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Introduction Retroperitoneal tumors account for 0.2% of all neoplasms. Among these tumors, retroperitoneal vascular malformations are particularly rare, with most previously reported cases being venous malformations. Case presentation A 72‐year‐old woman was diagnosed with a retroperitoneal tumor on abdominal computed tomography. The 27‐mm diameter tumor was located away from the right kidney and major vessels in the right perirenal adipose tissue. Contrast‐enhanced computed tomography revealed a heterogeneously enhanced tumor with well‐defined borders. Dynamic contrast‐enhanced magnetic resonance imaging revealed rapid enhancement in the arterial phase and a progressive filling‐in pattern in the delayed phase. Although vascular malformation was suspected, a definitive diagnosis could not be established. The retroperitoneal tumor was excised laparoscopically for therapeutic and diagnostic purposes, and the histopathological diagnosis confirmed it as a capillary arteriovenous malformation. Conclusion Herein, we presented a rare case of retroperitoneal capillary arteriovenous malformation that was difficult to definitively diagnose preoperatively.

Abstract Objectives This study aimed to investigate the relationship between postoperative reconstructed tongue flap volume (RTFV) and body mass index (BMI) and identify factors affecting the flap volume in patients with tongue squamous cell carcinoma. Methods Thirty‐two patients were evaluated for RTFV from computed tomography images and BMI. The first and second evaluations were done at 6 months and 1.5 years after surgery respectively. RTFV rate changes and BMI differences from the first and second evaluations were calculated. The correlation between RTFV rate change and BMI difference was assessed using Spearman's rank correlation coefficient. Multiple regression analysis evaluated the relationship between the flap volume rate change and age, sex, flap type, and BMI difference to identify influencing factors. Results The flap volume rate change and BMI difference correlated significantly (r = .594, p

Ezrin‐radixin‐moesin‐binding phosphoprotein 50 (EBP50) is a scaffold protein that is required for epithelial polarity. Knockout (KO) of membranous EBP50 (Me‐EBP50) in ovarian clear cell carcinoma (OCCC) cells induced an epithelial–mesenchymal transition (EMT)‐like phenotype, along with decreased proliferation, accelerated migration capability, and induction of cancer stem cell (CSC)‐like properties. Shotgun proteomics analysis of proteins that co‐immunoprecipitated with EBP50 revealed that Me‐EBP50 strongly interacts with myosin 9 (MYH9). Specific inhibition of MYH9 with blebbistatin phenocopied Me‐EBP50 KO, and blebbistatin treatment potentiated the effects of Me‐EBP50 KO. In OCCC cells from clinical samples, Me‐EBP50 and MYH9 were co‐localized at the apical plasma membrane. Patients with a combination of Me‐EBP50‐high and MYH9‐high scores had the best prognosis for overall and progression‐free survival. Our data suggest that Me‐EBP50 has tumor‐suppressive effects through the establishment and maintenance of epithelial polarization. By contrast, loss of Me‐EBP50 expression induces EMT‐like phenotypes, probably due to MYH9 dysfunction; this results in increased cell mobility and enhanced CSC‐like properties, which in turn promote OCCC progression.

Abstract Background Factors predicting the response to pembrolizumab plus platinum and pemetrexed combination therapy (Pemb‐Plt‐PEM) in nonsquamous non‐small cell lung cancer (non‐sq NSCLC) are unclear. We investigated the Glasgow Prognostic (GP) score, neutrophil‐to‐lymphocyte ratio (NLR), and body mass index (BMI) as predictors of response to initial treatment with combination therapy in individuals with advanced non‐sq NSCLC. Methods We retrospectively reviewed 236 patients who received initial treatment with combination therapy for non‐sq NSCLC at 13 institutions between December 2018 and December 2020. The usefulness of the GP score, NLR, and BMI as prognostic indicators was assessed. Cox proportional hazard models and the Kaplan–Meier method were used to compare progression‐free survival (PFS) and overall survival (OS). Results The response rate was 51.2% (95% CI: 44.9–57.5%). The median PFS and OS after beginning Pemb‐Plt‐PEM were 8.8 (95% CI: 7.0–11.9) months and 23.6 (95% CI: 18.7–28.6) months, respectively. The NLR independently predicted the efficacy of Pemb‐Plt‐PEM—the PFS and OS were more prolonged in individuals with NLR

Abstract Background ONO‐4538‐52/TASUKI‐52 was performed in Japan, Korea, and Taiwan to determine the oncological effectiveness and safety of combining nivolumab or placebo with bevacizumab plus platinum chemotherapy for the initial (first‐line) treatment of patients with advanced non‐squamous non‐small cell lung cancer (nsNSCLC). At the interim analysis (minimum follow‐up, 7.4 months), the independent radiology review committee‐assessed progression‐free survival was significantly longer in the nivolumab arm, but overall survival (OS) data were immature. Methods Here, we present the updated OS data. Patients with treatment‐naïve stage IIIB/IV or recurrent nsNSCLC without driver mutations in ALK, EGFR, or ROS1, were randomized 1:1 to receive either nivolumab or placebo. Patients in both arms received paclitaxel, carboplatin, and bevacizumab, administered 3‐weekly for a maximum of 6 cycles. Nivolumab/placebo and bevacizumab were subsequently continued until disease progression or unacceptable toxicity. Results Overall, 550 patients were randomized. At the time of the analysis (minimum follow‐up: 19.4 months), the median OS was longer in the nivolumab arm than in the placebo arm (30.8 vs. 24.7 months; hazard ratio 0.74, 95% confidence interval 0.58–0.94). The 12‐month OS rates were 81.3% vs. 76.3% in the nivolumab vs. placebo arms, respectively. The respective 18‐month OS rates were 69.0% vs. 61.9%. Conclusion Nivolumab plus platinum chemotherapy and bevacizumab demonstrated longer OS vs. the placebo combination. We believe this regimen is viable as a standard, first‐line treatment for patients with advanced nsNSCLC without driver mutations in ALK, EGFR, or ROS1.

