Supporting an integrated QTc risk assessment using the hERG margin distributions for three positive control agents derived from multiple laboratories and on multiple occasions.

BACKGROUND: Determination of a drug's potency in blocking the hERG channel is an established safety pharmacology study. Best practice guidelines have been published for reliable assessment of hERG potency. In addition, a set of plasma concentration and plasma protein binding fraction data were provided as denominators for margin calculations. The aims of the current analysis were five-fold: provide data allowing creation of consistent denominators for the hERG margin distributions of the key reference agents, explore the variation in hERG margins within and across laboratories, provide a hERG margin to 10 ms QTc prolongation based on several newer studies, provide information to use these analyses for reference purposes, and provide recommended hERG margin 'cut-off' values. METHODS: The analyses used 12 hERG IC50 'best practice' data sets (for the 3 reference agents). A group of 5 data sets came from a single laboratory. The other 7 data sets were collected by 6 different laboratories. RESULTS: The denominator exposure distributions were consistent with the ICH E14/S7B Training Materials. The inter-occasion and inter-laboratory variability in hERG IC50 values were comparable. Inter-drug differences were most important in determining the pooled margin variability. The combined data provided a robust hERG margin reference based on best practice guidelines and consistent exposure denominators. The sensitivity of hERG margin thresholds were consistent with the sensitivity described over the course of the last two decades. CONCLUSION: The current data provide further insight into the sensitivity of the 30-fold hERG margin 'cut-off' used for two decades. Using similar hERG assessments and these analyses, a future researcher can use a hERG margin threshold to support a negative QTc integrated risk assessment.

Static friction coefficient depends on the external pressure and block shape due to precursor slip.

Amontons' law states that the maximum static friction force on a solid object is proportional to the loading force and is independent of the apparent contact area. This law indicates that the static friction coefficient does not depend on the external pressure or object shape. Here, we numerically investigate the sliding motion of a 3D viscoelastic block on a rigid substrate using the finite element method (FEM). The macroscopic static friction coefficient decreases with an increase in the external pressure, length, or width of the object, which contradicts Amontons' law. Precursor slip occurs in the 2D interface between the block and substrate before bulk sliding. The decrease in the macroscopic static friction coefficient is scaled by the critical area of the precursor slip. A theoretical analysis of the simplified models reveals that bulk sliding results from the instability of the quasi-static precursor slip caused by velocity-weakening local friction. We also show that the critical slip area determines the macroscopic static friction coefficient, which explains the results of the FEM simulation.

[A Case of Neuroendocrine Carcinoma of the Extrahepatic Bile Duct].

A 77-year-old man visited a clinic because of nausea and chest discomfort. On blood test, hepatobiliary enzymes were elevated, and he referred to our hospital. Contrast-enhanced CT revealed stenosis of the extrahepatic bile duct and brush cytology of the bile duct showed adenocarcinoma. We therefore performed pancreatoduodenectomy for extrahepatic bile duct cancer. Pathological diagnosis was small cell neuroendocrine carcinoma, pT3N2M0, Stage ⅢA. The patient did not receive adjuvant chemotherapy and 3 months later contrast-enhanced CT and MRI showed multiple liver metastases. The patient was treated with cisplatin plus irinotecan in the first-line, cisplatin plus etoposide in the second-line, and amrubicin in the third-line and accordingly he died 1 year and 3 months after the surgery. Chemotherapy for neuroendocrine carcinoma of the bile duct is recommended as in small cell lung cancer, but the prognosis is extremely poor. We report this case with a review of some of the literature.

Evaluating prognostic significance of preoperative C-reactive protein to albumin ratio in older patients with pathological stage II/III colorectal cancer.

Purpose: This study was performed to evaluate the prognostic value of preoperative C-reactive protein to albumin ratio (CAR) in older patients with colorectal cancer (CRC) undergoing curative resection. Methods: We retrospectively analyzed 244 older patients (aged 75 years or higher) with pathological stage II/III CRC who underwent curative surgery between 2008 and 2016. The optimal value of CAR was calculated and its correlation with the clinicopathological factors and prognosis was examined. Results: The optimal cutoff value of the CAR was 0.085. High preoperative CAR was significantly associated with high carcinoembryonic antigen levels (P=0.001), larger tumor size (P<0.001), and T pathological (pT) factor (P=0.001). On multivariate analysis, high CAR was independent prognostic factor for relapse-free survival (P=0.042) and overall survival (P=0.001). Conclusion: Preoperative elevated CAR could be considered as an adverse predictor of both relapse-free survival and overall survival in older patients with CRC undergoing curative surgery.

