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3546 Background: CXC-chemokine receptor 4 (CXCR4) is a ubiquitous chemokine receptor activated by the CXCL12 ligand and is implicated in tumor invasion, metastasis, and immune cell (IC) trafficking. High CXCR4 expression is associated with poor prognosis in colorectal cancer (CRC). < 10% of metastatic CRC cases harbor microsatellite instability (MSI-H) and demonstrate lower tumor mutation burden (TMB), decreased IC infiltration, and lack of response to current immunotherapy regimens. This study aims to interrogate the role of CXCR4 mRNA expression on the the tumor microenvironment (TME) and its prognostic and predictive value to tailor immunotherapeutic treatment strategies in CRC. Methods: A total of 15,026 CRC samples were analyzed using whole-exome sequencing, whole-transcriptome sequencing, and immunohistochemistry (Caris Life Sciences, Phoenix, AZ). Study cohort was stratified by CXCR4 mRNA expression levels in quartiles (Q1 (low) vs Q4 (high)). IC fraction was calculated by QuantiSeq, and real-world overall survival information was obtained from insurance claims data and calculated from tissue collection time to last day of contact. Statistical significance was determined using chi-square/Fisher-Exact and adjusted for multiple comparisons (q < 0.05). Results: Samples obtained from metastatic sites showed higher CXCR4 mRNA expression than those from primary tumors (22.7 vs 18.6 median transcripts per million (TPM), p < 0.001). CXCR4 mRNA expression was significantly lower in liver metastases than in non-liver metastases (21.2 vs 24.8 TPM, p < 0.001). Median CXCR4 mRNA expression was highest in the consensus molecular subtypes 4 (33.3 TPM) and lowest in 3 (13.0 TPM, p < 0.05). CXCR4 mRNA expression was positively associated with TMB-H, MSI-H/dMMR, and positive PD-L1 IHC status. In the TME, high CXCR4 mRNA expression was observed in tumors with a higher IC infiltration including B cells, M1/M2 macrophages, NK cells, CD8+ T cells and T-regs, regardless of MSI status. High CXCR4 mRNA expression in the primary tumor was associated with poor prognosis (HR 0.77, 95% CI 0.70-0.85; p < 0.001), regardless of MSI-status. In metastatic tumors, low mRNA expression was correlated with improved survival (HR 0.89, 95% CI 0.80-0.99; p = 0.34); however, this did not reach statistical significance in the MSS cohort (HR 0.90, 95% CI 0.80-1.0; p = 0.06). Of note, high CXCR4 mRNA expression was associated with improved survival in all patients with CRC who received pembrolizumab (HR 2.12, 95% CI 1.16-3.91; p = 0.013). Conclusions: This is the largest clinical dataset to date demonstrating high CXCR4 expression as a predictor for poor survival in CRC. Furthermore, high CXCR4 expression was associated with improved outcome after checkpoint inhibition immunotherapy, indicating its strong potential as a predictive biomarker that could inform immunotherapeutic strategies in CRC.

Cholangiocarcinoma is a rare but lethal malignancy arising anywhere along the biliary ductal epithelium from the liver to the duodenum. The disease is classified based on anatomic location, and the mainstay of treatment is surgery. Complete resection is currently the only chance for cure despite significant advances in systemic and other nonsurgical therapies. In this chapter, we present a detailed evaluation of the anatomic classification of cholangiocarcinoma and preoperative evaluation, defining resectability, types of resections, and postoperative outcomes. Special attention is given to advances in the field and the future of surgery in the multidisciplinary management of cholangiocarcinoma.

Although malignant bowel obstruction (MBO) often is a terminal event, systemic therapies are advocated for select patients to extend survival. This study aimed to evaluate factors associated with receipt of chemotherapy after MBO and to determine whether chemotherapy after MBO is associated with survival.This retrospective cohort study investigated patients 65 years of age or older with metastatic gastrointestinal, gynecologic, or genitourinary cancers who were hospitalized with MBO from 2008 to 2012 using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Fine and Gray models were used to identify factors associated with receipt of chemotherapy accounting for the competing risk of death. Cox models identified factors associated with overall survival.Of the 2983 MBO patients, 39% (n = 1169) were treated with chemotherapy after MBO. No differences in receipt of chemotherapy between the surgical and medical patients were found in the univariable analysis (subdistribution hazard ratio [SHR], 0.96; 95% confidence interval [CI], 0.86-1.07; p = 0.47) or multivariable analysis (SHR, 1.12; 95% CI, 1.00-1.26; p = 0.06). Older age, African American race, medical comorbidities, non-colorectal and non-ovarian cancer diagnoses, sepsis, ascites, and intensive care unit stays were inversely associated with receipt of chemotherapy after MBO (p0.05). Chemotherapy with surgery was associated with longer survival than surgery (adjusted hazard ratio [aHR], 2.97; 95% CI, 2.65-3.34; p0.01) or medical management without chemotherapy (aHR, 4.56; 95% CI, 4.04-5.14; p0.01). Subgroup analyses of biologically diverse cancers (colorectal, pancreatic, and ovarian) showed similar results, with greater survival related to chemotherapy (p0.05).Chemotherapy plays an integral role in maximizing oncologic outcome for select patients with MBO. The data from this study are critical to optimizing multimodality care for these complex patients.