Abstract Objective Videoendoscopic evaluation of swallowing is an objective swallowing function evaluation method used in dysphagia rehabilitation. However, it is anatomically difficult to detect the entry of foreign substances through the posterior tracheal wall using a conventional endoscope (CE). In this study, we developed an endoscope that can observe the posterior tracheal wall and investigated its reliability and validity in healthy adults. Methods Twenty healthy adults were included. The trachea was observed from inside the larynx using a CE and a portable, flexible two‐step angulation endoscope (two‐AE) with a two‐step curved shaft tip. The visibility of the anterior and posterior walls was recorded. The time from the endoscope tip entering the larynx to the posterior tracheal wall was measured. Additionally, discomfort events were assessed after the examination. McNemar's test and a paired t‐test were used for statistical analysis. Kappa coefficients and concordance rates were calculated. Results The anterior tracheal wall was observed using both endoscopes. The posterior tracheal wall was significantly observed in 18 participants with the two‐AE (p

Abstract Background Additional ablation strategies after pulmonary vein isolation (PVI) for patients with nonparoxysmal atrial fibrillation (non‐PAF) lasting ≥2 years have not been fully effective. This is presumably because of insufficient identification of non‐PAF maintenance mechanisms. In this study, we employed a novel online and real‐time phase mapping system, ExTRa Mapping, to identify and modulate rotors as one of the non‐PAF maintenance mechanisms in patients with non‐PAF sustained after PVI. We investigated the relationship between outcomes of ExTRa Mapping‐guided rotor ablation (ExTRa‐ABL) and non‐PAF duration prior to this procedure. Methods This study consisted of 73 non‐PAF patients (63 ± 8 years, non‐PAF duration 31 ± 37 months) who underwent the first ExTRa‐ABL in patients with non‐PAF sustained after completion of PVI. Results Freedom from non‐PAF/atrial tachycardia (AT) recurrence at 12 months after ExTRa‐ABL was achieved in 50 (69%) of patients. The non‐PAF duration prior to ExTRa‐ABL was significantly longer in patients with non‐PAF/AT recurrence after ExTRa‐ABL compared with those without (56 ± 50 vs. 19 ± 22 months, p = .001). In patients with non‐PAF duration of ≤60 months prior to ExTRa‐ABL, compared with >60 months, non‐PAF/AT‐free rate was significantly higher (68.9% vs. 23.1%, p 60 months of non‐PAF duration.

Abstract Although meta‐analysis has become an essential tool in ecology and evolution, reporting of meta‐analytic results can still be much improved. To aid this, we have introduced the orchard plot, which presents not only overall estimates and their confidence intervals, but also shows corresponding heterogeneity (as prediction intervals) and individual effect sizes. Here, we have added significant enhancements by integrating many new functionalities into orchaRd 2.0. This updated version allows the visualisation of heteroscedasticity (different variances across levels of a categorical moderator), marginal estimates (e.g. marginalising out effects other than the one visualised), conditional estimates (i.e. estimates of different groups conditioned upon specific values of a continuous variable) and visualisations of all types of interactions between two categorical/continuous moderators. orchaRd 2.0 has additional functions which calculate key statistics from multilevel meta‐analytic models such as I2 and R2. Importantly, orchaRd 2.0 contributes to better reporting by complying with PRISMA‐EcoEvo (preferred reporting items for systematic reviews and meta‐analyses in ecology and evolution). Taken together, orchaRd 2.0 can improve the presentation of meta‐analytic results and facilitate the exploration of previously neglected patterns. In addition, as a part of a literature survey, we found that graphical packages are rarely cited (~3%). We plea that researchers credit developers and maintainers of graphical packages, for example, by citations in a figure legend, acknowledging the use of relevant packages.

Abstract Aims Patient reported outcomes (PROs) are gradually being incorporated into daily practice to assess individual health‐related quality of life (QOL). However, despite accumulating evidence of the prognostic utility of heart failure (HF)‐specific QOL indices, evidence on the generic QOL score is scarce, especially in patients with HF with preserved ejection fraction (HFpEF). Methods and results Patient data were extracted from the Prospective mUlticenteR obServational stUdy of patIenTs with Heart Failure with Preserved Ejection Fraction (PURSUIT HFpEF) study. EuroQol 5 dimensions 5‐level (EQ‐5D‐5L) data were obtained at discharge to evaluate patients' health‐related QOL. The study population (n = 864) was divided into tertiles based on their EQ‐5D‐5L index as follows: low EQ‐5D‐5L 0.038–0.664 (n = 287), middle EQ‐5D‐5L 0.665–0.867 (n = 293), and high EQ‐5D‐5L 0.871–1.000 (n = 284). A total of 206 patients died over a mean follow‐up period of 2.0 ± 1.2 years. Kaplan–Meier analysis revealed that the risk of mortality increased with the tertile of the EQ‐5D‐5L index (34% vs. 23% vs. 14%, P

