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Background: Colorectal cancer leads to peritoneal metastases (CRPM) in 10% of cases. Cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion (CRS-HIPEC) improves survival. Primary tumor location and abnormalities in RAS, BRAF, and mismatch repair/microsatellite stability (MMR/MSI) may affect post-CRS-HIPEC survival, but studies have not been consistent. We estimated the effects of primary tumor site and genomic alterations on post-CRS-HIPEC survival., Methods: This retrospective cohort study included CRS-HIPEC cases for CRPM at a high-volume center from 2001 to 2020. Next-generation sequencing and microsatellite testing defined the RAS, BRAF, and MMR/MSI genotypes. Adjusted effects of tumor sidedness and genomics on survival were evaluated using a multivariable Cox proportional hazards model. We analyzed these variables' effects on progression-free survival and the effects of immune checkpoint-inhibitors., Results: A total of 250 patients underwent CRS-HIPEC with testing for RAS, BRAF, and MMR/MSI; 50.8% of patients were RAS-mutated, 12.4% were BRAF-mutated, and 6.8% were deficient-MMR/MSI-high (dMMR/MSI-H). Genomic alterations predominated in right-sided cancers. After adjustment for comorbidities and oncological and perioperative variables, rectal origin [hazard ratio (HR) 1.9, p = 0.01], RAS mutation (HR 1.6, p = 0.01), and BRAF mutation (HR 1.7, p = 0.05) were associated with worse survival. RAS mutation was also associated with shorter progression-free survival (HR 1.6, p = 0.01 at 6 months post-operatively), and dMMR/MSI-H status was associated with superior survival (HR 0.3, p = 0.01 at 2 years). dMMR/MSI-H patients receiving immune checkpoint-inhibitors trended toward superior survival., Conclusions: Rectal origin, RAS mutations, and BRAF mutations are each associated with poorer survival after CRS-HIPEC for CRPM. Patients with CRPM and dMMR/MSI-H status have superior survival. Further research should evaluate benefits of immune checkpoint-inhibitors in this subgroup., (© 2023. Society of Surgical Oncology.)

We assessed CD8 + T-cell density in 351 resected stage II to III colon cancers from 2011 to 2015 and correlated the findings with disease-free survival and survival effect of adjuvant chemotherapy. Most tumors (70%) had high/intermediate CD8 + T-cell density, and this was significantly associated with mismatch repair deficiency compared with tumors with low CD8 + T-cell density (28% vs. 13%, P =0.003). Fewer tumors with high/intermediate CD8 + T-cell density had adverse histologic features compared with tumors with low CD8 + T-cell density including high tumor budding (16% vs. 27%) and venous (22% vs. 35%), lymphatic (54% vs. 65%), and perineural (23% vs. 33%) invasion (all with P <0.05). In the stage III cohort, high/intermediate CD8 + T-cell density was an independent predictor of disease-free survival on multivariate analysis (hazard ratio: 0.39, 0.21 to 0.71 95% CI, P =0.002). For stage III patients with high/intermediate CD8 + T-cell density, adjuvant chemotherapy was significantly associated with improved disease-free survival (hazard ratio: 0.28, 0.11 to 0.74 95% CI, P =0.01) whereas stage III patients with low CD8 + T-cell density did not have improved survival with adjuvant chemotherapy. In conclusion, in stage III colon cancer, CD8 + T-cell density is an independent prognostic biomarker for disease-free survival and may help to identify patients who benefit from adjuvant chemotherapy., Competing Interests: R.K.P. is a consultant for Alimentiv, and this relationship is unrelated to the content of this manuscript. The remaining authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Peritoneal metastases portend poor prognosis in the setting of standard chemotherapy. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) improves outcomes, but relapse is common. We report a phase II trial evaluating the safety and efficacy of adjuvant αDC1 vaccination with chemokine modulation (CKM) after CRS/HIPEC., Methods: Patients undergoing CRS/HIPEC for appendiceal cancer, colorectal cancer, or peritoneal mesothelioma were enrolled. In addition to standard adjuvant chemotherapy, patients received intranodal and intradermal injections of autologous tumor-loaded αDC1 vaccine. After each vaccine booster, patients received CKM over 4 days, consisting of celecoxib, interferon (IFN)-α, and rintatolimod., Results: Forty-six patients underwent CRS/HIPEC followed by αDC1 treatment, including 24 appendiceal primaries, 20 colorectal, and 2 mesotheliomas. DC maturation was successful, with 97% expressing HLA-DR and CD86. Tumor cell recovery from peritoneal tumors was challenging, resulting in only 17% of patients receiving the target dose of αDC1. The αDC1 and CKM regimen was well tolerated. CKM successfully modulated serum inflammatory cytokine and chemokine levels. Median progression-free survival (PFS) for appendiceal primaries was 50.4, 34.2, and 8.9 months for grade 1, 2, and 3 tumors, respectively, while median PFS for colorectal cancer was 20.5 and 8.9 months for moderately and poorly differentiated tumors, respectively., Conclusions: Adjuvant autologous tumor antigen-loaded αDC1 vaccine and CKM is well tolerated. The mucinous nature of peritoneal metastases limits the feasibility of obtaining adequate autologous tumor cells. The improvement in median PFS did not meet our predefined thresholds, leading us to conclude that αDC1 vaccination is not appropriate for patients undergoing CRS/HIPEC for peritoneal metastases.

