Correlation of Morphological Appearance of Peritoneal Lesions at Laparotomy and Disease at Pathological Assessment in Patients Undergoing Cytoreductive Surgery for Peritoneal Malignancy: Results of Phase I of the PRECINCT Study in 707 Patients.

BACKGROUND: The PRECINCT (Pattern of peritoneal dissemination and REsponse to systemic Chemotherapy IN Common and uncommon peritoneal Tumors) is a prospective, multicenter, observational study. This report from phase I of PRECINCT outlines variations in recording the surgical peritoneal cancer index (sPCI) at experienced peritoneal malignancy centers and the incidence of pathologically confirmed disease in morphologically different peritoneal lesions (PL). METHODS: The sPCI was recorded in a prespecified format that included the morphological appearance of PL. Six prespecified morphological terms were provided. The surgical and pathological findings were compared. RESULTS: From September 2020 to December 2021, 707 patients were enrolled at 10 centers. The morphological details are routinely recorded at two centers, structure bearing the largest nodule, and exact size of the largest tumor deposit in each region at four centers each. The most common morphological terms used were normal peritoneum in 3091 (45.3%), tumor nodules in 2607 (38.2%) and confluent disease in 786 (11.5%) regions. The incidence of pathologically confirmed disease was significantly higher in 'tumor nodules' with a lesion score of 2/3 compared with a lesion score of 1 (63.1% vs. 31.5%; p < 0.001). In patients receiving neoadjuvant chemotherapy, the incidence of pathologically confirmed disease did not differ significantly from those undergoing upfront surgery [751 (47.7%) and 532 (51.4%) respectively; p = 0.069]. CONCLUSIONS: The sPCI was recorded with heterogeneity at different centers. The incidence of pathologically confirmed disease was 49.2% in 'tumor nodules'. Frozen section could be used more liberally for these lesions to aid clinical decisions. A large-scale study involving pictorial depiction of different morphological appearances and correlation with pathological findings is indicated.

Multiplexed immunohistochemical analysis of the immune microenvironment of biliary tract cancers pre- & post-neoadjuvant chemotherapy: case series.

Background: Neoadjuvant chemotherapy (NACT) is increasingly being used in the management of locally advanced biliary tract cancer (BTC). The evidence suggests a contributing role of tumor infiltrating immune cells in the prognosis and response. We set out to characterize immune modulation of tumor immune microenvironment in BTC following NACT. Case Description: Patients with BTC who underwent diagnostic biopsy, then NACT then resection between 2014-2018 were identified. Multiplexed immunohistochemical consecutive staining on single slide (MICSSS) analysis was performed with a series of immune markers to characterize T-cells, immune checkpoints etc. on pre- & post-NACT tumor tissue. Density was calculated for each marker. The final analysis included five patients. Median age was 48 (range, 41-56) years, with 4 female, 4 intrahepatic cholangiocarcinoma and 1 gallbladder. All patients received gemcitabine/cisplatin as NACT (median of 5 cycles). Median time from diagnosis to surgery was 4.3 (range, 1.4-7.8) months. All patients were mismatch repair proficient (pMMR). NACT on average produced a depletion of all immune markers. Given small sample size, each patient was considered their own control and changes in mean cell densities post-NACT were calculated. Patient #2 with a 40-fold increase in PD-L1 expression & 5-fold decrease in CD8:FOXP3 ratio after NACT notably had the shortest disease-free interval (DFI). Patient #3 with the longest DFI had the largest increase in CD8:FOXP3 by about 8-fold with a decrease in PD-L1. Conclusions: Preliminary results suggest NACT may differentially modulate various compartments of the immune tumor contexture despite overall cell depletion. Future studies should focus on strategies to expand immune modulation of tumor microenvironment, including immune-oncology agents to augment the effects of chemotherapy.

Genetic Clustering of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy Patients of Colorectal Origin: KRAS and Not TP53 Cluster Alterations are Associated with Poor Outcomes.