Abstract Background Abnormal activation of Wnt/β‐catenin signaling is associated with various aspects of cancer development. This study explored the roles of novel target genes of the Wnt/β‐catenin signaling pathway in cancer cells. Methods Using the haploid chronic myelogenous leukemia cell line HAP1, RNA sequencing (RNA‐seq) was performed to identify genes whose expression was increased by APC disruption and reversed by β‐catenin knockdown (KD). The regulatory mechanism and function of one of the candidate genes was investigated in colorectal cancer (CRC) cells. Results In total, 64 candidate genes whose expression was regulated by Wnt/β‐catenin signaling were identified. Of these candidate genes, the expression levels of six were reduced by β‐catenin KD in HCT116 CRC cells in our previous microarray. One of these genes was Visinin‐like 1 (VSNL1), which belongs to the neuronal calcium‐sensor gene family. The expression of VSNL1 was regulated by the β‐catenin/TCF7L2 complex via two TCF7L2‐binding elements in intron 1. VSNL1 KD‐induced apoptosis in VSNL1‐positive CRC cells. Additionally, forced expression of wild‐type VSNL1, but not a myristoylation, Ca2+‐binding, or dimerization‐defective mutant, suppressed the apoptosis induced by camptothecin and doxorubicin in VSNL1‐negative CRC cells. Conclusion Our findings suggest that VSNL1, a novel target gene of the Wnt/β‐catenin signaling pathway, is associated with apoptosis resistance in CRC cells.

Combination chemotherapy with gemcitabine and cisplatin (GC) is recommended as the primary treatment for advanced bladder cancer (BC). However, the benefits of this approach are limited owing to the acquisition of drug resistance. Here, we found that gemcitabine‐resistant and cisplatin‐resistant BCs do not exhibit cross‐resistance, and that these BCs exhibit different mRNA patterns, as revealed using RNA sequence analysis. To overcome drug resistance, we used the newly developed pan‐RAS inhibitor Compound 3144. Compound 3144 inhibited cell viability through suppression of RAS‐dependent signaling in gemcitabine‐ and cisplatin‐resistant BCs. RNA sequencing revealed that several genes and pathways, particularly those related to the cell cycle, were significantly downregulated in Compound 3144‐treated BCs. These findings provide insights into potential therapeutic strategies for treating BC.

With advances in sequencing technology, metatranscriptome sequencing from a variety of environmental and biological sources has revealed the existence of various previously unknown RNA viruses. This review presents recent major RNA virome studies sampled from invertebrate and vertebrate species as well as aquatic environments. In particular, we focus on severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) and related RNA virus identification through metatranscriptome sequencing analyses. Recently developed bioinformatics software and databases for RNA virus identification are introduced. A relationship between newly identified RNA viruses and endogenous viral elements in host genomes is also discussed.

Abstract Suppression‐burst (SB) is an electroencephalographic pattern observed in neonatal‐ and infantile‐onset developmental and epileptic encephalopathies (DEEs), which are associated with high mortality in early life. However, the relation of SB electroencephalogram (SB‐EEG) with autonomic function requires clarification. We investigated the relationship between heart rate (HR) and phasic transition during SB‐EEG in DEEs to explore the mechanism of early death. Seven patients (two with KCNT1‐DEE) with neonatal‐ and infantile‐onset DEE who presented with SB‐EEG were retrospectively identified. Five‐minute SB‐EEGs were analyzed with simultaneous recording of electrocardiograms. Mean HR, suppression duration, and burst period were calculated by measuring RR intervals. Two patients with KCNT1‐DEE exhibited synchronous HR fluctuations, with an HR decrease during suppression and an increase during burst. The HR decrease was larger (−6.1% and −7.7%) and the median duration of suppression was longer (4.0 and 8.2 s) in patients with KCNT1‐DEE than the other five (range: −2.9% to 0.9% and 0.7‐1.7s, respectively). A strong negative correlation was confirmed between suppression duration and HR reduction rates in one patient with KCNT1‐DEE. SB phases may influence HR regulation in patients with KCTN1‐DEE.

Abstract Aims Several studies demonstrated that tricuspid regurgitation (TR) is associated with poor clinical outcomes. However, data on patients with TR who experienced acute heart failure (AHF) remains scarce. The purpose of this study is to evaluate the association between TR and clinical outcomes in patients admitted with AHF, using a large‐scale Japanese AHF registry. Methods and results The current study population consisted of 3735 hospitalized patients due to AHF in the Kyoto Congestive Heart Failure (KCHF) registry. TR grades were assessed according to the routine clinical practice at each participating centre. We compared the baseline characteristics and outcomes according to the severity of TR. The primary outcome was all‐cause death. The secondary outcome was hospitalization for heart failure (HF). The median age of the entire study population was 80 (interquartile range: 72–86) years. One thousand two hundred five patients (32.3%) had no TR, while mild, moderate, and severe TR was found in 1537 patients (41.2%), 776 patients (20.8%), and 217 patients (5.8%), respectively. Pulmonary hypertension, significant mitral regurgitation, and atrial fibrillation/flutter were strongly associated with the development of moderate/severe of TR, while left ventricular ejection fraction

