Clinical outcomes and prognostic factors of concurrent chemoradiotherapy for anal squamous cell carcinoma in Japan.

BACKGROUND: Concurrent chemoradiotherapy (CCRT) is the standard treatment for locoregional anal squamous cell carcinoma (ASCC) in western countries. However, there have been few reports on the clinical outcomes of CCRT in Japan. This study aimed to evaluate the clinical outcomes of CCRT, prognostic factors, and the clinical impact of programmed cell death-ligand 1 (PD-L1) expression of ASCC in Japan. METHODS: Patients with locoregional ASCC were enrolled between 2007 and 2017. All patients received CCRT consisting of ≥ 45 Gy of radiation, 5-fluorouracil, and mitomycin C. Disease-free survival (DFS), overall survival (OS), and adverse events (AEs) were estimated. Expression of p16 and PD-L1 were assessed by immunohistochemical staining (IHC). RESULTS: This study included 36 patients, of whom 30 (83.3%) were female. Among the participants, 32 (88.9%) achieved complete clinical remission, while six (16.7%) experienced recurrence. The five-year DFS and five-year OS were 72.2% and 84.7%, respectively. Grades ≥ 3 serious AEs included neutropenia in 10 (27.7%) and perianal dermatitis in eight (22.2%). In a univariate analysis, male sex, lymph node metastasis, and large tumor size were significantly associated with worse outcome. In a multivariate analysis, tumor size was an independent factor associated with short DFS. Of the 30 patients whose biopsy specimens were available for IHC, 29 (96.7%) were positive for p16, and 13 (43.3%) were positive for PD-L1. However, PD-L1 expression did not show any clinical impact. CONCLUSIONS: The comparative etiology, clinical outcomes, and prognostic factors of CCRT observed in Japanese patients with locoregional ASCC were consistent with western data.

Management of Patients Receiving Antiplatelet Therapy During Gastroenterological Surgery: A Multicenter Prospective Cohort Study (GSATT).

OBJECTIVE: This study aimed to evaluate the effect of continuing preoperative aspirin monotherapy on surgical outcomes in patients receiving antiplatelet therapy (APT). SUMMARY BACKGROUND DATA: The effectiveness of continuing preoperative aspirin monotherapy in patients undergoing APT in preventing thromboembolic consequences is mostly unknown. METHODS: This prospective multicenter cohort study on the Safety and Feasibility of Gastroenterological Surgery in Patients Undergoing Antithrombotic Therapy (GSATT study) conducted at 14 clinical centers enrolled and screened patients between October 2019 and December 2021. The participants (n=1,170) were assigned to the continued APT group, discontinued APT group, or non-APT group, and the surgical outcomes of each group were compared. Propensity score matching was performed between the continued and discontinued APT groups to investigate the effect of continuing preoperative aspirin therapy on thromboembolic complications. RESULTS: The rate of thromboembolic complications in the continued APT group was substantially lower than that in the non-APT or discontinued APT groups (0.5% vs. 2.6% vs. 2.9%; P=0.027). Multivariate investigation of the entire cohort revealed that discontinuation of APT (P<0.001) and chronic anticoagulant use (P<0.001) were independent risk factors for postoperative thromboembolism. The post-matching evaluation demonstrated that the rates of thromboembolic complications were significantly different between the continued and discontinued APT groups (0.6% vs. 3.3%; P=0.012). CONCLUSIONS: APT discontinuation following elective gastroenterological surgery increases the risk of thromboembolic consequences, whereas continuing preoperative aspirin greatly reduces this risk. The continuation of preoperative aspirin therapy in APT-received patients is considered one of the best alternatives for preventing thromboembolism during elective gastroenterological surgery.

Improvement of Protein Expression Profile in Three-Dimensional Renal Proximal Tubular Epithelial Cell Spheroids Selected Based on OAT1 Gene Expression: A Potential In Vitro Tool for Evaluating Human Renal Proximal Tubular Toxicity and Drug Disposition.

