A first-in-human clinical study of laparoscopic autologous myoblast sheet transplantation to prevent delayed perforation after duodenal endoscopic mucosal dissection.

BACKGROUND: The detection rate of superficial non-ampullary duodenal epithelial tumors (SNADETs) has recently been increasing. Large tumors may contain malignant lesions and early therapeutic intervention is recommended. Endoscopic mucosal dissection (ESD) is considered a feasible treatment modality, however, the anatomical and physiological characteristics of the duodenum create a risk of postoperative perforation after ESD. METHODS: To explore whether myoblast sheet transplantation could prevent delayed perforation after ESD, a first-in-human (FIH) clinical trial of laparoscopic autologous myoblast sheet transplantation after duodenal ESD was launched. Autologous myoblast sheets fabricated from muscle tissue obtained seven weeks before ESD were transplanted laparoscopically onto the serous side of the ESD. The primary endpoints were the onset of peritonitis due to delayed perforation within three days after surgery and all adverse events during the follow-up period. RESULTS: Three patients with SNADETs ≥ 20 mm in size underwent transplantation of a myoblast sheet onto the serous side of the duodenum after ESD. In case 1, The patient's postoperative course was uneventful. Endoscopy and abdominal computed tomography revealed no signs of delayed perforation. Despite incomplete mucosal closure in case 2, and multiple micro perforations during ESD in case 3, cell sheet transplantation could prevent the postoperative massive perforation after ESD, and endoscopy on day 49 after transplantation revealed no stenosis. CONCLUSIONS: This clinical trial showed the safety, efficacy, and procedural operability of this novel regenerative medicine approach involving transplanting an autologous myoblast sheet laparoscopically onto the serosa after ESD in cases with a high risk of delayed perforation. This result indicates the potential application of cell sheet medicine in treating various abdominal organs and conditions with minimal invasiveness in the future. TRIAL REGISTRATION: jRCT, jRCT2073210094. Registered November 8 2021, https://jrct.niph.go.jp/latest-detail/jRCT2073210094 .

(R)-ketamine restores anterior insular cortex activity and cognitive deficits in social isolation-reared mice.

Chronic social isolation increases the risk of mental health problems, including cognitive impairments and depression. While subanesthetic ketamine is considered effective for cognitive impairments in patients with depression, the neural mechanisms underlying its effects are not well understood. Here we identified unique activation of the anterior insular cortex (aIC) as a characteristic feature in brain-wide regions of mice reared in social isolation and treated with (R)-ketamine, a ketamine enantiomer. Using fiber photometry recording on freely moving mice, we found that social isolation attenuates aIC neuronal activation upon social contact and that (R)-ketamine, but not (S)-ketamine, is able to counteracts this reduction. (R)-ketamine facilitated social cognition in social isolation-reared mice during the social memory test. aIC inactivation offset the effect of (R)-ketamine on social memory. Our results suggest that (R)-ketamine has promising potential as an effective intervention for social cognitive deficits by restoring aIC function.

Clinical Validation of Computer-Aided Diagnosis Software for Preventing Retained Surgical Sponges.

BACKGROUND: We previously reported the successful development of a computer-aided diagnosis (CAD) system for preventing retained surgical sponges with deep learning using training data, including composite and simulated radiographs. In this study, we evaluated the efficacy of the CAD system in a clinical setting. STUDY DESIGN: A total of 1,053 postoperative radiographs obtained from patients 20 years of age or older who underwent surgery were evaluated. We implemented a foreign object detection application software on the portable radiographic device used in the operating room to detect retained surgical sponges. The results of the CAD system diagnosis were prospectively collected. RESULTS: Among the 1,053 images, the CAD system detected possible retained surgical items in 150 images. Specificity was 85.8%, which is similar to the data obtained during the development of the software. CONCLUSIONS: The validation of a CAD system using deep learning in a clinical setting showed similar efficacy as during the development of the system. These results suggest that the CAD system can contribute to the establishment of a more effective protocol than the current standard practice for preventing the retention of surgical items.