Abstract Everolimus has recently been used to prevent graft rejection in liver transplantation and reduces the incidence of kidney dysfunction caused by calcineurin inhibitors. In this study, a population pharmacokinetic analysis was conducted to improve the individualization of everolimus therapy. Japanese post‐liver transplant patients whose blood everolimus concentrations were measured between March 2018 and December 2020 were included in this study. A nonlinear mixed‐effect modeling program was used to explore covariates that affect everolimus pharmacokinetics. Individual everolimus pharmacokinetic parameters estimated by the post‐hoc Bayesian analysis using the final model were compared with the tacrolimus dose per trough concentration (D/C) ratio in each patient. The final model was extrapolated to pediatric liver transplant patients for external evaluation. A total of 937 concentrations from 87 adult patients were used in the model‐building process. Everolimus clearance was significantly affected by the estimated glomerular filtration rate, concomitant use of fluconazole, sex, as well as total daily dose of everolimus (TDM effect). The estimated individual apparent clearance of everolimus by the post‐hoc Bayesian analysis was moderately correlated with the D/C ratio of tacrolimus in each patient (R2 = 0.330, p

Abstract Although remdesivir, a prodrug of nucleoside analog (GS‐441524), has demonstrated clinical benefits in coronavirus disease 2019 (COVID‐19) treatment, its pharmacokinetics (PKs) in patients with COVID‐19 remain poorly understood. Therefore, in this study, the PKs of remdesivir and its major metabolite, GS‐441524, were evaluated using a population PK (PopPK) approach to understand the PK aspect and exposure–clinical outcome relationship. The serum concentrations of remdesivir and GS‐441524 (102 points in 39 patients) were measured using liquid chromatography–tandem mass spectrometry. All patients received 200 mg remdesivir on the first day, followed by 100 mg on 2–5 days, except for one patient who discontinued remdesivir on day 4. The median (range) age, body surface area, and estimated glomerular filtration rate (eGFR) were 70 (42–85), 1.74 m2 (1.36–2.03), and 68 mL/min/1.73 m2 (33–113), respectively. A compartment model with first‐order elimination combined with remdesivir and GS‐441524 was used for nonlinear mixed‐effects model analysis. Remdesivir was rapidly eliminated after infusion, whereas GS‐441524 was eliminated relatively slowly (half‐time = 17.1 h). The estimated apparent clearance (CL) and distribution volume of GS‐441524 were 11.0 L/h (intersubject variability [ISV]% = 43.0%) and 271 L (ISV% = 58.1%), respectively. The CL of GS‐441524 was significantly related to the eGFR (CL × [eGFR/68]0.745). The post hoc area under the curve of GS‐441524 was unrelated to the recovery rate or aspartate aminotransferase/alanine aminotransferase elevation. Overall, PopPK analysis showed the rapid elimination of remdesivir in the blood, and GS‐441524 accumulation depended on eGFR in patients with COVID‐19. However, no relevance of exposure–clinical outcome was not suggestive of the dose adjustment of remdesivir.

Abstract Background The prognosis of focal segmental glomerulosclerosis patients with nephrotic syndrome is estimated to be 10%–20% in 5 years and 30%–50% in 10 years, leading to end‐stage kidney disease. The response rate with steroid therapy is 40%–60%. Therapeutic low‐density lipoprotein‐apheresis (LDL‐A) may be effective in patients with steroid resistance. Information regarding the long‐term prognosis of patients with focal segmental glomerulosclerosis receiving this therapy is scarce. Methods We investigated the effectiveness of treatment in 50 patients with primary focal segmental glomerulosclerosis diagnosed between 1961 and 2017 at Kanazawa University Hospital and related facilities. The patients were observed at least 12 months after biopsy or until end‐stage kidney disease occurrence or death. Results LDL‐A was performed in four patients who presented with steroid‐resistant nephrotic syndrome (two patients had concurrent acute renal failure for which hemodialysis was performed). In comparison with 17 patients who did not receive LDL‐A after 1989, the LDL‐A group had higher urinary protein excretion (13.7 vs. 5.2 g/day, P = 0.053) and serum creatinine (4.11 vs. 1.65 mg/dL) levels at onset, and a numerically higher remission rate (75.0% vs. 58.7%) compared with the nonlipoprotein‐apheresis group. Conclusion Therapeutic LDL‐A can be performed for critical cases and may improve the remission rate.

Abstract Aim Postpsychotic depression is challenging to differentiate, yet it is clinically frequent, puts patients at risk for suicide, and affects their mental capacity. Treatment with antipsychotics for postpsychotic depression is desirable; however, there is no consensus on which antipsychotics are optimal. Case presentation We report the case of a young male patient with schizophrenia in his 20s who developed postpsychotic depression, including despair, overwhelming loss, humiliation, and suicidal ideation during treatment with paliperidone. As a result, we switched his medication to lurasidone, which relieved his depressive symptoms without any symptom relapse and his social functioning improved. Conclusion Postpsychotic depression has more psychic characteristics than behavioral. According to various international guidelines for the pharmacological treatment of schizophrenia, antipsychotics should be administered for depressive symptoms of schizophrenia. As evidenced in this case report, lurasidone may be a practical alternative for improving postpsychotic depression.

