodal basins do not map to interval nodes, and improved savings and workflow could be realized by selectively omitting routine LS in such patients.

Barriers to resection following neoadjuvant chemotherapy for resectable pancreatic adenocarcinoma: A national and local perspective.

BACKGROUND: Neoadjuvant chemotherapy (NAC) use for pancreatic ductal adenocarcinoma (PDAC) has increased, but some patients never get resection following NAC. METHODS: Data from January 2012 to December 2019 for all clinically resectable patients across two health networks were utilized, as well as data from the ACS NCDB registry. Univariate testing, multivariable logistic regression, and survival analyses were employed to evaluate failure to resection after neo-adjuvant chemotherapy. RESULTS: Of the 10 007 registry patients eligible for resection, the resected group was younger (64.6 vs. 69.5 years; p < 0.001) and had a slightly lower mean comorbidity index (0.41 vs. 0.45; p < 0.001) than the nonsurgical group. The nonsurgical group was composed of a higher percentage of Black and Hispanic patients (17.5 vs. 13.1%; p < 0.001). After adjusting for age and comorbidities, the factors associated with decreased probability of resection after NAC were evaluation at a community hospital (OR 2.4), Black or Hispanic race (OR 1.6), areas of increased high school drop-out rates (OR 1.4), and lack of private health insurance (OR 1.3). The median overall survival for nonsurgery was markedly worse than the surgical cohort (10.6 vs. 26.6 months; p < 0.001). The most frequent reasons for a lack of definitive resection were operative upstaging to unresectable (39.6%), patient preference (14.5%), progression on NAC (13.2%), deconditioning or comorbidity severity (12.5%), and nonreferral to a surgeon (8.8%). CONCLUSIONS: Racial, economic, and educational disparities have a considerable influence on the successful completion of a neoadjuvant approach for resectable PDAC. A comprehensive closed or highly collaborative/communicative multidisciplinary neoadjuvant program is optimal for treatment success and completion.

Combined pre-operative risk score predicts pancreatic leak after pancreatic resection.

BACKGROUND: Post-operative pancreatic fistula (POPF) is a major complication following pancreatectomy and is currently difficult to predict pre-operatively. This study aims to validate pre-operative risk factors and develop a novel combined score for the prediction of POPF in the pre-operative setting. METHODS: Data were collected from 2016 to 2021 for radiologic main pancreatic duct diameter (MPD), body mass index (BMI), physical status classified by American Society of Anesthesiologists (ASA), polypharmacy, mean platelet ratio (MPR), comorbidity-polypharmacy score (CPS), and a novel Combined Pancreatic Leak Prediction Score (CPLPS) (derived from MPD diameter, BMI, and CPS) were obtained from pre-operative data and analyzed for their independent association with POPF occurrence. RESULTS: In total, 166 patients who underwent pancreatectomy with pancreatic leak (Grade A, B, and C) occurring in 51(30.7%) of patients. Pre-operative radiologic MPD diameter < 4 mm (p < 0.001), < 5 mm (p < 0.001), < 6 mm (p = 0.001), BMI ≥ 25 (p = 0.009), and ≥ 30 (p = 0.017) were independently associated with the occurrence of pancreatic leak. CPLPS was also predictive of pancreatic leak following pancreatectomy on univariate (p = 0.005) and multivariate analysis (p = 0.036). CONCLUSION: MPD and BMI were independent risk factors predictive for the development of pancreatic leak. CPLPS, was an independent predictor of pancreatic leak following pancreatectomy and could be used to help guide surgical decision making and patient counseling.

Does Stage Migration Occur as a Consequence of Omitting Completion Lymph Node Dissection for Melanoma?

