BRAF V600E-induced distinct DNA damage response defines the therapeutic potential of p53 activation for TP53 wild-type colorectal cancer.

BRAF V600E, one of the most frequent mutations in the MAPK pathway, confers poor prognosis to colorectal cancers (CRCs), partly because of chemotherapeutic resistance. Oncogene-induced DNA damage responses (DDRs) that primarily activate p53 are important mechanistic barriers to the malignant transformation of cells; however, the mechanism underlying this impairment in cancer remains unknown. Here, we evaluated the responses of BRAFV600E-induced DDRs in two CRC cell lines, SW48 and LIM1215, both of which harbor wild-type TP53, KRAS, and BRAF. BRAFV600E transduction exhibited distinct phenotypes in these cells: SW48 cell proliferation markedly decreased, whereas that of LIM1215 increased. BRAFV600E expression induced the activation of oncogene-induced DDR signaling in SW48 cells, but not in LIM1215 cells, whereas chemotherapeutic agents similarly activated DDRs in both cell lines. Knockdown experiments revealed that these responses in SW48 cells were mediated by p53-p21 pathway activation. Comet assay (both alkaline and neutral) revealed that BRAFV600E increased single-strand breaks to the same extent in both cell lines; however, in case of LIM1215 cells, it only facilitated double-strand breaks. Furthermore, the proliferation of LIM1215 cells, wherein no oncogene-induced DDRs occurred, was synergistically inhibited upon MDM2 inhibitor-mediated p53 activation combined with MEK inhibition. Taken together, these distinct DDR signaling responses highlight the novel characteristics of BRAFV600E-mutated CRC cells and define the therapeutic potential of p53 activation combined with MAPK inhibition against TP53 wild-type CRC harboring a BRAFV600E mutation.

Surgery for multiple gastric gastrointestinal stromal tumors and large esophageal diverticulum related to germline mutation of the KIT gene: a case report.

BACKGROUND: Familial gastrointestinal stromal tumors (GISTs) are mesenchymal tumors of the digestive tract caused by germline gain-of-function mutations in the KIT gene or platelet-derived growth factor receptor alpha gene (PDGFRA). These mutations cause not only multiple GISTs but also diffuse hyperplasia of interstitial cells of Cajal (ICCs), which is related to esophageal motility disorder. CASE PRESENTATION: A 53-year-old man was referred to our hospital because of anemia and dysphagia. Fifteen years earlier, he had undergone a laparoscopic partial gastrectomy for multiple gastric GISTs with a germline mutation in exon 17 of the KIT gene. An upper gastrointestinal endoscopy revealed that the patient had multiple gastric GISTs and a large esophageal diverticulum directly above the esophagogastric junction. The largest gastric tumor was 7 cm, with a delle that might cause bleeding. Because the patient presented with dysphagia, we performed video-assisted thoracic esophagectomy and laparoscopic-assisted proximal gastrectomy simultaneously. The patient had survived without metastasis for 4 years after surgery and dysphagia had improved. CONCLUSIONS: This is the first report of successful laparoscopic-thoracoscopic surgery for a patient with familial gastric GISTs accompanied with a large esophageal diverticulum.

Feasibility and learning curve for robotic surgery in a small hospital: A retrospective cohort study.

Robotic surgery rates, typified by the use of the da Vinci Surgical System, have increased in recent years. However, robotic surgery is mostly performed in large hospitals and has not been fully implemented in small hospitals. Therefore, we aimed to verify the feasibility of robotic surgery in small hospitals and verify the number of cases in which perioperative preparation for robotic surgery is stable by creating a learning curve in small hospitals. Forty robot-assisted rectal cancer surgeries performed in large and small hospitals by a surgeon with extensive experience in robotic surgery were validated. Draping and docking times were recorded as perioperative preparation times. Unexpected surgical interruptions, intraoperative adverse events, conversion to laparoscopic or open surgery, and postoperative complications were recorded. Cumulative sum analysis was used to derive the learning curve for perioperative preparation time. Draping times were significantly longer in the small hospital group (7 vs 10 minutes, P = .0002), while docking times were not significantly different (12 vs 13 minutes, P = .098). Surgical interruptions, intraoperative adverse events, and conversions were not observed in either group. There were no significant differences in the incidence of severe complications (25% [5/20] vs 5% [1/20], P = .184). In the small hospital group, phase I of the draping learning curve was completed in 4 cases, while phase I of the docking learning curve was completed in 7 cases. Robotic surgery is feasible for small hospitals, and the preoperative preparation time required for robotic surgery stabilizes relatively early.

Simultaneous colonic metastasis of advanced gastric cancer: a case report.

BACKGROUND: Although distant metastasis in gastric cancer can be present at the time of the initial diagnosis, colonic metastasis is extremely rare. This report describes a case of simultaneous colonic metastasis of advanced gastric cancer. CASE PRESENTATION: The patient was a 78-year-old woman with nausea and epigastric pain. Upper gastrointestinal endoscopy revealed an advanced invasive ulcerative tumor in the lesser curvature of the stomach extending from the anterior to the middle portion. Colonoscopy revealed a 4-mm polyp-like lesion in the mid-transverse colon; therefore, a polypectomy was performed. Both gastric and colonic tumors showed poorly differentiated adenocarcinoma with signet ring cell carcinoma. After providing informed consent, the patient underwent a total gastrectomy. Histologic examination showed similar morphologic features of both gastric and colonic tumors. Immunohistochemistry staining showed that these tumor cells were positive for cytokeratin (CK) 7 and negative for CK20. CONCLUSIONS: This was an extremely rare case of simultaneous colonic metastasis of advanced gastric cancer. Because missed metastasis can result in a poorer prognosis, we propose a systemic search including colonoscopy for patients with advanced gastric cancer, especially cases involving poorly differentiated adenocarcinoma or signet ring cell carcinoma.