BACKGROUND: The prognostic impact of genetic mutations for patients who undergo cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) of colorectal origin (CRC) is not well defined. OBJECTIVE: We aimed to describe the genetic classifications in an unsupervised fashion, and the outcomes of this patient population. METHODS: A retrospective, bi-institutional study was performed on patients who underwent CRS-HIPEC with targeted mutation data with a median follow-up time of 61 months. Functional link analysis was performed using STRING v11.5. Genes with similar functional significance were clustered using unsupervised k-means clustering. Chi-square, Kaplan-Meier, and the log-rank test were used for comparative statistics. RESULTS: Sixty-four patients with peritoneal carcinomatosis from CRC origin underwent CRS-HIPEC between 2007 and 2022 and genetic mutation data were extracted. We identified 19 unique altered genes, with KRAS (56%), TP53 (33%), and APC (22%) being the most commonly altered; 12.5% had co-altered KRAS/TP53. After creating an interactome map, k-means clustering revealed three functional clusters. Reactome Pathway analysis on three clusters showed unique pathways (1): Ras/FGFR3 signaling; (2) p53 signaling; and (3): NOTCH signaling. Seventy-one percent of patients in cluster 1 had KRAS mutations and a median overall survival of 52.3 months (p < 0.05). CONCLUSIONS: Patients with peritoneal carcinomatosis (PC) of CRC origin who underwent CRS-HIPEC and with tumors that harbored mutations in cluster 1 (Ras/FGFR3 signaling) had worse outcomes. Pathway disruption and a cluster-centric perspective may affect prognosis more than individual genetic alterations in patients with PC of CRC origin.

Collaborative international partnership: Enabling the development of a state-of-the-art minimally invasive surgical center in rural Uganda through telementoring.

BACKGROUND: Access to minimally invasive surgery (MIS) is limited in Sub-Saharan African countries. In 2019, the Mount Sinai Department of Surgery in New York collaborated with local Ugandans to construct the Kyabirwa Surgical Center (KSC), an independent, replicable, self-sustaining ambulatory surgical center in Uganda. We developed a focused MIS training program using a combination of in-person training and supervised telementoring. We present the results of our initial MIS telementoring experience. METHODS: We worked jointly with Ugandan staff to construct the KSC in the rural province of Jinja. A solar-powered backup battery system ensured continuous power availability. Underground fiber optic cables were installed to provide stable high-speed Internet. The local Ugandan general surgeon (JOD) underwent a mini-fellowship in MIS and then trained extensively using the Fundamentals of Laparoscopic Surgery program. After a weeklong in-person session to train the Ugandan OR team, JOD performed laparoscopic cases with telementoring, which was conducted remotely by surgeons in New York via audiovisual feeds from the KSC OR. RESULTS: From October 2021 to February 2024, JOD performed 61 telementored laparoscopic operations at KSC including 37 appendectomies and 24 cholecystectomies. Feedback was provided regarding patient positioning, port placement, surgical technique, instrument use, and critical steps of the operation. There were no intra-operative complications. Postoperatively, field medical workers visited patients at home to collect follow-up information. Two superficial wound infections (3.3%) were reported in the short-term follow-up. CONCLUSION: Telementoring can be safely implemented to assist surgeons in previously underserved areas to provide advanced laparoscopic surgical care to the local patient population.

Prophylactic Cholecystectomy is Safe in Patients Undergoing Cytoreductive Surgery With Hyperthermic Intraperitoneal Chemotherapy.

BACKGROUND: While cholecystectomy is one of the most common operations performed in the United States, there is a continued debate regarding its prophylactic role in elective surgery. Particularly among patients with peritoneal carcinomatosis who undergo cytoreduction surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC), further abdominal operations may pose increasing morbidity due to intraabdominal adhesions and potential recurrence. This bi-institutional retrospective study aims to assess postoperative morbidity associated with prophylactic cholecystectomy at the time of CRS-HIPEC. METHODS: We performed a bi-institutional retrospective analysis of 578 patients who underwent CRS-HIPEC from 2011 to 2021. Postoperative outcomes among patients who underwent prophylactic cholecystectomy at the time of CRS-HIPEC were compared to patients who did not, particularly rate of bile leak, hospital length of stay, rate of Clavien-Dindo classification morbidity grade III or greater, and number of hospital re-admissions within 30 days. RESULTS: Of the 535 patients available for analysis, 206 patients (38.3%) underwent a prophylactic cholecystectomy. Of the 3 bile leaks (1.5%) that occurred among patients who underwent prophylactic cholecystectomy, all 3 occurred in patients who underwent a concomitant liver resection. There were no significant differences in hospital length of stay, postoperative morbidity, and number of hospital re-admissions among patients who underwent prophylactic cholecystectomy compared to those who did not. CONCLUSION: Prophylactic cholecystectomy in patients undergoing CRS-HIPEC is not associated with increased morbidity or increased bile leak risk compared to historical data. While the benefits of prophylactic cholecystectomy are not yet elucidated, it may be considered to avoid potential future morbid operations for biliary disease.