Endoscopic mucosal ischemic index for predicting anastomotic complications after esophagectomy: a prospective cohort study.

BACKGROUND: Postoperative complications related to gastric conduit reconstruction are still common issues after McKeown esophagectomy. A novel endoscopic mucosal ischemic index is desired to predict anastomotic complications after McKeown esophagectomy. AIMS AND METHODS: The purpose of this study was to prospectively evaluate the safety and efficacy of endoscopic examinations of the anastomotic region in the acute period after esophagectomy. Endoscopic examinations were performed on postoperative days (PODs) 1 and 8. The severity of ischemia was prospectively validated according to the endoscopic mucosal ischemic index (EMII). RESULTS: A total of 58 patients were included after evaluating the safety and feasibility of the endoscopic examination on POD 1 in 10 patients. Anastomotic leakage occurred in 6 patients. Stricture occurred in 13 patients. A greater than 67% circumference and lesion length greater than 20 mm of anastomotic ischemic area (AIA) on POD 1 were associated with developing anastomotic leakage after esophagectomy (OR: 14.5; 95% CI: 1.8-306.5; P = 0.03, OR: 19.4; 95% CI: 1.7-536.8; P = 0.03). More than 67% circumferential ischemic mucosa and ischemic mucosal lengths greater than 20 mm of AIA on POD 1 were associated with developing anastomotic strictures after esophagectomy (OR: 6.4; 95% CI: 1.4-31.7; P = 0.02, OR: 5.9; 95% CI: 1.2-33.1; P = 0.03). Patients with either more than 67% circumferential ischemic mucosa or ischemic mucosal lengths greater than 20 mm of AIA on POD 1 were defined as EMII-positive patients. The sensitivity, specificity, and positive and negative predictive values of EMII positivity on POD 1 for leakage were 100%, 78.8%, 35.3%, and 100%, respectively. The sensitivity, specificity, and positive and negative predictive values of the EMII positivity on POD 1 for strictures were 69.2%, 82.2%, 52.9%, and 90.2%, respectively. CONCLUSIONS: The application of an endoscopic classification system to mucosal ischemia after McKeown esophagectomy is both appropriate and satisfactory in predicting anastomotic complications. TRIAL REGISTRATION: Clinical Trial.gov Registry, ID: NCT02937389, Registration date: Oct 17, 2015.

A case of transanal barotrauma by high-pressure compressed air leading to transverse colon perforation with extensive colon serosal tear.

INTRODUCTION AND IMPORTANCE: Compressed air is used to apply paint, wash vehicles or machines, and remove water droplets after washing the precision instrument. Barotrauma due to high-pressure compressed air is extremely rare. CASE PRESENTATION: We report a case of transverse colon perforation caused by a compressed air gun in a 20-year-old male. He used a compressed air machine to dust after work, and a coworker inserted compressed air transanally as a joke. Although he returned home once, he consulted a former hospital with worsening abdominal pain. Radiography and computed tomography (CT) revealed a massive amount of free air. The patient was admitted to our hospital. The patient underwent emergency surgery. Transverse colon perforation with extensive serosal tears and massive air bubbles inside the omental bursa were observed. Double-barrel colostomy using transverse colon perforation point for decompression and diverting the stoma at the ileum end was performed with serosal tear repair and abdominal cleaning drainage. Four months after the surgery, the patient underwent colostomy and diverting stoma closure. CLINICAL DISCUSSION: The management of colon injury due to compressed air has two aspects: tension pneumoperitoneum and colon injury. The initial management of tension pneumoperitoneum is converted to open pneumoperitoneum and early emergency operation for colon injury is recommended as soon as full-thickness perforation is diagnosed. CONCLUSION: Transanal high-pressure compressed air can cause lethal situations, and we encountered a similar case that required surgical intervention.

Rapid and chronological expression of angiogenetic genes is a major mechanism involved in cell sheet transplantation in a rat gastric ulcer model.