Objective: We aimed to review data about delaying strategies for the management of hepatobiliary cancers requiring surgery during the covid-19 pandemic. Background: Given the covid-19 pandemic, many jurisdictions, to spare resources, have limited access to operating rooms for elective surgical activity, including cancer, thus forcing deferral or cancellation of cancer surgeries. Surgery for hepatobiliary cancer is high-risk and particularly resource-intensive. Surgeons must critically appraise which patients will benefit most from surgery and which ones have other therapeutic options to delay surgery. Little guidance is currently available about potential delaying strategies for hepatobiliary cancers when surgery is not possible. Methods: An international multidisciplinary panel reviewed the available literature to summarize data relating to standard-of-care surgical management and possible mitigating strategies to be used as a bridge to surgery for colorectal liver metastases, hepatocellular carcinoma, gallbladder cancer, intrahepatic cholangiocarcinoma, and hilar cholangiocarcinoma. Results: Outcomes of surgery during the covid-19 pandemic are reviewed. Resource requirements are summarized, including logistics and adverse effects profiles for hepatectomy and delaying strategies using systemic, percutaneous and radiation ablative, and liver embolic therapies. For each cancer type, the long-term oncologic outcomes of hepatectomy and the clinical tools that can be used to prognosticate for individual patients are detailed. Conclusions: There are a variety of delaying strategies to consider if availability of operating rooms decreases. This review summarizes available data to provide guidance about possible delaying strategies depending on patient, resource, institution, and systems factors. Multidisciplinary team discussions should be leveraged to consider patient- and tumour-specific information for each individual case. publishedVersion

Background There are many potential treatment options for patients with early stage hepatocellular carcinoma (HCC) and practice patterns vary widely. This project aimed to use a Delphi conference to generate consensus regarding the management of small resectable HCC. Methods A base case was established with review by members of AHPBA Research Committee. The Delphi panel of experts reviewed the literature and scored clinical case statements to identify areas of agreement and disagreement. Following initial scoring, discussion was undertaken, questions were amended, and scoring was repeated. This cycle was repeated until no further likelihood of reaching consensus existed. Results The panel achieved agreement or disagreement consensus regarding 27 statements. The overarching themes included that resection, ablation, transplantation, or any locoregional therapy as a bridge to transplant were all appropriate modalities for early or recurrent HCC. For larger lesions, consensus was reached that radiofrequency ablation and microwave ablation were not appropriate treatments. Conclusion Using a validated system for identifying consensus, an expert panel agreed that multiple treatment modalities are appropriate for early stage HCC. These consensus guidelines are intended to help guide physicians through treatment modalities for early HCC; however, clinical decisions should continue to be made on a patient-specific basis.

MINI: Patients with colorectal liver metastases and available KRAS data treated with resection and with or without adjuvant hepatic artery infusion chemotherapy were retrospectively evaluated. Adjuvant hepatic artery infusion was independently associated with improved outcomes regardless of KRAS mutational status. Adjuvant hepatic artery infusion may mitigate the worse outcomes seen in patients with resectable KRAS-MUT CRLM. OBJECTIVE To investigate the impact of adjuvant hepatic artery infusion (HAI) in relation to KRAS mutational status in patients with resected colorectal cancer liver metastases (CRLM). BACKGROUND Patients with KRAS-mutated CRLM have worse outcomes after resection. Adjuvant HAI chemotherapy improves overall survival after liver resection. METHODS Patients with resected CRLM treated at MSKCC with and without adjuvant HAI who had available KRAS status (wild-type, WT; mutated, MUT) were reviewed from a prospectively maintained institutional database. Correlations between KRAS status, adjuvant HAI, clinical factors, and outcomes were analyzed. Cox proportional hazard model was used to adjust for confounders. RESULTS Between 1993 and 2012, 674 patients (418 KRAS-WT, 256 MUT) with a median follow up of 6.5 years after resection were evaluated. Fifty-four percent received adjuvant HAI. Tumor characteristics (synchronous disease, number of lesions, clinical-risk score, 2-stage hepatectomy) were significantly worse in the HAI group; however, there were more patients with resected extrahepatic metastases in the no-HAI group. In KRAS-WT tumors, 5-year survival was 78% for patients treated with HAI versus 57% for patients without HAI [hazard ratio (HR) 0.51, P < 0.001]. In KRAS-MUT tumors, 5-year survival was 59% for patients treated with HAI versus 40% for patients without HAI (HR 0.56, P < 0.001). On multivariate analysis, HAI remained associated with improved OS (HR 0.53, P < 0.002) independent of KRAS status and other clinicopathologic factors. CONCLUSION Adjuvant HAI after resection of CRLM is independently associated with improved outcomes regardless of KRAS mutational status. Adjuvant HAI may mitigate the worse outcomes seen in patients with resectable KRAS-MUT CRLM.

Treatment options for locally advanced rectal cancer have continued to consist largely of chemotherapy, chemoradiation, and/or surgical resection. For patients who are unable to undergo these therapeutic modalities or who do not to experience a response to them, treatment options are limited. We report 3 cases of mismatch repair–deficient (dMMR) locally advanced adenocarcinoma of the rectum that showed significant response with neoadjuvant immunotherapy–based systemic treatment. The first patient was not eligible for standard therapy because of a history of radiotherapy to the prostate with concurrent comorbidities and therefore received single-agent pembrolizumab. The second patient did not respond to total neoadjuvant chemoradiation and subsequently received combined nivolumab and ipilimumab. The third patient had a known family history of Lynch syndrome and presented with locally advanced rectal cancer and a baseline carcinoembryonic antigen level of 1,566 ng/mL. She was treated using neoadjuvant pembrolizumab and FOLFOX (folinic acid, fluorouracil, oxaliplatin). In this small series, we suggest that single-agent and combined-modality neoadjuvant immunotherapy/chemotherapy appear to be safe and effective treatment options for patients with (dMMR) locally advanced rectal cancer. Our findings encourage further studies to investigate the role of neoadjuvant immunotherapy as a viable treatment strategy in this population.

Background and Aims: Azoospermia factor (AZF) region of the Ychromosome has several genes which are responsible for normal spermatogenesis. Microdeletions of these genes are associated with azoospermia and oligospermia. These microdeletions are too small to be detected by karyotyping. They can be easily identified using polymerase chain reaction. The aim of this study is to determine the frequencies of Ychromosome microdeletions in azoospermic and oligospermic Iranian infertile men and compare them with other studies in different ethnic groups. Materials and Methods: At first, karyotype analysis was performed in 80 infertile men and 30 healthy age-matched counterparts as control group using standard cytogenetic methods. Second, genomic DNA was extracted from all cases and genetic screening was conducted for Y chromosome microdeletions by multiplex polymerase chain reaction for AZF genes on both infertile and control men using 6 STS markers on the long arm of the Y chromosome. Results: Totally, 49 infertile men were azoospermic and 31 were oligospermic. Y-chromosome microdeletions in the AZFc region were detected in 4 of azoospermic patients. Y-chromosome microdeletions was not detected in any of the oligospermic patients and the control group. Conclusions: This finding recommends that genetic counseling and screening before starting assisted reproductive techniques such as in vitro fertilisation and intracytoplasmic sperm injection can prevent unnecessary treatment and transmission of genetic defects to offspring