[A Case of Right Kidney Metastasis of Gastric Cancer].

We experienced a case of kidney metastasis of a gastric tumor. An 81-year-old man underwent distal gastrectomy with D2 lymph node dissection and partial hepatic resection for antral gastric tumor with hepatic infiltration in July 2019. A histological examination showed undifferentiated tubular adenocarcinoma. The final stage was pT4bN1P0H0M0, Stage ⅢB. He rejected the recommended adjuvant chemotherapy. Seven months after surgery, abdominal enhanced CT showed a hypovascular mass, 20 mm in diameter, on the right upper pole of kidney. Eleven months after surgery, CT showed that the mass had enlarged to 35 mm, infiltrated the renal pelvis, and advanced to para-aortic lymph node metastasis. We performed a retroperitoneoscopic partial right nephrectomy and diagnosed kidney metastasis of the gastric tumor. His right flank pain worsened, and radiotherapy(50 Gy)was performed for the mass and para-aortic lymph node metastasis. His right flank pain resolved. Kidney metastasis of the gastric tumor is very rare. Radiotherapy effectively relieves pain.

[A Case of Perforation of the Diverticulum of the Appendix during Chemotherapy with Ramucirumab plus Nab-Paclitaxel for Gastric Cancer].

A 65-year-old woman underwent distal gastrectomy with D2 lymph node dissection for advanced gastric cancer in November 2016. The histopathological diagnosis was pT3N0M0, pStage ⅡA, HER2-negative. In August 2019, transverse colon stenosis due to peritoneal dissemination was detected, and an ileum-transverse colon anastomosis was performed. Postoperatively, she received chemotherapy with S-1 plus oxaliplatin. After 6 courses, CT revealed an increase in ascites and dissemination nodules. We diagnosed her with progressive disease and initiated second-line chemotherapy, a ramucirumab plus nab-paclitaxel regimen. On the 20th day during the 5th course of treatment, she visited our hospital with acute abdominal pain. CT revealed free air, and we diagnosed acute panperitonitis with a gastrointestinal perforation. Emergency surgery was performed, and perforation of the appendix end and mild cloudy ascites were observed. We performed an appendectomy and intraperitoneal drainage. Histopathological examination revealed perforation of the appendix, possibly as an adverse effect of the ramucirumab. It should be noted that angiogenesis inhibitors may cause the fatal adverse effect of gastrointestinal perforation.

[A Case of Refractory Chylothorax after Surgery for Esophageal Cancer in Which Lymphangiography and Thoracic Duct Ligation Was Useful].

Chylothorax after esophagectomy is a relatively rare complication that can be difficult to manage. Here, we report a case of refractory chylothorax after surgery for esophageal cancer treated with lymphatic duct lipiodol imaging by inguinal lymph node puncture to confirm patency of the thoracic duct and thoracic duct ligation. A 71-year-old female with esophageal cancer(cT3N0M0)underwent video-assisted thoracoscopic esophagectomy with 2-field lymph node dissection, intrathoracic gastric tube reconstruction, and an enterostomy. A chylothorax appeared when we started enteral nutrition on the day after surgery. She became markedly dehydrated due to over 2,000 mL/day of drainage from the chest drain, and we managed her general condition in the ICU. We started octreotide acetate on postoperative day(POD)6 and etilefrine on POD 8, but neither was effective. Lymphatic duct lipiodol imaging by bilateral inguinal lymph node puncture was performed, and we confirmed leakage from the main thoracic duct. On POD 11, a thoracic duct ligation performed via a thoracotomy revealed that the volume of the chylothorax was remarkably decreased. The chest tube was removed on re-POD 12.

Short-Term Outcomes from a Randomized Screening Phase II Non-inferiority Trial Comparing Omentectomy and Omentum Preservation for Locally Advanced Gastric Cancer: the TOP-G Trial.

BACKGROUND: Omentectomy is considered an essential part of curative gastrectomy for locally advanced gastric cancer (GC), albeit without solid evidence. We conducted a randomized phase II trial (the TOP-G trial) comparing omentectomy and omentum preservation for gastric cancer. This report describes the short-term findings regarding the trial's secondary endpoints. METHODS: The trial protocol was submitted to the University Hospital Medical Information Network Clinical Trials Registry ( http://www.umin.ac.jp/ctr/ : UMIN000005421). The key eligibility criteria were histologically confirmed cT2-4a and N0-2 gastric adenocarcinoma. Short-term surgical outcomes, including morbidity and mortality, were compared between the omentectomy group (group A, control arm) and the omentum-preserving surgery group (group B, test arm). All procedures were performed via an open approach. Based on a non-inferiority margin of 7%, statistical power of 0.7, and type I error of 0.2, the sample size was set to 250 patients. RESULTS: A total of 251 patients were eligible and randomized (group A: 125 patients, group B: 126 patients) between April 2011 and October 2018. After excluding patients who had peritoneal metastasis or laparotomy history, safety outcomes were analyzed for 247 patients. Group A had a significantly longer median operation time (225 min vs. 204 min, p = 0.022) and tended to have greater median blood loss (260 mL vs. 210 mL p = 0.073). The incidences of morbidity were similar and < 10% in both groups (8% vs. 9%, p = 1.000). There was no mortality in either group. CONCLUSIONS: Operative risk was generally similar between omentectomy and omentum-preserving surgery for locally advanced gastric cancer.

