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.

The effect of silent eating during school lunchtime on COVID-19 outbreaks.

Silent eating-no talking during mealtimes-has been used as a measure to reduce the spread of the COVID-19 infection because the emission of droplets during conversations has been considered a risk factor for spreading the virus. Japan implemented silent eating during school lunchtimes in May 2020, and it remained in effect until November 2022. However, concerns have been raised regarding its potential negative effects on children's well-being and educational attainment. More importantly, no study to date has examined its effectiveness in reducing the risk of COVID-19 outbreaks. This study aims to address this important knowledge gap by examining the impact of silent eating on the risk of COVID-19 outbreaks. In November 2022, the Japanese government announced that silent eating in public schools was no longer needed, which resulted in discontinuation of the measure in some schools while other schools maintained it. Taking advantage of this cancelation of the silent eating requirement as a natural experiment, we investigated whether silent eating was associated with a reduced risk of COVID-19 outbreaks. We measured the probability of class closures in public schools (the government's guidelines required class closure when more than one child was infected with COVID-19) by applying a Difference-in-Differences model with two-way fixed effects to panel data. We found no evidence that silent eating was associated with a reduced probability of class closures. Heterogeneity analysis also revealed that our findings did not vary by school characteristics. Our findings indicate that policymakers should be cautious about using silent eating at schools as a potential lever to control outbreaks of infectious diseases.

A case of fatal fulminant fat embolism syndrome saved by VA-ECMO in the acute phase of multiple trauma.

Fat embolism syndrome (FES) is a rare complication of long bone fractures, with fulminant FES developing within 12 h of injury and often proving fatal (Shaikh, 2009 [1]). Here, we present a case of fulminant FES in a patient who developed sudden right heart failure after undergoing external fixation of a lower leg fracture and required veno-arterial extracorporeal membrane oxygenation (VA-ECMO). A 79-year-old woman injured in a traffic accident was transferred to our emergency department. Upon arrival, her level of consciousness deteriorated, and she developed circulatory failure. We promptly performed transcatheter arterial embolization for the pelvic fracture and external fixation of the tibiofibular fracture. Within four hours of the injury, she was admitted to our intensive care unit (ICU). Two hours after ICU admission, her hemodynamic status worsened, necessitating the administration of maximum catecholamine dose. Echocardiography revealed petechial hemorrhage of the palpebral conjunctiva and enlargement of the right ventricle. Despite maximal supportive care, the patient remained cardiovascularly unstable. Therefore, VA-ECMO was initiated to stabilize her hemodynamic status. Thereafter, her hemodynamics stabilized, and ECMO support was weaned off and removed on day 3. Subsequent magnetic resonance imaging revealed evidence of cerebral fat embolism. On day 9, she underwent open reduction of the left lower leg with internal fixation and was transferred to another hospital on day 29. This report documents the successful management of fulminant FES during the acute phase of multiple traumas. Clinicians should consider VA-ECMO when suspecting uncontrolled circulatory failure due to fulminant FES, even in the acute phase of multiple trauma.

Dual linear lesions for right atrial flutter after mitral valve surgery via the superior transseptal approach.

BACKGROUND: The superior transseptal approach (STA) for mitral valve surgery is associated with a higher risk of developing macroreentrant incisional atrial flutter (AFL) than the left atrial approach. This study aimed to describe the linear lesions for the complex AFL circuit after the STA and to propose an option for the linear ablation target site. METHODS: Of the 26 patients who underwent radiofrequency catheter ablation for AFL after mitral valve surgery, data from seven patients with STA incisions were retrospectively analyzed. RESULTS: All patients who had undergone the STA had incisional AFL rotated in a long loop within the right atrium (RA) and cavo-tricuspid isthmus (CTI)-dependent AFL. The linear lesions were created in the CTI, the superior RA vestibule, and between the RA-free wall incision or the septal incision and the inferior vena cava. Procedural success was achieved with dual linear lesions in the CTI and superior RA vestibule. Two of seven patients had AFL recurrence during a mean observation period of 22.5 ± 16.7 months. The circuits of recurrent AFL were CTI-dependent AFL and perimitral AFL, respectively. No AFL recurrence was noted with reconduction of the superior RA vestibular lesion. CONCLUSION: Dual linear lesions in the CTI and superior RA vestibule are an effective treatment option for RA macroreentrant AFL after the STA.