The role of palliative surgery in the management of acute complications in patients with disseminated malignancy remains controversial given the complexity of assessing acute surgical risk and long-term oncologic outcome. With the emergence of checkpoint blockade immunotherapy, there appears to be an increasing role for historically palliative procedures as a bridge to systemic immunotherapy. This is especially evident in advanced microsatellite instability-high (MSI-H) colorectal cancer where malignant obstruction and fistula formation are more common and where immunotherapy with checkpoint blockade (anti-PD-1/PD-L1, anti-CTLA-4) has a high response rate with potential for favorable oncologic outcomes. We present a series of three patients with MSI-H metastatic colorectal cancer complicated by malignant bowel obstruction and fistula formation, who having progressed on standard chemotherapy, underwent palliative intervention as a bridge to immune checkpoint blockade with durable and clinically meaningful anti-cancer responses. These cases highlight the need to re-evaluate the role of historically palliative operations in the setting of disease progression for immunotherapy-responsive tumors.

BACKGROUND/AIM Competing mortality risks complicate treatment of elderly melanoma patients potentially leading to conservative management, including no sentinel lymph node biopsy. As systemic immunotherapy offers justification for nodal evaluation, we examined treatment trends among elderly melanoma patients. PATIENTS AND METHODS We performed a National Cancer Database analysis of melanoma patients from 2004-2015. Patients were categorized by age (elderly ≥80-years-old). Multivariable logistic regression analyses were performed comparing characteristics and treatment by age. RESULTS Of 187,814 patients, 2.7% were 1-25, 11.6% were 26-40, 46.6% were 41-64, 28.8% were 65-79, and 10.3% were ≥80-years-old with clinicopathologic and treatment differences between age cohorts. Nodal surgery was least common among elderly patients (43.1% vs. 60.7-69.8%, p

Preoperative biliary drainage (PBD) is often performed in patients with jaundice with the presumption that it will decrease the risk of postoperative complications. PBD carries its own risk of complications and, therefore, has been controversial. Multiple randomized controlled trials and metaanalyses have shown that PBD has significantly increased overall complications compared with surgery alone. As such, the routine application of PBD should be avoided except in a subset of clinical situations. This is discussed in detail in this article.

Every year, cancer claims millions of lives around the globe. Unfortunately, model systems that accurately mimic human oncology - a requirement for the development of more effective therapies for these patients - remain elusive. Tumor development is an organ-specific process that involves modification of existing tissue features, recruitment of other cell types, and eventual metastasis to distant organs. Recently, tissue engineered microfluidic devices have emerged as a powerful in vitro tool to model human physiology and pathology with organ-specificity. These organ-on-chip platforms consist of cells cultured in 3D hydrogels and offer precise control over geometry, biological components, and physiochemical properties. Here, we review progress towards organ-specific microfluidic models of the primary and metastatic tumor microenvironments. Despite the field's infancy, these tumor-on-chip models have enabled discoveries about cancer immunobiology and response to therapy. Future work should focus on the development of autologous or multi-organ systems and inclusion of the immune system.

Intercellular communication is a vital yet underdeveloped aspect of cancer pathobiology. This Opinion article reviews the importance and challenges of microscopic imaging of tunneling nanotubes (TNTs) in the complex tumor microenvironment. The use of advanced microscopy to characterize TNTs in vitro and ex vivo, and related extensions called tumor microtubes (TMs) reported in gliomas in vivo, has propelled this field forward. This topic is important because the identification of TNTs and TMs fills the gap in our knowledge of how cancer cells communicate at long range in vivo, inducing intratumor heterogeneity and resistance to treatment. Here we discuss the concept that TNTs/TMs fill an important niche in the ever-changing microenvironment and the role of advanced microscopic imaging to elucidate that niche.

Minimally invasive surgical techniques are an emerging option in the staging and management of gastric cancer in the United States and elsewhere. Although much of the current knowledge about these approaches and their outcomes has been generated in Eastern countries, experience in the United States is growing. This article discusses both laparoscopic and robotic approaches to gastric cancer management. Important aspects of patient selection are emphasized. Surgical and oncologic outcomes are presented and compared with traditional open gastrectomy. Technical considerations are discussed along with comments on the learning curve to achieve proficiency in each approach.

Hepatic artery infusion (HAI) chemotherapy is a locoregional therapy for colorectal cancer liver metastasis that has been available since the 1980s. Multiple clinical trials have demonstrated the safety and efficacy of HAI with higher response rates compared to systemic chemotherapy alone. Clinical trials have shown the benefit of using HAI as a bridge to conversion to resection at a higher rate than systemic chemotherapy alone with rates as high as 60% in heavily pretreated patients. HAI in combination with systemic chemotherapy has also been associated with prolonged recurrence free survival and overall survival in the adjuvant setting. Specifically, the addition of HAI continues to show a benefit in prolonging overall survival, despite increased effectiveness of modern systemic chemotherapy (i.e., oxaliplatin and irinotecan). Lower recurrence and improved survival rates associated with HAI and systemic chemotherapy persist regardless of RAS mutational status.

