De novo non-synonymous DPYSL2 (CRMP2) variants in two patients with intellectual disabilities and documentation of functional relevance through zebrafish rescue and cellular transfection experiments.

Collapsin response mediator protein 2 (Crmp2) is an evolutionarily well-conserved tubulin-binding cytosolic protein that plays critical roles in the formation of neural circuitry in model organisms including zebrafish and rodents. No clinical evidence that CRMP2 variants are responsible for monogenic neurogenic disorders in humans presently exists. Here, we describe two patients with de novo non-synonymous variants (S14R and R565C) of CRMP2 and intellectual disability associated with hypoplasia of the corpus callosum. We further performed various functional assays of CRMP2 variants using zebrafish and zebrafish Crmp2 (abbreviated as z-CRMP2 hereafter) and an antisense morpholino oligonucleotide [AMO]-based experimental system in which crmp2-morphant zebrafish exhibit the ectopic positioning of caudal primary (CaP) motor neurons. Whereas the co-injection of wild-type z-CRMP2 mRNA suppressed the ectopic positioning of CaP motor neurons in Crmp2-morphant zebrafish, the co-injection of R566C or S15R, z-CRMP2, which corresponds to R565C and S14R of human CRMP2, failed to rescue the ectopic positioning. Transfection experiments of zebrafish or rat Crmp2 using plasmid vectors in HeLa cells, with or without a proteasome inhibitor, demonstrated that the expression levels of mutant Crmp2 protein encoded by R565C and S14R CRMP2 variants were decreased, presumably because of increased degradation by proteasomes. When we compared CRMP2-tubulin interactions using co-immunoprecipitation and cellular localization studies, the R565C and S14R mutations weakened the interactions. These results collectively suggest that the CRMP2 variants detected in the present study consistently led to the loss-of-function of CRMP2 protein and support the notion that pathogenic variants in CRMP2 can cause intellectual disabilities in humans.

[Long-Term Suppression with First-Line Chemotherapy(FOLFIRI plus BV)for Peritoneal Metastasis].

A 72-year-old man underwent right hemicolectomy for transverse colon cancer(pT4aN1aM0, Stage ⅢB), after which he received adjuvant chemotherapy(capecitabine plus oxaliplatin[CAPOX])for 6 months. Three years after the first surgery, FDG-PET/CT revealed a tumor in the abdomen. He underwent a tumorectomy and adjuvant chemotherapy(CAPOX plus bevacizumab[BV])performed for 6 months. Two years after a tumorectomy, the CEA level rose again. He was diagnosed peritoneal metastasis again. A central venous(CV)port was implanted for access to the right internal jugular vein, and he received systemic chemotherapy(fluorouracil, Leucovorin, and irinotecan[FOLFIRI]plus BV)as an outpatient. One year after this recurrence, no peritoneal dissemination was detected by CT. Thereafter, total 49 courses of FOLFIRI plus BV were introduced, but chemotherapy was discontinued due to CV port-related infection. Three months later, low back pain appeared and became a diagnosis of spondylodiscitis. He had surgery, but follow-up CT performed 8 years after the first surgery detected multiple liver metastasis. It was considered necessary to take infection control measures during long-term chemotherapy.

The Japanese Epidemiologic Study for Perioperative Anaphylaxis, a prospective nationwide study: allergen exposure, epidemiology, and diagnosis of anaphylaxis during general anaesthesia.