Introduction: We hypothesized that repeat cytoreductive surgery-hyperthermic intraperitoneal chemoperfusion (CRS-HIPEC) for peritoneal metastases (PM) may be associated with suboptimal resection, more frequent postoperative complications, and worse oncologic outcomes., Methods: Using a prospectively maintained database, we compared clinicopathologic, perioperative, and oncologic outcome data in patients undergoing single or repeat CRS-HIPEC procedures. The Kaplan-Meier method was used to estimate survival. Multivariate analyses identified associations with perioperative and oncologic outcomes., Results: Of the 1294 patients undergoing CRS-HIPEC procedures at our institution, only one CRS-HIPEC procedure (single HIPEC cohort) was performed in 1169 patients (90.3%), whereas 125 patients (9.7%) underwent repeat CRS-HIPEC procedures (repeat HIPEC cohort). Of the 1440 CRS-HIPEC procedures at our institution, a first CRS-HIPEC procedure was performed in 1294 patients (89.9%), whereas subsequent second, third, and fourth CRS-HIPEC procedures were performed in 125 patients (8.7%), 18 patients (1.3%), and 3 patients (0.2%), respectively. Progression-free survival (PFS) following the second CRS-HIPEC procedure was negatively impacted by shorter PFS following the first CRS-HIPEC procedure, independent of other significant variables related to the second procedure, including completeness of cytoreduction and postoperative complications. Patients undergoing multiple CRS-HIPEC procedures were not at higher risk for suboptimal resection or postoperative complications and demonstrated equivalent PFS following each successive procedure compared to the first procedure., Conclusions: Repeat CRS-HIPEC procedures for PM were not associated with suboptimal perioperative and oncologic outcomes. Our data confirmed our ability to select patients appropriately for repeat CRS-HIPEC procedures.

Emerging evidence demonstrates that autophagy and apoptosis are interconnected and their interplay greatly affects cell death. However, the key regulators in this crosstalk remain elusive. Therefore, the role of N-terminal arginylated BiP (R-BiP)/Beclin-1/p62 complex was examined in the crosstalk between apoptosis and autophagy during combination chemotherapy with mitomycin C and bortezomib using immunoblot, immunoprecipitation, and cellular imaging assays in wild-type (WT) and genetically engineered colorectal cancer cells. In addition, the tumoricidal efficacy of the combinatorial treatment in a nude mouse tumor xenograft model of colorectal cancer was assessed. Bortezomib combined with mitomycin C synergistically induced cytotoxicity and apoptosis rather than autophagy. Mechanistically, this combination inactivated Akt and subsequently induced Beclin-1 ( BECN1 ) dephosphorylation at Ser 234/295. Dephosphorylation of Beclin-1 resulted in increased cleavage of Beclin-1 and disruption of the R-BiP/Beclin-1/p62 complex, which led to switching autophagy to the synergistic induction of apoptosis. Importantly, the combination significantly suppressed LS174T intraperitoneal xenograft tumor growth, induced Akt inactivation and Beclin-1 cleavage, and decreased autophagy in vivo Moreover, the tumoricidal efficacy of the combinatorial treatment was less effective, in vitro and in vivo , in HCT116 tumors harboring a Beclin-1 caspase 8 cleavage site mutant knock-in. Implications: This study uncovers that the R-BiP/Beclin-1/p62 complex has an important role in the crosstalk between apoptosis and autophagy. The results also propose how mono-drug resistance can be overcome using potent combinations to improve anticancer therapy. Mol Cancer Res; 16(7); 1077-91. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Background: To determine if a select subgroup of patients with combined liver and peritoneal colorectal metastases would derive oncologic benefit from surgical resection as a component of multimodality treatment., Materials and Methods: We retrospectively compared 32 patients with combined colorectal peritoneal and liver metastases (CRLM) and 173 patients with peritoneal metastases only (CRPM) undergoing cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion (CRS-HIPEC). Kaplan-Meier survival curves and multivariate Cox-regression models identified prognostic factors affecting survival., Results: Major postoperative complications (Clavien-Dindo grades 