[A Case of BRAF Mutant Cecal Cancer Treated with Encorafenib, Binimetinib, and Cetuximab Triple Therapy].

A Japanese woman in her early 70's presented to our hospital with abdominal pain and nausea. Abdominal computed tomography showed irregular wall thickening of the ileocecal region and small intestine dilatation. Colonoscopy revealed a tumor lesion at the ileocecal valve and adenocarcinoma was detected in the biopsy specimen. Accordingly, the diagnosis was cecal cancer and bowel obstruction. Right hemicolectomy was performed as palliative surgery, and laparotomy findings revealed peritoneal dissemination. The final staging was pT4a, pN2b, pM1c, pStage Ⅳc, harboring a BRAFV600E mutation. Rapid postoperative tumor progression occurred, leading to multiple liver metastases and ascites. Encorafenib, binimetinib, and cetuximab triple therapy was started as a second line regimen. The therapy was extremely effective. CA19-9 level decreased to within normal range, and the liver tumor size was visibly diminished. After receiving treatment for 2 months in outpatient care, she had to discontinue the treatment due to carcinomatous peritonitis. Unfortunately, she died 6 months after initial diagnosis. BRAF-mutated colon cancer is associated with poor prognosis. In Japan, encorafenib, binimetinib, and cetuximab triple therapy is a new BRAF targeting regimen approved in 2020. We report this clinical course in hopes of eventually achieving better outcomes for patients with this aggressive disease.

FAK loss reduces BRAFV600E-induced ERK phosphorylation to promote intestinal stemness and cecal tumor formation.

BRAFV600E mutation is a driver mutation in the serrated pathway to colorectal cancers. BRAFV600E drives tumorigenesis through constitutive downstream extracellular signal-regulated kinase (ERK) activation, but high-intensity ERK activation can also trigger tumor suppression. Whether and how oncogenic ERK signaling can be intrinsically adjusted to a 'just-right' level optimal for tumorigenesis remains undetermined. In this study, we found that FAK (Focal adhesion kinase) expression was reduced in BRAFV600E-mutant adenomas/polyps in mice and patients. In Vil1-Cre;BRAFLSL-V600E/+;Ptk2fl/fl mice, Fak deletion maximized BRAFV600E's oncogenic activity and increased cecal tumor incidence to 100%. Mechanistically, our results showed that Fak loss, without jeopardizing BRAFV600E-induced ERK pathway transcriptional output, reduced EGFR (epidermal growth factor receptor)-dependent ERK phosphorylation. Reduction in ERK phosphorylation increased the level of Lgr4, promoting intestinal stemness and cecal tumor formation. Our findings show that a 'just-right' ERK signaling optimal for BRAFV600E-induced cecal tumor formation can be achieved via Fak loss-mediated downregulation of ERK phosphorylation.

Is 10 cm ileal resection sufficient in locally advanced caecal cancer surgery?

BACKGROUND: There is no consensus as to how much ileal resection is sufficient when performing a right hemicolectomy for right colon cancers. Locally advanced caecal cancer has the highest incidence of peri-ileal lymph node metastasis. Therefore, this study investigated whether the 10 cm ileum resection suggested by the Japanese Society for Cancer of the Colon and Rectum is oncologically safe in stage II and III caecal cancer. METHODS: The prospectively collected medical records of stage II and III caecal cancer patients who underwent a right hemicolectomy with at least D2 lymph node dissection were reviewed retrospectively. The patients were divided into two groups according to the length of proximal ileal resected: group 1 (≤10 cm) and group 2 (>10 cm). Factors contributing to the 5-year overall survival (OS) were analysed. RESULTS: The study enrolled 89 patients with pathological stage II or III caecal cancer. The >10 cm group tended to be younger (P = 0.0938) with higher pathological N stages (P = 0.0899) than the ≤10 cm group. The 5-year OS did not differ between the two groups. No significant difference was found between the two groups according to stage. Age (HR = 1.06, 95% CI = 1.02-1.10, P = 0.0069) and N2 stage (HR = 5.38, 95% CI = 1.90-15.28, P = 0.0016) were significantly associated with OS in both uni- and multivariate analyses. CONCLUSIONS: There was no OS benefit to resecting >10 cm of ileum in either stage II or III caecal cancer patients. Hence, we suggest that the '10 cm rule' is sufficient for stage II and III caecal cancer patients.

[A Case of Cecal Cancer Diagnosed from Sister Mary Joseph's Nodule].