BACKGROUND: Diagnosis of perioperative anaphylaxis is often challenging. This study describes the utility of a newly developed tool for identifying patients with a high possibility of anaphylaxis, and aimed to investigate the frequency of anaphylaxis with each drug during the perioperative period in Japan. METHODS: This study included patients with anaphylaxis of Grade 2 or higher severity during general anaesthesia at 42 facilities across Japan in 2019 and 2020. We developed and adopted a unique objective evaluation tool yielding a composite score for diagnosing anaphylaxis, which includes the results of skin tests and basophil activation tests, and clinical scores for perioperative anaphylaxis. The number of cases using each drug and the total number of anaphylaxis cases were investigated to calculate the frequency of anaphylaxis. RESULTS: General anaesthesia was performed in 218 936 cases, which included 55 patients with suspected perioperative anaphylaxis. The developed composite score diagnosed 43 of them with a high probability of anaphylaxis. The causative agent was identified in 32 cases. Plasma histamine levels showed high diagnostic accuracy for anaphylaxis. The top causative agents were rocuronium (10 cases in 210 852 patients, 0.005%), sugammadex (7 cases in 150 629 patients, 0.005%), and cefazolin (7 cases in 106 005 patients, 0.007%). CONCLUSIONS: We developed a composite tool to diagnose anaphylaxis, and found that the combination of tryptase levels, skin testing, and basophil activation testing results and clinical score improved the certainty of anaphylaxis diagnosis. The incidence of perioperative anaphylaxis in our study was 1 in about 5000 general anaesthesia cases. CLINICAL TRIAL REGISTRATION: UMIN000035350.

[Three Cases of Conversion Surgery Resulted in Pathological Complete Response for Unresectable Pancreatic Cancer].

Conversion surgery(CS)post chemotherapy for unresectable pancreatic cancer is often reported recently. Although it is still controversial about adaptation of CS, it could possibly be one of the useful choices of treatment for unresectable pancreatic cancer. We report 3 cases of CS which eventually turned out to be pathological complete response.

[A Case of Jejunal Ectopic Pancreas Incidentally Found in Laparoscopic Rectal Cancer Surgery].

In laparoscopic surgery, intraabdominal examination is occasionally difficult due to restriction of operative field and palpation. This is a case report of a jejunal ectopic pancreas which was incidentally found during laparoscopic surgery. A 49-year- old male underwent endoscopic mucosal resection for a rectal polyp which pathologically resulted in 5,000 µm invasion in submucosa and lymphatic invasion. Laparoscopic low anterior resection was planned for the patient as an additional treatment. During the surgery, irregular shaped tumor-like lesion was incidentally found in jejunum which was located 30 cm distal side from the ligament of Treitz. Partial resection of jejunum was also performed for pathological diagnosis. Resected jejunal lesion was pathologically diagnosed as an ectopic pancreas of Heinrich classification type Ⅰ. Ectopic pancreas is defined as pancreatic tissue which is discontinuous to pancreas, asymptomatic in most cases, but some reported cases of pancreatitis, forming fistula or cancerous change. Reporting with some literature review.

Valproic Acid-Induced Anxiety and Depression Behaviors are Ameliorated in p39 Cdk5 Activator-Deficient Mice.

Valproic acid (VPA) is a drug used for the treatment of epilepsy, seizures, migraines, and bipolar disorders. Cyclin-dependent kinase 5 (Cdk5) is a Ser/Thr kinase activated by p35 or p39 in neurons and plays a role in a variety of neuronal functions, including psychiatric behaviors. We previously reported that VPA suppressed Cdk5 activity by reducing the expression of p35 in cultured cortical neurons, leaving p39 unchanged. In this study, we asked for the role of Cdk5 in VPA-induced anxiety and depression behaviors. Wild-type (WT) mice displayed increased anxiety and depression after chronic administration of VPA for 14 days, when the expression of p35 was decreased. To clarify their relationship, we used p39 knockout (KO) mice, in which p35 is the only Cdk5 activator. When p39 KO mice were treated chronically with VPA, unexpectedly, they exhibited fewer anxiety and depression behaviors than WT mice. The effects were p39 cdk5r2 gene-dosage dependent. Together, these results indicate that Cdk5-p39 plays a specific role in VPA-induced anxiety and depression behaviors.

[A Case of Descending Colon Cancer with Virchow and Axillary Lymph Node Metastasis].