Syncytin‐2 is a membrane fusion protein involved in placenta development that is derived from the endogenous retrovirus envelope gene acquired in the common ancestral lineage of New World and Old World monkeys (OWMs). It is known that syncytin‐2 is conserved between apes and OWMs, suggesting its functional importance; however, syncytin‐2 of common marmosets (Callithrix jacchus) exhibits lower fusogenic activity than those of humans and OWMs in human cell lines. To obtain insight into the functional diversity of syncytin‐2 genes in primates, we examined the syncytin‐2 gene in New World monkeys (NWMs). We experimentally evaluated the cell fusion ability of syncytin‐2 in humans, C. jacchus, and tufted capuchins (Sapajus apella). We found that the cell fusion ability of S. apella was lower than that of human syncytin‐2. Chimeric syncytin‐2 constructs revealed that the amino acid differences in the surface unit of S. apella syncytin‐2 were responsible for the weak cell fusion activity. In addition, genomic sequence analyses of syncytin‐2 revealed that the open reading frames (ORFs) of syncytin‐2 were highly conserved in seven apes and 22 OWMs; however, the syncytin‐2 ORFs of three of 12 NWM species were truncated. Our results suggest that syncytin‐2 in several NWMs may be of less importance than in OWMs and apes, and other syncytin‐like genes may be required for placental development in various NWM species.

Introduction Metastasectomy of oligometastatic prostate cancer has the potential to contribute to improving prognosis. We report on a case of metastasectomy of solitary liver tumor after radical prostatectomy. Case presentation An 80‐year‐old man underwent radical prostatectomy for prostate cancer, followed by radiotherapy after the operation because of increased serum prostate‐specific antigen levels of 0.529 ng/mL. Levels increased further to 0.997 ng/mL even after salvage therapy. The patient then received androgen deprivation therapy. Levels remained stable for 3 years, but rapidly increased to 19.781 ng/mL in the following 6 months. Abdominal computed tomography revealed a solitary liver tumor, and no metastasis to other sites was identified. The patient underwent liver segmentectomy. Microscopic examination of excised specimens revealed prostate cancer cells. Five years after surgery, serum prostate‐specific antigen maintained to the lowest level so far. Conclusion Metastasectomy might be a beneficial therapeutic option to improve the prognosis for solitary metastasis from prostate cancer.

Abstract Background and Aim Withdrawal time of the colonoscope is associated with adenoma detection. However, the association between cecal intubation time and adenoma detection remains unclear. This study aimed to evaluate the association between cecal intubation time and adenoma detection. Methods This retrospective study analyzed prospectively collected data from a randomized controlled trial on female patients who underwent colonoscopy in an academic hospital. The primary outcome was the mean number of all adenomas detected per patient. Secondary outcomes included the mean number of advanced, diminutive, small/large, right‐sided colonic, and left‐sided colonic adenomas detected per patient. Furthermore, the detection rates of all categories of adenoma were evaluated. Results The analysis included 216 female patients aged ≥20 years. The correlation analysis did not reveal a significant relationship (P = 0.473) between cecal intubation and withdrawal times. The mean number of all adenomas detected per patient declined by approximately 30% (1.05–0.70) from the fastest to the slowest insertion time quartile. Adjusted regression analysis showed a significant decrease in the mean number of all adenomas detected per patient with increased intubation time (relative risk, RR = 0.87; 95% confidence interval, 0.76–0.99, P = 0.045), whereas the mean number of other categories of adenomas detected per patient and the detection rates of all categories of adenoma were not associated with the cecal intubation time. Conclusions This study showed a significant association between prolonged cecal intubation time and decreased adenoma detection. The cecal intubation time may be a significant quality indicator for colonoscopy.

Abstract Background To evaluate whether urine laminin‐γ2 monomer (Ln‐γ2m) offers a useful biomarker for patients with non‐muscle‐invasive bladder cancer (NMIBC). Methods Participants comprised 297 patients, including 111 patients with NMIBC, 136 patients with benign genitourinary disease (BD) and 50 healthy donors (HD). Urine Ln‐γ2m was prospectively measured and accuracy was analyzed. Receiver operating characteristic (ROC) curves were determined and area under the ROC curve (AUC) was calculated for urine Ln‐γ2m, and compared to those of traditional urine tumor markers such as nuclear matrix protein 22 (NMP22), bladder tumor antigen (BTA) and cytology. The net benefits of combining urine markers were analyzed by decision curve analysis. Results Mean urine Ln‐γ2m was significantly higher in NMIBC than in BD or HD. The AUC for urine Ln‐γ2m was significantly higher than those for urine NMP22, BTA or cytology when comparing NMIBC with HD. In patients with low‐grade NMIBC, the AUC for urine Ln‐γ2m was higher than the AUCs for NMP22, BTA or cytology. A net benefit of combined examination using urine Ln‐γ2m/uCRN with NMP22 was demonstrated. Conclusion These results suggest urine Ln‐γ2m as a potentially useful biomarker for NMIBC, particularly in cases of low‐grade cancer.