The proximal tubule plays an important role in the kidney and is a major site of drug interaction and toxicity. Analysis of kidney toxicity via in vitro assays is challenging, because only a few assays that reflect functions of drug transporters in renal proximal tubular epithelial cells (RPTECs) are available. In this study, we aimed to develop a simple and reproducible method for culturing RPTECs by monitoring organic anion transporter 1 (OAT1) as a selection marker. Culturing RPTECs in spherical cellular aggregates increased OAT1 protein expression, which was low in the conventional two-dimensional (2D) culture, to a level similar to that in human renal cortices. By proteome analysis, it was revealed that the expression of representative two proximal tubule markers was maintained and 3D spheroid culture improved the protein expression of approximately 7% of the 139 transporter proteins detected, and the expression of 2.3% of the 4,800 proteins detected increased by approximately fivefold that in human renal cortices. Furthermore, the expression levels of approximately 4,800 proteins in three-dimensional (3D) RPTEC spheroids (for 12 days) were maintained for over 20 days. Cisplatin and adefovir exhibited transporter-dependent ATP decreases in 3D RPTEC spheroids. These results indicate that the 3D RPTEC spheroids developed by monitoring OAT1 gene expression are a simple and reproducible in vitro experimental system with improved gene and protein expressions compared with 2D RPTECs and were more similar to that in human kidney cortices. Therefore, it can potentially be used for evaluating human renal proximal tubular toxicity and drug disposition. SIGNIFICANCE STATEMENT: This study developed a simple and reproducible spheroidal culture method with acceptable throughput using commercially available RPTECs by monitoring OAT1 gene expression. RPTECs cultured using this new method showed improved mRNA/protein expression profiles to those in 2D RPTECs and were more similar to those of human kidney cortices. This study provides a potential in vitro proximal tubule system for pharmacokinetic and toxicological evaluations during drug development.

Novel approach of prophylactic radiation to reduce toxicities comparing 2-step40 with 56-Gy simultaneous integrated boost intensity-modulated radiation therapy for locally advanced squamous cell carcinoma of the head and neck, an intergroup phase III trial (JCOG1912, NEW BRIDGE).

BACKGROUND: Chemoradiotherapy (CRT) with concurrent cisplatin is the standard of care as a nonsurgical definitive treatment for patients with locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). However, CRT is associated with increased severe late adverse events, including swallowing dysfunction, xerostomia, ototoxicity, and hypothyroidism. Few strategies aimed at less invasive CRT without compromising treatment outcomes have been successful. The purpose of this study is to confirm the non-inferiority of reduced dose prophylactic radiation with 40 Gy compared to standard dose prophylactic radiation with 56 Gy in terms of the time to treatment failure (TTF) among patients with clinical stage III-IVB LA-SCCHN. METHODS: This study is a multicenter, two-arm, open-label, randomized phase III trial. Patients with LA-SCCHN excluding p16 positive oropharynx cancer are randomized to the standard arm or experimental arm. A total dose of 70 Gy for tumors with concurrent cisplatin at 100 mg/m2 are administered in both arms. For prophylactic field, patients in the standard arm receive a total dose of 56 Gy in 35 fractions for 7 weeks using simultaneous integrated boost (SIB56) and those in the experimental arm receive 40 Gy in 20 fractions using two-step methods for 4 weeks (2-step40). A total of 400 patients will be enrolled from 52 Japanese institutions within 5 years. The primary endpoint is TTF, and the secondary endpoints are overall survival, complete response rate, progression-free survival, locoregional relapse-free survival, acute and late adverse events, quality of life score, and swallowing function score. DISCUSSION: If the experimental arm is non-inferior to the standard arm in terms of TTF and superior on the safety endpoints, the 2-step40 procedure is the more useful treatment than SIB56 for definitive CRT. TRIAL REGISTRATION: This trial has been registered in the Japan Registry of Clinical Trials as jRCTs031210100 ( https://jrct.niph.go.jp/latest-detail/jRCTs031210100 ). Date of Registration: May 2021.

Mechanistic Static Model based Prediction of Transporter Substrate Drug-Drug Interactions Utilizing Atorvastatin and Rifampicin.

