Adjuvant Chemoradiation in Resected Biliary Adenocarcinoma: Evaluation of SWOG S0809 with a Large National Database.

BACKGROUND: There is a paucity of evidence supporting the use of adjuvant radiation therapy in resected biliary cancer. Supporting evidence for use comes mainly from the small SWOG S0809 trial, which demonstrated an overall median survival of 35 months. We aimed to use a large national database to evaluate the use of adjuvant chemoradiation in resected extrahepatic bile duct and gallbladder cancer. METHODS: Using the National Cancer Database, we selected patients from 2004 to 2017 with pT2-4, pN0-1, M0 extrahepatic bile duct or gallbladder adenocarcinoma with either R0 or R1 resection margins, and examined factors associated with overall survival (OS). We examined OS in a cohort of patients mimicking the SWOG S0809 protocol as a large validation cohort. Lastly, we compared patients who received chemotherapy only with patients who received adjuvant chemotherapy and radiation using entropy balancing propensity score matching. RESULTS: Overall, 4997 patients with gallbladder or extrahepatic bile duct adenocarcinoma with available survival information meeting the SWOG S0809 criteria were selected, 469 of whom received both adjuvant chemotherapy and radiotherapy. Median OS in patients undergoing chemoradiation was 36.9 months, and was not different between primary sites (p = 0.841). In a propensity score matched cohort, receipt of adjuvant chemoradiation had a survival benefit compared with adjuvant chemotherapy only (hazard ratio 0.86, 95% confidence interval 0.77-0.95; p = 0.004). CONCLUSION: Using a large national database, we support the findings of SWOG S0809 with a similar median OS in patients receiving chemoradiation. These data further support the consideration of adjuvant multimodal therapy in resected biliary cancers.

Recurrence patterns after complex multimodality therapy and hepatic arterial infusion for colorectal liver metastases: A reflection of biology and technique.

BACKGROUND AND METHODS: We characterized colorectal liver metastasis recurrence and survival patterns after surgical resection and intraoperative ablation ± hepatic arterial infusion pump (HAIP) placement. We estimated patterns of recurrence and survival in patients undergoing contemporary multimodal treatments. Between 2017 and 2021, patient, tumor characteristics, and recurrence data were collected. Primary outcomes included recurrence patterns and survival data based on operative intervention. RESULTS: There were 184 patients who underwent hepatectomy and intraoperative ablation. Sixty patients (32.6%) underwent HAIP placement. A total of 513 metastases were ablated, median total of 2 ablations per patient. Median time to recurrence was 31 [22-40] months. Recurrence patterns included tumor at ablative margin on first scheduled postoperative imaging (8, 4.3%), local tumor recurrence at ablative site (69, 37.5%), and non-ablated liver tumor recurrence (38, 20.6%). In patients who underwent HAIP placement, the rate of liver recurrence was reduced (45% vs 70.9%, p = 0.0001). Median overall survival was 64 [41-58] months and prolonged survival was associated with HAIP treatment (85 [66-109] vs 60 [51-70] months. CONCLUSIONS AND DISCUSSION: Hepatic recurrence is common and combination of intraoperative ablation and HAIP treatments were associated with prolonged survival. These data may reflect patient selection however, future work will clarify preoperative tumor and patient characteristics that may better predict recurrence expectations.

Tumor and Peritoneum-Associated Macrophage Gene Signature as a Novel Molecular Biomarker in Gastric Cancer.

A spectrum of immune states resulting from tumor resident macrophages and T-lymphocytes in the solid tumor microenvironment correlates with patient outcomes. We hypothesized that in gastric cancer (GC), macrophages in a polarized immunosuppressive transcriptional state would be prognostic of poor survival. We derived transcriptomic signatures for M2 (M2TS, MRC1; MS4A4A; CD36; CCL13; CCL18; CCL23; SLC38A6; FGL2; FN1; MAF) and M1 (M1TS, CCR7; IL2RA; CXCL11; CCL19; CXCL10; PLA1A; PTX3) macrophages, and cytolytic T-lymphocytes (CTLTS, GZMA; GZMB; GZMH; GZMM; PRF1). Primary GC in a TCGA stomach cancer dataset was evaluated for signature expressions, and a log-rank test determined overall survival (OS) and the disease-free interval (DFI). In 341 TCGA GC entries, high M2TS expression was associated with histological types and later stages. Low M2TS expression was associated with significantly better 5-year OS and DFI. We validated M2TS in prospectively collected peritoneal fluid of a GC patient cohort (n = 28). Single-cell RNA sequencing was used for signature expression in CD68+CD163+ cells and the log-rank test compared OS. GC patients with high M2TS in CD68+CD163+ cells in their peritoneal fluid had significantly worse OS than those with low expression. Multivariate analyses confirmed M2TS was significantly and independently associated with survival. As an independent predictor of poor survival, M2TS may be prognostic in primary tumors and peritoneal fluid of GC patients.

Conversion to open surgery in obese patients undergoing minimally invasive distal pancreatectomy: results from a multicenter analysis.