Abstract Aims Application of the latent class analysis to acute heart failure with preserved ejection fraction (HFpEF) showed that the heterogeneous acute HFpEF patients can be classified into four distinct phenotypes with different clinical outcomes. This model‐based clustering required a total of 32 variables to be included. However, this large number of variables will impair the clinical application of this classification algorithm. This study aimed to identify the minimal number of variables for the development of optimal subphenotyping model. Methods and results This study is a post hoc analysis of the PURSUIT‐HFpEF study (N = 1095), a prospective, multi‐referral centre, observational study of acute HFpEF [UMIN000021831]. We previously applied the latent class analysis to the PURSUIT‐HFpEF dataset and established the full 32‐variable model for subphenotyping. In this study, we used the Cohen's kappa statistic to investigate the minimal number of discriminatory variables needed to accurately classify the phenogroups in comparison with the full 32‐variable model. Cohen's kappa statistic of the top‐X number of discriminatory variables compared with the full 32‐variable derivation model showed that the models with ≥16 discriminatory variables showed kappa value of >0.8, suggesting that the minimal number of discriminatory variables for the optimal phenotyping model was 16. The 16‐variable model consists of C‐reactive protein, creatinine, gamma‐glutamyl transferase, brain natriuretic peptide, white blood cells, systolic blood pressure, fasting blood sugar, triglyceride, clinical scenario classification, infection‐triggered acute decompensated HF, estimated glomerular filtration rate, platelets, neutrophils, GWTG‐HF (Get With The Guidelines‐Heart Failure) risk score, chronic kidney disease, and CONUT (Controlling Nutritional Status) score. Characteristics and clinical outcomes of the four phenotypes subclassified by the minimal 16‐variable model were consistent with those by the full 32‐variable model. The four phenotypes were labelled based on their characteristics as ‘rhythm trouble’, ‘ventricular‐arterial uncoupling’, ‘low output and systemic congestion’, and ‘systemic failure’, respectively. Conclusions The phenotyping model with top 16 variables showed almost perfect agreement with the full 32‐variable model. The minimal model may enhance the future clinical application of this clustering algorithm.

Abstract Background Delayed neuropsychiatric sequelae (DNS) occurs in 10%–30% of acute carbon monoxide poisoning cases. Patients with this condition present higher brain dysfunction. Hyperbaric oxygen (HBO) therapy was reportedly an effective treatment for DNS in the acute phase. Favorable predictive factors affecting the prognosis of patients with DNS after HBO therapy include younger age and longer interictal periods. However, the relationship between these factors and neuroimaging findings remains unclear. Case Presentation The patient was a 59‐year‐old man with DNS, who developed major depressive disorder and attempted suicide with charcoal briquettes. He was diagnosed with carbon monoxide poisoning and underwent acute HBO therapy. After a 1‐month lucid period, the patient developed intermittent carbon monoxide poisoning with cognitive dysfunction, following which HBO therapy was re‐initiated. Following treatment, the patient returned to work for 10 years. Frontal lobe hypoperfusion, measured by single‐photon emission computed tomography and cognitive impairment, improved with HBO therapy. However, magnetic resonance imaging revealed brain volume atrophy over time. Conclusion This study reported a case of DNS that completely resolved within a 10‐year follow‐up period. Cerebral blood flow reduction, mainly in the frontal lobe, improved along with cognitive recovery during HBO therapy. Despite gradually progressive brain atrophy over the past decade, no noted deficits in cerebral blood flow were observed in the frontal lobes. These findings suggest that improvement in cerebral blood flow during HBO therapy and its retention may be factors associated with a favorable prognosis in patients with DNS.

Abstract Aim Hyperthymic temperament is a cheerful action orientation that is suggested to have a protective effect on depressive symptoms. We recently reported that hyperthymic temperament can positively predict activation of reward‐related brain areas in anticipation of monetary rewards, which could serve as a biomarker of hyperthymic temperament. However, the relationship between hyperthymic temperament and neural responsiveness to nonmonetary rewards (i.e., feedback indicating success in a task) remains unclear. Methods Healthy participants performed a modified monetary incentive delay task inside a functional magnetic resonance imaging scanner. To examine the effect of nonmonetary positive feedback, the participants performed feedback and no‐feedback trials. We explored brain regions whose neural responsiveness to nonmonetary rewards was predicted by hyperthymic temperament. Results There was premotor area activation in anticipation of a nonmonetary reward, which was negatively predicted by hyperthymic temperament. Moreover, brain areas located mainly in the primary somatosensory area and somatosensory association area were activated by performance feedback, which was positively predicted by hyperthymic temperament. Conclusion We found that hyperthymic temperament is related to neural responsiveness to both monetary and nonmonetary rewards. This may be related to the process of affective regulation in the somatosensory area.

Abstract Background and Aims Testosterone deficiency is often related to geriatric syndrome including erectile dysfunction, osteo‐porosis, depression, cognitive impairment, cardiovascular diseases and frailty. Despite the existence of many studies on short‐term exercise and serum testosterone levels, few research have focused on exercise habits from young age and testosterone values in middle‐aged male. In this study, we investigated whether belonging to an athletic club from school age could predict serum‐free testosterone (FT) levels. Methods The subjects were 1609 middle‐aged male outpatients aged 40 years or older (median: 61 years, interquartile range: 54–69) who visited our hospital. Participants had their FT values measured in the morning hours during the period from December 2007 to June 2009. A questionnaire survey on exercise habits was conducted at the same time as the measurements. The exercise habit questionnaire was created based on whether the patients belonged to an athletic club in (a) elementary school, (b) junior high school, (c) high school, (d) college, (e) adult life, and (f) at the time of the test. Results There was only one positive response to the questionnaire among 456 patients (28% of total), followed by zero for 358 patients (22% of total). The number of patients with low‐testosterone levels (FT