Introduction: Cell sheet technology has been applied in the treatment of patients with severe cardiac failure. Although the paracrine effect of cell sheets accelerating angiogenesis is thought to be the intrinsic mechanism for improvement of cardiac function, little is known about how a cell sheet would function in the abdomen. Methods: We used acetic acid-induced gastric ulcer rat model to elucidate the mechanisms of myoblast sheet transplantation in the abdomen. Myoblast sheet was implanted onto the serosal side of the gastric ulcer and the effect of sheet transplantation was analyzed. The maximal diameter of the ulcer and the changes in the gene expression of various growth factors in transplanted site was analyzed. The progenitor marker CD34 was also examined by immunohistochemistry. Results: Cell sheet transplantation accelerated the ulcer healing. qPCR showed that angiogenic growth factors were significantly upregulated around the ulcer in the transplantation group. In addition, at first, HIF-1a and SDF-1 continued to increase from 3 h after transplantation to 72 h, then VEGF increased significantly after 24 h with a slight delay. An immunohistochemical analysis showed a statistically significant increase in CD34 positivity in the tissue around the ulcer in the transplantation group. Conclusion: Myoblast sheet secreted various growth factors and cytokines immediately after transplantation onto the serosal side of artificial ulcer in the abdomen. Autonomous secretion, resulting in the time-dependent and well-orchestrated gene expression of various growth factors, plays a crucial role in the cell sheet function. Cell sheet transplantation is expected to be useful to support angiogenesis of the ischemic area in the abdominal cavity.

Cerebrocortical activation following unilateral labyrinthectomy in mice characterized by whole-brain clearing: implications for sensory reweighting.

Posture and gait are maintained by sensory inputs from the vestibular, visual, and somatosensory systems and motor outputs. Upon vestibular damage, the visual and/or somatosensory systems functionally substitute by cortical mechanisms called "sensory reweighting". We investigated the cerebrocortical mechanisms underlying sensory reweighting after unilateral labyrinthectomy (UL) in mice. Arc-dVenus transgenic mice, in which the gene encoding the fluorescent protein dVenus is transcribed under the control of the promoter of the immediate early gene Arc, were used in combination with whole-brain three-dimensional (3D) imaging. Performance on the rotarod was measured as a behavioral correlate of sensory reweighting. Following left UL, all mice showed the head roll-tilt until UL10, indicating the vestibular periphery damage. The rotarod performance worsened in the UL mice from UL1 to UL3, which rapidly recovered. Whole-brain 3D imaging revealed that the number of activated neurons in S1, but not in V1, in UL7 was higher than that in sham-treated mice. At UL7, medial prefrontal cortex (mPFC) and agranular insular cortex (AIC) activation was also observed. Therefore, sensory reweighting to the somatosensory system could compensate for vestibular dysfunction following UL; further, mPFC and AIC contribute to the integration of sensory and motor functions to restore balance.

Claustrum mediates bidirectional and reversible control of stress-induced anxiety responses.

The processing of stress responses involves brain-wide communication among cortical and subcortical regions; however, the underlying mechanisms remain elusive. Here, we show that the claustrum (CLA) is crucial for the control of stress-induced anxiety-related behaviors. A combined approach using brain activation mapping and machine learning showed that the CLA activation serves as a reliable marker of exposure to acute stressors. In TRAP2 mice, which allow activity-dependent genetic labeling, chemogenetic activation of the CLA neuronal ensemble tagged by acute social defeat stress (DS) elicited anxiety-related behaviors, whereas silencing of the CLA ensemble attenuated DS-induced anxiety-related behaviors. Moreover, the CLA received strong input from DS-activated basolateral amygdala neurons, and its circuit-selective optogenetic photostimulation temporarily elicited anxiety-related behaviors. Last, silencing of the CLA ensemble during stress exposure increased resistance to chronic DS. The CLA thus bidirectionally controls stress-induced emotional responses, and its inactivation can serve as a preventative strategy to increase stress resilience.

Highly feasible procedure for laparoscopic transplantation of cell sheets under pneumoperitoneum in porcine model.