A metastatic tumor of the umbilicus is called"Sister Mary Joseph's nodule", and patients with this tumor show a poor prognosis. Sister Mary Joseph's nodule is a rare occurrence, and there are few case reports. We report a case of cecal cancer first presented with the metastatic tumor in the umbilicus. A 90-year-old woman, complained umbilical induration and foul-smelling discharge, had been treated as omphalitis for 2 months. Because her symptom didn't improve, biopsy of the umbilical tumor was performed, and the findings revealed an adenocarcinoma. She was referred to our hospital. Abdominal CT showed wall thickening in the cecum, and multiple liver metastases. Therefore, we performed lower gastrointestinal endoscopy, which revealed a cecal tumor. We performed biopsy of the tumor and the findings were consistent with adenocarcinoma. Based on these results, we diagnosed the umbilical tumor as a metastasis from the colorectal cancer. Umbilical resection and ileocecal resection were performed, and multiple peritoneal metastases was detected. Post operative course was uneventful, she died 11 months after surgery. Umbilical metastases may worsen the patient's quality of life; thus, the local resection of umbilicus was recommended positively.

[A Case of Two-Stage Radical Resection with Neoadjuvant Chemotherapy for Cecal Cancer with Synchronous Peritoneal Metastasis(P3)].

A 63-year-old female patient was diagnosed with cecal cancer(cT3, N2a, M0)and underwent surgery for the first time. Only laparoscopic ileocecal resection(D3 dissection)was performed because intraperitoneal observation revealed peritoneal metastasis around the tumor and uterus. We decided to perform a radical resection because the peritoneal metastasis was localized by FDG-PET/CT. Five courses of neoadjuvant chemotherapy(mFOLFOX6)were performed to shrink the tumor. Unrecognized peritoneal metastases were found in other areas during the second surgery. Although the extent of the peritoneal metastasis was P3, all lesions had been resected. No perioperative complications occurred, and adjuvant chemotherapy was administered to the patient. Recurrence was not observed until 6 months postoperatively.

Feasibility of endoscopic submucosal dissection for cecal tumors involving the ileocecal valve or appendiceal orifice.

BACKGROUND AND AIM: Endoscopic resection of the ileocecal valve lesions (ICVL) and peri-appendiceal orifice lesions (PAOL), is challenging. This study aimed to evaluate the feasibility of endoscopic submucosal dissection (ESD) for ICVLs and PAOLs compared with other cecal lesions (OCEL). METHODS: This was a multicenter, retrospective cohort study conducted at a cancer center hospital and two community hospitals. Non-pedunculated cecal lesions that were intended to be treated by ESD followed by at least one surveillance colonoscopy were included. The main outcome was curative resection defined as en-bloc resection and R0 resection without risk factors of metastases. The secondary outcome was co lon preservation. RESULTS: A total of 206 patients with 206 cecal lesions, including 37 ICVL, 27 PAOL, and 142 OCEL, who were to be treated with ESD were included in this study. Curative resection rates were 75.7% for ICVL, 70.4% for PAOL, and 77.5% for OCEL (P = 0.67). In the multivariate analysis of predictors of curative resection, tumor size (<40 mm) (odds ratio [OR] 2.40; 95% confidence intervals [CI], 1.14-5.04; P = 0.02) and a negative non-lifting sign (OR 6.12; 95% CI, 2.55-14.60; P < 0.01) were significant. Colon preservation was achieved for 91.9% of the ICVL, 92.6% of the PAOL, and 90.8% of the OCEL (P = 0.947). CONCLUSIONS: Based on curative resection and colon preservation rates, ESD was found to be feasible for ICVL and PAOL. Large tumor size (≥ 40 mm) and positive non-lifting signs were significant factors for non-curative resection.

Adult Intestinal Intussusception: Practical Issues and Concerns.

CASE SUMMARY: A 37-year-old woman with no relevant past medical history presented to the emergency department after a 2-day-long period of crampy abdominal pain with an inability for oral intake because of persistent vomiting. The physical examination was unremarkable. Abdominal CT scan with water-soluble oral contrast revealed an ileocecal intussusception (Fig. 1). Because the patient was hemodynamically stable and no abdominal tenderness was found, a delayed surgical intervention was planned with laparoscopic approach. During intervention, the intestinal invagination was reduced, a cecal neoplasm suspected, and a right hemicolectomy with complete mesocolic excision was performed (Fig. 2). Postoperative recovery was uneventful, with discharge on postoperative day 5. The definite pathological report showed well-differentiated colon adenocarcinoma pT2N1aMx, with 1 of 49 positive lymph nodes.