Abstract Patulin is a toxic secondary metabolite synthesized by various fungal strains. This mycotoxin is generally toxic to microorganisms as well as mammals due to its reactivity with the important cellular antioxidant glutathione. In this study, we explored the presence of microorganisms capable of degrading patulin. Microorganisms were screened for the ability to both grow in culture medium containing patulin and reduce its concentration. Screening of 510 soil samples resulted in the isolation of two filamentous fungal strains, one of which, Acremonium sp. TUS‐MM1 was characterized in detail. Liquid chromatography‐mass spectrometry and nuclear magnetic resonance analyses revealed that TUS‐MM1 cells degraded patulin to desoxypatulinic acid. In addition, extracellular components of strain TUS‐MM1 also exhibited patulin‐transforming activity. High‐performance liquid chromatography analysis revealed that the extracellular components generated several products from patulin. Disc diffusion assay using Escherichia coli cells revealed that the patulin‐transformation products by the extracellular components are less toxic than patulin. We also demonstrated that a thermostable, low‐molecular‐weight compound within the extracellular components was responsible for the patulin‐transforming activity. These results suggest that strain TUS‐MM1 transforms patulin into less‐toxic molecules by secreting a highly reactive compound. In addition, once patulin enters the cells, strain TUS‐MM1 can transform it into desoxypatulinic acid to reduce its toxicity.

Abstract Objective Endovascular therapy (EVT) is performed for acute ischemic stroke (AIS) with large vessel occlusion (LVO), however, the treatment strategies and clinical outcomes differ between cardiac embolism (CE) and intracranial arteriosclerosis‐derived LVO (ICAS‐LVO). We analyzed whether the time‐to‐max (Tmax) volume derived from perfusion imaging predicted clinical classification in AIS patients before EVT. Methods Consecutive AIS patients with anterior circulation LVO evaluated by automated imaging software were retrospectively identified. Patients were classified into a CE group and an ICAS‐LVO group, and parameters were compared between groups. Results Thirty‐nine patients were included and Tmax volume and Tmax > 6 s volume/Tmax > 4 s volume were significantly greater in the CE group than in the ICAS‐LVO group (Tmax > 4 s volume: 261 mL vs. 149 mL, p = .01, Tmax > 6 s volume: 143 mL vs. 59 mL, p = .001, Tmax > 6 s volume/Tmax > 4 s volume: 0.59 vs. 0.40, p 6 s volume/Tmax > 4 s volume (p = .04). Conclusion The Tmax volume derived from perfusion imaging predicts the clinical classification of AIS patients before EVT.

Abstract Aims Considerable variation in the relationships between the indices of left atrial (LA) volume and pressure could possibly affect the selection of medications or efforts to improve the prognoses of patients with heart failure and preserved ejection fraction (HFpEF). We aimed to clarify the association between the prognostic endpoint and LA overload indices in elderly patients with HFpEF. Methods and results We analysed 898 patients with HFpEF hospitalized for acute decompensated heart failure (men/women: 406/492). Blood tests and transthoracic echocardiography were performed before discharge. The primary endpoint was re‐admission for heart failure or all‐cause mortality. Stroke volume (SV)/left atrial volume (LAV), an index for LA volume overload, was a significant prognostic factor of re‐admission for heart failure in the multivariable Cox hazard analysis adjusted for comorbidities [hazard ratio (HR) 0.616, 95% confidence interval (CI) 0.430–0.882, P = 0.008]. Additionally, the ratio of diastolic elastance (Ed) to arterial elastance (Ea), an index for LA pressure overload, was also significant (HR 1.444, 95% CI 1.014–2.058, P = 0.041). Furthermore, Ed/Ea, but not SV/LAV, was a significant prognostic factor of all‐cause mortality (HR 1.594, 95% CI 1.102–2.306, P = 0.013). Conclusions The index of LA overload for prognosis may differ according to the different endpoints in elderly patients with HFpEF.

Abstract Aims The effectiveness of angiotensin‐converting enzyme inhibitors (ACE‐I) and angiotensin II receptor blockers (ARB) has not been demonstrated in patients with heart failure with preserved ejection fraction (HFpEF). We recently reported significant interaction between the use of ACE‐I and/or ARB (ACE‐I/ARB) and frailty on prognosis in patients with HFpEF. In the present study, we examined the association between ACE‐I/ARB and prognosis in patients with HFpEF stratified by the presence or absence of frailty. Methods and results We examined the association between the use of ACE‐I/ARB and prognosis according to the presence [Clinical Frailty Scale (CFS) ≥ 5] or absence (CFS ≤ 4) of frailty in patients with HFpEF in a post hoc analysis of registry data. Primary endpoint was the composite of all‐cause mortality and heart failure admission. Secondary endpoints were all‐cause mortality and heart failure admission. Of 1059 patients, median age was 83 years and 45% were male. Kaplan–Meier analysis showed that the risk of composite endpoint (log‐rank P = 0.001) and all‐cause death (log‐rank P = 0.005) in patients with ACE‐I/ARB was lower in those with CFS ≥ 5, but similar between patients with and without ACE‐I/ARB in patients with CFS ≤ 4 (composite endpoint: log‐rank P = 0.830; all‐cause death: log‐rank P = 0.192). In a multivariable Cox proportional hazards model, use of ACE‐I/ARB was significantly associated with lower risk of the composite endpoint [hazard ratio (HR) = 0.52, 95% confidence interval (CI) = 0.33–0.83, P = 0.005] and heart failure admission (HR = 0.45, 95% CI = 0.25–0.83, P = 0.010) in patients with CFS ≥ 5, but not in patients with CFS ≤ 4 (composite endpoint: HR = 1.41, 95% CI = 0.99–2.02, P = 0.059; heart failure admission: HR = 1.43, 95% CI = 0.94–2.18, P = 0.091). The association between ACE‐I or ARB and prognosis did not significantly differ by CFS (CFS ≤ 4: log‐rank P = 0.562; CFS ≥ 5: log‐rank P = 0.100, for with ACE‐I vs. ARB, respectively). Adjusted HRs for CFS 1–4 were higher than 1.0 but were