The adverse characteristics of hepatocellular carcinoma in the non-cirrhotic liver disproportionately disadvantage Black patients.

BACKGROUND: Black patients have higher hepatocellular carcinoma (HCC)-related mortality than White patients and more often develop HCC in non-cirrhotic liver. HCC surveillance is primarily directed toward cirrhotic patients. We aimed to characterize HCC in non-cirrhotic patients and to identify factors associated with HCC beyond Milan criteria. METHODS: Demographic, imaging, laboratory, and pathology data of HCC patients at our institution, 2003-2018, were reviewed, retrospectively. Race/ethnicity were self-reported. Cirrhosis was defined as a Fibrosis-4 score ≥3.25. RESULTS: Compared to 1146 cirrhotic patients, 411 non-cirrhotic patients had larger tumors (median 4.7 cm vs. 3.1 cm, p < 0.01) and were less likely to be within Milan criteria (42.6% vs. 57.7%, p < 0.01). Among non-cirrhotic patients, Black patients had larger tumors (4.9 cm vs. 4.3 cm, p < 0.01) and a higher percentage of poorly differentiated tumors (39.4% vs. 23.1%, p = 0.02). Among cirrhotic patients, Black patients had larger tumors (3.3 cm vs. 3.0 cm, p = 0.03) and were less likely to be within Milan criteria (52.3% vs. 83.2%, p < 0.01). In multivariable analysis, lack of commercial insurance (OR 1.45 [CI 95% 1.19-1.83], p < 0.01), male sex (OR 1.34 [CI 95% 1.05-1.70], p < 0.01), absence of cirrhosis (OR 1.58 [CI 95% 1.27-1.98], p < 0.01) and Black race/ethnicity (OR 1.34 [CI 95% 1.09-1.66], p = 0.01) were associated with HCC beyond Milan criteria. Black patients had lower survival rates than other patients (p < 0.01). CONCLUSIONS: Non-cirrhotic patients had more advanced HCC than cirrhotic patients. Black patients (with or without cirrhosis) had more advanced HCC than comparable non-Black patients and higher mortality rates. Improved access to healthcare (commercial insurance) may increase early diagnosis (within Milan criteria) and reduce disparities.

Actual 5-Year Survival After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Patients with Peritoneal Carcinomatosis of Colorectal Origin.

BACKGROUND: Cytoreductive surgery and heated intraperitoneal chemotherapy (CRS/HIPEC) improves survival compared with chemotherapy alone in patients with peritoneal carcinomatosis (PC) of colorectal (CRC) origin, however, long-term survival data are lacking. We report the actual survival of patients who underwent CRS/HIPEC for PC of CRC origin with a minimum potential 5-year follow-up period to identify factors that preclude long-term survival. METHODS: We performed a retrospective analysis of a prospective database, analyzing patients undergoing CRS/HIPEC for PC of CRC origin from 2007 to 2017. Patients with aborted CRS/HIPEC, postoperative follow-up <90 days, or non-CRC histology were excluded. Overall survival (OS) and disease-free survival (DFS) were measured from date of surgery. Surviving patients with <60 months of follow-up were censored at date of last follow-up. RESULTS: A total of 103 patients met inclusion criteria and were analyzed. CC score 0-1 was achieved in 89.3% of patients, and median peritoneal cancer index (PCI) was 9 (interquartile range [IQR] 5-17). Ninety-day mortality was 2.9%. The median follow-up of survivors was 88 months. Five-year OS was 36%, and median OS was 42.5 months. Factors independently associated with poor survival included high PCI (PCI = 14-20, hazard ratio [HR] 3.1, p = 0.007, and PCI > 20, HR 5.3, p ≤ 0.001) and incomplete CRS (CC score-2, HR 2.96, p = 0.02). Patients with low PCI (0-6) had 5-year OS 60.7%. CONCLUSIONS: Actual 5-year OS was 36% and median OS was 42.5 months. Our study demonstrates that patients with PC from CRC origin with low PCI who undergo complete surgical resection can achieve favorable long-term survival.

