Multiple gastrointestinal stromal tumors caused by a novel germline KIT gene mutation (Asp820Gly): a case report and literature review.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract; most of them have gain-of-function mutations of the KIT gene. There have been rare cases of families with multiple GISTs, that had autosomal dominant germline KIT mutations. Here, we present a case of multiple GISTs caused by a novel germline KIT mutation. Intraoperatively, the main tumor was present in the body of the stomach, and multiple small nodules were detected mainly in the upper and middle part of the gastric wall; several nodules were also present in the small bowel wall. The main tumor and surrounding nodules were resected. DNA sequencing of the tumor tissue, adjacent normal mucosal tissue, and peripheral blood leukocytes revealed that the patient had germline Asp820Gly mutation in exon 17 of the KIT gene. This is the first case with germline Asp820Gly mutation in exon 17 of the KIT gene.

Systemic steroid application for treatment of edematous anastomotic stenosis following delta-shaped anastomosis in laparoscopic distal gastrectomy: a case report.

BACKGROUND: Delta-shaped anastomosis is a common method of intracorporeal gastroduodenostomy in totally laparoscopic distal gastrectomy. One common postoperative complication of this procedure is anastomotic stenosis, and endoscopic balloon dilatation is a major remedy for such complications. Other treatment strategies are necessary to manage unsuccessful endoscopic balloon dilatation. CASE PRESENTATION: We present a case where systemic steroid treatment was applied in sustained anastomotic stenosis after endoscopic balloon dilatation. We performed delta-shaped anastomosis in laparoscopic distal gastrectomy to treat early-stage gastric cancer in a patient. The patient experienced abdominal pain post-surgery; subsequent investigation revealed edematous anastomotic stenosis. The stenosis sustained even after endoscopic balloon dilatation and local steroid injection. Consequently, we applied systemic steroid treatment. CONCLUSION: Systemic steroid treatment improved the stenosis and no recurrence was observed. These results suggest that systemic steroid application could be useful to treat anastomotic stenosis.

[Surgical Dissection for an Abdominal Para-Aortic Lymph Node Recurrence after Curative Resection for Early Gastric Cancer - Report of a Case].

A 72-year-old man underwent endoscopic submucosal dissection for early gastric cancer at antrum in July 2015. The histopathological examination revealed an adenocarcinoma invading the deep submucosal layer(SM2)with lymphatic invasion, consistent with the diagnosis of non-curative resection. Additional surgery was recommended, and he underwent laparoscopic distal gastrectomy in August 2015. The histopathological examination of resected specimen revealed there were no lymph node metastases, and postoperative diagnosis was Stage I A. However, 8 months after the surgery, abdominal enhanced computed tomography(CT)revealed an enlargement of para-aortic lymph node. Positron emission tomography-CT showed high accumulation at the enlarged lymph node. A para-aortic lymph node metastasis was suspected, and laparoscopic lymph node dissection was performed in July 2016. The histopathological examination revealed lymph node metastasis of gastric cancer. He was given systematic chemotherapy using S-1 plus cisplatin after the surgery, and has been followed-up without recurrences for 21 months after the first operation. Although recurrence of the para-aortic lymph nodes was assumed as part of a systemic metastasis, some population certainly benefit from multidisciplinary treatment including surgical approach.

[A Case of Recurrent Colorectal Cancer with Bilateral Ovarian Metastases That Were Reduced with Regorafenib Therapy].

A 63-year-old woman had recurrences of metastatic rectal cancer in the lung, peritoneum, and ovary. Regorafenib was administered at 160mg/day as third-line chemotherapy. The patient developed Grade(Gr)3 hand-foot syndrome(HFS) and Gr 2 rash, but the abdominal distension and pain were relieved by the 1st course. Analgesics could be reduced and regorafenib was administrated at reduced dosage. The patient received keishi-bukuryo-gan(EK-25)and sai-rei-tou(TJ-114) for HFS. At the beginning of therapy, ovarian metastases were not reduced and showed poor contrast enhancement on CT. Serum levels of lactate dehydrogenase(LDH)and tumor markers were increased. During the 4th course of therapy, ovarian metastases tended to shrink and serum levels of LDH and tumor markers were decreased. Ovarian metastases showed a partial response(PR)after the 6th course. Lung metastases showed a progressive disease during the 2nd course, but a PR after the 3rd course, and were not apparent after the 6th course. Reduction of metastases was maintained at 16 months after the start of therapy, and HFS was assessed at Gr 2 or lower. Physical, laboratory, and imaging findings should be carefully evaluated prior to long-term administration of regorafenib.

