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Elevated tumor-infiltrating T-cell density is associated with favorable outcomes in patients with rectal cancer treated with neoadjuvant chemoradiotherapy (CRT). Here, we evaluated the significance of programmed cell death 1 (PD-1)-positive cells, regulatory T cells, and macrophages in response to CRT and prognosis.We assessed CD8+, PD-1+, FOXP3+, CD68+, and CD163+ intratumoral and stromal cell densities by immunohistochemistry using pre-treatment biopsies from 275 patients with rectal cancer treated with neoadjuvant CRT. We determined the impact of these measurements on response to CRT and survival. Response to CRT was determined by tumor regression grade (TRG) of surgical specimens, with good responders defined as TRG3-4.Intratumoral CD8+ and PD-1+ cell densities were significantly higher in good responders than in poor responders, whereas stromal CD68+ cell density was significantly lower in good responders as compared with poor responders. The multivariable analysis revealed high intratumoral CD8+ and PD-1+ cell densities to be independently associated with good responders (CD8: odds ratio [OR], 2.27; 95% confidence interval [CI], 1.21 - 4.34, P = .010; PD-1: OR, 1.97; 95%CI, 1.03 - 3.84, P = .039), and improved recurrence-free survival (CD8: hazard ratio [HR], 0.56; 95%CI, 0.32 - 0.98, P = .044; PD-1: HR, 0.37; 95%CI, 0.19 - 0.71, P = .002). Only high intratumoral CD8+ cell density was associated with improved overall survival (P = .022).Pre-treatment high intratumoral PD-1+ and CD8+ cell densities were independently associated with good response to CRT and improved recurrence-free survival, with high intratumoral CD8+ cell density additionally associated with improved overall survival. These values may serve as predictive and prognostic biomarkers in rectal cancer.

Previous studies have reported the utility of systemic inflammatory markers and CD8+ tumor-infiltrating lymphocyte (TIL) separately in predicting response to chemoradiotherapy (CRT) in rectal cancer; however, the efficacy of combining these markers remains unclear. This study aimed to elucidate the predictive efficacy of systemic inflammatory markers combined with CD8+ TIL density on response to neoadjuvant CRT in locally advanced rectal cancer. Ten systemic inflammatory markers and CD8+ TIL density were assessed in 267 patients with rectal cancer using pretreatment clinical data and biopsy samples. Response to CRT was determined using the Dworak tumor regression grade (TRG), with good responders classified as TRG3–4. Receiver operating characteristic curve analysis showed high areas under the curve for the lymphocyte-to-C-reactive protein ratio (LCR) and neutrophil × monocyte (N × M) value (0.58 and 0.62, respectively). In the multivariate analysis, LCR, N × M value, and CD8+ TIL density were independently associated with good responders (p = 0.016, 0.005, and 0.002, respectively). Stratified analysis with these three markers showed a positive correlation between TRG3–4 ratio and the number of positive predictive factors (8.2%, 20.0%, 34.2%, and 59.1% in patients with 0, 1, 2, and 3 predictors, respectively). Overall and disease-free survival were significantly worse in patients with zero factors present compared with those with one to three factors present. LCR, N × M value, and CD8+ TIL density are independently associated with response to CRT. Assessing local TIL density along with systemic inflammatory markers may be useful for selecting a multimodal neoadjuvant approach in rectal cancer therapy.

Background A clutch cutter is a scissor-type knife used in endoscopic submucosal dissection (ESD) for gastrointestinal tract tumors. The assistant during the ESD using a clutch cutter (ESD-C) needs to rotate the device and grasp the target tissue appropriately; therefore, the assistant's skill may affect the technical outcomes of ESD-C. Aim To determine how assistant skill level affected the technical outcomes of gastric ESD-C using an ex vivo porcine training model. Methods In this pilot study, mock lesions of 15-30 mm in diameter were created in the middle or lower third of the porcine stomach. A total of 32 ESD-C procedures were performed by 16 trainees. Each trainee operator performed two ESD-C procedures; one ESD-C was assisted by an expert (ESD-C-E), and the other was assisted by a non-expert (ESD-C-NE). The total procedure time of the ESD was set as the primary outcome, and en bloc resection rate, complete procedure rate, perforation rate, and each procedure time/speed for mucosal incision or submucosal dissection were set as the secondary outcomes. In addition, we investigated factors associated with the difficulty of ESD including incompletion of ESD procedure, a long procedure time (≥ 20 min) or intraoperative perforation. Results The median total procedure time of the ESD-C-E was significantly shorter than that of the ESD-C-NE (12.9 min vs 21.9 min, P = 0.001). The en bloc resection rate was 100% in both groups. Complete resection rates of the ESD-C-E and ESD-C-NE groups were 100% and 93.8%, respectively. No intraoperative perforation was observed in both groups. In the multivariate analysis, assistant skill was significantly associated with the difficulty of ESD, with the highest odds ratio of 16.5. Conclusion Assistance by an expert is an important factor when trainees perform ESD-C procedures.