4104 Background: Biliary tract cancers are rare tumors with a median overall survival (OS) of 16 months for node-positive (N+) and 37 months for node-negative (N0) disease despite resection. Lymph node status is a known strong prognostic factor for local recurrence with an average estimated 2-year disease-free survival (DFS): 65.5% for N0 and 29.7% for N+ tumors. The Phase II Intergroup Trial S0809 showed that adjuvant capecitabine and gemcitabine followed by radiotherapy and concurrent capecitabine improved OS in patients with extrahepatic cholangiocarcinoma (EHCC) and gallbladder cancer (GBC) compared to historical controls. We hypothesized that nodal status is a prognostic factor for local recurrence in this patient population who received adjuvant therapy. Methods: This analysis included patients with stage pT2-4, N+ or positive margin EHCC or GBC. Treatment included four cycles of gemcitabine (1,000 mg/m2 intravenously on days 1 and 8) and capecitabine (1,500 mg/m2 per day on days 1 to 14) every 21 days followed by concurrent capecitabine (1,330 mg/m2 per day) and radiotherapy (45 Gy to regional lymphatics; 52.5 to 59.4 Gy to tumor bed). S0809 patients who did not receive radiotherapy were excluded from analysis. Correlations between nodal status, resection margin, and other clinicopathological factors, patterns of recurrence and survival were analyzed, and Cox regression models were used to estimate the prognostic significance of nodal status. A Z-test was used to compare DFS rates between these patients and historical data. Results: A total of 69 patients [EHCC n = 46 (66%); GBCA n = 23 (33%)] were evaluated with a median age of 61.7 (26.1-80.6). The majority of N0 patients were female (17/24, 70.8%), whereas most N+ patients were male (25/45, 55.6%; p < 0.04). Distribution of R0 (66.7%) and R1 (33.3%) resections was similar in the N0 and N+ groups. Thirty-four patients with EHCC had N+ disease (73.9%) compared with 11 patients with GBCA (47.8%, p = 0.03). Nodal status did not significantly impact OS (HR = 2.03, 95% CI 0.92-4.49, p = 0.08) or DFS (HR = 1.75, 95% CI 0.85-3.59, p = 0.13). Two-year OS was 70.6% for N0 and 60.9% for N+ disease (p = 0.11). Nodal status was not significantly associated with 2-year DFS: 62.5% for N0 and 49.8% for N+ (p = 0.20). N+ vs N0 tumors showed higher rates of distant failure (51.1% vs 25.0%, p < 0.04), but similar local recurrence (17.8% vs 12.5%, p = 0.88). The observed 2-year DFS in patients with N+ tumors was significantly longer compared to the historical rate of 29.7% (p = 0.004). Conclusions: This combination adjuvant treatment regimen following curative resection for EHCC and GBCA provides favorable outcomes regardless of nodal status. These data suggest that adjuvant chemoradiation may positively impact local control in N+ patients. These findings need to be validated in future clinical trials. Clinical trial information: NCT00789958.

To analyze clinical outcomes and prognostic variables of patients undergoing hepatic resection for BRAF mutant (BRAF-mut) colorectal liver metastases (CRLM).Outcomes following hepatectomy for BRAF-mut CRLM have not been well studied.All patients who underwent hepatectomy for CRLM with complete resection and known BRAF status during 2001 to 2016 at 3 high-volume centers were analyzed.Of 4124 patients who underwent hepatectomy for CRLM, 1497 had complete resection and known BRAF status. Thirty-five (2%) patients were BRAF-mut, with 71% of V600E mutation. Compared with BRAF wild-type (BRAF-wt), BRAF-mut patients were older, more commonly presented with higher ASA scores, synchronous, multiple and smaller CRLM, underwent more major hepatectomies, but had less extrahepatic disease. Median overall survival (OS) was 81 months for BRAF-wt and 40 months for BRAF-mut patients (P0.001). Median recurrence-free survival (RFS) was 22 and 10 months for BRAF-wt and BRAF-mut patients (P0.001). For BRAF-mut, factors associated with worse OS were node-positive primary tumor, carcinoembryonic antigen (CEA)200 μg/L, and clinical risk score (CRS) ≥4. Factors associated with worse RFS were node-positive primary tumor, ≥4 CRLM, and positive hepatic margin. V600E mutations were not associated with worse OS or RFS. A case-control matching analysis on prognostic clinicopathologic factors confirmed shorter OS (P0.001) and RFS (P0.001) in BRAF-mut.Patients with resectable BRAF-mut CRLM are rare among patients selected for surgery and more commonly present with multiple synchronous tumors. BRAF mutation is associated with worse prognosis; however, long-term survival is possible and associated with node-negative primary tumors, CEA ≤ 200 μg/L and CRS4.

Background This study sought to develop a clinical risk score for resectable colorectal liver metastasis (CRLM) by combining clinicopathological and clinically available biological indicators, including KRAS. Methods A cohort of patients who underwent resection for CRLM at the Johns Hopkins Hospital (JHH) was analysed to identify independent predictors of overall survival (OS) that can be assessed before operation; these factors were combined into the Genetic And Morphological Evaluation (GAME) score. The score was compared with the current standard (Fong score) and validated in an external cohort of patients from the Memorial Sloan Kettering Cancer Center (MSKCC). Results Six preoperative predictors of worse OS were identified on multivariable Cox regression analysis in the JHH cohort (502 patients). The GAME score was calculated by allocating points to each patient according to the presence of these predictive factors: KRAS-mutated tumours (1 point); carcinoembryonic antigen level 20 ng/ml or more (1 point), primary tumour lymph node metastasis (1 point); Tumour Burden Score between 3 and 8 (1 point) or 9 and over (2 points); and extrahepatic disease (2 points). The high-risk group in the JHH cohort (GAME score at least 4 points) had a 5-year OS rate of 11 per cent, compared with 73·4 per cent for those in the low-risk group (score 0–1 point). Importantly, in cohorts from both the JHH and MSKCC (747 patients), the discriminatory capacity of the GAME score was superior to that of the Fong score, as demonstrated by the C-index and the Akaike information criterion. Conclusion The GAME score is a preoperative prognostic tool that can be used to inform treatment selection.

Background Metastatic squamous cell carcinoma (SCC) to the axillary or inguinal lymph nodes from an unknown primary source is rarely encountered. We sought to evaluate a cohort of patients with metastatic SCC managed by lymphadenectomy to determine their survival and to determine which clinicopathologic factors were associated with outcome. Methods All patients undergoing axillary or inguinal lymphadenectomy for SCC at our institution were identified retrospectively. Patients were stratified by unknown primary (UP) vs known skin primary (KP) tumors. Pertinent data on patient, tumor, and treatment variables was collected. Results We identified 51 patients who met inclusion criteria. Of those, 20 patients (39%) had UP metastatic SCC and 31 patients (61%) had KP. The 5-year overall survival for UP was 65%, as compared to 49% for KP (p = 0.16). Cumulative incidence of recurrence was 46%. Cox regression failed to demonstrate a significant association between KP vs UP, HPV status, chemotherapy, or radiation with survival. Conclusions Nearly two-thirds of patients undergoing axillary or inguinal lymphadenectomy for metastatic SCC of unknown primary were alive five years following the procedure.