INTRODUCTION: Completion lymph node dissection (CLND) is no longer recommended routinely in the treatment of melanoma. CLND omission may understage patients for whom the distinction between stage IIIA and IIIB-C could alter adjuvant therapy recommendations. The aim of this study is to determine if stage migration has occurred with the declining use of CLND. METHODS: Patients with clinically node-negative ≥ T1b cutaneous melanoma were identified from the National Cancer Database (NCDB) from 2012 to 2018. CLND utilization and changes in AJCC staging were analyzed. Patients undergoing sentinel lymph node biopsy (SLNB) alone were compared with those undergoing SLNB + CLND. RESULTS: Overall, 68,933 patients met inclusion criteria and 60,536 underwent SLNB, of which 9031 (14.9%) were tumor positive. CLND was performed in 3776 (41.8%). Patients undergoing CLND were younger (58 versus 62 years, p < 0.0001) and more likely male (61.5% versus 57.9%, p = 0.0005). Patients were more likely to have an N classification >N1a if they received SLNB + CLND (36.8%) versus SLNB alone (19.3%), p < 0.0001. This translated to a small difference in stage IIIA patients between groups (SLNB alone 34.0%, SLNB + CLND 31.8%, p < 0.0001). Of the patients with T1b/T2a tumors who would be upstaged from IIIA to IIIC with identification of additional positive nodes, IIIC incidence was only slightly higher after SLNB + CLND compared with SLNB alone (4.4% versus 1.1%, p < 0.0001). CLND utilization dramatically decreased from 59% in 2012 to 12.6% in 2018, p < 0.0001. However, the incidence of stage IIIA disease for all patients remained stable over the 7-year study period. CONCLUSIONS: While the utilization of CLND after positive SLNB has declined dramatically in the last 7 years, stage migration that may affect adjuvant therapy decisions has not occurred to a clinically meaningful degree.

Preventing Futile Liver Resection: A Risk-Based Approach to Surgical Selection in Major Hepatectomy for Colorectal Cancer.

BACKGROUND: Early recurrence following liver resection for metastatic colorectal cancer generally portends poor survival. We sought to identify factors associated with early disease recurrence after major hepatectomy for metastatic colorectal cancer in order to improve patient selection and prevent futile hepatectomy. METHODS: Sequential major (four or more segments) liver resections performed for metastatic colorectal cancer between 1995 and 2019 were selected from our prospectively maintained database. Univariate analyses, multivariable regression modelling, and survival analyses were used to identify predictors of futile resection (recurrence within 6 months of hepatectomy). RESULTS: Of 259 patients included, the median age was 61.3 years (interquartile range [IQR] 15.3) and the median number of liver tumors was 3.0 (IQR 2.0); 78.0% of patients received prehepatectomy chemotherapy. Surgeries were right (56.4%), left (19.3%), and extended hepatectomy (24.3%). Futile resection occurred in 26 (12.6%) patients. Margin positivity was similar in the futile resection group compared with the non-futile resection group (11.5% vs. 11.4%). Extrahepatic disease that disappeared with chemotherapy was present in 23.1% of patients with a futile resection and 7.2% of those without (p = 0.019). After multivariable regression, the factors predictive of futile resection were extrahepatic disease (odds ratio [OR] 5.6; p = 0.004), more than three liver lesions (OR 4.9; p = 0.001), and extended hepatectomy (OR 2.6; p = 0.038). Notably, 70.8% of futile recurrences occurred within the liver remnant and 20.8% were pulmonary metastases. Overall survival was 11.7 months (95% confidence interval [CI] 7.1-16.2) for the futile resection cohort versus 45.6 (95% CI 39.1-52.1) for non-futile hepatectomies (p < 0.001). CONCLUSIONS: Futile hepatic resection can be predicted based on preoperative factors and carries a poor prognosis. Improved risk stratification for futility will aid in patient selection and treatment discussions.

Drug-Eluting Bead, Irinotecan Therapy of Unresectable Intrahepatic Cholangiocarcinoma (DELTIC) with Concomitant Systemic Gemcitabine and Cisplatin.