BACKGROUND The selection of endoscopic treatments for superficial non-ampullary duodenal epithelial tumors (SNADETs) is controversial. AIM To compare the efficacy and safety of endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) for SNADETs. METHODS We retrospectively analyzed the data of patients with SNADETs from a database of endoscopic treatment for SNADETs, which included eight hospitals in Fukuoka, Japan, between April 2001 and October 2017. A total of 142 patients with SNADETs treated with EMR or ESD were analyzed. Propensity score matching was performed to adjust for the differences in the patient characteristics between the two groups. We analyzed the treatment outcomes, including the rates of en bloc/complete resection, procedure time, adverse event rate, hospital stay, and local or metastatic recurrence. RESULTS Twenty-eight pairs of patients were created. The characteristics of patients between the two groups were similar after matching. The EMR group had a significantly shorter procedure time and hospital stay than those of the ESD group [median procedure time (interquartile range): 6 (3-10.75) min vs 87.5 (68.5-136.5) min, P < 0.001, hospital stay: 8 (6-10.75) d vs 11 (8.25-14.75) d, P = 0.006]. Other outcomes were not significantly different between the two groups (en bloc resection rate: 82.1% vs 92.9%, P = 0.42; complete resection rate: 71.4% vs 89.3%, P = 0.18; and adverse event rate: 3.6% vs 17.9%, P = 0.19, local recurrence rate: 3.6% vs 0%, P = 1; metastatic recurrence rate: 0% in both). Only one patient in the ESD group underwent emergency surgery owing to intraoperative perforation. CONCLUSION EMR has significantly shorter procedure time and hospital stay than ESD, and provides acceptable curability and safety compared to ESD. Accordingly, EMR for SNADETs is associated with lower medical costs.

Brush-like polymer samples consisting of sodium poly(styrene sulfonate) were obtained by sulfonating polymacromonomers consisting of polystyrene with 110 monomeric units on each side chain. By fractional precipitation of the sample, fractions with narrow molecular weight distributions were obtained. Light scattering measurements were made to determine the mean-square radius of gyration for each fraction in aqueous NaCl as a function of the weight-average molecular weight and the salt concentration. By analyzing the data using the theory for the wormlike chain model, the stiffness parameters λ−1 of the molecule were obtained. It was found that the dependence of λ−1 on the salt concentration was not as strong as that for linear sodium poly(styrene sulfonate). This was interpreted as the reflection of the shielded charge–charge interactions at the local ionic strength in the brush which is much higher than that of the outside solution. Salt concentration dependence of NaPSS polymacromonomer with 110 monomeric units on each side chain (unfilled circles) cannot be explained by the theory assuming the Debye–Hűckel (DH) potential under the ionic strength outside the brush (dotted line), but can be explained using the DH potential under the ionic strength inside the brush (dashed line) along with the interactions without ionic ones (dot-dashed line).

Cell-free and concentrated ascites reinfusion therapy(CART)is useful for relief of the symptoms caused by malignant ascites. We experienced 2 cases of untreated gastric cancer with massive ascites due to peritoneal dissemination, to whom chemotherapy was successfully introduced as a result of improvement of general conditions achieved by CART. Case 1: A 56-year-old woman with massive ascites was introduced for the treatment of gastric cancer. After a CART, oral ingestion became possible and S-1 plus oxaliplatin(SOX)therapy was introduced. Three courses of SOX therapy were possible until just before her death with 6 times of maintenance CART in total. Case 2: An 80-year-old man was introduced for the same reason. After a CART, he was treated with 4 courses of trastuzumab plus capecitabine plus oxaliplatin(Tra plus CapeOX)therapy with 5 times of maintenance CART in total.CART is useful for alleviating symptoms caused by malignant ascites and makes systemic chemotherapy possible because it improves and maintains the general conditions.