INTRODUCTION: Cell sheet technology is one of the most successful methodologies in regenerative medicine. Various applications of cell sheets have been introduced in first-in-human studies in several clinical fields. When transplanting a cell sheet into internal organs, a relatively large incision is required for delivery due to difficulty handling the sheet. We developed a laparoscopic delivery procedure for safe and easy transplantation of cell sheets in a porcine model. METHODS: Pneumoperitoneum was established by inflation with CO2. First, to increase the strength during handling, fibrin was sprayed onto the surface of the cell sheet, and then a myoblast sheet was placed onto the newly developed carrier. The sheets were pinched with laparoscopic forceps to insert into the abdominal cavity through the laparoscopic port. Myoblast sheets were then applied to the surface of the liver, colon, small intestine, and stomach, and procedure times were measured. At three days post transplantation, a histopathological examination was performed to confirm engraftment of the sheet. The function and engraftment were also analyzed in a duodenal endoscopic submucosal dissection (ESD) model. RESULTS: The fibrin-processed myoblast sheet was able to be managed with conventional laparoscopic forceps without breaking. Despite the drastic change in air pressure by passing through the laparoscopic port, the sheets suffered no apparent damage. The transplantation procedure times did not markedly differ among transplant sites. A histopathological examination revealed thin-layered, desmin-positive cells at each transplant site. With transplantation following ESD, the engrafted myoblast sheets effectively prevented delayed perforation. CONCLUSIONS: Our procedure is simple, and the system involves a carrier made of medically fit silicon, commercially available fibrin glue and conventional laparoscopic forceps. Our procedure is a powerful tool for laparoscopical cell sheet transplantation.

Novel Computer-Aided Diagnosis Software for the Prevention of Retained Surgical Items.

BACKGROUND: Retained surgical items are a serious human error. Surgical sponges account for 70% of retained surgical items. To prevent retained surgical sponges, it is important to establish a system that can identify errors and avoid the occurrence of adverse events. To date, no computer-aided diagnosis software specialized for detecting retained surgical sponges has been reported. We developed a software program that enables easy and effective computer-aided diagnosis of retained surgical sponges with high sensitivity and specificity using the technique of deep learning, a subfield of artificial intelligence. STUDY DESIGN: In this study, we developed the software by training it through deep learning using a dataset and then validating the software. The dataset consisted of a training set and validation set. We created composite x-rays consisting of normal postoperative x-rays and surgical sponge x-rays for a training set (n = 4,554) and a validation set (n = 470). Phantom x-rays (n = 12) were prepared for software validation. X-rays obtained with surgical sponges inserted into cadavers were used for validation purposes (formalin: Thiel's method = 252:117). In addition, postoperative x-rays without retained surgical sponges were used for the validation of software performance to determine false-positive rates. Sensitivity, specificity, and false positives per image were calculated. RESULTS: In the phantom x-rays, both the sensitivity and specificity in software image interpretation were 100%. The software achieved 97.7% sensitivity and 83.8% specificity in the composite x-rays. In the normal postoperative x-rays, 86.6% specificity was achieved. In reading the cadaveric x-rays, the software attained both sensitivity and specificity of >90%. CONCLUSIONS: Software with high sensitivity for diagnosis of retained surgical sponges was developed successfully.

[A Case of Unresectable Gastric Cancer with Paraaortic Lymph Node Metastasis Treated with Conversion Therapy].

We present a case of advanced gastric cancer with paraaortic lymph node metastasis successfully treated by conversion therapy. The patient was a 71‒year‒old male. Because of paraaortic lymph node metastasis, we initiated intensive chemotherapy with S‒1, oxaliplatin, and trastuzumab. After 6 courses, CT examination revealed that the size of the primary tumor decreased, suggesting a complete response(CR). Furthermore, the metastatic lymph nodes decreased in both number and size, suggesting a partial response(PR). We continued chemotherapy, changing to S‒1 and trastuzumab only because of Grade 3 neutropenia, and conducted continuous infusion chemotherapy. After 5 courses, we performed an upper gastrointestinal endoscopy. The primary tumor recurred, suggesting a progressive disease(PD), while metastasis to the paraaortic lymph nodes disappeared. We decided that a curative resection was possible and performed distal gastrectomy with D2 and paraaortic lymph node dissection. The postoperative courses were uneventful, and the patient was discharged from the hospital 12 days postoperation. The patient is well without any recurrence of cancer at 1 year 3 months postoperation. Conversion therapy may offer the possibility of prolonged survival for patients with gastric cancer previously considered unresectable.