BACKGROUND: Unresectable intrahepatic cholangiocarcinoma (ICC) carries a poor prognosis, and currently there are moderately established chemotherapeutic [gemcitabine/cisplatin (Gem/Cis)] treatments to prolong survival. The purpose of this study was to assess the efficacy of irinotecan drug-eluting beads (DEBIRI) therapy by transarterial infusion in combination with systemic therapy in unresectable ICC. PATIENTS AND METHODS: This is a prospective, multicenter, open-label, randomized phase II study (Clin Trials: NCT01648023-DELTIC trial) of patients with ICC randomly assigned to Gem/Cis with DEBIRI or Gem/Cis alone. The primary endpoint was response rate. RESULTS: The intention-to-treat population comprised 48 patients: 24 treated with Gem/Cis and DEBIRI and 22 with Gem/Cis alone (2 screen failures). The two groups were similar with respect to the extent of liver involvement (35% versus 38%) and presence of extrahepatic disease (29% versus 14%, p = 0.12). Median numbers of chemotherapy cycles were similar (6 versus 6), as were rates of grade 3/4 adverse events (34% for the Gem/Cis-DEBIRI group versus 36% for the Gem/Cis group). The overall response rate was significantly greater in the Gem/Cis-DEBIRI arm versus the Gem/Cis arm at 2 (p < 0.04), 4 (p < 0.03), and 6 months (p < 0.05). There was significantly more downsizing to resection/ablation in the Gem/Cis-DEBIRI arm versus the Gem/Cis arm (25% versus 8%, p < 005), and there was improved median progression-free survival [31.9 (95% CI 8.5-75.3) months versus 10.1 (95% CI 5.3-13.5) months, p = 0.028] and improved overall survival [33.7 (95% CI 13.5-54.5) months versus 12.6 (95% CI 8.7-33.4) months, p = 0.048]. CONCLUSION: Combination Gem/Cis with DEBIRI is safe, and leads to significant improvement in downsizing to resection, improved progression-free survival, and overall survival.

Locally advanced pancreatic cancer: a reliable contraindication to resection in the modern era?

BACKGROUND: The aim of this study is to present radiologically designated LAPC found to be resectable upon surgical exploration and evaluate the outcomes of such resections. METHODS: Sequential LAPC patients between 2013 and 2019 were staged and underwent resection were included in the analysis of both perioperative and long-term outcomes. RESULTS: Twenty-eight patients with radiologically-designated LAPC underwent surgical resection after chemotherapy with a median follow-up of 31.7 m,75% underwent pancreaticoduodenectomy. The margin positivity and local recurrence rates were 21.4% and 35.7%, respectively. When compared to the 30 BRPC controls, the LAPC group had a higher rates of an arterial resection (11vs.1; p = 0.002), but the groups were similar with regard to all other preoperative and intraoperative variables (p < 0.05). Perioperative morbidity rates were similar (25.9%vs21.4%; p = 0.53). The LAPC and BRPC groups were also equivalent with respect to median recurrence-free survival (9.0mo; 95%CI 6.3, 11.7vs.8.3mo; 95%CI 5.4, 11.2) and median overall survival (19.9mo; 95%CI 17.0, 22.7 vs. 19.9mo; 95%CI 14.8, 25.1), respectively. CONCLUSION: Despite a radiologic designation of locally advanced pancreatic cancer, certain subtypes of LAPC warrant surgical exploration provided the operative surgeon is prepared for major arterial and/or venous resection. Pancreatectomy in these patients has acceptable morbidity and oncologic outcomes, similar to patients who are radiologically borderline resectable.

An Improved Staging System for Locally Advanced Pancreatic Cancer: A Critical Need in the Multidisciplinary Era.