3-5) occurred in 32% (CRLM) and 17% (CRPM) of patients (P = 0.08). After an estimated median follow-up from surgery of 57 mo, propensity score-adjusted median progression-free survival was 5.1 mo (CRLM) and 7.6 mo (CRPM), whereas median overall survival was 13 mo (CRLM) and 21 mo (CRPM). Multivariate Cox-regression analysis of the CRLM group identified number of liver metastases to be the only independent predictor of poor survival (hazard ratio: 2.3, P = 0.03), with a dramatic decrease in survival in patients with more than three liver metastases., Conclusions: Simultaneous resection of colorectal liver metastases at the time of cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion for peritoneal metastases may be associated with worse survival, especially in patients with more than three liver metastases., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Peritoneal metastasis in colorectal carcinoma is associated with a dismal prognosis; however, features that correlate with patterns of metastatic spread are not well characterized. We analyzed the clinicopathologic and molecular features of 166 patients with colorectal carcinomas stratified by metastases to the peritoneum or liver. Mucinous and signet ring cell differentiation were more frequently observed in colorectal carcinoma with peritoneal dissemination compared to colorectal carcinoma with liver metastasis (mucinous differentiation: 62% vs 23%, P < .001; signet ring cell differentiation: 21% vs 0%, P < .0001). The significant association of mucinous differentiation with peritoneal dissemination compared with liver metastasis was identified in patients with both synchronous and metachronous development of metastasis ( P < .01). In contrast, colorectal carcinomas with liver metastasis were more frequently low-grade (90% vs 72%, P = .005) and associated with dirty necrosis (81% vs 56%, P = .001) compared with colorectal carcinomas with peritoneal dissemination. No significant differences were identified between colorectal carcinoma with peritoneal metastasis versus liver metastasis with respect to KRAS mutations, BRAF mutation, or high levels of microsatellite instability. Patients with tumors involving the peritoneum had a significantly worse overall survival in comparison to patients with liver metastasis lacking peritoneal involvement ( P = .02). When including only those patients with peritoneal metastasis, the presence of any mucinous or signet ring cell differentiation was associated with a significantly worse overall survival ( P = .006). Our findings indicate that mucinous and signet ring cell differentiation may be histologic features that are associated with an increased risk of peritoneal dissemination and poor overall survival in patients with peritoneal metastasis.

Background: Several studies suggest that young patients may derive less oncologic benefit from surgical resection of cancers compared with older patients. We hypothesized that young patients may have worse outcomes following cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion (CRS/HIPEC) for peritoneal metastases., Methods: Perioperative and oncologic outcomes in adolescent and young adults (AYA), defined as younger than age 40 years (n = 135), undergoing CRS/HIPEC between 2001 and 2015 were reviewed and compared with middle-aged adults, defined as aged 40-65 years (n = 684)., Results: The two groups were similar with regards to perioperative characteristics except that AYA were more likely to be symptomatic at presentation (65.2 vs. 50.9%, p = 0.003), had lower Charleson comorbidity index (median 6 vs. 8, p < 0.001), were less likely to receive neoadjuvant chemotherapy (32.8 vs. 42.5%, p = 0.042), and had longer operative times (median 543 vs. 493 min, p = 0.010). Postoperative Clavien-Dindo grade 3-4 morbidity was lower in AYA (17 vs. 26%, p = 0.029), and they required fewer reoperations for complications (3.7 vs. 10.4%, p = 0.014). AYA had longer median overall survival (103.6 vs. 73.2 months, p = 0.053). In a multivariate Cox regression analysis, age was an independent predictor of improved overall survival [hazard ratio 0.705; 0.516-0.963, p = 0.028]., Conclusions: Young patients with peritoneal metastases derive similar benefits from CRS/HIPEC as middle-aged patients. Young age should not be a deterrent to consideration of CRS/HIPEC for peritoneal metastases.