MQTT is one of the best-known communication protocols for the Internet of Things (IoI). Its light-weight design and loose-coupling nature by publish/subscribe messaging model enable effective information exchange among various devices. Since MQTT brokers could be performance bottlenecks due to the massive amount of data from the increasing loT devices, their performance holds interest from researchers and engineers. Furthermore, the performance characteristics of MQTT version 5.0, which was released in 2019 and accompanied by new functionalities e.g., shared-subscription, have not become clear. To provide a way to measure MQTT broker performance efficiently and accurately, we have developed an open-source load testing tool MQTTLoader. In this demonstration, we introduce MQTTLoader with its capabilities and features. We also show how it works by using our demonstration environment and describe some results of benchmarking MQTT brokers.

Background This study aimed to review and evaluate the surgical outcomes, particularly intraoperative severe blood loss and postoperative blood complications, of emergency gastrointestinal surgery in patients undergoing antithrombotic therapy (AT). Emergency surgeries for patients with antithrombotic medication have been increasing in the aging population. However, the effect of AT on intraoperative blood loss and perioperative complications remains unclear. Methods We retrospectively reviewed 732 patients who underwent emergency gastrointestinal surgery between April 2014 and March 2019. Patients were classified into AT group and Non-AT group, and propensity score-matched analysis was performed to compare the short surgical outcomes between the groups. Additionally, risk factors in severe estimated blood loss (EBL) and postoperative bleeding complications were assessed. Results Altogether, 64 patients received AT; 50 patients and 12, and 2 were given antiplatelet and anticoagulant, and both drugs, respectively. After propensity score matching, EBL (101 vs. 99 mL; p = 0.466) and postoperative complications (14 vs. 16 patients; p = 0.676) were similar between the groups (63 patients matched paired). Intraoperative severe bleeding (EBL ≥ 492 mL) occurred in 44 patients. Multivariate analysis using the full cohort revealed that antithrombotic drug use was not an independent risk factor for severe bleeding and postoperative bleeding complications. Conclusions This study demonstrated antithrombotic drugs do not adversely affect the perioperative outcomes of emergency gastrointestinal surgery.

Background This study aimed to evaluate the efficacy and the safety of polyethylene glycol conjugated granulocyte colony-stimulating factor (PEG-G-CSF) for preventing neutropenia in metastatic colorectal cancer (mCRC) patients that received fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus bevacizumab (Bev) in clinical practice. Methods We retrospectively analyzed mCRC patients who received FOLFOXIRI plus Bev between December 2015 and December 2017. We evaluated the efficacy of PEG-G-CSF as preventing or treating grade 3 or 4 neutropenia, the overall response rate (ORR) according to the Response Evaluation Criteria in Solid Tumors version 1.1, progression-free survival (PFS), overall survival (OS), and adverse events of FOLFOXIRI plus Bev based on the Common Terminology Criteria for Adverse Events version 4.0. Results A total of 26 patients (median age 53.5 years) were included. The ORR rate was 65.3%, the median PFS was 9.6 months (7.2–16.9), and the median OS was 24.2 months (13.6–NA). Grade 3 or 4 neutropenia occurred in 53.8% of the patients, and febrile neutropenia occurred in 7.7%. PEG-G-CSF was given to 77.0% of the patients, including prophylactically (n = 9) and after the development of grade 3 or 4 neutropenia (n = 11). No patients experienced grade 3 or 4 neutropenia after the administration of PEG-G-CSF. In seven of the nine patients who received PEG-G-CSF prophylactically (77.8%), no dose adjustment was required. Conclusions PEG-G-CSF is useful in preventing severe neutropenia in mCRC patients treated with FOLFOXIRI plus Bev.

The Arf (ADP-ribosylation factor) GAPs (GTPase-activating proteins) regulate membrane trafficking and actin cytoskeleton. The molecular mechanism of how Arf GAPs regulate actin cytoskeleton remains to be elucidated. We identified AGAP1, a subtype of Arf GAP, as a binding protein of FilGAP, a Rac-specific GAP, in mammalian cells. AGAP1 binds to C-terminus of FilGAP whereas FilGAP binds to N-terminus of AGAP1 containing GLD domain. FilGAP co-localized with AGAP1 at intracellular vesicles and targeting of FilGAP at the vesicles requires its interaction with AGAP1. Consistently, depletion of endogenous AGAP1 induced the accumulation of endogenous FilGAP into paxillin-positive focal adhesions and actin cytoskeletal structures. Knockdown of endogenous AGAP1 suppressed cell spreading on collagen and the suppression was released by depletion of endogenous FilGAP. Moreover, depletion of AGAP1 in MDA-MB-231 cells promoted cell invasion in extracellular matrices and depletion of FilGAP blocked the invasion. Taken together, the present study suggests that AGAP1 may regulate subcellular localization of FilGAP and control cell migration and invasion through interaction with FilGAP.

