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.

[A Case of Internal Hernia Incarceration of a Mesenteric Defect following Laparoscopic Ileocecal Resection].

A 75-year-old man underwent laparoscopic ileocecal and partial small bowel resections for the management of appendiceal cancer. The pathological diagnosis was cecal cancer(T4b[ileum, abdominal wall],N0[0/13], M0, pStage Ⅱc). After 4 months of surgery, he suddenly experienced abdominal pain and vomiting and was presented to our emergency room. He was diagnosed with bowel obstruction following which, conservative treatment was initiated through a nasogastric ileus tube implantation; however, he did not show any improvement. Subsequently, he underwent experimental laparotomy on the 18th day of the disease. Intraabdominal examination revealed herniated small intestine through a mesenteric defect, which was closed following repositioning of the herniated small intestine. The postoperative course was good, and the patient was discharged on the 10th day after surgery. No recurrence of intestinal obstruction has been observed after 1 year and 6 months. Closure of the mesenteric defect, although not commonly performed in laparoscopic colorectal surgery, is worth considering because of the risk of developing an internal hernia requiring surgical treatment, as in our case.

[A Case of Three Metachronous Metastases Excised Non-Simultaneously More than Six Years after Resection of Sigmoid Colon Cancer].

A 57-year-old man underwent curative resection for Stage Ⅰ sigmoid colon cancer; 6 years later, lung metastasis was detected and subsequently resected. Eight years after the first curative resection, retroperitoneal metastasis was detected and subsequently resected. Nine years after the first curative resection, a growing tumor was detected at the bottom of the right lower lobe of the lung. Partial lung resection was performed; pathological examination revealed a secondary tumor formed as a result of colon cancer metastasis. When we searched previous cases of late recurrence in colorectal cancer, the primary colorectal cancer was classified as StageⅠ or Ⅱ in more than half of the cases. Therefore, even after curative resection of Stage Ⅰ colon cancer, late recurrences may occur.

[A Case of Elderly Advanced Rectal Cancer Treated with Abdominoperineal Resection after 16 Months of Chemoradiotherapy].

An 81-year-old woman underwent preoperative chemoradiotherapy(CRT)for advanced lower rectal cancer with vaginal invasion. However, she refused surgery and received additional radiotherapy. We detected a rectal-vaginal leak, so we performed ileostomy with double orifices and chemotherapy. As the tumor and vaginal leak increased, we performed laparoscopy- assisted abdominoperineal resection and vaginal posterior wall resection after 16 months of CRT. Although adhesion occurred due to inflammation and tumor invasion after the CRT, surgery could be performed safely. Despite the advanced age of the patient, complications did not occur, and no recurrence was observed for 66 month after the surgery. In rectal cancer, operation is usually performed until 6 to 8 weeks after CRT, but in our case, the surgery was performed after a long interval, with good results. Thus, we report the case herein.

[A Case of Resected Combined Pancreatic Mixed Ductal Adenocarcinoma and Neuroendocrine Tumor].

A 63-year-old man was followed-up for diabetes mellitus. During follow-up, computed tomography(CT)showed dilatation of the main pancreatic duct in the tail of the pancreas. Abdominal enhanced CT revealed a 25 mm tumor in the body of the pancreas. Endoscopic ultrasound-fine needle aspiration(EUS-FNA)was performed, and the pathological diagnosis was adenocarcinoma. Therefore, based on the diagnosis of pancreatic body carcinoma, distal pancreatectomy with splenectomy was performed. The postoperative course was uneventful. Histological and immunohistochemical examination revealed that the tumor consisted of a ductal carcinoma and a neuroendocrine component. Therefore, combined pancreatic tumor (fT3N1M0, StageⅡB)was diagnosed. The patient subsequently received postoperative adjuvant chemotherapy(S-1 100mg/ day), and survived without recurrence 6 months after the operation. We report this case of combined pancreatic tumors with a review of the literature.

Hybrid approach with laparoscopic wall-inversion surgery and single-incision intragastric surgery for intraluminal gastrointestinal stromal tumor: A case report.

Laparoscopic wedge resection (LWR) for intraluminal gastrointestinal stromal tumor (GIST) leads to excessive resection of normal gastric wall. We report a case of GIST around the cardia successfully treated with full-thickness partial resection using a hybrid approach of laparoscopic surgery and single-incision intragastric surgery (SIIGS). A 69-year-old woman had a 5 cm intraluminal GIST at the posterior wall around the cardia. Submucosal injection of glycerin and indigo carmine was performed with transoral endoscopy. Circumferential seromuscular incision followed by placement of seromuscular sutures to invert the lesion into the stomach was performed under laparoscopy. By SIIGS, resection of the inverted mucosa and retrieval of the tumor were completed. A hybrid approach consisting of laparoscopic wall-inversion surgery and SIIGS was useful for intraluminal GIST and may expand the indications for laparoscopic wall-inversion surgery by removing size limitations.