Modified Glasgow Prognostic Score and Carcinoembryonic Antigen Predict Poor Prognosis in Elderly Patients with Colorectal Cancer.

OBJECTIVE: To investigate the prognostic values of the preoperative modified Glasgow Prognostic Score (mGPS) and carcinoembryonic antigen (CEA) alone and combined in elderly patients with colorectal cancer (CRC) planning to receive curative surgery. METHODS: We retrospectively analyzed 130 elderly patients (aged ≥80 years) with CRC who received curative surgery between 2008 and 2016. The preoperative mGPS and CEA levels were calculated. RESULTS: Elevated preoperative mGPS or CEA level was significantly associated with shorter relapse-free survival (p = 0.005, both) and cancer-specific survival (p = 0.011 and p < 0.001, respectively). Combined use of these two factors improved the predictive accuracy for tumor recurrence relative to that of either factor. CONCLUSION: Both mGPS and CEA were independent prognostic factors of CRC in elderly patients receiving curative surgery, but their combination was more accurate.

GABARAPs dysfunction by autophagy deficiency in adolescent brain impairs GABAA receptor trafficking and social behavior.

Dysfunctional mTOR signaling is associated with the pathogenesis of neurodevelopmental and neuropsychiatric disorders. However, it is unclear what molecular mechanisms and pathogenic mediators are involved and whether mTOR-regulated autophagy continues to be crucial beyond neurodevelopment. Here, we selectively deleted Atg7 in forebrain GABAergic interneurons in adolescent mice and unexpectedly found that these mice showed a set of behavioral deficits similar to Atg7 deletion in forebrain excitatory neurons. By unbiased quantitative proteomic analysis, we identified γ-aminobutyric acid receptor-associated protein-like 2 (GABARAPL2) to differentially form high-molecular weight species in autophagy-deficient brains. Further functional analyses revealed a novel pathogenic mechanism involving the p62-dependent sequestration of GABARAP family proteins, leading to the reduction of surface GABAA receptor levels. Our work demonstrates a novel physiological role for autophagy in regulating GABA signaling beyond postnatal neurodevelopment, providing a potential mechanism for the reduced inhibitory inputs observed in neurodevelopmental and neuropsychiatric disorders with mTOR hyperactivation.

[The Strategy for the Treatment of Perforated Gastric Cancer].

Perforated gastric cancer reported to be relatively rare and to have a poor prognosis. This study examined 9 patients with perforated gastric cancer. Two-thirds of the patients were male and the median age was 69 years. The timing of the diagnosis of gastric cancer was preoperative clinical findings in 4 cases, intraoperative surgical findings in 3 cases, and postoperative examination in 2 cases. The depths of tumor invasion were T3 in 3 cases, T4a in 4 cases, and T4b in 2 cases and 5 patients were Stage Ⅳ. Four patients underwent palliative gastrectomy and only 1 patient underwent curative(R0)gastrectomy. Four patients underwent repair surgery, 2 of which underwent omental patch repair during the initial surgery. One of patients with omental patch repair received 2-stage curative gastrectomy; the other patient received chemotherapy after recovering from acute peritonitis. The median overall survival was 17.9 months and the prognosis was favorable in cases with curative resection or chemotherapy. For patients with perforated gastric cancer, if curative resection cannot be expected, the initial surgery should be directed toward the treatment of peritonitis and radical oncological surgery or systemic chemotherapy should be planned following patient recovery.

[Clinical Outcomes of Palliative Radiation Therapy for Gastric Cancer Bleeding].