Background Examination of at least 16 lymph nodes (LNs) has been traditionally recommended during gastric adenocarcinoma resection to optimize staging, but the impact of this strategy on survival is uncertain. Because recent randomized trials have demonstrated a therapeutic benefit from extended lymphadenectomy, we sought to investigate the impact of the number of LNs removed on prognosis after gastric adenocarcinoma resection. Study Design We analyzed patients who underwent gastrectomy for gastric adenocarcinoma from 2000 to 2012, at 7 US academic institutions. Patients with M1 disease or R2 resections were excluded. Disease-specific survival (DSS) was calculated using the Kaplan-Meier method and compared using log-rank and Cox regression analyses. Results Of 742 patients, 257 (35%) had 7 to 15 LNs removed and 485 (65%) had ≥16 LNs removed. Disease-specific survival was not significantly longer after removal of ≥16 vs 7 to 15 LNs (10-year survival, 55% vs 47%, respectively; p = 0.53) for the entire cohort, but was significantly improved in the subset of patients with stage IA to IIIA (10-year survival, 74% vs 57%, respectively; p = 0.018) or N0-2 disease (72% vs 55%, respectively; p = 0.023). Similarly, for patients who were classified to more likely be "true N0-2," based on frequentist analysis incorporating both the number of positive and of total LNs removed, the hazard ratio for disease-related death (adjusted for T stage, R status, grade, receipt of neoadjuvant and adjuvant therapy, and institution) significantly decreased as the number of LNs removed increased. Conclusions The number of LNs removed during gastrectomy for adenocarcinoma appears itself to have prognostic implications for long-term survival.

Background Leiomyosarcoma (LMS) can originate from the retroperitoneum, uterus, extremity, and trunk. It is unclear whether tumors of different origin represent discrete entities. We compared clinicopathologic features and outcomes following surgical resection of LMS stratified by site of origin. Methods : Patients with LMS undergoing resection at a single institution were retrospectively reviewed. Clinicopathologic variables were compared across sites. Survival was calculated using the Kaplan–Meier method and compared using log-rank and Cox regression analyses. Results From 1983 to 2011, 138 patients underwent surgical resection for LMS. Retroperitoneal and uterine LMS were larger, higher grade, and more commonly associated with synchronous metastases. However, disease-specific survival, recurrence-free survival, and recurrence patterns were not significantly different across the four sites. Synchronous metastases (HR 3.20, P

While previously thought to be clinically indolent, recent data suggest significant late metastatic capacity of solitary fibrous tumors (SFTs). We define prognostic factors for recurrence and disease-specific death (DSD) in resected primary SFTs. Resected primary SFTs from 1982 to 2015 were identified from a prospective, single institutional database. Risk factors for local (LR) and distant recurrence (DR), and DSD were assessed using competing risk analysis. A total of 219 patients with median follow-up of 6.1 (0.1–22) years were included. Five- and 10-year cumulative DSD was 9 and 11%, respectively. Size greater than the median 8 cm, gender, location, and complete gross resection were significantly associated with DSD (p

Minimally invasive gastric resections carry several advantages, including less intraoperative blood loss, faster recovery time, reduced pain, and decreased hospital length of stay and quicker return to work. Numerous trials have proved that laparoscopic and robotic-assisted gastrectomy provides equivalent surgical and oncologic outcomes to open approaches. As with any minimally invasive approach, advanced minimally invasive training and good judgment by a surgeon are paramount in selecting patients in whom a minimally invasive approach is feasible. With increasing research in patient populations with more advanced disease, the indications are likely to continue to expand.

Minimally invasive surgical techniques are an emerging option in the staging and management of gastric cancer in the United States and elsewhere. Although much of the current knowledge about these approaches and their outcomes has been generated in Eastern countries, experience in the United States is growing. This article discusses both laparoscopic and robotic approaches to gastric cancer management. Important aspects of patient selection are emphasized. Surgical and oncologic outcomes are presented and compared with traditional open gastrectomy. Technical considerations are discussed along with comments on the learning curve to achieve proficiency in each approach.

TPS57 Background: Hepatocellular carcinoma (HCC) is a frequent cause of cancer-related death worldwide and incidence is rising. Sorafenib and lenvatinib are approved for first-line use in unresectable HCC; however, survival benefit remains low. Nivolumab, a human monoclonal antibody to programmed death-1 (PD1) receptor, has been approved as second-line therapy in patients with unresectable HCC refractory to sorafenib. BMS-986205 selectively inhibits human indoleamine-2,3- dioxygenase 1 (IDO1), an intracellular enzyme expressed in various malignancies that promotes immune tolerance. Thus, the combination of PD-1 antibody and IDO1 inhibitor is a promising strategy to augment immunotherapy against HCC. We aim to evaluate the combination of BMS-986205 with nivolumab 3 mg/kg every 2 weeks in unresectable and metastatic HCC. Methods: Primary objectives were to identify tolerable dosing of BMS-986205, and to evaluate safety, tolerability, and efficacy of combination therapy, the latter defined by objective response rate. Secondary objectives were to evaluate disease control rate, duration of response, progression free survival, and overall survival. Phase I (dose escalation phase) will monitor two dose levels of BMS-986205: 50mg daily with conditional escalation to 100mg daily depending on dose-limiting toxicity. Phase II (expansion phase) will begin after maximum tolerated dose is reached. The phase II cohort will be run as a Simon two-stage design to allow for early trial stoppage for futility. Estimated study duration is 36 months with a 24-month accrual period for a total of 17 patients. Patients will be followed for 100 days after the last dose of treatment or until all treatment-related clinical toxicities resolve to baseline or grade ≤ 1. Assessments prior to therapy include imaging, tissue biopsy, serum correlatives, and stool samples. Tissue biopsy will be repeated at 4 weeks. Imaging will be repeated at 8 and 16 weeks, then every 12 weeks until end of treatment. Serum correlatives will be repeated intermittently throughout. At progression, imaging, tissue biopsy, and serum correlatives will be repeated. Data will be reported using 95% confidence intervals, Kaplan-Meier estimates, and frequency tables. Clinical trial information: NCT03695250.