OBJECTIVE: An in vitro relative activity factor (RAF) technique combined with mechanistic static modeling was examined to predict drug-drug interaction (DDI) magnitude and analyze contributions of different clearance pathways in complex DDIs involving transporter substrates. Atorvastatin and rifampicin were used as a model substrate and inhibitor pair. METHODS: In vitro studies were conducted with transfected HEK293 cells, hepatocytes and human liver microsomes. Prediction success was defined as predictions being within twofold of observations. RESULTS: The RAF method successfully translated atorvastatin uptake from transfected cells to hepatocytes, demonstrating its ability to quantify transporter contributions to uptake. Successful translation of atorvastatin's in vivo intrinsic hepatic clearance (CLint,h,in vivo) from hepatocytes to liver was only achieved through consideration of albumin facilitated uptake or through application of empirical scaling factors to transporter-mediated clearances. Transporter protein expression differences between hepatocytes and liver did not affect CLint,h,in vivo predictions. By integrating cis and trans inhibition of OATP1B1/OATP1B3, atorvastatin-rifampicin (single dose) DDI magnitude could be accurately predicted (predictions within 0.77-1.0 fold of observations). Simulations indicated that concurrent inhibition of both OATP1B1 and OATP1B3 caused approximately 80% of atorvastatin exposure increases (AUCR) in the presence of rifampicin. Inhibiting biliary elimination, hepatic metabolism, OATP2B1, NTCP, and basolateral efflux are predicted to have minimal to no effect on AUCR. CONCLUSIONS: This study demonstrates the effective application of a RAF-based translation method combined with mechanistic static modeling for transporter substrate DDI predictions and subsequent mechanistic interpretation.

Laparoscopic-assisted robotic distal gastrectomy for gastric cancer by Billroth II reconstruction.

BACKGROUND: There are several reconstructions in distal gastrectomy for gastric cancer, and there is no clear definition regarding the method selection. The optimal reconstruction is likely to vary according to the surgical setting, and the optimal reconstruction for robotic distal gastrectomy is urgently needed. In addition, as robotic gastrectomy is getting popular, cost and operative time are pressing issues of robotic gastrectomy. METHODS: Gastrojejunostomy was planned with Billroth II reconstruction using a linear stapler arranged specifically for a robotic approach. After firing the stapler, the common insertion orifice of the stapler was closed using a 30 cm long non-absorbable barbed suture, and continuously, the afferent loop of the jejunum was lifted to the stomach with the same barbed suture. In addition, we introduced laparoscopic-assisted robotic gastrectomy, using extracorporeally inserted laparoscopic devices from the assistant port. Scissors, clips, and linear staplers were all laparoscopic tools inserted extracorporeally. RESULTS: Twenty-one gastric cancer patients underwent laparoscopic-assisted robotic distal gastrectomy by Billroth II reconstruction with our modifications. There were no anastomosis-related complications such as leakage, stenosis, or bleeding. There were 2 cases of aspiration pneumonia (Clavien-Dindo grade 2), 1 case of pancreatic juice leakage (grade 3a), and 1 case of delayed gastric emptying (grade 1). CONCLUSION: We successfully arranged Billroth II reconstruction for robotic distal gastrectomy with fewer operative and postoperative complications. Laparoscopic-assisted robotic gastrectomy using extracorporeally inserted devices, and continuous suturing using a barbed suture will reduce the time and cost of robotic gastrectomy.

PCO2 on arrival as a predictive biomarker in patients with out-of-hospital cardiac arrest.