Background: Hepatic artery infusion (HAI) chemotherapy can be combined with systemic chemotherapy for the treatment of isolated unresectable colorectal liver metastases (IU-CRLM) and intrahepatic cholangiocarcinoma (U-ICC). However, HAI pump placement requires a major laparotomy that may be associated with morbidity. We hypothesized that the computer-assisted robotic platform would be well suited for this procedure and report the first single institutional case series of robotic assisted HAI pump placement for primary and secondary malignancies of the liver., Methods: A retrospective review of patients who underwent robotic assisted HAI pump placement from January 2008 to January 2016. Peri-operative outcomes were evaluated., Results: A total of 24 consecutive patients underwent robotic assisted HAI pump placement. Median age was 61 years and 50% were females. Main indications were colorectal cancer = 17 (71%) and intrahepatic cholangiocarcinoma = 4 (17%). The majority (87.5%) of patients had bilobar disease with a median of 6 liver lesions. Concurrent procedures including ablation +/- resection and colectomies were performed in 58% of the patients. Median operative time was 282 min, with median blood loss of 100 ml and length of stay 6 days. Conversion to open was required in one (4%) case. Grade 3 or higher complications were seen in 13% of cases and pump related complications were seen in 21% of patients. All except one HAI pumps could be used for pump chemotherapy. CUSUM analysis of operative time indicated a learning curve of eight cases., Conclusion: Robotic assisted placement of HAI pump placement is safe, feasible, and obviates the need for major laparotomy. J. Surg. Oncol. 2016;114:342-347. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Unlabelled: Colorectal peritoneal carcinomatosis (CPC) exhibits severe tumor hypoxia, leading to drug resistance and disease aggressiveness. This study demonstrates that the combination of the chemotherapeutic agent mitomycin C with the proteasome inhibitor bortezomib induced synergistic cytotoxicity and apoptosis, which was even more effective under hypoxia in colorectal cancer cells. The combination of mitomycin C and bortezomib at sublethal doses induced activation of c-Jun NH2-terminal kinase and p38 mitogen-activated protein kinase and resulted in Bcl-xL phosphorylation at Serine 62, leading to dissociation of Bcl-xL from proapoptotic Bak. Interestingly, the intracellular level of p53 became elevated and p53 translocated to the mitochondria during the combinatorial treatment, in particular under hypoxia. The coordinated action of Bcl-xL phosphorylation and p53 translocation to the mitochondria resulted in conformational activation of Bak oligomerization, facilitating cytochrome c release and apoptosis induction. In addition, the combinatorial treatment with mitomycin C and bortezomib significantly inhibited intraperitoneal tumor growth in LS174T cells and increased apoptosis, especially under hypoxic conditions in vivo. This study provides a preclinical rationale for the use of combination therapies for CPC patients., Implications: The combination of a chemotherapy agent and proteasome inhibitor at sublethal doses induced synergistic apoptosis, in particular under hypoxia, in vitro and in vivo through coordinated action of Bcl-xL and p53 on Bak activation., (©2015 American Association for Cancer Research.)

Background: Cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) are used to treat peritoneal carcinomatosis from a variety of primary tumor sites. Little is known about the in vivo effects of CRS and HIPEC., Methods: We examined tumor and non-neoplastic peritoneal tissue samples from 38 patients undergoing CRS and HIPEC for appendiceal or colorectal carcinomatosis, using conventional histologic analysis and immunohistochemical analysis for markers of early DNA damage (phosphorylated H2AX, γH2AX) and early necrosis (extracellular HMGB1). Findings were correlated with clinicopathologic features and oncologic outcome., Results: Histologic findings corresponding with CRS and HIPEC included extensive submesothelial inflammatory infiltrate, endothelial activation, mesothelial karyolysis and surface fibrin deposition. Endothelial activation in submesothelial vessels exhibited high specificity for samples obtained following HIPEC relative to samples obtained following CRS but prior to HIPEC. Mesothelial nuclear γH2AX staining and submesothelial extracellular HMGB1 staining increased progressively following CRS and HIPEC, consistent with DNA damage and necrosis. No significant increase in tumor staining for markers was seen with CRS or HIPEC. Submesothelial HMGB1 staining was associated with increased progression-free survival on univariate analysis., Conclusions: The immediate histologic effects of CRS and HIPEC are defined and provide evidence that DNA damage and early steps of necrosis are underway in mesothelial tissues at the conclusion of the procedure. Further research will be necessary to investigate the impact of these findings on long-term oncologic outcome, and may provide insight into the downstream effects of CRS and HIPEC that could facilitate refinement of regional therapeutic regimens for carcinomatosis.