Bile duct reconstruction using scaffold-free tubular constructs created by Bio-3D printer.

INTRODUCTION: Biliary strictures after bile duct injury or duct-to-duct biliary reconstruction are serious complications that markedly reduce patients' quality of life because their treatment involves periodic stent replacements. This study aimed to create a scaffold-free tubular construct as an interposition graft to treat biliary complications. METHODS: Scaffold-free tubular constructs of allogeneic pig fibroblasts, that is, fibroblast tubes, were created using a Bio-3D Printer and implanted into pigs as interposition grafts for duct-to-duct biliary reconstruction. RESULTS: Although the fibroblast tube was weaker than the native bile duct, it was sufficiently strong to enable suturing. The pigs' serum hepatobiliary enzyme levels remained stable during the experimental period. Micro-computed tomography showed no biliary strictures, no biliary leakages, and no intrahepatic bile duct dilations. The tubular structure was retained in all resected specimens, and the fibroblasts persisted at the graft sites. Immunohistochemical analyses revealed angiogenesis in the fibroblast tube and absence of extensions of the biliary epithelium into the fibroblast tube's lumen. CONCLUSIONS: This study's findings demonstrated successful reconstruction of the extrahepatic bile duct with a scaffold-free tubular construct created from pig fibroblasts using a novel Bio-3D Printer. This construct could provide a novel regenerative treatment for patients with hepatobiliary diseases.

Downstaging and Histological Effects Might Be Reliable Predictors of the Efficacy of DOC+CDDP+5-FU (DCF) as Neoadjuvant Therapy for Stage III or Borderline Resectable Esophageal Cancer: a Single Institute Experience.

PURPOSE: In Japan, two courses of CDDP+5-FU (CF) therapy followed by surgery are accepted as a standard treatment for stage II/III esophageal cancer (EC) based on the results of the JCOG9907 trial. To gain a better survival, benefit especially for stage III patients in comparison with CF therapy, a three-arm phase III trial (neoadjuvant setting: CF vs. CF + radiation vs. DOC+CF [DCF]) is ongoing. We have aggressively performed DCF therapy for stage III or IV patients since October 2014. We herein review the outcomes of DCF therapy. METHODS: We retrospectively reviewed the cases of 27 patients with stage III or IV EC (male, n = 24; female, n = 3; median age, 70.0 years) who received DCF therapy. RESULTS: The response rate was 48.1%. Downstaging was achieved over the course of treatment in 14 patients (51.9%). Twenty-six patients transitioned to surgery, with 25 receiving R0 resection. DCF-treated patients who achieved downstaging showed significantly longer relapse-free survival (RFS) than those without downstaging (p = 0.0002). DCF-treated patients with a grade ≥ 1b histological effect showed significantly longer RFS than those with a grade < 1b effect (p = 0.0282). The multivariate analysis showed that downstaging was the only factor significantly associated with RFS in DCF-treated patients. CONCLUSIONS: DCF therapy for stage ≥ III esophageal carcinoma is both feasible and effective. These findings suggest that downstaging and the histological effect might predict the effects of DCF therapy for EC.

Establishment of an in-vivo porcine delayed perforation model after duodenal endoscopic submucosal dissection.