BACKGROUND: Treating patients with out-of-hospital cardiac arrest (OHCA) requires early prediction of outcome, ideally on hospital arrival, as it can inform the clinical decisions involved. This study evaluated whether partial pressure of carbon dioxide (PCO2) on arrival is associated with outcome at one month OHCA patients. METHODS: This was a single-center retrospective study of adult OHCA patients treated between January 2016 and December 2020. Outcomes were defined along the Cerebral Performance Category (CPC) scale. Primary outcome was mortality (CPC 5) at one month. Secondary outcomes were death or unfavorable neurological outcome (CPC 3-5) and unfavorable neurological outcome (CPC 3-4) at one month. Multivariable analysis was adjusted for age, sex, witnessed cardiac arrest, bystander cardiopulmonary resuscitation, initial shockable rhythm, and time from call to emergency medical services to hospital arrival. RESULTS: Out of 977 OHCA patients in the study period, 19 were excluded because they were aged under 18 years, 79 because they underwent extracorporeal cardiopulmonary resuscitation, and 101 due to lack of PCO2 data. This study included 778 patients total; mortality (CPC 5) at one month was observed in 706 (90.7%), death or unfavorable neurological outcome (CPC 3-5) in 743 (95.5%), and unfavorable neurological outcome (CPC 3-4) in 37 (4.8%). In multivariable analysis, high PCO2 levels showed significant association with mortality (CPC 5) at one month (odds ratio [OR] [per 5 mmHg], 1.14; 95% confidence interval [CI], 1.08-1.21), death or unfavorable neurological outcome (CPC 3-5) (OR [per 5 mmHg], 1.29; 95% CI, 1.17-1.42), and unfavorable neurological outcome (CPC 3-4) (OR [per 5 mmHg], 1.21; 95% CI, 1.04-1.41). CONCLUSIONS: High PCO2 on arrival was significantly associated with mortality and unfavorable neurological outcome in OHCA patients.

Factors associated with quality of life in patients receiving lung transplantation: a cross-sectional study.

BACKGROUND: With improved prognosis after lung transplantation (LTx), improving health-related quality of life (HRQL) in patients who have undergone LTx is a key goal. Although HRQL is improved significantly after transplantation, it is poorer than that in ordinary healthy people. However, the factors associated with poor HRQL remain unclear. This cross-sectional study aimed to identify the factors associated with poor HRQL in patients who have undergone LTx. METHODS: Between December 2018 and May 2022, 80 patients who had undergone LTx completed St. George's Respiratory Questionnaire (SGRQ) as a disease-specific quality of life measure, the Short Form-12 (SF-12) as a generic quality of life measure, and modified Medical Research Council (mMRC) scale of dyspnea. The groups were assigned according to the median SGRQ-total score and the Japanese population standard for SF-12, and those with good HRQL were compared with those with poor HRQL. Independent factors were evaluated using multivariate analysis. RESULTS: With regard to the SGRQ, there were significant differences in the forced expiratory volume in 1 s (FEV1) (P = 0.041), use of bronchodilators (P = 0.026), 6-min walk distance (6MWD) (P < 0.001), and Mmrc (P < 0.001) between better and poorer HRQL. For the SF-12 physical component summary score (PCS), age (P = 0.017), sex (P = 0.011), FEV1 (P < 0.001), forced vital capacity (FVC) (P < 0.001), diagnosis (P = 0.011), handgrip force (P = 0.003), 6MWD (P < 0.001), and Mmrc (P < 0.001) varied. Multivariate analyses revealed that Mmrc was the only independent factor in the SGRQ (P < 0.001, odds ratio [OR] = 6.65, 95% confidence interval [CI]: 2.49-17.74) and SF-12 PCS (P = 0.001, OR = 0.185, 95% CI: 0.07-0.52). There were significant correlations between the SGRQ-Total score and SF-12 PCS (correlation coefficient = -0.612, P < 0.001). CONCLUSIONS: Dyspnea may be an independent factor of poor disease-specific and generic HRQL in LTx patients. The management of dyspnea may improve the HRQL in patients who have undergone LTx.

Long-term outcomes and prognostic factors of extracorporeal cardiopulmonary resuscitation in patients older than 75 years: a single-centre retrospective study.

BACKGROUND: Few studies have assessed older adult patients who received extracorporeal cardiopulmonary resuscitation (ECPR) after cardiac arrest, and outcomes and prognostic factors of ECPR in this population remain unclear. This study aimed to assess the long-term outcomes and prognostic factors among patients older than 75 years who received ECPR after experiencing cardiac arrest. METHODS: This is a single-centre, retrospective case-control study conducted between August 2010 and July 2019. Consecutive patients older than 75 years who had in-hospital (IHCA) or out-of-hospital cardiac arrest (OHCA) and received ECPR at the Emergency Department in the Hyogo Emergency Medical Center, Hyogo, Japan, were included. The primary outcome was a favourable neurological outcome, defined as a Cerebral Performance Category score of 1-2 at 1 year after the event. Univariate logistic regression was used to determine the association between variables and patient outcomes. RESULTS: Of the 187 patients with cardiac arrest who received ECPR, 30 were older than 75 years and 28 (15% of the cohort receiving ECPR) were examined in this study. The median age of the patients was 79 years (IQR 77-82), and there were 13 (46%) male patients. Neurological outcomes were favourable for seven (25%) patients, five of whom had IHCA and two with out-of-hospital OHCA. On univariate analysis, patients with a favourable outcome had a shorter median total collapse time (TCT) than those with an unfavourable outcome (favourable: 18.0 min (IQR 13.0-33.5) vs unfavourable: 44.0 min (IQR 25.0-53.0); p=0.049). CONCLUSION: In selected patients older than 75 years, ECPR could be beneficial by providing a shorter TCT, which may contribute to favourable neurological outcomes. Nevertheless, further studies are needed to validate these findings.

