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 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 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 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.

Evaluation of choroidal thickness, macular thickness, and aqueous flare after cataract surgery in patients with and without diabetes: a prospective randomized study.

BACKGROUND: In diabetic eyes, various choroidal abnormalities are noted in addition to changes in the retinal circulation, and the risk of increased aqueous flare and retinal thickening after cataract surgery is higher in diabetic eyes. Inflammation caused by surgery induces breakdown of the blood-retinal barrier and affects the retina, although the influence on the choroid is unknown. Several researchers have evaluated the choroidal thickness (CT) after cataract surgery in patients with diabetes; however, the results are inconsistent. The purpose of this study was to evaluate the influence of uneventful small-incision phacoemulsification cataract surgery on the subfoveal choroidal thickness (SCT), the central macular thickness (CMT), and aqueous flare in patients with diabetes. METHODS: This study included 59 randomly selected eyes (33 eyes of patients with diabetes and 26 eyes of control patients without diabetes) undergoing small-incision cataract surgery. Among the diabetic eyes, 26 were without diabetic retinopathy, and the remaining eyes had non-proliferative diabetic retinopathy. Aqueous flare, CMT, and SCT measurements were performed before and at 1 week, 1 month, and 3 months after surgery. RESULTS: The postoperative CMT continued to increase significantly until 3 months in both groups. Although the CMT was more in patients with diabetes than in patients without diabetes during the follow-up period, there was no significant difference between the two groups. The aqueous flare value increased until 3 months after surgery in both groups. Although the increase was significant at 3 months after surgery in patients with diabetes, the increase in controls was not significant. The aqueous flare values differed significantly between the two groups before and at 3 months after surgery. There was no significant within-group or between-group difference in pre- and postoperative SCT values. CONCLUSION: In diabetic eyes with early stage of retinopathy, even small-incision cataract surgery can induce increased aqueous flare and macular thickening until 3 months, although there is no significant change in the choroidal thickness. Further studies are essential to evaluate choroidal changes after the cataract surgery in diabetic eyes.

[Bladder-Infiltrating Sigmoid Colon Cancer Successfully Treated with Neoadjuvant Chemotherapy and Radical Resection-A Case Report].

A 71-year-old man presented with the chief complaints of constipation, melena, and weight loss, and sigmoid colon cancer was suspected on lower gastrointestinal endoscopy. The cancer was diagnosed as RAS wild type adenocarcinoma(tub2)on biopsy. Abdominal contrast-enhanced CT revealed a mass with a maximum diameter of 55mm in the sigmoid colon; therefore, bladder infiltration was suspected. The Group 1 lymph nodes were bulky, with a maximum diameter of 50 mm, and No. 253 lymph node was enlarged. No fistulas were found on cystoscopy. The sigmoid colon cancer was cT4b(bladder), N3, M0, cStage Ⅲc. After performing a colostomy, neoadjuvant chemotherapy with mFOLFOX6 plus panitumumab was started. Radical surgery was performed after 3 courses of chemotherapy. The clinical treatment effect was PR, and the final histopathologi- cal examination revealed ypT3, ypN0(0/17), R0, ypStageⅡa. The therapeutic effect was Grade 2a. Postoperative adjuvant chemotherapy was performed for 6 months with mFOLFOX, and there have been no signs of cancer recurrence for 9 postoperative months. We experienced a case of colon cancer with suspected bladder infiltration, successfully treated with neoadjuvant chemotherapy and radical surgery.

[A Case of Long-Term Survival in a Patient with Advanced Gastric Cancer with Virchow's Lymph Node Metastasis Which Received Multidisciplinary Treatment].