Preoperative Frailty and Malnutrition in Surgical Oncology Patients Predicts Higher Postoperative Adverse Events and Worse Survival: Results of a Blinded, Prospective Trial.

BACKGROUND: Frailty, a multidimensional state leading to reduced physiologic reserve, is associated with worse postoperative outcomes. Despite the availability of various frailty tools, surgeons often make subjective assessments of patients' ability to tolerate surgery. The Risk Analysis Index (RAI) is a validated preoperative frailty assessment tool that has not been studied in cancer patients with plans for curative-intent surgery. METHODS: In this prospective, surgeon-blinded study, patients who had abdominal malignancy with plans for resection underwent preoperative frailty assessment with the RAI and nutrition assessment by measurement of albumin, prealbumin, and C-reactive protein (CRP). Postoperative outcomes and survival were assessed. RESULTS: The study included 220 patients, 158 (72%) of whom were considered frail (RAI ≥21). Frail patients were more likely to be readmitted within 30 and 90 days, (16% vs. 3% [P = 0.006] and 16% vs. 5% [P = 0.025], respectively). Patients with abnormal CRP, prealbumin, and albumin experienced higher rates of unplanned intensive care unit admission (CRP [27% vs. 8%; P < 0.001], albumin [30% vs. 10%; P < 0.001], prealbumin [29% vs. 9%; P < 0.001]) and increased postoperative mortality at 90 and 180 days. Survival was similar for frail and non-frail patients. In the multivariate analysis, frailty remained an independent risk factor for readmission (hazard ratio, 5.58; 95% confidence interval, 1.39-22.15; P = 0.015). In the post hoc analysis using the pre-cancer RAI score, the postoperative outcomes did not differ between the frail and non-frail patients. CONCLUSION: In conjunction with preoperative markers of nutrition, the RAI may be used to identify patients who may benefit from additional preoperative risk stratification and increased postoperative follow-up evaluation.

Actual and perceived gender differences in virtual tumor board participation.

Introduction: Participant characteristics are known to affect group discourse and discussion outcomes. In medicine, many decisions are made by group consensus, therefore an understanding of these factors is highly relevant. We aimed to measure the effects of participant characteristics on tumor board discussions. Methods: We performed a prospective, multi-institution, quantitative study of multi-disciplinary virtual tumor board meetings. Participant characteristics included age, gender, and clinical discipline. Outcomes of interest were speech events, duration, and discourse style. Participant impressions was assessed by a post-hoc survey. Results: A total of 361 cases were discussed across 32 virtual meetings. Of the 283 attendees, 66.4 % were women, and all moderators were men. Women comprised 43 % of the 54 speakers, thus speaking less than male attendees (p < 0.001). No significant differences were detected in the duration or style of speech between men and women. Women participants commented more frequently on cases where the clinical attending was a woman (4.09 comments by women vs. 2.99 comments by men, p < 0.001), and less frequently when the attending was a man (2.48 comments by women vs. 3.20 comments by men, p < 0.001). On post hoc survey, men responded that they introduced ideas, guided discussions, and succeeded in influencing decisions significantly more than women reported that they did. Conclusion: Women physicians were underrepresented in tumor boards as moderators, speakers, and attendings of record. Women physicians commented less on men physicians' patients. Women felt less impactful than their men counterparts, despite having the same duration and style of speech. Prompted participation, moderator feedback, talking points, and limiting the number of cases can be used to balance representation in discussions.

Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy: Effects of postoperative fluids beyond the first 24 h.