BACKGROUND: Locally-advanced pancreatic cancer (LAPC) is traditionally considered stage III unresectable disease. Advances in induction systemic therapy regimens, surgical technique, and perioperative care have led to successful resection of an increasing number of these tumors with reasonable perioperative outcomes and disease-free intervals. Certain anatomic characteristics that meet criteria for locally-advanced disease, however, are more likely to result in a successful surgical outcome. METHODS: A practical and consistent system is needed to communicate such nuance between surgical and nonsurgical oncologists for optimal treatment planning and to improve recording for cancer registries and research studies. RESULTS: The present study proposes a novel subclassification system for stage III pancreatic cancers based on their pattern of vascular involvement and examines the current evidence for resection in each scenario. Introducing needed detail into the current catch-all stage III categorization will help to direct patient referrals and increase the body of knowledge about the variable presentations of this complex malignancy. CONCLUSION: This proposed staging revision for LAPC is designed to convey more actionable tumor descriptions for treating oncologists, clinical trial eligibility, and surgical patient selection in the era of effective induction systemic therapy.

Effect of the Ductal Carcinoma In Situ Margin Consensus Guideline Implementation on Re-Excision Rates, Satisfaction, and Cost.

INTRODUCTION: The 2016 consensus guideline on margins for breast-conserving surgery (BCS) with whole-breast irradiation (WBI) for ductal carcinoma in situ (DCIS) recommended 2 mm margins to decrease local recurrence rates. We examined re-excision rates, cost, and patient satisfaction before and after guideline implementation. METHODS: From an Institutional Review Board-approved database, patients with DCIS who underwent BCS with over 1 year of follow-up at one academic institution and one community cancer center were evaluated. Two groups were compared based on when they received treatment, i.e. before (pre-consensus [PRE]) and after November 2016 (post consensus [POST]), with respect to outcome and cost parameters. RESULTS: After consensus guideline implementation, re-excision rate (32.1% vs. 20.0%) and mastectomy conversion (8.3% vs. 2.3%) significantly increased, although total resection volume, operative cost per patient, and satisfaction with breast scores did not differ. Not all patients with <2 mm margins were re-excised, although the re-excision rate among this subset significantly increased (62.4% vs. 31.3%). On multivariable analysis controlling for age, estrogen receptor status, WBI use, and margin status, surgery after consensus guideline publication was independently associated with a higher re-excision rate (odds ratio [OR] 1.97, 95% confidence interval [CI] 1.08-3.59, p = 0.03) and a higher rate of conversion to mastectomy (OR 6.84, 95% CI 1.67-28.00, p = 0.007). CONCLUSIONS: Implementation of the 2016 margin consensus guideline for DCIS resulted in an increase in re-excisions and mastectomy conversions at two institutions. Research is needed for operative tools and strategies to decrease DCIS re-excision rates.

A Phase II Trial of Once Weekly Hypofractionated Breast Irradiation for Early Stage Breast Cancer.

PURPOSE: To report an interim analysis of a phase II trial of once weekly, hypofractionated breast irradiation (WH-WBI) following breast conserving surgery (BCS). METHODS: Patients had stage 0-II breast cancer treated with breast BCS with negative margins. WH-WBI was 28.5 or 30Gy delivered to the whole breast using tangential beams with no elective coverage of lymph nodes. The primary endpoint was ipsilateral breast tumor recurrence (IBTR). Secondary endpoints were distant disease-free survival (DDFS), recurrence free survival (RFS), overall survival (OS), adverse events and cosmesis. RESULTS: From 2011 to 2015, 158 patients received WH-WBI. Median follow up was 4.4 years (range 0.2-8.1). Stage distribution was DCIS 22%; invasive pN0 68%; invasive pN1 10%. 80 patients received 30 Gy and 78 received 28.5 Gy with median follow up times of 5.6 and 3.7 years, respectively. There were 5 IBTR events, all in the 30 Gy group. The 5- and 7- year risks of IBRT for all patients were 2.2% (95% CI 0.6-5.8) and 6.0% (95% CI 1.1-17.2), respectively. The 7-year rates of DDFS, RFS, and OS were 96.3%, 91.5% and 89.8%, respectively. Improvement in IBTR-free time was seen in DCIS, lobular histology, low grade tumors, Her2 negative tumors and 28.5 Gy dose (all p < 0.0001). CONCLUSIONS: Disease-specific outcomes after WH-WBI are favorable and parallel those seen with conventional radiation techniques for stage 0-II breast cancer.

