Multiomic molecular characterization of the response to combination immunotherapy in MSS/pMMR metastatic colorectal cancer.

BACKGROUND: Immune checkpoint inhibitor (ICI) combinations represent an emerging treatment strategies in cancer. However, their efficacy in microsatellite stable (MSS) or mismatch repair-proficient (pMMR) colorectal cancer (CRC) is variable. Here, a multiomic characterization was performed to identify predictive biomarkers associated with patient response to ICI combinations in MSS/pMMR CRC for the further development of ICI combinations. METHODS: Whole-exome sequencing, RNA sequencing, and multiplex fluorescence immunohistochemistry of tumors from patients with MSS/pMMR CRC, who received regorafenib plus nivolumab (REGONIVO) or TAS-116 plus nivolumab (TASNIVO) in clinical trials were conducted. Twenty-two and 23 patients without prior ICI from the REGONIVO and TASNIVO trials were included in this study. A biomarker analysis was performed using samples from each of these studies. RESULTS: The epithelial-mesenchymal transition pathway and genes related to cancer-associated fibroblasts were upregulated in the REGONIVO responder group, and the G2M checkpoint pathway was upregulated in the TASNIVO responder group. The MYC pathway was upregulated in the REGONIVO non-responder group. Consensus molecular subtype 4 was significantly associated with response (p=0.035) and longer progression-free survival (p=0.006) in the REGONIVO trial. CD8+ T cells, regulatory T cells, and M2 macrophages density was significantly higher in the REGONIVO trial responders than in non-responders. Mutations in the POLE gene and patient response were significantly associated in the TASNIVO trial; however, the frequencies of other mutations or tumor mutational burden were not significantly different between responders and non-responders in either trial. CONCLUSIONS: We identified molecular features associated with the response to the REGONIVO and TASNIVO, particularly those related to tumor microenvironmental factors. These findings are likely to contribute to the development of biomarkers to predict treatment efficacy for MSS/pMMR CRC and future immunotherapy combinations for treatment.

Redo laparoscopic colorectal resection: a retrospective analysis with propensity score matching.

PURPOSE: Reports of redo laparoscopic colorectal resection (Re-LCRR) are scarce. In order to evaluate the safety and short-term outcomes of Re-LCRR, we performed a matched case-control analysis of patients who underwent this procedure for colorectal cancer. METHOD: This was a retrospective, monocentric study that included patients who underwent Re-LCRR for colorectal cancer between January 2011 and December 2019 at our institution. The patients were compared to a 2:1 matched sample. Matching was conducted based on age, sex, BMI, surgical procedure, and clinical stage. RESULT: Twenty-nine patients underwent Re-LCRR (RCRR group) and were compared to 58 patients selected by matching who underwent LCRR as primary resection (PCRR group). The median of age of the 29 patients of RCRR group was 75 (IQR 56-81) years and the RCRR group included 14 males. The median operative time of the RCRR group was 167 (IQR 126-232) minutes, and the median intraoperative blood loss was 5 (IQR 2-35) ml. In the RCRR group, there were no cases that required conversion to laparotomy. The short-term outcomes of the two groups did not differ to a statistical extent with respect to operative time (p = 0.415), intraoperative blood loss (p = 0.971), rate of conversion to laparotomy (p = 0.477), comorbidity (p = 0.215), and postoperative hospital stay (p = 0.809). No patients in either group experienced postoperative anastomotic leakage or required re-operation due to postoperative complications, and there was no procedure-related death. However, in terms of oncological factors, although there was no difference in the number of cases with a positive radical margin between the two groups (p = 1.000), the number of harvested lymph nodes in the RCRR group was significantly lower than that in the PCRR group (p = 0.015) and the RCRR group included 10 cases with less than 12 harvested lymph nodes. CONCLUSION: Re-LCRR is associated with good short-term results and can be safely performed; however, the number of harvested lymph nodes is significantly reduced in comparison to primary resection cases, and further studies are needed to evaluate its long-term prognosis.