Functional coupling of organic anion transporter OAT10 (SLC22A13) and monocarboxylate transporter MCT1 (SLC16A1) influencing the transport function of OAT10.

OAT10 (SLC22A13) is a transporter highly expressed in renal tubules and transporting organic anions including nicotinate, ß-hydroxybutyrate, p-aminohippurate, and orotate. In transport assays using Xenopus oocytes and HEK293 cells, we found that apparent substrate selectivity of OAT10 was different between the expression systems, particularly less pronounced uptake of ß-hydroxybutyrate in HEK293 cells. Because functional coupling between transporters may interfere with functional properties of the transporter, we searched for endogenous transporters in HEK293 cells that could affect OAT10. By means of comprehensive approach with co-immunoprecipitation followed by LC-MS/MS analysis, we identified monocarboxylate transporter MCT1 (SLC16A1) as physically coupled with OAT10. The knockdown of MCT1 in OAT10-expressing HEK293 cells increased the uptake of ß-hydroxybutyrate and nicotinate, common substrates of OAT10 and MCT1, whereas the uptake of orotate, a substrate of only OAT10, was not affected. MCT1 is supposed to act as an escape route and mediate the efflux of nicotinate and ß-hydroxybutyrate taken up by OAT10 localized nearby MCT1, as suggested by co-immunoprecipitation. This functional coupling would explain altered apparent substrate selectivity in HEK293 cells compared with Xenopus oocytes. The findings in this study warn in transporter studies that the expression system can interfere with assessing correct transport properties due to unexpected interactions with endogenous transporters.

Gender-Difference in Hair Length as Revealed by Crispr-Based Production of Long-Haired Mice with Dysfunctional FGF5 Mutations.

Fibroblast growth factor 5 (FGF5) is an important molecule required for the transition from anagen to catagen phase of the mammalian hair cycle. We previously reported that Syrian hamsters harboring a 1-bp deletion in the Fgf5 gene exhibit excessive hair growth in males. Herein, we generated Fgf5 mutant mice using genome editing via oviductal nucleic acid delivery (GONAD)/improved GONAD (i-GONAD), an in vivo genome editing system used to target early embryos present in the oviductal lumen, to study gender differences in hair length in mutant mice. The two lines (Fgf5go-malc), one with a 2-bp deletion (c.552_553del) and the other with a 1-bp insertion (c.552_553insA) in exon 3 of Fgf5, were successfully established. Each mutation was predicted to disrupt a part of the FGF domain through frameshift mutation (p.Glu184ValfsX128 or p.Glu184ArgfsX128). Fgf5go-malc1 mice had heterogeneously distributed longer hairs than wild-type mice (C57BL/6J). Notably, this change was more evident in males than in females (p < 0.0001). Immunohistochemical analysis revealed the presence of FGF5 protein in the dermal papilla and outer root sheath of the hair follicles from C57BL/6J and Fgf5go-malc1 mice. Histological analysis revealed that the prolonged anagen phase might be the cause of accelerated hair growth in Fgf5go-malc1 mice.

Monocyte-Independent and -Dependent Regulation of Regulatory T-Cell Development in Mycoplasma Infection.

