[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.

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.

[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.

[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.

[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.

Developmental RacGAP α2-Chimaerin Signaling Is a Determinant of the Morphological Features of Dendritic Spines in Adulthood.

Morphological characteristics of dendritic spines form the basis of cognitive ability. However, molecular mechanisms involved in fine-tuning of spine morphology during development are not fully understood. Moreover, it is unclear whether, and to what extent, these developmental mechanisms determine the normal adult spine morphological features. Here, we provide evidence that α2-isoform of Rac-specific GTPase-activating protein α-chimaerin (α2-chimaerin) is involved in spine morphological refinement during late postnatal period, and furthermore show that this developmental α2-chimaerin function affects adult spine morphologies. We used a series of mice with global and conditional knock-out of α-chimaerin isoforms (α1-chimaerin and α2-chimaerin). α2-Chimaerin disruption, but not α1-chimaerin disruption, in the mouse results in an increased size (and density) of spines in the hippocampus. In contrast, overexpression of α2-chimaerin in developing hippocampal neurons induces a decrease of spine size. Disruption of α2-chimaerin suppressed EphA-mediated spine morphogenesis in cultured developing hippocampal neurons. α2-Chimaerin disruption that begins during the juvenile stage results in an increased size of spines in the hippocampus. Meanwhile, spine morphologies are unaltered when α2-chimaerin is deleted only in adulthood. Consistent with these spine morphological results, disruption of α2-chimaerin beginning in the juvenile stage led to an increase in contextual fear learning in adulthood; whereas contextual learning was recently shown to be unaffected when α2-chimaerin was deleted only in adulthood. Together, these results suggest that α2-chimaerin signaling in developmental stages contributes to determination of the morphological features of adult spines and establishment of normal cognitive ability. SIGNIFICANCE STATEMENT: Recent studies of neurodevelopmental disorders in humans and their animal models have led to an attractive hypothesis that spine morphogenesis during development forms the basis of adult cognition. In particular, the roles of Rac and its regulators, such as Rac-specific GTPase-activating proteins (RacGAPs) and Rac guanine nucleotide exchange factors, are a topic of focus in spine morphogenesis and cognitive ability. Using a series of mice with global and conditional knock-out (KO) of RacGAP α-chimaerin isoforms (α1-chimaerin and α2-chimaerin), we provide compelling evidence demonstrating that α2-chimaerin is involved in spine morphological refinement during late postnatal development and that this developmental α2-chimaerin function affects adult spine morphologies. Furthermore, our results clearly showed that α2-chimaerin signaling during late postnatal development contributes to normal cognitive ability in adult mice.

[Evaluation of Postoperative Complications after Gastrectomy in Elderly Patients Aged Over 80 Years].

PURPOSE: The aim of this study was to evaluate the safety and feasibility of gastrectomy in elderly patients aged over 80 years. PATIENTS AND METHODS: A total of 393 patients who underwent gastrectomy for gastric cancer were assigned to 2 groups: those aged over 80 years(n=48; elderly group)and those less than 80 years(n=345).Clinicopathological features, operative factors, post-operative complications(Clavien-Dindo Grade II or higher), and mortality were retrospectively analyzed. RESULTS: Rates of distal gastrectomy(73% vs 59%, p=0.043)and D1 or D1+dissection(73% vs 58%, p=0.046)were significantly higher in the elderly group.There were no significant differences in post-operative complication rates(23% vs 20.3%, p=0.255)or mortality rates(2.1% vs 0.6%). CONCLUSION: Our results indicate that gastrectomy in elderly patients aged over 80 years may be safe and feasible.

[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.

[The Safety of Laparoscopic Lower Anterior Resection at Community Hospitals - A Multi Center Retrospective Cohort Study].

There is a high rate of leakage after laparoscopic lower anterior resection(Lap-LAR).We examined the safety of Lap-LAR at community hospitals.We investigated 54 patients who underwent Lap-LAR at the 10 hospitals related to the Department of Surgery at Yokohama City University between April 2013 and March 2014.T he median patient age was 67 years, and 32 patients were men.Forty -eight(88%)cases were higher than pathological Grade T3, and 37(69%)patients had undergone D3 lymph node dissection.A diverting stoma(DS)was created in 13(24%)patients.An anus drain was placed in 23 (40%)patients.The clinical anastomotic leakage rate(13%)is comparable with the rate of the DS study(12.9%).The rate of anastomotic leakage was acceptable.Lap -LAR at a community hospital could be safely performed for rectal cancer by making appropriate case choices and implementing preventive measures against anastomotic leakage.

Netrin-G/NGL complexes encode functional synaptic diversification.

Synaptic cell adhesion molecules are increasingly gaining attention for conferring specific properties to individual synapses. Netrin-G1 and netrin-G2 are trans-synaptic adhesion molecules that distribute on distinct axons, and their presence restricts the expression of their cognate receptors, NGL1 and NGL2, respectively, to specific subdendritic segments of target neurons. However, the neural circuits and functional roles of netrin-G isoform complexes remain unclear. Here, we use netrin-G-KO and NGL-KO mice to reveal that netrin-G1/NGL1 and netrin-G2/NGL2 interactions specify excitatory synapses in independent hippocampal pathways. In the hippocampal CA1 area, netrin-G1/NGL1 and netrin-G2/NGL2 were expressed in the temporoammonic and Schaffer collateral pathways, respectively. The lack of presynaptic netrin-Gs led to the dispersion of NGLs from postsynaptic membranes. In accord, netrin-G mutant synapses displayed opposing phenotypes in long-term and short-term plasticity through discrete biochemical pathways. The plasticity phenotypes in netrin-G-KOs were phenocopied in NGL-KOs, with a corresponding loss of netrin-Gs from presynaptic membranes. Our findings show that netrin-G/NGL interactions differentially control synaptic plasticity in distinct circuits via retrograde signaling mechanisms and explain how synaptic inputs are diversified to control neuronal activity.

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.

[A case of adenocarcinoma of small intestine surviving for many years].

In adenocarcinoma of the small intestine, delays in diagnosis are frequent. The majority of patients present with advancedstage disease, and have either lymph node involvement or distant metastatic disease. Surgical resection is a mainstay in treatment of this disease, and the effectiveness of chemotherapy for advanced-stage or metastatic disease has been reported. We report a case of adenocarcinoma of the small intestine surviving for many years after surgical resection and chemotherapy. A 47-year-old woman underwent a small intestine resection, because she had a small intestinal tumor with obstruction. Histopathological examination revealed moderately-differentiated adenocarcinoma with lymph node metastasis. Adjuvant chemotherapy with S-1 was administered for a year, but in March 2006, a recurrent lesion at the right ovary was detected, and she underwent right adnexectomy. Because the ascites cytology revealed class V, chemotherapy was administered. In December 2008, CA19-9 elevated and magnetic resonance imaging showed a tumor behind the uterus, which was diagnosed as a recurrent disease. Because the tumor invaded the rectum, she received a low anterior resection, hysterectomy, and left adnexectomy. After surgical resection, UFT/UZEL was administered for half a year. In July 2010, computed tomography showed multiple lung metastases, and chemotherapy was performed again. However, the regimen was changed because her tumor marker elevated. She is being treated using a combination of cisplatin and irinotecan.

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.

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.