BACKGROUND AND OBJECTIVES: There are no guidelines for intravenous fluid (IVF) administration after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). This study assessed rates of post-CRS/HIPEC morbidity according to perioperative IVF administration. METHODS: All patients undergoing CRS/HIPEC March 2007 to June 2018 were reviewed, recording clinicopathologic, operative, and postoperative variables. Patients were divided by peritoneal cancer index (PCI), comparing IVF volumes and types administered intraoperatively and during the first 72 h postoperatively. Optimal IVF rate cutoffs calculated using area under the receiver operating characteristic curves and Youden's index determined associations with complications. RESULTS: Overall, 185 patients underwent CRS/HIPEC, and 81 (51%) had low PCI (<10) and 77 (49%) had high PCI (≥10). In low-PCI patients, high IVF rates on postoperative days (POD) #0-2 were associated with higher overall complications: POD#0 (46% vs. 89%, p = 0.001), POD#1 (40% vs. 86%, p < 0.05), and POD#2 (42% vs. 72%, p < 0.05). High IVF rates were associated with respiratory distress (7% vs. 26%, p = 0.02) on POD#0, ileus (14% vs. 47%, p = 0.007) and intensive care unit stay (11% vs. 33%, p = 0.022) on POD#1, and ICU stay (8% vs. 33%, p = 0.003) on POD#2. CONCLUSIONS: For low PCI patients undergoing CRS/HIPEC, higher IVF rates were associated with postoperative complications. Post-CRS/HIPEC, IVF rates should be limited to prevent morbidity.

Major Postoperative Complications Limit Adjuvant Therapy Administration in Patients Undergoing Pancreatoduodenectomy for Distal Cholangiocarcinoma or Pancreatic Ductal Adenocarcinoma.

INTRODUCTION: Guidelines for perioperative systemic therapy administration in patients undergoing pancreatoduodenectomy for pancreatic adenocarcinoma (PDAC) and distal cholangiocarcinoma (dCCA) are evolving. Decisions regarding adjuvant therapy are influenced by postoperative morbidity, which is common after pancreatoduodenectomy. We evaluated whether postoperative complications are associated with receipt of adjuvant therapy after pancreatoduodenectomy. METHODS: A retrospective analysis of patients undergoing pancreatoduodenectomy for PDAC or dCCA from 2015 to 2020 was conducted. Demographic, clinicopathologic, and postoperative variables were analyzed. RESULTS: Overall, 186 patients were included-145 with PDAC and 41 with dCCA. Postoperative complication rates were similar for both pathologies (61% and 66% for PDAC and dCCA, respectively). Major postoperative complications (MPCs), defined as Clavien-Dindo >3, occurred in 15% and 24% of PDAC and dCCA patients, respectively. Patients with MPCs received lower rates of adjuvant therapy administration, irrespective of primary tumor (PDAC: 21 vs. 72%, p = 0.008; dCCA: 20 vs. 58%, p = 0.065). Recurrence-free survival (RFS) was worse for patients with PDAC who experienced an MPC [8 months (interquartile range [IQR] 1-15) vs. 23 months (IQR 19-27), p < 0.001] or who did not receive any perioperative systemic therapy [11 months (IQR 7-15) vs. 23 months (IQR 18-29), p = 0.038]. In patients with dCCA, 1-year RFS was worse for patients who did not receive adjuvant therapy (55 vs. 77%, p = 0.038). CONCLUSION: Patients who underwent pancreatoduodenectomy for either PDAC or dCCA and who experienced an MPC had lower rates of adjuvant therapy and worse RFS, suggesting that clinicians adopt a standard neoadjuvant systemic therapy strategy in patients with PDAC. Our results propose a paradigm shift towards preoperative systemic therapy in patients with dCCA.

Piperacillin-Tazobactam Compared With Cefoxitin as Antimicrobial Prophylaxis for Pancreatoduodenectomy: A Randomized Clinical Trial.