Glycolysis in gastrointestinal stromal tumor: a brief overview.

Gastrointestinal stromal tumor (GIST) is the most prevalent mesenchymal tumor of the digestive tract. Its growth is primarily influenced by mutations in KIT or PDGFRA. Surgery is the primary treatment option for GIST; however, KIT inhibitors, such as imatinib, are used for inoperable cases. Resistance to imatinib is an upcoming challenge, especially because the effectiveness of alternative drugs is limited. Enhancement of the glycolysis pathway in cancer cells has been identified as a key feature in cancer. This unique metabolic activity has implications on tumor growth, prognosis, and resistance to therapy, even in GIST. Members of the glucose transporter (GLUT) family (particularly GLUT-1) play a significant role in GIST progression and response to treatment. Diagnostic imaging using 18F-fluorodeoxyglucose positron emission tomography/computed tomography, which enables visualization of glucose metabolism, can aid in GIST diagnosis and risk assessment. The interplay between glycolysis and GIST can lead to the development of various therapeutic strategies, especially those involving glycolysis-related molecules, such as hexokinase and lactate dehydrogenase. However, further research is required to understand the full spectrum of glycolysis in GIST and its therapeutic potential. Herein, we present an exhaustive overview and analysis of the role of glycolysis in GIST, especially as a therapeutic target.

Antitumor effects of chemically modified miR-143 lipoplexes in a mouse model of pelvic colorectal cancer via myristoylated alanine-rich C kinase substrate downregulation.

Replenishing tumor-suppressor miRNAs (TS-miRNAs) is a potential next-generation nucleic acid-based therapeutic approach. Establishing an effective miRNA delivery system is essential to successful TS-miRNA therapy. To overcome vulnerability to RNA nucleases, we previously developed a chemically modified miRNA143-3p (CM-miR-143). In clinical practice, colorectal cancer (CRC) pelvic recurrence is an occasional challenge following curative resection, requiring a novel therapy because reoperative surgery poses a significant burden to the patient. Hence, we considered the use of CM-miR-143 as an alternative treatment. In this study, we used a mouse model bearing pelvic CRC adjacent to the rectum and investigated the anticancer effects of CM-miR-143 lipoplexes formulated from miRNA and a cationic liposome. Compared with commercial synthetic miR-143, CM-miR-143 lipoplexes accumulated heavily in regions of the pelvic CRC tumor where the blood flow was high. As a result, systemic administration of CM-miR-143 lipoplexes improved animal survival by significantly suppressing pelvic CRC tumors and relieving a lethal bowel obstruction caused by rectal compression. Detailed protein analysis revealed that the myristoylated alanine-rich C kinase is a novel target for CM-miR-143 lipoplexes. Our results suggest that CM-miR-143 is a potential next-generation drug candidate in the treatment of CRC pelvic recurrence.

Recurrence of a congenital diaphragmatic hernia 57 years postoperatively: A case report and review of the literature.

RATIONALE: Postoperative recurrence of congenital diaphragmatic hernia (CDH) in adults is very rare. There is currently no precedent and no established treatment. We encountered a case of CDH which recurred 57 years, postoperatively. PATIENT CONCERNS: A 57-year-old man with dyspnea on exertion was referred to our hospital. He had undergone surgery at the same hospital for CDH when he was 46 days old. DIAGNOSIS AND INTERVENTIONS: Laboratory studies, except diagnostic imaging and spirometry, were otherwise within normal limits. He was diagnosed with recurrent CDH based on computed tomography and underwent laparoscopic surgery. OUTCOMES: His postoperative course was uneventful, and there was no recurrence on follow-up. LESSONS: We reported our encounter with a case of recurrent CDH, more than 50 years after the initial surgery. When managing diaphragmatic hernias, prompt surgical treatment, with consideration to prior surgical history for CDH, leads to satisfactory results.