Background The purpose of this work was to examine the ability of an oncolytic vaccinia virus expressing the human sodium iodine transporter (hNIS) to provide real time monitoring of viral therapy and effective treatment of malignant pleural mesothelioma (MPM). Methods Infectivity and cytotoxic effects of GLV-1h153 on mesothelioma cell lines of all histologic subtypes were assayed in vitro. Viral replication was examined by standard viral plaque assay. Orthotopic MPM xenografts were generated in athymic nude mice, treated with intrapleural GLV-1h153, and assessed for effect on tumor burden and survival. Orthotopic tumors were also imaged on single photon emission computed tomography (SPECT)/computed tomography (CT) after 131 I administration. Results GLV-1h153–infected and killed all cell lines in a time- and concentration-dependent manner. Viral replication demonstrated a >2.5-log increase in titer over 4 days. Intrapleural treatment of orthotopic MPM xenografts resulted in a significant decrease in tumor burden 1 week after treatment and an improvement in survival. Infection of orthotopic xenografts was both therapeutic and facilitated monitoring by 131 I-SPECT/CT via expression of hNIS in infected tissue. Conclusion Our results suggest that GLV-1h153 may be a promising therapeutic agent for MPM and warrants further investigation.

Background Electroporation uses an electric field to induce pores in the cell membrane that can transfer macromolecules into target cells. Modulation of electrical parameters leads to irreversible electroporation (IRE), which is being developed for tissue ablation. We sought to evaluate whether the application of IRE may induce a lesser electric field in the periphery where reversible electroporation may occur, facilitating gene transfer of a granulocyte macrophage colony-stimulating factor (GM-CSF) plasmid to produce its biologic response. Methods Yorkshire pigs underwent laparotomy, and IRE of the liver was performed during hepatic arterial infusion of 1 or 7 mg of a naked human GM-CSF plasmid. The serum, liver, lymph nodes, and bone marrow were harvested for analysis. Results Human GM-CSF level rose from undetectable to 131 pg/mL in the serum at 24 hours after IRE and plasmid infusion. The liver demonstrated an ablation zone surrounded by an immune infiltrate that had greater macrophage intensity than when treated with IRE or plasmid infusion alone. This dominance of macrophages was dose dependent. Distant effects of GM-CSF were found in the bone marrow, where proliferating myeloid cells increased from 14% to 25%. Conclusion IRE facilitated gene transfer of the GM-CSF plasmid and brought about a local and systemic biologic response. This technique holds potential for tumor eradication and immunotherapy of residual cancer.

Objective: The aim of this study was to describe postoperative outcomes of total gastrectomy at our institution for patients with hereditary diffuse gastric cancer (HDGC). Background: HDGC, which is mainly caused by germline mutations in the E-cadherin gene (CDH1), renders a lifetime risk of gastric cancer of up to 70%, prompting a recommendation for prophylactic total gastrectomy. Methods: A prospective gastric cancer database identified 41 patients with CDH1 mutation who underwent total gastrectomy during 2005 to 2015. Perioperative, histopathologic, and long-term data were collected. Results: Of the 41 patients undergoing total gastrectomy, median age was 47 years (range 20 to 71). There were 14 men and 27 women, with 25 open operations and 16 minimally invasive operations. Median length of stay was 7 days (range 4 to 50). In total, 11 patients (27%) experienced a complication requiring intervention, and there was 1 peri-operative mortality (2.5%). Thirty-five patients (85%) demonstrated 1 or more foci of intramucosal signet ring cell gastric cancer in the examined specimen. At 16 months median follow-up, the median weight loss was 4.7 kg (15% of preoperative weight). By 6 to 12 months postoperatively, weight patterns stabilized. Overall outcome was reported to be “as expected” by 40% of patients and “better than expected” by 45%. Patient-reported outcomes were similar to those of other patients undergoing total gastrectomy. Conclusion: Total gastrectomy should be considered for all CDH1 mutation carriers because of the high risk of invasive diffuse-type gastric cancer and lack of reliable surveillance options. Although most patients have durable weight loss after total gastrectomy, weights stabilize at about 6 to 12 months postoperatively, and patients report outcomes as being good to better than their preoperative expectations. No patients have developed gastric cancer recurrence after resections.

This study aimed to investigate the therapeutic impact of a new oncolytic vaccinia virus in a triple-negative breast cancer (TNBC) murine model and its potential for treating distant metastatic disease.TNBCs are aggressive tumors associated with a high metastatic rate. Their lack of targets for hormonal/biological therapy presents significant clinical challenges and a dire need for novel therapies.GLV-1h153, a replication-competent vaccinia virus, was tested against multiple cell lines. Cytotoxicity and viral replication were determined. Intratumoral (IT) or intravenous (IV) injection of GLV-1h153 (1 × 10(7) plaque-forming units) or phosphate buffered saline was tested in an orthotopic murine model, which reliably produces systemic metastasis. Tumors, lymph nodes, and metastatic organs (lung, liver, and brain) were harvested 5 and 8 weeks after treatment and prepared for histopathological review. Demonstration of metastasis was performed using immunofluorescence and hematoxylin and eosin (HE) staining.GLV-1h153 infected, replicated in, and killed all TNBC cell lines in vitro. In vivo, mean tumor volume 2 weeks after treatment was 22 (IT), 29 (IV) versus 245 mm(3) (control; P0.002). Five weeks after treatment, all harvested lymph nodes and organs showed no evidence of metastatic cells. All harvested tumors showed complete response to treatment, with only necrosis and fibrosis on HE staining 8 weeks after treatment.This is the first study to demonstrate that TNBCs are killed by a novel vaccinia virus both in vitro and in vivo. Our results suggest that GLV-1h153 is a promising therapeutic agent for preventing and treating metastatic TNBC and warrants further clinical testing in patients.