Importance: Despite improvements in perioperative mortality, the incidence of postoperative surgical site infection (SSI) remains high after pancreatoduodenectomy. The effect of broad-spectrum antimicrobial surgical prophylaxis in reducing SSI is poorly understood. Objective: To define the effect of broad-spectrum perioperative antimicrobial prophylaxis on postoperative SSI incidence compared with standard care antibiotics. Design, Setting, and Participants: Pragmatic, open-label, multicenter, randomized phase 3 clinical trial at 26 hospitals across the US and Canada. Participants were enrolled between November 2017 and August 2021, with follow-up through December 2021. Adults undergoing open pancreatoduodenectomy for any indication were eligible. Individuals were excluded if they had allergies to study medications, active infections, chronic steroid use, significant kidney dysfunction, or were pregnant or breastfeeding. Participants were block randomized in a 1:1 ratio and stratified by the presence of a preoperative biliary stent. Participants, investigators, and statisticians analyzing trial data were unblinded to treatment assignment. Intervention: The intervention group received piperacillin-tazobactam (3.375 or 4 g intravenously) as perioperative antimicrobial prophylaxis, while the control group received cefoxitin (2 g intravenously; standard care). Main Outcomes and Measures: The primary outcome was development of postoperative SSI within 30 days. Secondary end points included 30-day mortality, development of clinically relevant postoperative pancreatic fistula, and sepsis. All data were collected as part of the American College of Surgeons National Surgical Quality Improvement Program. Results: The trial was terminated at an interim analysis on the basis of a predefined stopping rule. Of 778 participants (378 in the piperacillin-tazobactam group [median age, 66.8 y; 233 {61.6%} men] and 400 in the cefoxitin group [median age, 68.0 y; 223 {55.8%} men]), the percentage with SSI at 30 days was lower in the perioperative piperacillin-tazobactam vs cefoxitin group (19.8% vs 32.8%; absolute difference, -13.0% [95% CI, -19.1% to -6.9%]; P < .001). Participants treated with piperacillin-tazobactam, vs cefoxitin, had lower rates of postoperative sepsis (4.2% vs 7.5%; difference, -3.3% [95% CI, -6.6% to 0.0%]; P = .02) and clinically relevant postoperative pancreatic fistula (12.7% vs 19.0%; difference, -6.3% [95% CI, -11.4% to -1.2%]; P = .03). Mortality rates at 30 days were 1.3% (5/378) among participants treated with piperacillin-tazobactam and 2.5% (10/400) among those receiving cefoxitin (difference, -1.2% [95% CI, -3.1% to 0.7%]; P = .32). Conclusions and Relevance: In participants undergoing open pancreatoduodenectomy, use of piperacillin-tazobactam as perioperative prophylaxis reduced postoperative SSI, pancreatic fistula, and multiple downstream sequelae of SSI. The findings support the use of piperacillin-tazobactam as standard care for open pancreatoduodenectomy. Trial Registration: ClinicalTrials.gov Identifier: NCT03269994.

Perineural Invasion of Pancreatic Ductal Adenocarcinoma is Associated with Early Recurrence after Neoadjuvant Therapy Followed by Resection.

BACKGROUND: Neoadjuvant therapy (NAT) is increasingly utilized in the treatment of pancreatic ductal adenocarcinoma (PDAC). However, there are limited data on risk factors and patterns of recurrence after surgical resection. This study aimed to analyze timing and recurrence patterns of PDAC after NAT followed by curative resection. METHODS: The medical charts of patients with PDAC treated with NAT followed by curative-intent surgical resection at a single health system from January 1, 2012 to January 1, 2020 were retrospectively reviewed. Early recurrence was defined as recurrence within 12 months of surgical resection. RESULTS: 91 patients were included and median follow up was 20.1 months. Recurrence occurred in 50 (55%) patients, with median recurrence free survival (RFS) of 11.9 months. Overall, 18 (36%) patients had local and 32 (64%) had distant recurrences. Median RFS and overall survival (OS) between local and distant recurrence were similar. Perineural invasion (PNI) and the presence of a T2 + tumor was significantly higher in recurrence group than in no recurrence group. PNI was a significant risk factor for early recurrence. CONCLUSION: After NAT and surgical resection of PDAC, disease recurrence was common, with distant metastasis being the most common. PNI was significantly higher in the recurrence group.

T1 Gastric Cancer Is Associated With a High Incidence of Regional Lymph Node Metastases.