OBJECTIVES: Duodenal endoscopic submucosal dissection (ESD) for superficial non-ampullary duodenal epithelial tumors has a significant incidence rate of delayed perforation. Although several methods have been proposed to prevent delayed perforation, the most appropriate methods remain unclear. Currently, there is no appropriate animal model to validate methods for preventing duodenal delayed perforation. This study aimed to establish an in-vivo porcine delayed perforation model after duodenal submucosal dissection. METHODS: Two porcine models underwent either ESD or surgical submucosal dissection. In the surgical dissection model, an inverted duodenal mucosa was resected with electrosurgical energy. In the ESD model, a gauze was placed behind the duodenum with grasped transverse part to improve endoscopic maneuverability. The mucosal defects after dissection were treated with omental coverage without suture in both models. All models were euthanized 0-5 days after procedure. Body weight; resection size; procedure dissection time; presence of intraoperative perforation and delayed perforation; and adhesion score were assessed. RESULTS: There were no significant differences in body weight and adhesion score between the two models. Resection size was significantly larger in the surgical dissection models than in the ESD models (19 mm vs 14.3 mm, P < 0.01). Procedure time was significantly longer in the ESD models than in the surgical models (45.2 minutes vs 4.5 minutes, P < 0.01). Delayed perforation rates in the surgical dissection models and the ESD models were 0% (0/5) and 100% (5/5), respectively (P < 0.01). CONCLUSIONS: This study indicated that our in-vivo porcine duodenal ESD model is beneficial to evaluate a prevention strategy for delayed perforation.

A rare case of meningeal carcinomatosis and internal auditory canal metastasis presenting with the deafness for gastric cancer.

BACKGROUND: Meningeal carcinomatosis is a very rare metastatic site of gastric cancer and meningeal carcinomatosis without other metastatic sites is much extremely rare. Herein, we report our experience with a very rare case of meningeal carcinomatosis which was difficult to diagnose the recurrence by general systemic examination and was found due to the deafness despite the sustained high tumor markers. CASE PRESENTATION: A 68-year-old man consulted a hospital with vomiting and hematemesis. Laboratory tests revealed severe anemia. He was referred to our hospital and underwent an emergency gastroscopy, which revealed Borrman type 3 tumor and oozing of blood. Biopsy specimen showed gastric cancer. After several examinations, total gastrectomy was performed and tegafur-gimeracil-oteracil potassium (S-1) was initiated as adjuvant chemotherapy one month after surgery. Tumor marker levels (CEA and CA19-9) remained high for three months after surgery. S-1 was continued while shortening the imaging study follow-up period. Nine months after surgery, he noticed difficulty in hearing with facial paralysis, dizziness, tinnitus, and appetite loss. He was diagnosed with meningeal carcinomatosis and bilateral internal auditory canal metastasis. He died approximately two months later. CONCLUSION: Meningeal carcinomatosis should be considered if bilateral deafness and vestibulopathy develop after gastrectomy, even if no recurrence is apparent in the abdominal cavity.

The Efficacy of Autologous Myoblast Sheet Transplantation to Prevent Perforation After Duodenal Endoscopic Submucosal Dissection in Porcine Model.

The recent advent of endoscopy has enabled the endoscopic submucosal dissection (ESD) of superficial nonampullary duodenal epithelial tumors. However, the substantially thin wall and presence of bile and pancreatic juice make it technically difficult to perform duodenal ESD without perforation, which leads to lethal complications. The present study evaluated the efficacy of autologous myoblast sheet transplantation for the prevention of late perforation after duodenal ESD in a porcine model. Two weeks before ESD, skeletal muscle was surgically excised from the femur of pigs, and myoblasts were isolated and seeded in temperature-responsive culture dishes to prepare sheets. Immediately after ESD, the autologous myoblast sheets were attached to the serosal surface at the ESD site with omentopexy. The pigs were divided into two groups: the autologous myoblast sheet group (n = 5), where the myoblast cell sheet was attached to the ESD ulcer part from the duodenal serous side, and the Omentum group (n = 5), where only the omentum was used. The pigs were sacrificed and analyzed macroscopically and histologically on postoperative day 3. The macroscopic examination of the abdominal cavity revealed perforation in the ESD ulcer area and leakage of bile in the Omentum group but no perforation in the Sheet group. A histopathological examination revealed that continuity of the duodenal wall at the ESD site was maintained with dense connective tissue in the Sheet group. In conclusion, autologous myoblast sheets were useful for preventing perforation after duodenal ESD.

[Locally Advanced Rectal Cancer Curatively Resected after Modified FOLFOXIRI plus Bevacizumab Chemotherapy-A Case Report].