Association of bone health by calcaneal quantitative ultrasound with quadriceps strength and function one year after unilateral total knee arthroplasty.

Introduction: Although total knee arthroplasty (TKA) effectively improves knee pain and functional decline due to knee osteoarthritis, hip fractures are more likely to occur in the first year after surgery. Bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA) decreases in the first year after TKA, but it is not clear whether BMD measured by quantitative ultrasound (QUS) also shows a decrease. This study aimed to evaluate the change in QUS parameters before and 1 year after TKA and to investigate the association of QUS parameters with quadriceps strength and function 1 year after TKA. Methods: This prospective cohort study included 30 patients scheduled for their unilateral TKA. We assessed BMD using QUS before and 1 year after surgery. Quadriceps strength was assessed using a hand-held dynamometer, and function was assessed using a self-reported questionnaire. A linear mixed model estimated the mean difference in QUS parameters before and 1 year after TKA. A general linear model was also used to examine the association of QUS parameters with quadriceps strength and self-reported function at 1 year after surgery. Results: We found no significant decrease in the QUS parameters on either the surgical or non-surgical side at 1 year postoperatively compared to preoperatively. The QUS parameters were not associated with quadriceps strength or self-reported function on either the surgical or non-surgical side at 1 year postoperatively. Conclusions: QUS alone may not be sufficient to detect changes in BMD from before surgery to 1 year after TKA. Clinicians should evaluate BMD preoperatively to identify patients at high risk for hip fractures and develop a program to prevent postoperative hip fractures. Level of evidence: Level 3, Cohort study.

Refractory Intestinal Behçet-Like Disease Associated with Trisomy 8 Myelodysplastic Syndrome Resolved by Parenteral Nutrition.

Intestinal Behçet disease (BD), associated with myelodysplastic syndrome (MDS), is often refractory to treatment. An 80-year-old man with trisomy 8 MDS (refractory anemia) developed intermittent fever. Despite investigations to exclude infectious disease, autoimmune disease, and malignancy as the cause of the fever, the etiology could not be determined. A colonoscopy revealed several shallow round ulcers in the ileocecal region and ascending colon, and the biopsy specimens showed nonspecific inflammation. Thereafter, the patient experienced abdominal pain and diarrhea. Other than an oral aphthous ulcer, the patient did not show symptoms to meet the diagnostic criteria for BD. The patient was diagnosed with intestinal ulcers (intestinal BD-like disease) with MDS and trisomy 8. After treatment failure with 5-aminosalicylic acid, steroid, colchicine, and azacitidine, cerebral infarction occurred. Eating was difficult because of the patient's impaired consciousness; hence, total parenteral nutrition (TPN) was commenced. The fever and abdominal symptoms improved with bowel rest over approximately 1 month. Small amounts of food were orally administered to the patient following recovery from the after-effects of the cerebral infarction, but diarrhea and fever repeatedly flared up. Therefore, TPN was continued at home. The patient has not experienced any further intestinal BD symptoms for approximately 1 year with bowel rest. Nutritional therapy, including bowel rest, may be an effective treatment option for intestinal BD with MDS, and might be used as an induction therapy of remission or a supportive therapy for other treatments.

A novel approach to typical atrioventricular nodal reentrant tachycardia with high-resolution mapping using the CARTO 3 cardiac mapping system.

BACKGROUND: We hypothesized that high-resolution activation mapping during sinus rhythm (SR) in Koch's triangle (KT) can be used to describe the most delayed atrial potential around the atrioventricular node and evaluated whether ablation targeting of this potential is safe and effective for the treatment of patients with typical atrioventricular nodal reentrant tachycardia (AVNRT). METHODS: We conducted a prospective, non-randomized, observational study using high-resolution activation mapping from the sinus node to KT with a PENTARAY or OCTARAY catheter using the CARTO 3 cardiac mapping system (Biosense Webster) during SR in 62 consecutive patients (22 men; age [mean ± standard deviation] = 55 ± 14 years) treated for typical AVNRT at our institution from August 2021 to March 2023. RESULTS: In all cases, the most delayed atrial potential was observed near the His potential within KT. Ablation targeting of this potential helped successfully treat each case of AVNRT, with a junctional rhythm observed at the ablation site. Initial ablation was deemed successful in 55/62 patients (89%); in the remaining seven patients, lesion expansion resolved AVNRT. One procedural complication occurred, namely, a transient atrioventricular block lasting 45 s. One patient experienced a transient tachycardic episode by the 1-month follow-up, but no further episodes were noted up to the 1-year follow-up. CONCLUSION: Activation mapping at KT during SR with the high-resolution CARTO system clearly revealed the most delayed atrial potential near the His potential within KT. Targeting this potential was a safe and effective treatment method for patients with typical AVNRT in our study.