BACKGROUND: Although minimally invasive distal pancreatectomy (MIDP) is considered a standard approach it still presents a non-negligible rate of conversion to open that is mainly related to some difficulty factors, as obesity. The aim of this study is to analyze the preoperative factors associated with conversion in obese patients with MIDP. METHODS: In this multicenter study, all obese patients who underwent MIDP at 18 international expert centers were included. The preoperative factors associated with conversion to open surgery were analyzed. RESULTS: Out of 436 patients, 91 (20.9%) underwent conversion to open, presenting higher blood loss, longer operative time and similar rate of major complications. Twenty (22%) patients received emergent conversion. At univariate analysis, the type of approach, radiological invasion of adjacent organs, preoperative enlarged lymphnodes and ASA ≥ III were significantly associated with conversion to open. At multivariate analysis, robotic approach showed a significantly lower conversion rate (14.6 % vs 27.3%, OR = 2.380, p = 0.001). ASA ≥ III (OR = 2.391, p = 0.002) and preoperative enlarged lymphnodes (OR = 3.836, p = 0.003) were also independently associated with conversion. CONCLUSION: Conversion rate is significantly lower in patients undergoing robotic approach. Radiological enlarged lymphnodes and ASA ≥ III are also associated with conversion to open. Conversion is associated with poorer perioperative outcomes, especially in case of intraoperative hemorrhage.

Using Oncolytic Virus to Retask CD19-Chimeric Antigen Receptor T Cells for Treatment of Pancreatic Cancer: Toward a Universal Chimeric Antigen Receptor T-Cell Strategy for Solid Tumor.

BACKGROUND: Chimeric antigen receptor (CAR) T cells targeting the B-cell antigen CD19 are standard therapy for relapsed or refractory B-cell lymphoma and leukemia. CAR T cell therapy in solid tumors is limited due to an immunosuppressive tumor microenvironment and a lack of tumor-restricted antigens. We recently engineered an oncolytic virus (CF33) with high solid tumor affinity and specificity to deliver a nonsignaling truncated CD19 antigen (CD19t), allowing targeting by CD19-CAR T cells. Here, we tested this combination against pancreatic cancer. STUDY DESIGN: We engineered CF33 to express a CD19t (CF33-CD19t) target. Flow cytometry and ELISA were performed to quantify CD19t expression, immune activation, and killing by virus and CD19-CAR T cells against various pancreatic tumor cells. Subcutaneous pancreatic human xenograft tumor models were treated with virus, CAR T cells, or virus+CAR T cells. RESULTS: In vitro, CF33-CD19t infection of tumor cells resulted in >90% CD19t cell-surface expression. Coculturing CD19-CAR T cells with infected cells resulted in interleukin-2 and interferon gamma secretion, upregulation of T-cell activation markers, and synergistic cell killing. Combination therapy of virus+CAR T cells caused significant tumor regression (day 13): control (n = 16, 485 ± 20 mm 3 ), virus alone (n = 20, 254 ± 23 mm 3 , p = 0.0001), CAR T cells alone (n = 18, 466 ± 25 mm 3 , p = NS), and virus+CAR T cells (n = 16, 128 ± 14 mm 3 , p < 0.0001 vs control; p = 0.0003 vs virus). CONCLUSIONS: Engineered CF33-CD19t effectively infects and expresses CD19t in pancreatic tumors, triggering cell killing and increased immunogenic response by CD19-CAR T cells. Notably, CF33-CD19t can turn cold immunologic tumors hot, enabling solid tumors to be targetable by agents designed against liquid tumor antigens.

Diffuse-Type Histology Is Prognostic for All Siewert Types of Gastroesophageal Adenocarcinoma.

PURPOSE: The optimal treatment for gastroesophageal junction adenocarcinoma (GEJA) remains controversial. We evaluated the treatment patterns and outcomes of patients with locally advanced GEJA according to the histological type. MATERIALS AND METHODS: We conducted a single-institution retrospective cohort study of patients with locally advanced GEJA who underwent curative-intent surgical resection between 2010 and 2020. Perioperative therapies as well as clinicopathologic, surgical, and survival data were collected. The results of endoscopy and histopathological examinations were assessed for Siewert and Lauren classifications. RESULTS: Among the 58 patients included in this study, 44 (76%) were clinical stage III, and all received neoadjuvant therapy (72% chemoradiation, 41% chemotherapy, 14% both chemoradiation and chemotherapy). Tumor locations were evenly distributed by Siewert Classification (33% Siewert-I, 40% Siewert-II, and 28% Siewert-III). Esophagogastrectomy (EG) was performed for 47 (81%) patients and total gastrectomy (TG) for 11 (19%) patients. All TG patients received D2 lymphadenectomy compared to 10 (21%) EG patients. Histopathological examination showed the presence of 64% intestinal-type and 36% diffuse-type histology. The frequencies of diffuse-type histology were similar among Siewert groups (37% Siewert-I, 36% Siewert-II, and 33% Siewert-III). Regardless of Siewert type and compared to intestinal-type, diffuse histology was associated with increased intraabdominal recurrence rates (P=0.03) and decreased overall survival (hazard ratio, 2.33; P=0.02). With a median follow-up of 31.2 months, 29 (50%) patients had a recurrence, and the median overall survival was 50.5 months. CONCLUSIONS: Present in equal proportions among Siewert types of esophageal and gastric cancer, a diffuse-type histology was associated with high intraabdominal recurrence rates and poor survival. Histopathological evaluation should be considered in addition to anatomic location in the determination of multimodal GEJA treatment strategies.