We report a case of long-term survival in a 75-year-old male with advanced gastric cancer and Virchow's lymph node metastasis[cT3N3M1(LYM)H0P0, cStage Ⅳ]which received multidisciplinary treatment. Over 1 year and 6 months, 5 courses of S-1 plus CDDP, 14 courses of S-1 plus docetaxel, and 3 courses of S-1 plus CPT-11 were administered. Following chemotherapy, FDG-PET/CT showed FDG uptake only in the primary tumor and regional lymph nodes. Total gastrectomy and D2 dissection were performed. The pathological diagnosis was Type 5, 55×50 mm, L, Less, tub1>tub2, T3, int, INF b, ly2, v1, pPM0, pDM0, pN2(3/29), HER2(-). S-1 was used as adjuvant chemotherapy. Four years and 7 months after resection, cervical lymph node swelling was detected. The cervical lymph node was resected, followed by radiotherapy administration(56 Gy/28 Fr). No relapse occurred, and the patient has survived more than 7 years and 1 month and 8 years and 11 months after conversion surgery and diagnosis, respectively.

[A Case Report of Accessory Breast Cancer in the Right Axillary Region].

An 80-year-old woman visited a previous hospital complaining of a lump in the right axillary region. Because it was suspected of accessory breast cancer from the findings of image inspection, she was referred for surgery. Based on mammography and ultrasonography, both bilateral mammary glands were reported normal, but an irregular mass was found in the right axillary region. Resection biopsy showed adenocarcinoma like invasive ductal carcinoma. In addition, ER and PgR were positive. With a preoperative diagnosis of accessory breast cancer, she underwent wide local resection of the right axillary region with lymph-node dissection(Level Ⅰ), and local pedicle flap formation. Histopathological findings revealed that the tumor was composed of invasive ductal carcinoma. The center of tumor was consisted of ductal tissue discontinuous with normal mammary gland. So, a diagnosis of accessory breast cancer in the right axillary region was confirmed. She is currently in recurrence-free survival. Accessory breast cancer is relatively rare. We report a case of accessory breast cancer in the axillary region with some review of the literature.

Cyclin-dependent kinase 5 promotes proteasomal degradation of the 5-HT1A receptor via phosphorylation.

Serotonin (5-HT) is a major neurotransmitter in mammalian brains and is involved in brain development and psychiatric disorders. The 5-HT1A receptor (5-HT1AR) is a G-protein-coupled receptor (GPCR) associated with an inhibitory G-protein (Gi) with the widest and most abundant expression. It is not known; however, how expression or activity of 5-HTlAR is regulated. We studied here phosphorylation of 5-HT1AR by cyclin-dependent kinase 5 (Cdk5), a neuron-specific membrane-bound Ser/Thr kinase that is activated by binding of the p35 Cdk5 activator. 5-HT1AR was phosphorylated by the Cdk5-p35 complex at Thr314 in the third cytoplasmic loop. The phosphorylation stimulated the degradation of 5-HT1AR by the proteasome, resulting in neutralization of the inhibitory action of 5-HT1AR on intracellular cAMP concentration. These results suggest that Cdk5-p35 modulates 5-HT signaling through phosphorylation-dependent degradation of 5-HTlAR.

[Measures to Ensure Safety of Docetaxel plus Ramucirumab for Advanced Non-Small-Cell Lung Cancer as the Second- or Later-Line].

With the standpoint ofref ining the chemotherapy regimen, we retrospectively reviewed adverse events encountered by the initial 10 cases during the first course of docetaxel plus ramucirumab for non-small-cell lung cancer that progressed after platinum-based chemotherapy. Febrile neutropenia(FN)was observed in 40% ofcases, and a halfofall patients experienced oral mucositis, including 2 Grade 3 cases. These results were concordant with a previous randomized phaseⅡstudy on Japanese patients. We amended the treatment regimen by adding the prophylactic use ofpegf ilgrastim. Post-amendment, FN was not observed in all 10 cases. However, the frequency and severity of chemotherapy-induced oral mucositis were not affected; Therefore, some patients discontinued treatment due to this toxicity as well as diarrhea. In conclusion, prophylactic granulocyte-colony stimulating factor is considered effective for reducing the risk of FN. Further intervention by an oral care team is required to validate our findings.

[A Case Report of Long-Term Survival of Metastatic Breast Cancer Treated with Mohs Paste and Systemic Therapy].