[A Case of Descending Colon Cancer with Distant Metastasis That Was Controlled Severe Side Effects of Chemotherapy and Achieved Long-Term CR].

A 69-year-old male patient with descending colon cancer with para-aortic lymph node metastasis underwent surgery to resect the primary tumor. After the surgery mFOLFOX6 plus panitumumab was introduced. Because 2 times drug-induced lung disease and Stevens Johnson syndrome were occurred, changes in chemotherapy regimen were required. 18 months after administration, complete response was achieved. The chemotherapy was discontinued 48 months after administration. He is alive without recurrence for 32 months after completion of treatment.

Low G9a expression is a tumor progression factor of colorectal cancer via IL-8 promotion.

The histone methyltransferase G9a is expressed in various types of cancer cells, including colorectal cancer (CRC) cells. Interleukin 8 (IL)-8, also known as C-X-C motif chemokine ligand 8 (CXCL8), is a chemokine that plays a pleiotropic function in the regulation of inflammatory responses and cancer development. Here, we examined the relationship between G9a and IL-8 and the clinical relevance of this association. We immunohistochemically analyzed 235 resected CRC samples to correlate clinical features. Samples with high G9a expression had better overall survival and relapse-free survival than those with low G9a expression. Univariate and multivariate analyses demonstrated that low G9a expression remained a significant independent prognostic factor for increased disease recurrence and decreased survival (P < 0.05). G9a was expressed at high levels in commercially available CRC cell lines HCT116 and HT29. Knockdown of G9a by siRNA, shRNA or the G9a-specific inhibitor BIX01294 upregulated IL-8 expression. The number of spheroids was significantly increased in HCT116 cells with stably suppressed G9a expression, and the number of spheroids was significantly decreased in HCT116 cells with stably suppressed IL-8 expression. Thus, the suppression of IL-8 by G9a may result in a better prognosis in CRC cases with high G9a expression. Furthermore, G9a may suppress cancer stemness and increase chemosensitivity by controlling IL-8. Therefore, G9a is a potential novel marker for predicting CRC prognosis, and therapeutic targeting of G9a in CRC should be controversial.

High postoperative carcinoembryonic antigen as an indicator of high-risk stage II colon cancer.

Postoperative carcinoembryonic antigen (post-CEA) has recently been reported to be a reliable prognostic factor for colon cancer. However, most clinicians decide whether or not to conduct adjuvant chemotherapy (AC) for stage II colon cancer according to major guidelines, which do not include post-CEA in their high-risk criteria. The present study aimed to assess post-CEA in stage II colon cancer for which the significance of AC is unknown. The present study analyzed 199 consecutive patients with stage II colon cancer who underwent curative surgery between January 2007 and December 2016. The CEA value was considered high when it was ≥5.0 ng/ml. The prognostic value of high post-CEA values was assessed. Overall, 19 patients exhibited high post-CEA levels. Kaplan-Meier survival curve analysis demonstrated that patients with high post-CEA levels had significantly worse relapse-free survival (RFS) and overall survival (OS) than those with normal post-CEA [RFS, 63.5 (high post-CEA) vs. 88.0% (normal post-CEA), P=0.003; OS, 76.5 (high post-CEA) vs. 96.8% (normal post-CEA), P<0.001]. Multivariate analysis demonstrated that high post-CEA remained a significant independent risk factor for worse RFS [hazard ratio (HR), 3.98; P=0.006]. The same was also demonstrated for patients without AC (HR, 5.43; P=0.008). To the best of our knowledge, the present study was the first to demonstrate that high post-CEA levels may be an indicator of high-risk stage II colon cancer, even for patients without AC. These results highlight the need for a multicenter prospective study.

Grip strength as a predictor of postoperative delirium in patients with colorectal cancers.

Background: The population is aging rapidly, and the population of patients who undergo surgeries is aging, too. Elderly patients have much risk of postoperative delirium, which increases the number of adverse events. The aim of this study was to investigate the risk factors of postoperative delirium in elderly patients with colorectal cancer. Methods: We conducted a retrospective cohort analysis of consecutive patients aged 70 years and older who underwent surgeries for colorectal cancer at our department in the period from May 2012 to October 2019. We investigated the correlation between the incidence of postoperative delirium and Comprehensive Geriatric Assessment (CGA) scores, comorbidities, and perioperative factors. Postoperative delirium was retrospectively diagnosed by checking clinical records. Results: Postoperative delirium was diagnosed in 36 of 271 patients (13.3%) with colorectal cancer. Among many comorbidities, only renal disease was significantly associated with postoperative delirium. Among the items in the CGA, age; Mini-Mental State Exam (MMSE), Barthel Index, Instrumental Activities of Daily Living (IADL), Vitality Index, and Geriatric Depression Scale (GDS) scores; and grip strength were associated with postoperative delirium. Among perioperative factors, blood transfusion was associated with postoperative delirium. Multivariate logistic regression analysis identified older age, MMSE, GDS, and grip strength as significant independent risk factors for postoperative delirium. Conclusions: This single-center retrospective observational study demonstrated that grip strength is an independent predictor of postoperative delirium, along with age, MMSE, and GDS.