INTRODUCTION: Early stage gastric cancer, particularly T1 disease, is associated with high recurrence-free and overall survival rates following resection with curative intent. However, rare cases of T1 gastric cancer have nodal metastasis and this is associated with poor outcomes. METHODS: Data from gastric cancer patients treated with surgical resection and D2 lymph node (LN) dissection at a single tertiary care institution from 2010 to 2020 were analyzed. Patients with early stage (T1) tumors were assessed in detail to identify variables associated with regional LN metastasis including histologic differentiation, signet ring cells, demographics, smoking history, neoadjuvant therapy, and clinical staging by endoscopic ultrasound (EUS). We used standard statistical techniques including Mann-Whitney U and Chi-squared tests. RESULTS: Of 426 patients undergoing surgery for gastric cancer, 34% (n = 146) were diagnosed with T1 disease on surgical pathology. Among 146 T1 (T1a, T1b) gastric cancers, 24 patients [(17%) T1a (n = 4), T1b (n = 20)] had histologically confirmed regional LN metastases. The age at diagnosis ranged between 19 and 91 y and 54.8% were male. Prior smoking status was not associated with nodal positivity (P = 0.650). Of the 24 patients with positive LN on final pathology, seven patients received neoadjuvant chemotherapy. EUS was performed on 98 (67%) of the 146 T1 patients. Of these patients, 12 (13.2%) had positive LN on final pathology; however, none (0/12) were detected on preoperative EUS. There was no association between node status on EUS and node status on final pathology (P = 0.113). The sensitivity of EUS for N status was 0%, specificity was 84.4%, negative predictive value was 82.2% and positive predictive value was 0%. Signet ring cells were identified in 42% of node negative T1 tumors and 64% of node positive T1 tumors (P = 0.063). For LN positive cases on surgical pathology, 37.5% had poor differentiation, 42% had lymphovascular invasion, and regional nodal metastases were associated with increasing T stage (P = 0.003). CONCLUSIONS: T1 gastric cancer is associated with a substantial risk (17%) of regional LN metastasis, when pathologically staged following surgical resection and D2 lymphadenectomy. Clinically staged N+ disease by EUS was not significantly associated with pathologically staged N+ disease in these patients.

Association of Systemic Chemotherapy Approaches With Outcomes in Appendiceal Peritoneal Metastases.

INTRODUCTION: Many patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) for appendiceal adenocarcinoma peritoneal metastases (APM) undergo preoperative systemic chemotherapy. The primary aim of this study is to evaluate differences in oncologic outcomes among two popular chemotherapy approaches in patients with APM undergoing CRS-HIPEC. METHODS: We performed a multicenter retrospective review of patients who underwent CRS-HIPEC for APM due to high or intermediate grade disease between 2013 and 2019. Patients in the total neoadjuvant therapy group (TNT) received 12 cycles of preoperative chemotherapy. Patients in the "sandwich" chemotherapy group (SAND) received six cycles of preoperative chemotherapy with a maximum of six cycles of postoperative chemotherapy. The primary outcomes were overall survival (OS) and recurrence-free survival (RFS) defined as months from date of first treatment or surgery, respectively. RESULTS: A total of 39 patients were included in this analysis, with 25 (64%) patients in the TNT group and 14 (36%) patients in the SAND group. Patients in the TNT group had a median OS of 62 mo, while median OS in the SAND group was 45 mo (P = 0.01). In addition, patients in the TNT group had significantly longer RFS compared to the SAND group (35 versus 12 mo, P = 0.03). In a multivariable analysis, TNT approach was independently associated with improved OS and RFS. CONCLUSIONS: In this multicenter retrospective analysis, a TNT approach was associated with improved overall and recurrence-free survival compared to a sandwiched chemotherapy approach in patients undergoing CRS-HIPEC for high or intermediate grade APM.

Postoperative Respiratory Failure Following Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy is Associated with Volume of Intraoperative Crystalloid Administration and Worse Survival.