The patient was a 75-year-old woman who had experienced left breast cancer(BT plus AX)in 1988. Local recurrences in the skin of the left chest wall appeared and were treated with operation, radiotherapy, and systemic therapy. Twenty-four years later, she developed continuous bleeding due to skin metastasis of the breast cancer and received Mohs chemosurgery and continued systemic therapy. After using Mohs paste 10 times, the skin surface healed and dried up. Improving the quality of life of patients with several symptoms such as skin cancer or metastatic skin lesions is essential in multidisciplinary therapy and Mohs paste was useful for the local control of the unresectable skin lesion.

[A Case of a Bulky Axillary Ectopic Breast Cancer Which Successfully Resected after Chemotherapy(Docetaxel)].

A 78-year-old woman presented with a right axillary mass.With an incisional biopsy a diagnosis of invasive ductal carcinoma was achieved.In the whole body search, any primary focus including the breast was unclear, advanced occult breast cancer with supraclavicular lymph node metastases was diagnosed.Administration of 3 courses of docetaxel achieved disappearance of supraclavicular lymph node and reduction of an axillary mass.Right axillary lymph node dissection could be successfully performed.Pathological report showed a right ectopic cancer with right axillary lymph node metastases.The patient has been well without any relapse for 3 years.

[Prolonged Survival Achieved with Surgical Resection and Multidisciplinary Therapy for Acinar Cell Carcinoma of the Pancreas with Liver Metastases].

We report 2 cases of prolonged survival achieved with surgical resection and multidisciplinary therapy for acinar cell carcinoma of the pancreas with liver metastases.Case 1: The patient was a 55-year-old woman.She presented with upper right abdominal pain and anemia.We diagnosed a tumor originating from the pancreas and multiple liver metastases.To avoid death caused by bleeding from the tumor, we performed pancreaticoduodenectomy and right-hemi hepatectomy, and a rapid diagnosis of acinar cell carcinoma of the pancreas was confirmed intraoperatively.After the hospital discharge, we administered hepatic intra-arterial chemotherapy and performed microwave ablation for the remnant liver metastases.Additionally, systemic chemotherapy with gemcitabine was administered; however, multiple metastases of the lung and liver became uncontrollable and she died 2 and half years postoperatively.Case 2: The patient was a 42-year-old woman.Through a medical checkup, gastric varix and elevated tumor markers were detected.The examination revealed a tumor at the tail of the pancreas and liver metastasis.We performed distal pancreatomy and partial liver resection.The pathological diagnosis was acinar cell carcinoma and liver metastasis.We administered adjuvant chemotherapy by using gemcitabine and achieved 5 years of relapse-free survival.The prognosis of ACC is better than that for PDAC.However, prognosis of unresectable cases is still unfavorable.Therapeutic strategies including aggressive surgical resection for metastatic ACC are worthy of consideration.

[A Case of Sigmoid Colon Cancer with Locally Advanced Infiltration Curatively Resected after CapeOX Therapy].

A 68-year-old man presented with malaise and abdominal swelling.Lower gastrointestinal endoscopy revealed a type 2 circumferential sigmoid colon cancer.Computed tomography suggested the cancer infiltrating bladder and abdominal wall with abscess.Because of locally advanced infiltration, the patient was treated with capecitabine plus oxaliplatin(CapeOX) plus bevacizumab therapy after loop-colostomy.After 2 courses of chemotherapy, a CT revealed tumor reduction and increased abscess, which was punctured drainage.After 4 courses of chemotherapy, a CT revealed abscess reduction, we tried to operation.Sigmoidectomy with combined resection of abdominal wall and bladder total hysterectomy and fascia lata grafting were performed.The pathological diagnosis was tub1, T4b, ly2, v2, PN0, N0, M0, Stage II, pR0, Grade I a.We reported a case of curative resection of locally advanced sigmoid colon cancer treated with combined resection of bladder and abdominal wall after CapeOX therapy.