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.

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.

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.

Assessing the Performance of GPT-3.5 and GPT-4 on the 2023 Japanese Nursing Examination.

Purpose The purpose of this study was to evaluate the changes in capabilities between the Generative Pre-trained Transformer (GPT)-3.5 and GPT-4 versions of the large-scale language model ChatGPT within a Japanese medical context. Methods The study involved ChatGPT versions 3.5 and 4 responding to questions from the 112th Japanese National Nursing Examination (JNNE). The study comprised three analyses: correct answer rate and score rate calculations, comparisons between GPT-3.5 and GPT-4, and comparisons of correct answer rates for conversation questions. Results ChatGPT versions 3.5 and 4 responded to 237 out of 238 Japanese questions from the 112th JNNE. While GPT-3.5 achieved an overall accuracy rate of 59.9%, failing to meet the passing standards in compulsory and general/scenario-based questions, scoring 58.0% and 58.3%, respectively, GPT-4 had an accuracy rate of 79.7%, satisfying the passing standards by scoring 90.0% and 77.7%, respectively. For each problem type, GPT-4 showed a higher accuracy rate than GPT-3.5. Specifically, the accuracy rates for compulsory questions improved from 58.0% with GPT-3.5 to 90.0% with GPT-4. For general questions, the rates went from 64.6% with GPT-3.5 to 75.6% with GPT-4. In scenario-based questions, the accuracy rates improved substantially from 51.7% with GPT-3.5 to 80.0% with GPT-4. For conversation questions, GPT-3.5 had an accuracy rate of 73.3% and GPT-4 had an accuracy rate of 93.3%. Conclusions The GPT-4 version of ChatGPT displayed performance sufficient to pass the JNNE, significantly improving from GPT-3.5. This suggests specialized medical training could make such models beneficial in Japanese clinical settings, aiding decision-making. However, user awareness and training are crucial, given potential inaccuracies in ChatGPT's responses. Hence, responsible usage with an understanding of its capabilities and limitations is vital to best support healthcare professionals and patients.

Neurologic outcome and location of cardiac arrest in out-of-hospital cardiac arrest patients who underwent extracorporeal cardiopulmonary resuscitation: A multicentre retrospective cohort in Japan.

Aim: We examined the association between the location of cardiac arrest and outcomes of patients with out-of-hospital cardiac arrest (OHCA) who underwent extracorporeal cardiopulmonary resuscitation (ECPR). Methods: This was a secondary analysis of SAVE-J II, a multicentre retrospective registry with 36 participating institutions across Japan, which enrolled adult patients with OHCA who underwent ECPR. The outcomes of interest were favourable neurologic outcome at discharge. We compared the outcome between OHCA cases that occurred at residential and public locations, using a multilevel logistic regression model allowing for the random effect of each hospital. Results: Among 1,744 enrolled OHCAs, 809 and 935 occurred at residential (house: 603; apartment: 206) and public (street: 260; workplace: 210; others: 465) locations, respectively. The proportion of favourable neurologic outcomes was lower in OHCAs at residential locations than those at public locations (88/781 (11.3%) vs.131/891 (14.7%); adjusted odds ratio, 0.72 [95% confidence interval, 0.53-0.99]). However, subgroup analyses for patients with EMS aged <65 years call to hospital arrival within 30 minutes or during daytime revealed less difference between residential and public locations. Conclusion: When cardiac arrests occurred at residential locations, lower proportions of favourable neurologic outcomes were exhibited among patients with OHCA who underwent ECPR. However, the event's location may not affect the prognosis among appropriate and select cases when transported within a limited timeframe.

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.

Delayed Tension Hemothorax With Nondisplaced Rib Fractures After Blunt Thoracic Trauma.