A 72-year-old man was referred to our department with suspected intestinal obstruction. CT showed irregular descending colon wall thickening. Lower endoscopy showed severe descending colon stenosis. Biopsy results were group 1. FDG accumulation of significant SUV was found in the lymph nodes on the left supraclavicular region, left axilla, right mediastinum, posterior part of the right diaphragmatic leg, around the abdominal aorta, and in the liver. The accumulation in the descending colon was not definitely neoplastic. Consequently of left axillary lymph node biopsy, axillary lymph node metastasis of colorectal cancer was suspected, and laparoscopic left semicolon resection was performed. Among the simultaneous distant colorectal cancer metastases, Virchow's and left axillary lymph node metastases are extremely rare(0.1%). We report a case of descending colon cancer with simultaneous Virchow's and left axillary lymph node metastases, with some literature discussion.

[A Case of Meningeal Carcinomatosis of Gastric Cancer Successfully Controlled with Nab-Paclitaxel].

We report a 76-year-old woman with meningeal carcinomatosis after gastric cancer surgery. During adjuvant chemotherapy, metastasis to the left axillary and Virchow's lymph node was suspected. A resection biopsy revealed gastric cancer metastasis, and PTX plus RAM therapy was started. Due to RAM adverse events, the treatment was changed to weekly nab- PTX, which was continued for about 6 months. During the 8th course, she was hospitalized due to worsening headache and lightheadedness. Meningeal carcinomatosis was diagnosed by cytology of CSF examination and MRI findings. She died on the 16th day after admission. Meningeal carcinomatosis has a rapidly progressive course with poor prognosis. This case shows nab-PTX may have been able to control the progression.

[A Case Report of Carcinoma of the Appendix Which Was Diagnosed with Ascites One Year after Appendicitis Operation].

A 68-year-old man visited our hospital in October 201X, giving abdominal bloating as his primary symptom. We found tenderness at McBurney's point, high WBC values from a blood test, and swelling of the appendix in a CT scan, so he was diagnosed with acute appendicitis. On the same day, he had an emergency laparoscopic appendectomy, and he made good progress and was discharged from the hospital on the fourth day after the surgery. In the histopathological examination, he was diagnosed with acute gangrenous appendicitis and examination was concluded. August of the following year, ascites accumulation was found by CT scan, and he was introduced to the department of gastroenterology of this hospital for further testing. Lower endoscopy showed swelling of the appendix root, and he was diagnosed with adenocarcinoma in the biopsy. A CT scan found increased granular concentration in the omentum. Because of a diagnosis of appendix cancer/peritoneal dissemination, he underwent laparoscopic examination in October. Nodules were found scattered in the small intestinal mesentery and the omentum, and peritoneal dissemination was suspected during intraoperative rapid diagnosis. The operation was concluded with only laparoscopic examination. Because of the diagnosis of appendix cancer/peritoneal dissemination, mFOLFOX6 plus bevacizumab was implemented. Primary appendix cancer is a relatively rare disease, often diagnosed after surgery for appendicitis, reported of here 0.03% to 0.5% of cases undergoing appendectomy. We report a case of primary appendix cancer diagnosed 1 year after appendectomy, with the discussion of the literature.

[A Case of Neuroendocrine Tumor of the Second Part of the Duodenum].

A 69-year-old woman was referred to our hospital when the upper gastrointestinal endoscopy performed by the previous physician for detailed examination of upper abdominal discomfort indicated a duodenal tumor. Upper gastrointestinal endoscopy revealed a submucosal tumor with a central depression in the descending part of the duodenum. Contrast- enhanced computed tomography of the abdomen revealed a 23 mm tumor with contrast effect in the descending part of the duodenum contralateral to the Vater papilla. There was no lymphadenopathy or distant metastasis. Duodenal gastrointestinal stromal tumor was suspected, and localized duodenectomy was planned. Intraoperative findings showed that the tumor was located in the descending part contralateral to the Vater papilla with no evidence of surrounding invasion. Localized duodenectomy was performed, and on intraoperative rapid histopathological examination, an adenocarcinoma was suspected. As a result, the surgery was changed into pancreaticoduodenectomy. Based on the results of immunostaining, neuroendocrine tumor grade 2 was diagnosed. No lymph node metastasis was observed. The patient did not have recurrence of lesion 7 months after surgery.