Predictors of Nonsentinel Lymph Node Metastasis in Cutaneous Melanoma: A Systematic Review and Meta-Analysis.

BACKGROUND: Although completion lymph node dissection (CLND) is not routinely performed for a positive sentinel lymph node (SLN) anymore, adjuvant therapy depends on the risk factors available from SLN biopsy, including the risk of nonsentinel node metastases (NSNM). A systematic review and meta-analysis was performed in an attempt to identify risk factors that could be used to predict the risk of NSNM. MATERIALS AND METHODS: Medline, Web of Science, Embase, and Cochrane were searched for articles discussing predictive factors for NSNM. PRISMA guidelines were followed, and RevMan software was used to calculate pooled odds ratios (OR) using the Mantel-Haenszel test. RESULTS: Fifty publications were suitable for additional analysis. The clinical and primary tumor factors that were consistently identified as risk factors for NSNMs were: age >50, T stage 3 or 4, Clark level IV/V, ulceration, microsatellitosis, lymphovascular invasion, nodular histology, and extremity versus trunk primary tumor location. SLN factors that predicted NSNMs were >1 positive SLN, SLN micrometastatic tumor burden, diameter >2 mm, extracapsular extension, nonsubcapsular location (Dewar), and Rotterdam > 1 mm or ≥ 0.1 mm. CONCLUSIONS: The findings in this study support that many clinical and pathologic risk factors that can be assessed with SLN biopsy alone can be used to predict the risk of NSNMs. The factors identified in this review should be evaluated in clinical prediction models to predict the risk of NSNMS, a prediction that may be used to select patients for adjuvant therapy in high-risk melanoma.

Evaluating the effect of neoadjuvant chemotherapy on surgical outcomes after breast conserving surgery.

BACKGROUND: Neoadjuvant chemotherapy (NAC) increases breast-conserving surgery (BCS) rates with comparable locoregional control and survival outcomes to adjuvant therapy. More women are receiving NAC and achieving pathologic complete responses (pCR). This study sought to evaluate the effect of NAC on surgical outcomes after the adoption of a "no-ink-on-tumor" margin policy in patients undergoing primary BCS (PBSC). METHODS: An IRB approved database was queried for women undergoing BCS for invasive breast cancer after March 2014. We compared patients who underwent NAC followed by BCS versus PBCS. Demographic, tumor, treatment, and outcome variables were compared using both univariate and multivariable analysis. RESULTS: A total of 162 patients were evaluated. NAC patients had significantly lower re-excision rates (0% NAC vs. 9% PBCS, p = .03), margin positivity (0% NAC vs. 5% PBCS, p = .01), and greater patient satisfaction with breast cosmesis (97 NAC vs. 77 PBCS, p = .01). On multivariable analysis, NAC was not an independent predictor of lower final resection volume, total complications, or greater satisfaction with breasts when controlling for age and T category at diagnosis. CONCLUSION: NAC followed by BCS may offer less margin positivity, lower re-excision rates, and greater patient satisfaction when compared to a contemporary PBCS cohort in the "no-ink-on-tumor" era.

Comparative gene expression analysis in melanocytes driven by tumor cell-derived exosomes.

Abundant with organelle-like membranous structures, the tumor microenvironment is composed of cancer cells that secrete exosomes. Studies have shown that these secreted exosomes transport RNA and active molecules to other cells to reshape the tumor microenvironment and promote tumor growth. In fact, we found that exosomes derived from melanoma cells drive pre-malignant transition in primary melanocytes. However, there is little available in the scientific literature on how exosomes modulate melanocytes in the microenvironment to optimize conditions for tumor progression and metastasis. We therefore focused this current study on identifying these conditions genetically. Through RNA sequencing, we analyzed gene expression levels of melanocytes driven by exosomes derived from melanoma and lung cancer cells compared with those without exosome controls. Significant differences were found in gene expression patterns of melanocytes driven by exosomes derived from melanoma and lung cancer cells. In the melanocytes responding to exosomes derived from melanoma cells, genes of lipopolysaccharide and regulation of leukocyte chemotaxis were predominant. In the melanocytes responding to exosomes derived from lung cancer cells, genes of DNA replication and mitotic nuclear division played an important role. These results provide further mechanistic understanding of tumor progression promoted by tumor-derived exosomes. This will also help identify potential therapeutic targets for melanoma progression.