BACKGROUND: Although Mycoplasma pneumoniae (MP) infection has been implicated in the pathogenesis of allergic diseases, the mechanism of this trigger remains unknown. We explored the mechanism for how MP infection could tilt the balance between regulatory T cells (Tregs) and Th17 cells. METHODS: We analyzed the frequency, phenotype, and function of Tregs in patients at the different stages of MP and various virus infections over a period of more than 1 year. We examined the effect of monocytes to elucidate signals that can regulate the balance between Treg and Th17 cells. RESULTS: The functional activity of Tregs was profoundly impaired during the acute stage of MP as well as viral infections. Upon resolution, however, the Treg function remained impaired even 1 year after MP infection. In the resolution stage, the impaired Treg function was associated with an increase in interleukin (IL) 17A+ Tregs and Th17 cells. Development of Th17 cells was dependent on the "aberrant" proinflammatory monocytes (pMOs), characterized by potent ability to produce IL-6 in a Toll-like receptor 2-dependent manner. CONCLUSIONS: Depending on the prevalence of the pMOs, Tregs and Th17 cells could mutually regulate the number and function of the other. The pMOs/IL-6 could be crucial therapeutic targets against MP-induced allergic diseases.

[A Case of Primary Adenocarcinoma of the Duodenal Bulb with Laparoscopic Distal Gastrectomy].

A 66-year-old male presented with a torose lesion at the duodenal bulb, detected via endogastroduodenoscopy(EGD) during a medical check-up. It was histopathologically diagnosed as a low-grade adenoma. He was referred to the Department of Gastroenterology for follow-up observation. An endoscopic mucosal resection(EMR)was performed due to the increasing tumor size. The pathological findings of the resected specimen showed a tubular adenoma. The patient was then followed up as an outpatient. Two months later, a follow-up EGD revealed a mass lesion, suspected to be a remnant tumor. A laparoscopic distal gastrectomy, #3, #4sb, #5, #6 dissection, and Billroth Ⅱ+Braun anastomosis reconstruction were performed. Pathological examination showed a tubular adenocarcinoma in adenoma, tub1, with depth M, and no lymph node metastasis. Non-papillary duodenal carcinoma is a rare disease that has no established guidelines for radical surgery and the extent of lymph node dissection. Pancreaticoduodenectomy is often performed in advanced cases. However, due to the increasing number of patients and the risk of complications, limited resection should be considered as an alternative management option.

Irinotecan and Gemcitabine as Second-Line Treatment in Patients with Malignant Pleural Mesothelioma following Platinum plus Pemetrexed Chemotherapy: A Retrospective Study.

BACKGROUND: Cisplatin-pemetrexed combination chemotherapy is the current standard primary treatment for malignant pleural mesothelioma (MPM). It was first approved for untreated and unresectable MPM in the 2003 National Comprehensive Cancer Network (NCCN) guidelines. However, to date, standard treatments for patients with MPM who previously underwent chemotherapy, as recommended by the NCCN Malignant Pleural Mesothelioma guidelines, have been inadequate. To explore treatment options for such patients, we performed this retrospective study of patients who received irinotecan plus gemcitabine as second-line therapy for MPM. METHODS: We investigated 62 patients diagnosed with unresectable MPM between January 2008 and October 2017 who experienced recurrence following cisplatin treatment (or carboplatin) plus pemetrexed or pemetrexed monotherapy as first-line treatment, and who underwent irinotecan plus gemcitabine combination therapy as second-line treatment. Irinotecan (60 mg/m2) and gemcitabine (800 mg/m2) were administered on days 1 and 8 every 3 weeks, including a 1-week washout period. Our endpoints were efficacy, survival period, and toxicity. RESULTS: patients' median age was 65 years (range 50-79), and the histological MPM types were epithelioid (n = 48), sarcomatoid (n = 6), biphasic (n = 6), and desmoplastic (n = 2). One patient experienced a partial response, 40 had stable disease, and 21 had progressive disease. The disease control rate was 66.1% and the response rate 2.1%. Additionally, the median progression-free and overall survival time were 5.7 and 11.3 months, respectively. The most common adverse events were neutropenia (32.2%), loss of appetite (16.1%), nausea/diarrhea (11.3%), and thrombocytopenia/phlebitis (9.7%). Grade 3 adverse events included neutropenia (12.9%) and thrombocytopenia/phlebitis (2.1%); however, all adverse events were managed with symptomatic therapy. CONCLUSIONS: Despite the fact that second-line irinotecan plus gemcitabine combination therapy did not produce marked tumor shrinkage, it achieved a relatively high disease control rate of >65% with an acceptable toxicity profile. Hence, the combination of irinotecan plus gemcitabine may be considered for MPM treatment, with consideration of combination with immune checkpoint inhibitors as a potential next step.