Glucose transporter­1 inhibition overcomes imatinib resistance in gastrointestinal stromal tumor cells.

Imatinib mesylate (imatinib) is the primary agent of choice used to treat gastrointestinal stromal tumors (GIST). However, drug resistance to imatinib poses a major obstacle to treatment efficacy. In addition, the relationship between imatinib resistance and glycolysis is poorly understood. Glucose transporter (GLUT)­1 is a key component of glycolysis. The present study aimed to assess the potential relationship between components in the glycolytic pathway and the acquisition of imatinib resistance by GIST cells, with particular focus on GLUT­1. An imatinib­resistant GIST cell line was established through the gradual and continuous imatinib treatment of the parental human GIST cell line GIST­T1. The expression of glycolysis­related molecules (GLUT­1, hexokinase 2, pyruvate kinase M2 and lactate dehydrogenase) was assessed in parental and imatinib­resistant cells by western blotting, reverse transcription­quantitative PCR and glucose and lactate measurement kits. In addition, clinical information and transcriptomic data obtained from the gene expression omnibus database (GSE15966) were used to confirm the in vitro results. The potential effects of GLUT­1 inhibition on the expression of proteins in the glycolysis (GLUT­1, hexokinase 2, pyruvate kinase M2 and lactate dehydrogenase) and apoptosis pathways (Bcl­2, cleaved PARP, caspase-3 and caspase-9) in imatinib­resistant cells were then investigated following gene silencing and treatment using the GLUT­1 inhibitor WZB117 by western blotting. For gene silencing, the mature siRNAs for SLC2A1 were used for cell transfection. Annexin V­FITC/PI double­staining followed by flow cytometry was used to measure apoptosis whereas three­dimensional culture experiments were used to create three­dimensional spheroid cells where cell viability and spheroid diameter were measured. Although imatinib treatment downregulated GLUT­1 expression and other glycolysis pathway components hexokinase 2, pyruvate kinase M2, and lactate dehydrogenase in parental GIST­T1 cells even at low concentrations. By contrast, expression of these glycolysis pathway components in imatinib­resistant cells were increased by imatinib treatment. WZB117 administration significantly downregulated AKT phosphorylation and Bcl­2 expression in imatinib­resistant cells, whereas the combined administration of imatinib and WZB117 conferred synergistic growth inhibition effects in apoptosis assay. WZB117 was found to exert additional inhibitory effects by inducing apoptosis in imatinib­resistant cells. Therefore, the present study suggests that GLUT­1 is involved in the acquisition of imatinib resistance by GIST cells, which can be overcome by combined treatment with WZB117 and imatinib.

Anti-tumor effect of boron neutron capture therapy in pelvic human colorectal cancer in a mouse model.

Local recurrence of colorectal cancer (CRC) can occur in patients after curative resection, and additional surgical resection may therefore be required; however, this is a significant burden for patients, because additional surgical resection may necessitate the resection of other organs such as the bladder, prostate, uterus, or sacral bone. Therefore, there is a need for alternative therapeutic strategies. We focused on boron neutron capture therapy (BNCT) as a treatment modality that can selectively target tumor cells without excessive damage to normal tissues. The usefulness of BNCT to pelvic CRC remains unknown. This study investigated the anti-cancer effect of boronophenylalanine (BPA)-mediated BNCT in a previously established mouse model of pelvic recurrence of CRC. Uptake of BPA in CRC was observed both in vitro and in vivo, and the concentrations were sufficient for BNCT. Our results are the first to show that BPA-mediated BNCT prolonged the survival of experimental mice with pelvic tumors; moreover, it did not cause any obvious severe side effects in the treated animals. In conclusion, BPA-mediated BNCT could contribute to treating local recurrence of pelvic CRC.