The New Era of Immunotherapy in Gastric Cancer.

Immune checkpoint inhibitors (ICIs) such as anti-programmed cell death-1 (PD-1) or programmed cell death ligand-1 (PD-L1) monoclonal antibodies have prolonged survival in various types of malignancies, including advanced gastric cancer (AGC). Nivolumab, a monoclonal anti-PD-1 antibody, showed an improvement in overall survival at a later-line therapy in unselected AGC patients in the ATTRACTION-2 study or in combination with chemotherapy as first-line therapy in the global CheckMate-649 study. Another monoclonal anti-PD-1 antibody, pembrolizumab, showed single agent activity in tumors with high microsatellite instability or high tumor mutational burden. Furthermore, a recent KEYNOTE-811 study demonstrated significant improvement in response rate with pembrolizumab combined with trastuzumab and chemotherapy for HER2-positive AGC. Based on these results, ICIs are now incorporated into standard treatment for AGC patients. As a result of pivotal clinical trials, three anti-PD-1 antibodies were approved for AGC: nivolumab combined with chemotherapy as first-line treatment or nivolumab monotherapy as third- or later-line treatment in Asian countries; pembrolizumab for previously treated microsatellite instability-high (MSI-H) or tumor mutational burden-high AGC, or pembrolizumab combined with trastuzumab and chemotherapy for HER2-positive AGC in the United States; and dostarlimab for previously treated MSI-H AGC in the United States. However, a substantial number of patients have showed resistance to ICIs, highlighting the importance of the better selection of patients or further combined immunotherapy. This review focused on molecular and immunological profiles, pivotal clinical trials of ICIs with related biomarkers, and investigational immunotherapy for AGC.

Hepatectomy for liver metastasis from rectal cancer in a patient with mitochondrial disease.

We herein report a woman who was suffering from type 1 diabetes and hearing impairment and whose mother had mitochondrial disease. Abdominal ultrasound identified a hepatic tumour, and a further examination led to the diagnosis of rectal cancer with synchronous multiple liver metastases. A genetic test led to the diagnosis of mitochondrial disease with a mitochondrial gene 3243A>G mutation. After neoadjuvant chemotherapy, we performed hepatectomy and low anterior resection in one stage. Hepatic vascular exclusion was not performed in order to prevent damage to hepatocytes due to liver ischaemia, and Ringer's lactate solution was not used to prevent lactic acidosis. The postoperative course was uneventful. Only one other case involving hepatectomy being performed in a patient with mitochondrial disease has been reported. Considering the extreme rarity of such cases and the importance of perioperative management, we report this case here.

Study protocol: a multicenter randomized controlled trial to evaluate the length of hospital stay of intracorporeal versus extracorporeal anastomosis in laparoscopic colectomy for colon cancer (CONNECT study).

BACKGROUND: Randomized controlled trials (RCTs) comparing intracorporeal anastomosis (IA) and extracorporeal anastomosis (EA) could not prove a significant reduction in postoperative stay and therefore did not provide sufficient evidence of IA. Recently, we reported a new intracorporeal anastomosis method and intracorporeal end-to-end anastomosis (IEEA). However, there have been no studies comparing intracorporeal side-to-side anastomosis (ISSA) to IEEA. PURPOSE: The main purpose of this study is to verify the superiority of IA over EA. The secondary purpose is to compare IEEA with ISSA. METHODS: Patients scheduled to undergo laparoscopic colectomy for colon cancer are recruited to the CONNECT study (multicenter, single-blind, randomized controlled study), cases in which anastomosis by the double-stapling technique is planned will be excluded. The target sample size is set at 300 cases in total, which will be randomized into 3 groups (EA, IEEA, and ISSA) in a 2:1:1 ratio. The primary endpoint is the length of postoperative hospital stay in the IA and EA groups; the secondly endpoint is the anastomotic time in IEEA and ISSA groups. We will also evaluate SF-36 ver.2, EORTC QLQ-C30 ver.3, operator stress using SURG-TLX, and the long-term outcomes, such as 5-year disease-free survival and overall survival. CONCLUSIONS: This RCT will compare the postoperative length of stay between IA and EA in twice the number of cases of previous RCTs. Concurrently, although as a secondary purpose, this will be the first study to compare IEEA and ISSA. TRIAL REGISTRATION: This trial was registered with the UMIN Clinical Trials Registry in September 2020 as UMIN000041565.