Only a few studies have been conducted regarding the palliative radiation therapy(RT)for gastric cancer(GC)bleeding. Data of 9 patients with gastric cancer requiring blood transfusions due to gastric bleeding who were treated with RT were reviewed. All patients were men with a median age of 83(range, 70-91)years. The clinical stage was ⅡB in 2 patients, Ⅲin 1, ⅣA in 1, and ⅣB in 5. Performing gastrectomy was difficult in 4 patients with distant metastasis or tumor invasion to adjacent organ, 3 with poor performance status, and 2 with advanced age. The median hemoglobin levels before RT was 6.0 (range, 3.3-7.7)g/dL, and all patients received blood transfusions before RT. Seven patients received 30 Gy RT and 2 patients received 50 Gy. Two patients received concurrent chemotherapy. A total of 2 hematological and 4 non-hematological treatment-related adverse events occurred. All patients improved conservatively. Hemorrhage occurred in 8 patients, except for 1. Of the 8 patients who responded to RT, 1 had rebleeding on day 81. The median rebleeding-free survival time from the beginning of RT was 125(range, 21-421)days. Palliative radiation therapy was useful for bleeding control in nonresectable gastric cancer.

[Short-Term Outcomes of Laparoscopic-Assisted Total Gastrectomy Using the Endoscopic Purse-String Suture Instrument ENDO-PSI].

Laparoscopic-assisted total gastrectomy(LATG)has several complications early during the introduction of the procedure, so a careful approach is necessary. In this study, we evaluated short-term outcomes after LATG at our hospital. From 2014 to 2017, 21 patients underwent LATG using ENDO-PSI. A 6-cm midline incision was made at the epigastrium, and the abdominal esophagus was transected using ENDO-PSI. The anvil head was fixed with extracorporeal ligation, and an end loop was added to the proximal side of the first suture. Reconstruction was performed with the Roux-en-Y method. The jejunojejunal anastomosis was performed extracorporeally, and esophagojejunostomy was performed using a circular stapler through the small incision. There were 15 men and 6 women, with a mean age of 74 years. The mean operation time was 296 min, and volume of blood loss was 75 mL. The median fasting period was 3(3-10)days, and the postoperative hospitalization period was 12(8-28)days. The postoperative complications were Grade Ⅱ in 4 patients and Grade Ⅲ in 1 patient. The complication due to esophagojejunostomy was anastomotic leakage in 1 patient, while no anastomotic stenosis was found. LATG using ENDO-PSI can be safely performed.

[Short-Term Comparison between Trans-Anal Ileus Tube and Self-Expandable Metallic Stent for Obstructive Colorectal Cancer].

The aim of this study was to compare the outcome of using trans-anal ileus tube and self-expandable metallic stent(SEMS) for obstructive colorectal cancer. METHODS: Between 2014 and 2018, 14 patients received trans-anal ileus tube placement (group I)and 34 received SEMS insertion as bridge to surgery(BTS)and underwent primary resection. RESULTS: The technical success rate was 100%in both groups, and the clinical success rate was 85.7%(12/14 cases)in group I and 91.2%(31/34 cases)in group S. In group S, the CROSS score significantly improved, the rates of stoma construction and postoperative complications were significantly lower, and the period until oral intake and hospital discharge was significantly short. CONCLUSION: SEMS insertion is more effective than trans-anal ileus tube placement in terms of short-term outcome.

[Clinical Assessment of 33 Patients with Perforated Colorectal Cancer Who Underwent Surgery].

The aim of this study was to clarify the risk factors of severe postoperative complications and prognostic factors in patients who underwent emergent surgery for colorectal cancer perforation. ASA-PSB3 and Mannheim Prognostic Index(MPI)B27 were selected as the independent risk factors for postoperative severe complications on multivariate analysis. Moreover, severe postoperative complications and non-curative surgery were selected as the independent factors of poor prognosis.

Randomized phase II study of TJ-54 (Yokukansan) for postoperative delirium in gastrointestinal and lung malignancy patients.

The present study evaluated the efficacy and safety of TJ-54 (Yokukansan; a traditional Japanese medicine) for the prevention and/or treatment of postoperative delirium in a randomized phase II trial of patients receiving surgery for gastrointestinal and lung malignancies. Patients ≥70 years of age who underwent surgery for gastrointestinal or lung malignancy were eligible for participation in the study. The 186 eligible patients were randomly assigned at a 1:1 ratio to receive TJ-54 or control during their peri-operative care (between 7 days prior to surgery and 4 days following surgery, except for the operation day). The signs and symptoms of delirium were assessed using the Diagnostic and Statistical Manual of Mental Disorders-IV by the investigator during the peri-operative period. A total of 186 eligible gastrointestinal or lung malignancy patients were analyzed (93, TJ-54; 93, control). There were no marked differences between the two randomized groups. The incidence of delirium was 6.5% (6 patients) in the TJ-54 group and 9.7% (9 patients) in the control group, with no significant difference (P=0.419). However, of the patients categorized with a mini-mental state examination (MMSE) score of ≤26, the incidence of postoperative delirium was 9.1% in the TJ-54 group and 26.9% in the control group [risk ratio, 0.338; 95% confidence interval (0.078-1.462), P=0.115]. Treatment with TJ-54 reduced the incidence of postoperative delirium compared with the control group. Although TJ-54 did not demonstrate any contribution to preventing or treating postoperative delirium in patients following surgery for gastrointestinal or lung malignancy, TJ-54 reduced the risk of postoperative delirium in the patients who were classified as MMSE ≤26. Further phase III studies with a larger sample size are required in order to clarify the effects of TJ-54 against postoperative delirium.