Multifocal in situ mantle cell neoplasia of the ileocecal region: a case report with simultaneous nodal and extranodal involvement.

In situ mantle cell neoplasia (ISMCN) is a rare entity of disputed clinical significance. We report an additional case, unusual by its presentation in the large intestine and its multifocal involvement of several nodal and extranodal sites. The diagnosis was made in a 46-year-old male patient from a surgical specimen resected for cecal adenocarcinoma. Gross examination showed multiple small polypoid lesions surrounding the ileocecal valve, corresponding to lymphoid aggregates with hyperplastic follicles. Numerous cyclin D1/SOX11+ lymphoid cells, harboring the t(11;14)(q13;q32) translocation, were present in the inner layers of mantle zones. The same lesions were found in the ileum, the appendix, and the regional lymph nodes. The final diagnosis was multifocal ISMCN of the ileocecal region, with both nodal and extra-nodal involvement. A simple surveillance was decided. Our observation expands the clinical spectrum of the disease and underlines the necessity to closely examine even normal-appearing reactive lymphoid tissues.

[A cecum carcinoma and liver and peritoneal lesions]. / Een caecumtumor én lever- en peritoneumafwijkingen.

A 37-year-old male presented with acute lower right abdominal pain. A CT-scan showed a cecal mass. During laparoscopic right colectomy, multiple liver lesions and peritoneal deposits were seen. Histology confirmed pT4aN0 cecum carcinoma, but the liver lesions were consistent with sarcoidosis, and the peritoneal deposits were suggestive of benign mesothelioma.

Competitive Risk Analysis of Prognosis in Patients With Cecum Cancer: A Population-Based Study.

BACKGROUND: The presence of competing risks means that the results obtained using the classic Cox proportional-hazards model for the factors affecting the prognosis of patients diagnosed with cecum cancer (CC) may be biased. OBJECTIVE: The purpose of this study was to establish a competitive risk model for patients diagnosed with CC to evaluate the relevant factors affecting the prognosis of patients, and to compare the results with the classical COX proportional risk model. METHODS: We extracted data on patients diagnosed with CC registered between 2004 and 2016 in the Surveillance, Epidemiology, and End Results (SEER) database. The univariate analysis utilized the cumulative incidence function and Gray's test, while a multivariate analysis was performed using the Fine-Gray, cause-specific (CS), and Cox proportional-hazards models. RESULTS: The 54463 eligible patients diagnosed with CC included 24387 who died: 12087 from CC and 12300 from other causes. The multivariate Fine-Gray analysis indicated that significant factors affecting the prognosis of patients diagnosed with CC include: age, race, AJCC stage, differentiation grade, tumor size, surgery, radiotherapy, chemotherapy and regional lymph nodes metastasis. Due to the presence of competitive risk events, COX model results could not provide accurate estimates of effects and false-negative results occurred. In addition, COX model misestimated the direction of association between regional lymph node metastasis and cumulative risk of death in patients diagnosed with CC. Competitive risk models tend to be more advantageous when analyzing clinical survival data with multiple endpoints. CONCLUSIONS: The present study can help clinicians to make better clinical decisions and provide patients diagnosed with CC with better support.

Proposal of a Classification System for Adenocarcinoma Involving the Ileocecal Valve (Bauhin's Valve): A Retrospective Study of 689 Right Hemicolectomized Patients.

BACKGROUND/AIM: As of 2020, adenocarcinoma arising in the ileocecal valve (ICV-A) has been examined along with cecal and right colon cancer (RCC) under the collective heading "ileocecal" tumor. We propose a new classification system for this cancer. PATIENTS AND METHODS: We retrospectively analyzed RCC patients from 2003 to 2019. The scheme was: i) Type I cancer for adenocarcinomas residing in ICV; ii) Type II, if they reside 1 to 5 mm from ICV; iii) Type III, 6 mm to 10 mm from ICV; iv) Type IV, at 1,1 to 5 cm; v) Type V, at more than 5 cm (ascending colon cancer). RESULTS: Of 689 hemicolectomized patients, there were 91 (13.2%) Type I, 87 Type II (12.6%), 38 (5.5%) Type III, 157 (22.8%) Type IV and 314 (45.6%) Type V. Each type was associated with at least one clinicopathologic feature. CONCLUSION: ICV-A was classified into five types (I-V) according to the distance from ICV. Further studies are needed in order to corroborate our findings.