Optimal extent of central lymphadenectomy for right-sided colon cancers: is lymphadenectomy beyond the superior mesenteric vein meaningful?

PURPOSE: The objective of the current study was to assess the therapeutic benefit of lymphadenectomy according to the extent of lymphadenectomy. METHODS: Patients undergoing colectomy for right-sided colon cancer were identified. Distribution of lymph node metastases (DLNM) of 1, 2 and 3 were defined as lymph node metastasis (LNM) in the pericolic nodes, the intermediate nodes and the front of the SMV near the origin of the major artery, respectively. The therapeutic index (TI) was calculated based on the frequency of LNM and the 5 year overall survival (OS) rate of patients with LNM. RESULTS: Among 344 patients who met the inclusion criteria, roughly half had LNM (n = 150, 43.7%). While 107 (31.1%) and 30 (8.7%) patients had DLNM1 and DLNM2, respectively, only 13 patients (3.8%) were defined as DLNM3. However, there was no significant difference in 5 year OS by DLNM (DLNM1 71.1%, DLNM2 78.7%, DLNM3 50.4%, p = 0.61). Overall, the TI of lymphadenectomy for D3 area was approximately 1/10 of the TI for D1 (1.9 vs.22.1), given the low frequency of LNM (3.8%) and poor 5 year OS of patients with LNM (50.4%). This trend was consistent irrespective of primary tumor locations. CONCLUSION: The survival benefit from central lymphadenectomy namely D3 was low among patients with right-sided colon cancers.

Risk factors of chemotherapy-induced nausea and vomiting in patients with metastatic colorectal cancer: a prospective cohort study (YCOG1301).

PURPOSE: Although the effectiveness of antiemetic therapy for colorectal cancer chemotherapy has improved with further drug development, some patients still suffer from chemotherapy-induced nausea and vomiting (CINV) even with only 5-hydroxytryptamine-3 receptor antagonist and dexamethasone. The present study investigated the risk factors of CINV in patients who received chemotherapy for colorectal cancer and clarified which patients need additional neurokinin 1 receptor antagonist. METHODS: Patients with colorectal cancer receiving moderate-emetic-risk chemotherapy (MEC) were enrolled in this prospective single-arm study with intravenous palonosetron 0.75 mg and dexamethasone 9.9 mg before chemotherapy and with paroral dexamethasone 8 mg on days 2 and 3. The primary endpoint was the complete response (CR) rate for delayed-phase CINV. RESULTS: A total of 179 patients were eligible for this study. The delayed CR rate was 84.9% (152/179). There were no significant differences in any risk factors, but women with a low body mass index (BMI) (a combination of "female sex" and "BMI < 20") showed a significantly lower rate of CC (complete control) (odds ratio [OR] = 0.45, 95% confidence interval [CI] = 0.17-1.13; p = 0.039), and young patients with a low BMI (combination of "age < 65" and "BMI < 20") showed a significantly lower rate of CR (OR = 0.34, 95% CI = 0.13-0.88; p = 0.022) than the other patients. CONCLUSIONS: This study failed to identify any single risk factors associated with delayed CINV in patients who received chemotherapy for advanced colorectal cancer. However, combinations of "thin and women" or "young and thin patients" might be possible predictive conditions, thus, candidates for NK1 receptor antagonist administration in MEC. Further investigations are required to develop criteria for the supplementation of NK1 receptor antagonist.