Impact of perioperative aspirin continuation on bleeding complications in laparoscopic colorectal cancer surgery: a propensity score-matched analysis.

BACKGROUND: In laparoscopic surgery for colorectal cancer (CRC) for patients who receive antiplatelet therapy (APT), it remains unclear whether APT should be continued or temporarily withdrawn. We investigated the safety of perioperative aspirin continuation, specifically focused on bleeding complications. METHODS: We performed retrospective analysis utilizing propensity score-matching (PSM). In total, 789 patients satisfied the inclusion criteria, and were divided into two groups. Patients in the continued aspirin monotherapy (cAPT) group continued treatment perioperatively with not more than 2 days of withdrawal (n = 140). Patients with more than 3 days withdrawal of aspirin or who did not receive APT at all were assigned to the non-cAPT group (n = 649). After 1:1 PSM, 105 patients were extracted from each group. Perioperative APT management was determined based on our institutional committee-approved guidelines for antithrombotic management. RESULTS: In PSM cohorts, all patient demographics were comparable between the groups. Regarding intraoperative outcomes, we found no significant difference in operation duration (p = 0.969), blood loss (p = 0.068), and blood transfusion (p = 0.517). Postoperative overall morbidity was 20.0% and 13.3% in the cAPT and non-cAPT groups, respectively (p = 0.195). The incidence of bleeding complications was also comparable between the groups (2.9% vs. 1.0%, p = 0.317). Assessing the 14 cases with bleeding complications overall in the full cohort, all 7 cases in the non-cAPT group had anastomotic bleeding, which was generally observed shortly after surgery [median postoperative day (POD) 1]. All 7 cases in the cAPT group received additional antithrombotics other than aspirin; bleeding occurred at various sites relatively later (median POD 7), mostly after reinstitution of additional antithrombotic agents. CONCLUSIONS: For patients receiving APT, perioperative continuation of aspirin monotherapy could be safe in laparoscopic CRC surgery; however, careful consideration is required at reinstitution of additional antithrombotics where multiple antithrombotic agents are used.

Quantitative Ultrasound of the Heel in Women With Knee Osteoarthritis.

The prevalence of multiple falls is higher in older women, and knee pain is associated with multiple falls in women; thus, it is important to detect individuals at risk of fractures among women with knee osteoarthritis. We aimed to clarify the association between knee osteoarthritis and the quantitative ultrasound (QUS) parameter, and investigate the clinical relevance of the QUS parameter with osteoarthritis-related characteristics in women with knee osteoarthritis. This was a cross-sectional study. We recruited 101 women with knee osteoarthritis at a local orthopedic hospital and 102 healthy individuals from the community. Heel QUS measurements were performed using the QUS device, measuring the stiffness index. We also assessed knee pain, quadriceps strength, and physical activity in women with knee osteoarthritis. We fitted a multiple regression model to estimate the association between knee osteoarthritis and the stiffness index. We also fitted 3 multiple regression models to investigate the clinical relevance of the QUS parameter with osteoarthritis-related characteristics in women with knee osteoarthritis. Compared with the control group, individuals with grade 2 osteoarthritis did not demonstrate a significant difference in stiffness index (p = 0.68); however, those with grade 3 osteoarthritis (p < 0.001) and 4 (p < 0.001) showed a lower stiffness index than that of the control group. Additionally, although the QUS parameter did not show an association with knee pain score (p = 0.70) or quadriceps strength (p = 0.11), we found a significant association between the QUS parameter and physical activity (p = 0.003). Our results demonstrate that women with moderate or severe knee osteoarthritis showed lower QUS parameters compared to healthy women, and the QUS parameter was associated with physical activity in women with knee osteoarthritis.

Pancreatic atrophy after gastrectomy for gastric cancer.