Yusuke Kitagawa, Hiroki Osumi, Eiji Shinozaki, Yumiko Ota, Izuma Nakayama, Takeshi Suzuki, Takeru Wakatsuki, Takashi Ichimura, Mariko Ogura, Akira Ooki, Daisuke Takahari, Mitsukuni Suenaga, Keisho Chin, Kensei YamaguchiDepartment of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, JapanPurpose: Patients with gastrointestinal neuroendocrine carcinoma (GI-NEC) have poor prognoses. Although platinum-based combination chemotherapy is commonly used as first-line treatment, the benefit of amrubicin (AMR) and salvage chemotherapy in those who develop platinum-refractory GI-NEC remains unknown. This study aimed to evaluate the efficacy and safety of AMR monotherapy in patients with platinum-refractory GI-NEC.Patients and methods: Platinum-refractory GI-NEC patients who received AMR monotherapy between April 2012 and September 2017 were retrospectively analyzed. The overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse events were evaluated. PFS and OS were estimated using Kaplan-Meier methods and compared using log-rank tests.Results: In total, 16 patients were enrolled. Of them, 13 (81.3%), 1 (6.2%), and 2 (12.5%) received cisplatin plus irinotecan, cisplatin plus etoposide, and fluoropyrimidine plus platinum, respectively, before AMR monotherapy. The primary sites of NEC included the esophagus (N=3, 18.8%), stomach (N=10, 62.5%), duodenum (N=1, 6.2%) and colorectum (N=2, 12.5%). Patients were administered a median of 3 (range, 1–15) cycles of AMR. The ORR was 6.3%, and the median PFS and OS were 2.9months (95% CI: 1.7–7.4) and 13.8months (95% CI: 7.9–23.5), respectively. Neutropenia was the most serious adverse event. Grade 3 or higher neutropenia and febrile neutropenia occurred in 50.0% and 6.2% of patients, respectively. Other nonhematological toxicities were not severe, and no treatment-related deaths occurred. The 10 patients who received subsequent chemotherapy after AMR had significantly longer OS than those who did not (17.3months vs 8.9months; p=0.018). The median PFS of those who received organ-specific subsequent chemotherapy after AMR was 3.8months, which was longer than that of those who received prior AMR.Conclusion: AMR is feasible with minimal side effects for platinum-refractory GI-NEC. Organ-specific subsequent chemotherapy after AMR may improve patient survival.Keywords: amrubicin monotherapy, platinum refractory, gastrointestinal neuroendocrine carcinoma

This is the first report of laparoscopic-endoscopic cooperative surgery (LECS) for an ileal tumor. A 50-year-old man was admitted to our hospital with a positive fecal occult blood test. Colonoscopy detected a submucosal tumor with intussusception located in the ileum, 10 cm oral from the Bauhin valve. On further examination, he was diagnosed with an ileal lipoma. There were no signs of malignancy. LECS was performed for the ileal tumor. After submucosal elevation by injecting saline solution, a mucosal incision was made circumferentially along the tumor. A full-thickness incision was created endoscopically and laparoscopically on the circumferential mucosal incisional line. The tumor was withdrawn intraluminally by endoscopy. The defect of the ileal wall was closed laparoscopically in an axial direction with linear staplers. Histologically, the tumor was a 25-mm ileal lipoma with negative resection margins and no malignancy.

Highlights • Appendiceal mucinous neoplasms account for less than 1% of all cancers. • LAMNs have an aggressive biological potential. • Preoperative diagnosis of appendiceal mucinous neoplasms is difficult. • Here, we used emergency MRI to identify nodules in the appendix before operation., Introduction and importance We report the case of a patient with a low-grade appendiceal mucinous neoplasm (LAMN) who underwent emergency laparoscopic ileocecal resection to avoid the metastatic spread of tumor cells due to an impending rupture. Case presentation A 55-year-old woman presented to our hospital with pain in the right lower quadrant of the abdomen. Computed tomography revealed a markedly tense appendiceal mucinous tumor with surrounding inflammation, and laboratory test results showed elevated serum C-reactive protein (7.47 mg/dL), indicating impending rupture of the appendix. Magnetic resonance imaging revealed nodules inside the appendix, suggesting the possibility of appendiceal cancer. We performed emergency laparoscopic ileocecal resection with regional lymph node dissection. The tumor was pathologically diagnosed as a LAMN without rupture. Clinical discussion LAMN is classified as a clinically malignant tumor because it can cause pseudomyxoma peritonei due to perforation or the presence of residual tissue. Although an appendectomy would be appropriate for LAMN if the tumor margin is secured, ileocecal resection with lymph node dissection is necessary when preoperative discrimination of appendiceal cancer is impossible. Conclusion Further studies of preoperative imaging for appropriate differential diagnosis were necessary.