A literature-based treatment algorithm for low-grade neuroendocrine liver metastases.

BACKGROUND: The optimal timing of treatment of liver metastases from low-grade neuroendocrine tumors (LG-NELM) varies significantly due to numerous treatment modalities and the literature supporting various treatment(s). This study sought to create and validate a literature-based treatment algorithm for LG-NELM. METHODS: A treatment algorithm to maximize overall survival (OS) was designed using peer-reviewed articles evaluating treatment of LG-NELM. This algorithm was retrospectively applied to patients treated for LG-NELM at our institution. Deviation was determined based on whether or not a patient received treatment consistent with that recommended by the algorithm. Patients who did and did not deviate from the algorithm were compared with respect to OS and number of treatments. RESULTS: Applying our algorithm to a 149-patient cohort, 57 (38%) deviated from recommended treatment. Deviation occurred in the form of alternative (28, 49%) versus additional procedures (29, 51%). Algorithm deviators underwent significantly more procedures than non-deviators (median 1 vs. 2, p < 0.001). Cox model indicated no difference in OS associated with algorithm deviation (HR 1.19, p = 0.58) when controlling for age and tumor characteristics. CONCLUSION: This literature-based algorithm helps standardize treatment protocols in patients with LG-NELM and can reduce cost and risk by minimizing unnecessary procedures. Prospective implementation and validation is required.

Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma.

BACKGROUND: Sentinel-lymph-node biopsy is associated with increased melanoma-specific survival (i.e., survival until death from melanoma) among patients with node-positive intermediate-thickness melanomas (1.2 to 3.5 mm). The value of completion lymph-node dissection for patients with sentinel-node metastases is not clear. METHODS: In an international trial, we randomly assigned patients with sentinel-node metastases detected by means of standard pathological assessment or a multimarker molecular assay to immediate completion lymph-node dissection (dissection group) or nodal observation with ultrasonography (observation group). The primary end point was melanoma-specific survival. Secondary end points included disease-free survival and the cumulative rate of nonsentinel-node metastasis. RESULTS: Immediate completion lymph-node dissection was not associated with increased melanoma-specific survival among 1934 patients with data that could be evaluated in an intention-to-treat analysis or among 1755 patients in the per-protocol analysis. In the per-protocol analysis, the mean (±SE) 3-year rate of melanoma-specific survival was similar in the dissection group and the observation group (86±1.3% and 86±1.2%, respectively; P=0.42 by the log-rank test) at a median follow-up of 43 months. The rate of disease-free survival was slightly higher in the dissection group than in the observation group (68±1.7% and 63±1.7%, respectively; P=0.05 by the log-rank test) at 3 years, based on an increased rate of disease control in the regional nodes at 3 years (92±1.0% vs. 77±1.5%; P<0.001 by the log-rank test); these results must be interpreted with caution. Nonsentinel-node metastases, identified in 11.5% of the patients in the dissection group, were a strong, independent prognostic factor for recurrence (hazard ratio, 1.78; P=0.005). Lymphedema was observed in 24.1% of the patients in the dissection group and in 6.3% of those in the observation group. CONCLUSIONS: Immediate completion lymph-node dissection increased the rate of regional disease control and provided prognostic information but did not increase melanoma-specific survival among patients with melanoma and sentinel-node metastases. (Funded by the National Cancer Institute and others; MSLT-II ClinicalTrials.gov number, NCT00297895 .).

The Sunbelt Melanoma Trial.