[Appropriate Range of Lymph Node Dissection in Elderly Patients with Colorectal Cancer].

In elderly patients, surgical procesure is decided considering the general condition and surgical invasion. The aim of this study was to clarify the appropriate rage of lymph node dissection for elderly colorectal cancer patients. One hundred forty one colorectal cancer patients aged 75 years or more, who underwent R0 colorectal resection with D2 or D3 lymph node dissection in clinical T3/T4 or clinical N+, were enrolled in this study. The patients whose tumor located in the rectum below the peritoneal reflection(Rb)were excluded. Five-year overall survival(OS)rate and disease specific survival(DSS)rate were 79.1% and 89.4%, respectively. More than 2 preoperative co-morbidities and macroscopic type 3-5 were independent prognostic factors in OS, whereas the rage of lymph node dissection was not risk factor. When comparing the outcomes of D2 and D3 dissections by age, D3 dissection was better tendency in DSS in patients aged under 80, however, D2 dissection was better tendency in patients aged 80 or more. In elderly colorectal cancer patients, there was no difference in prognosis between D2 and D3 dissection, and especially in patients aged 80 years or more, D2 might be sufficient if R0 resection was possible.

Diversification of behavior and postsynaptic properties by netrin-G presynaptic adhesion family proteins.

BACKGROUND: Vertebrate-specific neuronal genes are expected to play a critical role in the diversification and evolution of higher brain functions. Among them, the glycosylphosphatidylinositol (GPI)-anchored netrin-G subfamily members in the UNC6/netrin family are unique in their differential expression patterns in many neuronal circuits, and differential binding ability to their cognate homologous post-synaptic receptors. RESULTS: To gain insight into the roles of these genes in higher brain functions, we performed comprehensive behavioral batteries using netrin-G knockout mice. We found that two netrin-G paralogs that recently diverged in evolution, netrin-G1 and netrin-G2 (gene symbols: Ntng1 and Ntng2, respectively), were responsible for complementary behavioral functions. Netrin-G2, but not netrin-G1, encoded demanding sensorimotor functions. Both paralogs were responsible for complex vertebrate-specific cognitive functions and fine-scale regulation of basic adaptive behaviors conserved between invertebrates and vertebrates, such as spatial reference and working memory, attention, impulsivity and anxiety etc. Remarkably, netrin-G1 and netrin-G2 encoded a genetic "division of labor" in behavioral regulation, selectively mediating different tasks or even different details of the same task. At the cellular level, netrin-G1 and netrin-G2 differentially regulated the sub-synaptic localization of their cognate receptors and differentiated the properties of postsynaptic scaffold proteins in complementary neural pathways. CONCLUSIONS: Pre-synaptic netrin-G1 and netrin-G2 diversify the complexity of vertebrate behaviors and differentially regulate post-synaptic properties. Our findings constitute the first genetic analysis of the behavioral and synaptic diversification roles of a vertebrate GPI protein and presynaptic adhesion molecule family.

[Evaluation of Complications after Gastrectomy with Clavien-Dindo Classification in Patients Aged Over 85 Years].

PURPOSE: The aim of this study is to evaluate complications of gastrectomy for gastric cancer in patients aged over 85 years. PATIENTS AND METHODS: Thirteen patients received curative gastrectomy between April 2007 and March 2008. The surgical complications were evaluated using the Clavien-Dindo classification. RESULTS: There were 11 patients aged 85-89 years and 2 who were over 90 years old. The median body mass index was 18. Nine patients underwent distal gastrectomy and 4 underwent total gastrectomy. The median operation time was 142 minutes and the median blood loss was 148 mL. Complications greater than Grade 2 were observed in 5 patients(38.5%). All complications were Grade 2. No surgical mortality was observed. DISCUSSION: The morbidity rate in elderly patients over 85 years of age may be higher than in patients aged 75 and lower. Our results suggest that gastrectomy for patients aged over 85 years is acceptable.