Outpatient and Ambulatory Extended Recovery Robotic Hepatectomy: Multinational Study of 307 Cases.

BACKGROUND: For open minor hepatectomy, morbidity and recovery are dominated by the incision. The robotic approach may transform this "incision dominant procedure" into a safe outpatient procedure. STUDY DESIGN: We audited outpatient (less than 2 midnights) robotic hepatectomy at 6 hepatobiliary centers in 2 nations to test the hypothesis that the robotic approach can be a safe and effective short-stay procedure. Establishing early recovery after surgery programs were active at all sites, and home digital monitoring was available at 1 of the institutions. RESULTS: A total of 307 outpatient (26 same-day and 281 next-day discharge) robotic hepatectomies were identified (2013 to 2023). Most were minor hepatectomies (194 single segments, 90 bi-segmentectomies, 14 three segments, and 8 four segments). Thirty-nine (13%) were for benign histology, whereas 268 were for cancer (33 hepatocellular carcinoma, 27 biliary, and 208 metastatic disease). Patient characteristics were a median age of 60 years (18 to 93 years), 55% male, and a median BMI of 26 kg/m 2 (14 to 63 kg/m 2 ). Thirty (10%) patients had cirrhosis. One hundred eighty-seven (61%) had previous abdominal operation. Median operative time was 163 minutes (30 to 433 minutes), with a median blood loss of 50 mL (10 to 900 mL). There were no deaths and 6 complications (2%): 2 wound infections, 1 failure to thrive, and 3 perihepatic abscesses. Readmission was required in 5 (1.6%) patients. Of the 268 malignancy cases, 25 (9%) were R1 resections. Of the 128 with superior segment resections (segments 7, 8, 4A, 2, and 1), there were 12 positive margins (9%) and 2 readmissions for abscess. CONCLUSIONS: Outpatient robotic hepatectomy in well-selected cases is safe (0 mortality, 2% complication, and 1.6% readmission), including resection in the superior or posterior portions of the liver that is challenging with nonarticulating laparoscopic instruments.

Management considerations for the surgical treatment of Colorectal Cancer during the Global COVID-19 pandemic

The COVID-19 pandemic requires to conscientiously weigh ''timely surgical intervention'' for colorectal cancer against efforts to conserve hospital resources and protect patients and health care providers. Professional societies provided ad-hoc guidance at the outset of the COVID-19 pandemic on deferral of surgical and perioperative interventions, but these lack specific parameters to determine the optimal timing of surgery. Using the GRADE system, published evidence was analyzed to generate weighted statements for stage, site, acuity of presentation, and hospital setting to specify when surgery should be pursued, the time and duration of oncologically acceptable delays, and when to utilize nonsurgical modalities to bridge the waiting period. Colorectal cancer surgeries­prioritized as emergency, urgent with imminent emergency or oncologically urgent, or elective­were matched against the phases of the pandemic. Surgery in COVID-19-positive patients must be avoided. Emergent and imminent emergent cases should mostly proceed unless resources are exhausted. Standard practices allow for postponement of elective cases and deferral to nonsurgical modalities of stage II/ III rectal and metastatic colorectal cancer. Oncologically urgent cases may be delayed for 6(­12) weeks without jeopardizing oncological outcomes. Outside established principles, administration of nonsurgical modalities is not justified and increases the vulnerability of patients. The COVID-19 pandemic has stressed already limited health care resources and forced rationing, triage, and prioritization of care in general, specifically of surgical interventions. Established guidelines allow for modifications of optimal timing and type of surgery for colorectal cancer during an unrelated pandemic.

International consensus statement on robotic pancreatic surgery

The robotic surgical system has been applied to various types of pancreatic surgery. However, controversies exist regarding a variety of factors including the safety, feasibility, efficacy, and cost-effectiveness of robotic surgery. This study aimed to evaluate the current status of robotic pancreatic surgery and put forth experts' consensus and recommendations to promote its development. Based on the WHO Handbook for Guideline Development, a Consensus Steering Group* and a Consensus Development Group were established to determine the topics, prepare evidence-based documents, and generate recommendations. The GRADE Grid method and Delphi vote were used to formulate the recommendations. A total of 19 topics were analyzed. The first 16 recommendations were generated by GRADE using an evidence-based method (EBM) and focused on the safety, feasibility, indication, techniques, certification of the robotic surgeon, and cost-effectiveness of robotic pancreatic surgery. The remaining three recommendations were based on literature review and expert panel opinion due to insufficient EBM results. Since the current amount of evidence was low/meager as evaluated by the GRADE method, further randomized controlled trials (RCTs) are needed in the future to validate these recommendations.