The Sunbelt Melanoma Trial, a multicenter, prospective randomized clinical study, evaluated the role of high-dose interferon alfa-2b (HDI) therapy for patients with a single positive sentinel lymph node (SLN) metastasis treated with a completion lymph node dissection (CLND). A second protocol in the trial evaluated the prognostic significance of using molecular markers to identify submicroscopic metastases in sentinel lymph nodes that were negative by routine pathologic analysis. The role of CLND with or without adjuvant HDI was evaluated in this group of patients. The results of the study demonstrated that adjuvant HDI offered no survival benefit for patients with a single positive SLN in terms of disease-free or overall survival. Molecular staging using polymerase chain reaction (PCR) for melanoma markers did not identify a high-risk group of patients at increased risk of melanoma recurrence. Additional treatment of these patients who were PCR-positive with either CLND alone or CLND plus HDI did not improve their survival. Additional studies from the Sunbelt Melanoma Trial helped to validate the operational standards of the SLN biopsy procedure and defined the complication rates for both SLN biopsy and CLND. A prognostic risk calculator has been developed from trial data, and the importance of different micrometastatic tumor burden measurements was reported. Although the Sunbelt Melanoma Trial did not demonstrate an improvement in survival with HDI, it is an important trial that highlights the significance of surgeon-initiated randomized clinical trials that incorporate surgical techniques, molecular biomarkers, and adjuvant therapy.

Identifying Factors Predicting Prolonged Opioid Use After Mastectomy.

BACKGROUND: Women who undergo mastectomy for breast cancer may be prone to prolonged opioid use (POU). However, risk factors for long-term opioid use after mastectomy remain unclear. This study seeks to identify risk factors for POU after mastectomy. PATIENTS AND METHODS: A single-institution database was queried for women who underwent mastectomy for breast cancer between January 2016 and December 2017. Patients were stratified based on opioid use < 90 or ≥ 90 days after mastectomy or completion of their reconstruction. Clinicopathologic and operative parameters as well as preoperative and postoperative opioid usage were compared. RESULTS: Patients with opioid use ≥ 90 days after last procedure (POU) had a history of preoperative opioid use (29.3% vs 8.2%, p = 0.002), were more likely to have concomitant psychiatric illness (70% vs 35.6%, p < 0.001), and had received adjuvant chemotherapy (43.1% vs 24.7%, p = 0.03). Patients with POU also had greater daily opioid doses prescribed upon discharge (59.6 mg vs 44.6 mg, p < 0.001). On multivariable analysis, preoperative opioid use (OR 3.61, 95% CI 1.16-11.22, p = 0.03), daily oral morphine equivalents prescribed at discharge (OME-D) (OR 1.02, 95% CI 1.01-1.05, p = 0.003), and psychiatric illness (OR 4.48, 95% CI 1.85-10.89, p < 0.001) were independently associated with POU. Among opioid-naïve patients, 37% were found to have POU. Among these patients, OME at discharge (OR 1.02, 95% CI 1.003-1.04, p = 0.02) and psychiatric illness (OR 3.23, 95% CI 1.25-8.31, p = 0.02) independently predicted POU. CONCLUSIONS: Preoperative opioid use, psychiatric illness, and daily OME at discharge independently predict POU after mastectomy.

COVID-19 Pandemic and Surgical Oncology: Preserving the Academic Mission.

BACKGROUND: The global pandemic of respiratory disease cause by the novel human coronavirus (SARS-CoV-2) has caused untold suffering, loss of life and upheaval in society. The pandemic has lead to massive redirection of health care resources to treat the surge of COVID-19 patients, and enforcement of social distancing to reduce the rate of transmission. METHODS: Editorial Board members provided observations of the implications of the pandemic on academic surgical oncology. RESULTS: Delivery of health care to other populations including cancer patients has been significantly disrupted. The implications both short term and long term threaten preservation of the academic mission in medicine at large, and certainly in the field of surgical oncology. CONCLUSIONS: The effects on surgical oncology training, research and clinical trials are major.