Blunt thoracic trauma often causes rib fractures, hemothorax, and pneumothorax. Although there is no established definition regarding the duration and management of delayed hemothorax, it commonly occurs in a few days and exhibits at least one displaced rib fracture. Moreover, delayed hemothorax rarely develops tension hemothorax. A 58-year-old male who had a motorcycle accident received conservative treatment from his orthopedic doctor. He felt a sudden severe chest pain 19 days after the accident. Contrast-enhanced computed tomography (CT) of the chest revealed multiple left-sided rib fractures without displacement, left pleural effusion, and extravasation near the intercostal space of the seventh rib fracture. After transfer to our hospital and a plain CT scan, which showed a more mediastinal shift toward the right, his condition deteriorated with cardiorespiratory embarrassment, such as restlessness, hypotension, and neck vein distention. We diagnosed him with obstructive shock due to tension hemothorax. Immediate chest drainage ameliorated restlessness and elevated blood pressure. Here, we report an extremely rare and atypical case of delayed tension hemothorax after blunt thoracic trauma without displaced rib fractures.

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.

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.

Combination therapy with anti-programmed cell death 1 antibody plus angiokinase inhibitor exerts synergistic antitumor effect against malignant mesothelioma via tumor microenvironment modulation.

Malignant pleural mesothelioma (MPM) is an asbestos-related fatal malignant neoplasm. Although there has been no reliable chemotherapeutic regimen other than combination therapy of cisplatin and pemetrexed for two decades, combination of ipilimumab plus nivolumab brought about a better outcome in patients with MPM. Thus, cancer immunotherapy using immune checkpoint inhibitor (ICI) is expected to play a central role in the treatment of MPM. To maximize the antitumor effect of ICI, we evaluated whether nintedanib, an antiangiogenic agent, could augment the antitumor effect of anti-programmed cell death 1 (PD-1) antibody (Ab). Although nintedanib could not inhibit the proliferation of mesothelioma cells in vitro, it significantly suppressed the growth of mesothelioma allografts in mice. Moreover, combination therapy with anti-PD-1 Ab plus nintedanib reduced tumor burden more dramatically compared with nintedanib monotherapy via inducing remarkable necrosis in MPM allografts. Nintedanib did not promote the infiltration of CD8+ T cells within the tumor when used alone or in combination with anti-PD-1 Ab but it independently decreased the infiltration of tumor-associated macrophages (TAMs). Moreover, immunohistochemical analysis and ex vivo study using bone marrow-derived macrophages (BMDMs) showed that nintedanib could polarize TAMs from M2 to M1 phenotype. These results indicated that nintedanib had a potential to suppress protumor activity of TAMs both numerically and functionally. On the other hand, ex vivo study revealed that nintedanib upregulated the expression of PD-1 and PD-ligand 1 (PD-L1) in BMDMs and mesothelioma cells, respectively, and exhibited the impairment of phagocytic activity of BMDMs against mesothelioma cells. Co-administration of anti-PD-1 Ab may reactivate phagocytic activity of BMDMs by disrupting nintedanib-induced immunosuppressive signal via binding between PD-1 on BMDMs and PD-L1 on mesothelioma cells. Collectively, combination therapy of anti-PD-1 Ab plus nintedanib enhances the antitumor activity compared with respective monotherapy and can become a novel therapeutic option for patients with MPM.

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.

Agarose native gel electrophoresis analysis of thermal aggregation controlled by Hofmeister series.

The effects of salting-in and salting-out salts defined by Hofmeister series on the solution state of bovine serum albumin (BSA) in 50 mM Tris-HCl buffer at pH 7.4 before and after thermal unfolding at 80 °C for 5 min were examined using agarose native gel electrophoresis and mass photometry. Gel electrophoresis showed that salting-in MgCl2, CaCl2 and NaSCN resulted in formation of intermediate structures of BSA upon heating on native gel, while heating in buffer alone resulted in aggregated bands. Mass photometry showed large loss of monomer and oligomers when heated in this buffer, but retaining these structures in the presence of 1 M MgCl2 and NaSCN. To our surprise, salting-out MgSO4 also showed a similar effect on gel electrophoresis and mass photometry. Salting-out NaCl and (NH4)2SO4 resulted in smearing and aggregated bands, which were supported by mass photometry. Aggregation-suppressive ArgHCl also showed oligomer aggregates upon gel electrophoresis and mass photometry.