Background Anaplastic thyroid carcinoma (ATC) is fatal with resistance to radiotherapy because of the loss of intrinsic human sodium iodine symporter (hNIS). We determined whether vaccinia virus carrying hNIS kills and induces hNIS reexpression in ATC cells, facilitating deep-tissue imaging. Methods Vaccinia virus (GLV-1h153) carrying hNIS was tested against ATC lines for killing and replication via cytotoxicity and viral plaque assays. Cellular radiouptake was determined using radiouptake assays. GLV-1h153–infected ATC xenografts were imaged via 99m Tc-pertechnetate. Results GLV-1h153 infected, replicated in, and killed all ATC cell lines. GFP expression confirmed viral infection by 24 hours. At a multiplicity of infection (MOI) of 1.0, GLV-1h153 reached near 100% cytotoxicity in 8305c and FRO by day 5 and 70% in the least sensitive cell line, 8505c. GLV-1h153–infected ATC cells had a 14-fold increase of hNIS-specific radiouptake compared with uninfected control 24 hours after infection at an MOI of 1.0. In vivo, GLV-1h153 facilitated imaging of hNIS expression in 8505c tumors using 99m Tc-pertechnetate. Conclusion GLV-1h153 is an effective oncolytic agent against ATC. The results show hNIS-specific radiouptake in infected ATC cells, facilitating deep-tissue imaging. GLV-1h153 is a promising candidate for treatment and imaging, and potentially enhancing susceptibility to radioiodine therapy by converting non–hNIS-expressing cells into hNIS-expressing ATC cells.

Cytological analysis of body fluids is currently used for detecting cancer. The objective of this study was to determine if the herpes virus carrying an enhanced green fluorescent protein (EGFP) could detect rare cancer cells in body fluids against millions of normal cells. Human cancer cells suspended with normal murine cells were infected with NV1066 at a multiplicity of infection (MOI) of 0.5 and 1.0 for 18 h. Fluorescent microscopy and flow cytometry were used for EGFP detection of cancer cells. EGFP-expressing cells were confirmed as cancer cells with specific markers by immunohistochemistry staining. Limits of detection of cancer cells in body fluid were measured by serial dilutions. Applicability of technique was confirmed with samples from patients with malignant pleural effusions. NV1066 expressed EGFP in 111 human cancer cell lines detected by fluorescent microscopy at an MOI of 0.5. NV1066 selectively infected cancer cells and spared normal cells as confirmed by immunohistochemistry. Sensitivity of detecting fluorescent green cells was 92% (confidence interval [CI] 83% to 97%) at a ratio of 1 cancer cell to 1 million normal cells. EGFP-positive cells were detected by fluorescent microscopy in patients' malignant pleural effusion samples. Our data show proof of the concept that NV1066-induced EGFP expression allows detection of a single cancer cell against a background of 1 million normal cells. This method was demonstrated to be a reliable screening tool for human cancer cells in a suspension of normal murine cells as well as clinical specimens of malignant pleural effusions.

e21563Background: As pediatric melanoma is rare, treatment strategies are largely influenced by adult guidelines despite known clinicopathologic and prognostic differences between pediatric and adu...

776 Background: Patients with a right-sided (R) and/or KRAS-mutated (KRAS-MUT) primary tumors have inferior outcomes compared to patients with left sided (L) and/or KRAS-wildtype (KRAS-WT) cancers. Adjuvant hepatic artery pump infusion (HAI) chemotherapy improves overall survival (OS) in patients with colorectal liver metastases (CRLM). We investigated the impact of HAI in relation to the laterality and KRAS status of the primary tumors. Methods: Patients with resected CRLM and available KRAS-status, treated with and without adjuvant HAI were reviewed from a prospective institutional database. Rectal tumors were excluded. Correlations between adjuvant HAI, clinicopathological factors including laterality, KRAS status and OS were analyzed. Cox proportional hazard regression was used to assess survival outcomes comparing R (cecum to transverse colon, excluding appendix) versus L (splenic flexure to sigmoid) colon cancers. Results: 490 patients (R, n = 183; L, n = 307) were evaluated between 1993-2012 (median follow up of 6.5 years). Fifty-six percent (n = 277) received adjuvant HAI. Adjuvant HAI was associated with improved median OS in both R (7.0 vs. 4.4 years, p = 0.006) and L tumors (10.5 vs. 5.4 years, p < 0.01). On multivariate analysis, HAI remained associated with improved OS (HR 4.49, p = 0.001) independent of primary tumor site and other clinical predictors (Table). Conclusions: Adjuvant HAI after resection of CRLM is independently associated with improved OS regardless of laterality of primary tumor. Treatment with adjuvant HAI correlates with improved prognosis in patients with resectable L/KRAS-MUT and R/KRAS-WT tumors. The biological difference for these outcomes requires further investigation. [Table: see text]

Small pediatric recipients of an adult-sized kidney have insufficient renal blood flow early after transplantation, with secondary chronic hypoperfusion and irreversible histological damage of the tubulo-interstitial compartment. It is unknown whether this is reflected by renal resistive indices. We measured renal graft resistive indices and volumes of 47 healthy pediatric kidney transplant recipients of an adult-sized kidney in a prospective study for six months post-transplant. A total of 205 measurements were performed. The smallest recipients (BSAor=0.75 m(2)) had higher resistive indices compared to recipients with a BSA between 0.75 and 1.5 m(2) (p0.0001) and to recipients with a BSAor= 1.5 m(2) (p0.0001). Resistive indices increased during the first six months in the smallest recipients (p = 0.02), but not in the two larger recipient groups (BSA 0.75-1.5 m(2) andor=1.5 m(2)). All three BSA groups showed a reduction in renal volume after transplantation, with the greatest reduction occurring in the smallest recipients. In conclusion, renal transplant resistive indices reflect pediatric recipient BSA dependency. The higher resistance to intra-renal vascular flow and significant decrease in renal volume in the smallest group likely reflect accommodation of the size discrepant transplanted adult-sized kidney to the smaller pediatric recipient vasculature with associated lower renal artery flow.