BACKGROUND: Postoperative respiratory failure (PRF) is associated with increased morbidity after surgery. This retrospective study explores preoperative and perioperative risk factors associated with PRF in patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) and the resultant impact on survival. METHODS: We identified all patients who underwent CRS/HIPEC at our institution between 2007 and 2017. PRF was defined as mechanical ventilation for more than 48 h after surgery or reintubation not related to an additional procedure within the first 30 days postoperatively. The relationship between clinicopathologic variables and PRF was examined using Kaplan-Meier log-rank survival analysis and multivariable Cox regression models with 90-day, 1-year and 5-year overall survival (OS). RESULTS: Overall, 314 patients underwent CRS/HIPEC, of whom 24 patients (7.6%) developed PRF. On univariable analysis, chronic obstructive pulmonary disease (COPD) was the only preoperative risk factor associated with PRF (p = 0.049). Of the intraoperative risk factors, diaphragmatic resection (p = 0.008), Peritoneal Cancer Index (PCI) > 20 (p < 0.001), and volume of intraoperative crystalloid (p < 0.001) were all associated with PRF. On multivariable Cox regression, only intraoperative crystalloid was significantly associated with PRF (p < 0.001), with a volume above 5.3 L (area under the curve [AUC] 0.77) having a high predictive accuracy for PRF. Five-year OS was significantly decreased in patients with PRF (30.2% vs. 52.6%, hazard ratio 2.6, 95% confidence interval 1.5-4.4; p < 0.001). CONCLUSIONS: Liberal intraoperative crystalloid volume resuscitation is a potential independent, modifiable intraoperative risk factor for PRF following CRS/HIPEC that may contribute to decreased long-term OS.

A total neoadjuvant chemotherapy approach is associated with improved recurrence-free survival in patients with colorectal peritoneal metastases undergoing cytoreductive surgery and HIPEC.

BACKGROUND: The primary aim of this study is to evaluate the oncologic outcomes of two popular systemic chemotherapy approaches in patients with colorectal peritoneal metastases (CPM) undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). METHODS: We performed a dual-center retrospective review of consecutive patients who underwent CRS-HIPEC for CPM due to high or intermediate-grade colorectal cancer. Patients in the total neoadjuvant therapy (TNT) group received 6 months of preoperative chemotherapy. Patients in the "sandwich" (SAND) chemotherapy group received 3 months of preoperative chemotherapy with a maximum of 3 months of postoperative chemotherapy. RESULTS: A total of 34 (43%) patients were included in the TNT group and 45 (57%) patients in the SAND group. The median overall survival (OS) in the TNT and SAND groups were 77 and 61 months, respectively (p = 0.8). Patients in the TNT group had significantly longer recurrence-free survival (RFS) than the SAND group (29 vs. 12 months, p = 0.02). In a multivariable analysis, the TNT approach was independently associated with improved RFS. CONCLUSION: In this retrospective study, a TNT approach was associated with improved RFS, but not OS when compared with a SAND approach. Further prospective studies are needed to examine these systemic chemotherapeutic approaches in patients with CPM undergoing CRS-HIPEC.

Prolonged hypernutrition impairs TREM2-dependent efferocytosis to license chronic liver inflammation and NASH development.

Obesity-induced chronic liver inflammation is a hallmark of nonalcoholic steatohepatitis (NASH)-an aggressive form of nonalcoholic fatty liver disease. However, it remains unclear how such a low-grade, yet persistent, inflammation is sustained in the liver. Here, we show that the macrophage phagocytic receptor TREM2, induced by hepatocyte-derived sphingosine-1-phosphate, was required for efferocytosis of lipid-laden apoptotic hepatocytes and thereby maintained liver immune homeostasis. However, prolonged hypernutrition led to the production of proinflammatory cytokines TNF and IL-1ß in the liver to induce TREM2 shedding through ADAM17-dependent proteolytic cleavage. Loss of TREM2 resulted in aberrant accumulation of dying hepatocytes, thereby further augmenting proinflammatory cytokine production. This ultimately precipitated a vicious cycle that licensed chronic inflammation to drive simple steatosis transition to NASH. Therefore, impaired macrophage efferocytosis is a previously unrecognized key pathogenic event that enables chronic liver inflammation in obesity. Blocking TREM2 cleavage to restore efferocytosis may represent an effective strategy to treat NASH.