A 69-year-old man with dyschezia was diagnosed with locally advanced colorectal cancer invading the urinary bladder and pelvis. We performed ileostomy to avoid passage disturbance because curative resection was difficult. The patient received 2 courses of modified FOLFOXIRI plus bevacizumab. The size of the primary tumor and lymph nodes decreased after chemotherapy. High anterior resection with D3 lymph node dissection was performed. Histopathological analysis revealed that the tumor stage was pT3, N0, M0, StageⅡ. The patient has been receiving adjuvant chemotherapy with oral UFT/UZEL for 6months. No recurrence has been observed for the past 4 months.

S-1 and CPT-11 Plus Ramucirumab (IRIS+Rmab) as Second-Line Chemotherapy for Patients with Oxaliplatin-Refractory Metastatic Colorectal Cancer (mCRC): A Multicenter Phase II Study in Japan (N-DOCC-F-C-1701).

This multicenter phase II N-DOCC-F-C-1701 trial is being planned in order to investigate the efficacy and safety of CPT-11+S-1 +Ramucirumab (IRIS+Rmab), which is anticipated to have a stronger anti-tumor effect than IRIS+Bmab in patients with metastatic colorectal cancer (mCRC) previously treated with oxaliplatin (L-OHP) containing regimen, in consideration of the result of RAISE, FIRIS and some phase II trials of IRIS+Bevacicizumab (Bmab). The number of patients is set at 38 for the statistical analysis, assuming an expected median PFS of 5.0 months (threshold: 3.0 months). The primary endpoint of the study is the progression free survival (PFS), and the secondary endpoints are the overall response rate (ORR), overall survival (OS), adverse events (AE), quality of life (QOL) and review of nausea and vomiting. This trial is registered in the UMIN Clinical Trials Registry as UMIN000028170. We intend to start conducting the trial in September 1, 2017. If this trial meets the endpoint, IRIS+Rmab might be supported as a new optional standard regimen for mCRC.

Neurotransmission through dopamine D1 receptors is required for aversive memory formation and Arc activation in the cerebral cortex.

Dopaminergic neurotransmission is considered to play an important role not only in reward-based learning, but also in aversive learning. Here, we investigated the role of dopaminergic neurotransmission via dopamine D1 receptors (D1Rs) in aversive memory formation in a passive avoidance test using D1R knockdown (KD) mice, in which the expression of D1Rs can conditionally and reversibly be controlled by doxycycline (Dox) treatment. We also performed whole-brain imaging after aversive footshock stimulation in activity-regulated cytoskeleton protein (Arc)-dVenus D1RKD mice, which were crossbred from Arc-dVenus transgenic mice and D1RKD mice, to examine the distribution of Arc-controlled dVenus expression in the hippocampus and cerebral cortex during aversive memory formation. Knockdown of D1R expression following Dox treatment resulted in impaired performance in the passive avoidance test and was associated with a decrease in dVenus expression in the cerebral cortex (visual, somatosensory, and motor cortices), but not the hippocampus, compared with control mice without Dox treatment. These findings indicate that D1R-mediated dopaminergic transmission is critical for aversive memory formation, specifically by influencing Arc expression in the cerebral cortex.

Pathogenic POGZ mutation causes impaired cortical development and reversible autism-like phenotypes.

Pogo transposable element derived with ZNF domain (POGZ) has been identified as one of the most recurrently de novo mutated genes in patients with neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), intellectual disability and White-Sutton syndrome; however, the neurobiological basis behind these disorders remains unknown. Here, we show that POGZ regulates neuronal development and that ASD-related de novo mutations impair neuronal development in the developing mouse brain and induced pluripotent cell lines from an ASD patient. We also develop the first mouse model heterozygous for a de novo POGZ mutation identified in a patient with ASD, and we identify ASD-like abnormalities in the mice. Importantly, social deficits can be treated by compensatory inhibition of elevated cell excitability in the mice. Our results provide insight into how de novo mutations on high-confidence ASD genes lead to impaired mature cortical network function, which underlies the cellular pathogenesis of NDDs, including ASD.