Background: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemoperfusion (HIPEC) for peritoneal carcinomatosis (PC) of colorectal origin increases survival (OS) compared to systemic chemotherapy alone. Signet ring histology demonstrates aggressive behavior with poor survival. We sought to determine whether CRS/HIPEC increases survival in this subset of patients., Methods: We reviewed 67 patients with PC of appendiceal (AP, n = 37) or colorectal origin (CRC, n = 30) with signet cell histology from a prospective database between May 2001 and August 2011. Survival analysis and multivariate Cox regression were used to determine prognostic factors for survival., Results: Complete CRS (CC-0/1) was achieved in 77 % (CRC) and 73 % (AP) of patients. Progression-free survival (PFS) and OS were 9 and 12 months in CRC and 12 and 21 months in AP patients. In the CRC group, univariate predictors of poor survival included female gender, age, American Society of Anesthesiologists score, preoperative albumin, completeness of cytoreduction, and morbidity. In a multivariate Cox regression model, incomplete cytoreduction (CC-2/3) and female gender were joint significant predictors of poor survival. In the AP group, significant univariate predictors of poor survival included higher EBL and PCI score. In a multivariate Cox regression model, blood loss of >500 ml and a body mass index of <25 kg/m(2) were joint significant predictors of poor survival., Conclusions: AP signet cell tumors demonstrate a more favorable outcome than CRC signet cell tumors after CRC/HIPEC for carcinomatosis, suggesting an underlying difference in biology. CRS/HIPEC does not confer survival benefit in colorectal signet ring carcinomatosis unless complete cytoreduction can be achieved, whereas appendiceal signet ring carcinomatosis may benefit, regardless of resectability.

We evaluated a consecutive series of signet ring cell colorectal carcinomas in an attempt to correlate the histopathologic pattern of infiltration with molecular alterations and prognosis. Of the 4760 primary colorectal carcinomas surgically resected between the years 2002 and 2012, 53 (1%) were composed of >50% signet ring cells. Of the 53 signet ring cell carcinomas, 40 (75%) were composed of >50% extracellular mucin with signet ring cells floating within pools of mucin and were subclassified as mucin-rich signet ring cell carcinomas. Thirteen (25%) carcinomas were characterized by diffusely infiltrating carcinomas with minimal to no extracellular mucin and were subclassified as mucin-poor signet ring cell carcinomas. All 13 mucin-poor signet ring cell carcinomas were either stage III or IV, whereas many cases of mucin-rich signet ring cell carcinoma were stage I or II (17 cases) (P=0.005). Compared with mucin-rich tumors, mucin-poor signet ring cell carcinomas more frequently demonstrated adverse histologic features such as lymphatic invasion (13/13, 100% vs. 22/40, 55%; P=0.002), venous invasion (6/13, 46% vs. 3/40, 8%; P=0.004), and perineural invasion (11/13, 85% vs. 9/40, 23%; P=0.0001). Twenty-three of 53 (43%) signet ring cell carcinomas demonstrated high levels of microsatellite instability (MSI-H). Twenty-two of 23 (96%) MSI-H signet ring cell carcinomas were mucin rich; only 1 MSI-H signet ring carcinoma was mucin poor (P=0.0033). Mucin-poor signet ring cell carcinoma had significantly reduced overall and recurrence-free survival compared with mucin-rich signet ring cell carcinomas (P=0.0035 and 0.0001, respectively), even when adjusting for tumor stage. Mucin-poor signet ring cell carcinoma had a higher propensity for peritoneal dissemination (5/13, 38%) compared with mucin-rich signet ring cell carcinoma (5/40, 12.5%), although this was not statistically significant (P=0.052). Finally, MSI-H and microsatellite-stable signet ring cell carcinomas had similar overall and recurrence-free survival (P=0.2266 and 0.1055, respectively), even when adjusting for tumor stage. In conclusion, we identified a unique subset of signet ring cell colorectal carcinoma with diffuse infiltration and minimal to no extracellular mucin (mucin-poor signet ring cell carcinoma), which lacks MSI-H and has a dismal prognosis with an aggressive clinical course often with peritoneal dissemination. Further, our results confirm that MSI does not affect survival in colorectal signet ring cell carcinomas.