PURPOSE: To investigate the phenomenon of pancreatic atrophy after gastrectomy for gastric cancer, using computed tomography (CT) volumetry. METHODS: The subjects of this retrospective study were 77 patients who underwent distal gastrectomy (DG) or total gastrectomy (TG) for pStage I gastric cancer in 2014. The relative pancreatic volume ratio was assessed preoperatively, and then 1 and 5 years postoperatively and the results were compared between surgical procedures RESULTS: A total of 14 patients underwent TG with Roux-en-Y (RY) reconstruction, 24 underwent DG with Billroth-I (BI) reconstruction, and 39 underwent DG with RY reconstruction. We observed that the pancreatic volume continued to decrease over the 5 years after DG or TG. Furthermore, the incidence of pancreatic atrophy 5 years postoperatively was significantly greater after TG than after DG. In patients who underwent DG, a greater incidence of pancreatic atrophy was observed after RY reconstruction than after BI reconstruction, 5 years postoperatively. CONCLUSION: The pancreatic volume continued to decrease after DG and TG for gastric cancer 5 years after treatment. TG was associated with a significantly greater incidence of pancreatic atrophy than DG 5 years postoperatively, as was RY reconstruction vs. BI reconstruction after DG.

Favorable Effects of Impella on Takotsubo Syndrome Complicated with Cardiogenic Shock.

Reportedly, approximately 9.9%-12.4% of patients with Takotsubo syndrome (TTS) are complicated with cardiogenic shock (CS) and its prognosis remains poor even with the support of conventional mechanical circulatory assist devices including intra-aortic balloon pumping and venoarterial extracorporeal membrane oxygenation. Impella, a novel percutaneous left ventricular assist device, provides strong circulatory support together with the unloading of the left ventricle, and it is theoretically a promising mechanical circulatory assist device for TTS. In this case study, we report four consecutive patients with TTS complicated with CS who were successfully resuscitated using the Impella support.

Tumor-associated macrophage-derived inflammatory cytokine enhances malignant potential of malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is an asbestos-related aggressive malignant neoplasm. Due to the difficulty of achieving curative surgical resection in most patients with MPM, a combination chemotherapy of cisplatin and pemetrexed has been the only approved regimen proven to improve the prognosis of MPM. However, the median overall survival time is at most 12 mo even with this regimen. There has been therefore a pressing need to develop a novel chemotherapeutic strategy to bring about a better outcome for MPM. We found that expression of interleukin-1 receptor (IL-1R) was upregulated in MPM cells compared with normal mesothelial cells. We also investigated the biological significance of the interaction between pro-inflammatory cytokine IL-1ß and the IL-1R in MPM cells. Stimulation by IL-1ß promoted MPM cells to form spheroids along with upregulating a cancer stem cell marker CD26. We also identified tumor-associated macrophages (TAMs) as the major source of IL-1ß in the MPM microenvironment. Both high mobility group box 1 derived from MPM cells and the asbestos-activated inflammasome in TAMs induced the production of IL-1ß, which resulted in enhancement of the malignant potential of MPM. We further performed immunohistochemical analysis using clinical MPM samples obtained from patients who were treated with the combination of platinum plus pemetrexed, and found that the overexpression of IL-1R tended to correlate with poor overall survival. In conclusion, the interaction between MPM cells and TAMs through a IL-1ß/IL-1R signal could be a promising candidate as the target for novel treatment of MPM (Hyogo College of Medicine clinical trial registration number: 2973).

Adenosine Deaminase in Pleural Effusion and Its Relationship with Clinical Parameters in Patients with Malignant Pleural Mesothelioma.

Pleural effusion adenosine deaminase (ADA) levels are elevated in various diseases. We investigated whether pleural effusion ADA levels differ among patients with malignant pleural mesothelioma (MPM), lung cancer (LC), and benign diseases, including tuberculous pleurisy. We examined 329 patients from February 2002 to July 2013. There were 131 MPM cases with ADA levels of 32.29 IU/L; 117 LC cases with ADA levels of 21.12 IU/L; 54 benign disease cases with ADA levels of 20.98 IU/L. A significant difference existed in pleural effusion ADA levels between MPM and benign disease patients. Pleural effusion ADA levels were significantly higher in MPM patients.