An aberrant bi-apical Follicucullus specimen (Albaillellaria, Radiolaria) has been discovered from an upper Guadalupian (Middle Permian) chert block of the Kamiaso Unit of the Mino terrane, central Japan. If this specimen was formed with double malformation, it would be the oldest record of this phenomenon in radiolarians and the first record of its kind in Albaillellaria.

We describe a patient with a giant Brunner’s gland hamartoma in the duodenum who was safely treated by endoscopic mucosal resection (EMR). A 64-year-old woman visited our hospital for a workup of severe anaemia (haemoglobin level: 5 g/dL). Oesophagogastroduodenoscopy revealed a large pedunculated and elongated polypoid lesion measuring approximately 70 mm in longitudinal diameter, located at the anterior wall of the duodenal bulb . We diagnosed her as having gastrointestinal bleeding originating from this lesion. Although we considered surgical intervention initially, en bloc EMR, a less invasive treatment, was finally accomplished safely by placing endoclips before resection. The histological examination of the specimen revealed a hamartomatous lesion consisting of Brunner’s glands with cystic change and adipose tissue separated by the septa of smooth muscle fibers. Ultimately, we diagnosed her as having Brunner’s gland hamartoma. Notably, there were tiny foci of heterotopic pancreatic tissue containing islets and duct epithelium. Although this type of lesion is benign, a larger one may cause clinical symptoms such as obstruction or bleeding, and thus, local resection is preferable.

Endocrine disruptors that act like hormones in the endocrine system might have toxic effects. Therefore, it is important to develop a portable device that can detect hormone active chemicals in samples rapidly and easily. In this study, a microfluidic device was developed for the detection of hormone active chemicals using genetically engineered yeast cells. The yeast cells were used as biosensors since they were genetically engineered to respond to the presence of hormone active chemicals by synthesizing beta-galactosidase (beta-gal). For achieving further sensitivity, we incorporated interdigitated array (IDA) electrodes (width, 1.2 microm; gap, 0.8 microm) with 40 electrode fingers into the analytical chamber of the microfluidic device. The yeast cells precultured with a hormone active chemical, 17beta-estradiol (E2), were trapped from the main channel of the device to the analytical camber by electrophoresis. After trapping in the analytical chamber, we performed electrochemical detection of beta-gal induced in the yeast cells with the IDA electrodes. Actually, electrochemical detection was performed on p-aminophenol that was converted from p-aminophenyl-beta-D-galactopyranoside with beta-gal. The electrochemical signals from the yeast cells precultured with 17beta-estradiol were successfully detected with the device. Furthermore, the inhibitory effects of antagonists such as tamoxifen were also detected electrochemically by using the device. Thus, the present microfluidic device can be used for highly sensitive detection of hormone active chemicals.

Individual stress analysis of a bone based on X-ray CT data provides useful information for diagnoses and medical treatments. Many studies on the stress analyses have been reported, however little attention has given to partial volume effect in the CT data. The partial volume effect may cause lower reliability in the analytical results because CT values on a bony part are changed by the effect. This paper proposes a method to correct CT values influenced by the partial volume effect. The correction method transforms CT values using a regression curve of an exponential function. The validity of the proposed method is confirmed by use of CT images of femurs of a pig and human mandibles.

Recently, design support tools have been used to improve the efficiency of design work. These tools support design verification at each design stage, and succeed to some extent in improving the efficiency of the design work. However, the management of scattered design information and data conversion have lately become difficult because designers often require two or more tools. In this paper, we focus on the detailed design of mechanism parts made by injection molding and used in precision consumer products. We propose a design product model which describes the detailed design of such parts. The model describes the mechanism parts based on sets of faces, which are basic units in design work. In this way, the model can express design information in both two- and three-dimensional forms. We also define the procedures used to operate the model. Finally, the effectiveness of this model is shown by applying it to an experimental system.