Background Peritoneal carcinomatosis (PC) is a terminal progression of colorectal cancer (CRC). Poor response to cytoreductive operation and chemotherapy coupled with the inability to reliably track disease progression by the use of established diagnostic methods, make this a deadly disease. We examined the effectiveness of the oncolytic vaccinia virus GLV-1h153 as a therapeutic and diagnostic vehicle. We believe that viral expression of the human sodium iodide transporter (hNIS) provides both real-time monitoring of viral therapy and effective treatment of colorectal peritoneal carcinomatosis (CRPC). Methods Infectivity and cytotoxic effect of GLV-1h153 on CRC cell lines was assayed in vitro. Viral replication was examined by standard viral plaque assays. Orthotopic CRPC xenografts were generated in athymic nude mice and subsequently administered GLV-1h153 intraperitoneally. A decrease in tumor burden was assessed by mass. Orthotopic tumors were visualized by single-photon emission computed tomography/computed tomography after Iodine (131I) administration and by fluorescence optical imaging. Results GLV-1h153 infected and killed CRC cells in a time- and concentration-dependent manner. Viral replication demonstrated greater than a 2.35 log increase in titer over 4 days. Intraperitoneal treatment of orthotopic CRPC xenografts resulted in a substantial decrease in tumor burden. Infection of orthotopic xenografts was therapeutic and facilitated monitoring by 131I–single-photon emission computed tomography/computed tomography via expression of hNIS in infected tissue. Conclusion GLV-1h153 kills CRC in vitro effectively and decreases tumor burden in vivo. We demonstrate that GLV-1h153 can be used as an agent to provide accurate delineation of tumor burden in vivo. These findings indicate that GLV-1h153 has potential for use as a therapeutic and diagnostic agent in the treatment of CRPC.

351 Background: A significant number of patients with colorectal liver metastases (CRLM) present with unresectable bilobar disease. Two-stage hepatectomy with portal vein embolization (PVE) have been described as a treatment for CRLM allowing for volume regeneration of a functional liver remnant. No large-scale multi-institutional studies exist. The aim of this project was to describe outcomes following two-stage hepatectomy, including overall survival (OS), recurrence-free survival (RFS), and complications. Methods: Patients completing two-stage hepatectomy for CRLM at five US institutions were identified and retrospectively analyzed (2000-2015). Overall survival and recurrence-free survival following second-stage surgery, short-term mortality, Clavien-Dindo complications, and readmission rates were examined. Results: A total of 209 patients were identified. Mean age was 52 (SD +/-11.4), 59.8% were male, and 87.0% had synchronous disease. A total of 65.1% of patients underwent PVE, and 27.3% underwent hepatic artery infusion pump placement. 88.3% of cases underwent neoadjuvant chemotherapy. Following the first stage, 30-day morbidity was 24.4%, with 4.8% major (Clavien-Dindo grade ≥3) complications, and 30-day readmission was 6.7%. Mean time between first and second stage was 4.1 months (S.D. +/-3.1), and 57.5% received systemic chemotherapy between the two resections. Following the second stage, overall complications were 47.4% with 23.9% major complications, and 30-day readmission was 9.7%. Mortality following second stage was 3.8% at 30 days, and 5.3% at 90-days. Following the second stage, RFS at 1-, 3-, and 5-years was 80%, 46%, and 29% respectively. OS at 1-, 3-, and 5-years was 87%, 64%, and 45% respectively. Conclusions: Two-stage hepatectomy for CRLM provides acceptable recurrence-free and overall survival in the context of advanced bilobar disease. Major complications and readmission following the first stage are rare. Following the second stage, short-term major morbidity, mortality, and readmissions are also acceptable. For well-selected patients, two-stage hepatectomy remains a safe and effective treatment for CRLM, with potential for more widespread adoption.

Vascular endothelial growth factor (VEGF) expression is higher in triple-negative breast cancers (TNBC) compared to other subtypes and is reported to predict incidence of distant metastases and shorter overall survival. We investigated the therapeutic impact of a vaccinia virus (VACV) GLV-1h164 (derived from its parent virus GLV-1h100), encoding a single-chain antibody (scAb) against VEGF (GLAF-2) in an orthotopic TNBC murine model. GLV-1h164 was tested against multiple TNBC cell lines. Viral infectivity, cytotoxicity, and replication were determined. Mammary fat pad tumors were generated in athymic nude mice using MDA-MB-231 cells. Xenografts were treated with GLV-1h164, GLV-1h100, or PBS and followed for tumor growth. Viral infectivity was time- and concentration-dependent. GLV-1h164 killed TNBC cell lines in a dose-dependent fashion with greater than 90% cytotoxicity within 4 days at a multiplicity of infection of 5.0. In vitro, cytotoxicity of GLV-1h164 was identical to GLV-1h100. GLV-1h164 replicated efficiently in all cell lines with an over 400-fold increase in copy numbers from the initial viral dose within 4 days. In vivo, mean tumor volumes after 2 weeks of treatment were 73, 191, and 422 mm(3) (GLV-1h164, GLV-1h100, and PBS, respectively) (p < 0.05). Both in vivo Doppler ultrasonography and immuno-staining showed decreased neo-angiogenesis in GLV-1h164-treated tumors compared to both GLV-1h100 and PBS controls (p < 0.05). This is the first study to demonstrate efficient combination of oncolytic and anti-angiogenic activity of a novel VACV on TNBC xenografts. Our results suggest that GLV-1h164 is a promising therapeutic agent that warrants testing for patients with TNBC.

Leiomyosarcoma (LMS) can originate from the retroperitoneum, uterus, extremity, and trunk. It is unclear whether tumors of different origin represent discrete entities. We compared clinicopathologic features and outcomes following surgical resection of LMS stratified by site of origin.Patients with LMS undergoing resection at a single institution were retrospectively reviewed. Clinicopathologic variables were compared across sites. Survival was calculated using the Kaplan-Meier method and compared using log-rank and Cox regression analyses.From 1983 to 2011, 138 patients underwent surgical resection for LMS. Retroperitoneal and uterine LMS were larger, higher grade, and more commonly associated with synchronous metastases. However, disease-specific survival, recurrence-free survival, and recurrence patterns were not significantly different across the four sites. Synchronous metastases (HR 3.20, P 0.001), but not site of origin, size, grade, or margin status, were independently associated with worse DSS. A significant number of recurrences and disease-related deaths were noted beyond 5 years.Although larger and higher grade, retroperitoneal and uterine LMS share similar survival and recurrence patterns with their trunk and extremity counterparts. LMS of various anatomic sites may not represent distinct disease processes based on clinical outcomes. The presence of metastatic disease remains the most important prognostic factor for LMS.