Abstract High‐grade fetal lung adenocarcinoma (H‐FLAC) is a rare tumor, with little known of its response to chemotherapy with or without an immune checkpoint inhibitor or of its molecular profile. We report the first case of a 56‐year‐old man with stage IV H‐FLAC who was successfully treated with carboplatin plus nab‐paclitaxel in combination with atezolizumab. In addition, the tumor was found to be positive for amplification of the human epidermal growth factor receptor 2 gene.

Abstract As life expectancy increases, the older population continues to grow rapidly, resulting in increased requirement for surgery for older patients with gastrointestinal cancer. Older individuals represent a heterogeneous group in terms of physiological reserves, co‐morbidity, cognitive impairment, and disability. Owing to the lack of treatment guidelines for vulnerable patients with gastrointestinal cancer, these patients are more likely to be at risk of undertreatment or overtreatment. Hence, the identification of frail patients with gastrointestinal cancer would improve cancer treatment outcomes. Although there is no standardized geriatric assessment tool, a growing body of research has shown associations of frailty with adverse postoperative outcomes and poor prognosis after resection of gastrointestinal tract and hepatobiliary‐pancreatic cancers. Emerging evidence suggests that prehabilitation, which includes exercise and nutritional support, can improve preoperative functional capacity, postoperative recovery, and surgical outcomes, particularly in frail patients with gastrointestinal cancer. We reviewed major geriatric assessment tools for identification of frail patients and summarized clinical studies on frailty and surgical outcomes, as well as prehabilitation or rehabilitation in gastrointestinal tract and hepatobiliary‐pancreatic cancers. The integration of preoperative geriatric assessment and prehabilitation of frail patients in clinical practice may improve surgical outcomes. In addition, improving preoperative vulnerability and preventing functional decline after surgery is important in providing favorable long‐term survival in patients with gastrointestinal cancer. Further clinical trials are needed to examine the effects of minimally invasive surgery, and chemotherapy in frail patients with gastrointestinal cancer.

Macrophages distributed in tissues throughout the body contribute to homeostasis. In the inflammatory state, macrophages undergo mechanical stress that regulates the signal transduction of immune responses and various cellular functions. However, the effects of the inflammatory response on macrophages under physiological cyclic stretch are unclear. We found that physiological cyclic stretch suppresses inflammatory cytokine expression in macrophages by regulating NF‐κB activity. NF‐κB phosphorylation at Ser536 in macrophages was inhibited, suggesting that tank‐binding kinase (TBK1) regulates NF‐κB activity during physiological stress. Moreover, TBK1 expression was suppressed by physiological stretch, and TBK1 knockdown by siRNA induced the suppression of NF‐κB phosphorylation at Ser536. In conclusion, physiological stretch triggers suppression of a TBK1‐dependent excessive inflammatory response, which may be necessary to maintain tissue homeostasis.

Abstract Aim This study aimed to clarify the usefulness of tumor markers from peritoneal lavage in selecting patients with a high risk of recurrence and predicting site‐specific recurrence in patients with pancreatic cancer. Methods The levels of serum carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19–9 (sCEA/sCA 19–9) and paired peritoneal lavage CEA and CA 19–9 (pCEA/pCA 19–9) were measured in 90 patients with pancreatic cancer who underwent surgery. Using the cutoff values determined by maximally selected rank statistics for disease‐free survival (DFS), the risk of recurrence and its patterns were evaluated in combination with different markers and different test specimens. Results In univariate and multivariate analysis, an elevated pCA 19–9 level (>1.3 U/mL) was an independent prognostic marker for both DFS (hazard ratio [HR], 2.391; P = .018) and overall survival (HR, 3.194; P = .033). Combination analyses contributed to further stratification of a very high risk of recurrence. Of the 58 patients with resectable pancreatic cancer who underwent curative resection, elevated pCA19–9 was also associated with inferior DFS and overall survival (OS). Patients with elevated pCA 19–9 levels were more likely to have an earlier onset of peritoneal recurrence than those with normal pCA 19–9 levels (P = .048, Gehan–Breslow–Wilcoxon test). Conclusion pCA 19–9 is a reliable marker for predicting postoperative recurrence in patients with pancreatic cancer after surgery. Further risk stratification can be achieved by using combination assays. The combination of pCA 19–9 and sCA19–9 also serves as a predictor of recurrence site‐specific recurrence.

Abstract Estimating abundance or biomass using eDNA metabarcoding is a powerful emerging tool that may provide an alternative to conventional laborious methods for biological monitoring. However, inferring aquatic macroorganism abundance or biomass using eDNA concentrations remains challenging, especially in lotic environments, because of several potential confounding factors. In this study, we tested whether quantitative eDNA metabarcoding that uses internal standard DNA can be used to estimate the abundance of four fish species. We collected eDNA samples and concurrently estimated fish densities using the conventional removal method in small tributaries in four seasons during a year. The effects of potential confounding factors, including the body mass of the individuals, water temperature, and discharge volume, were assessed using an allometric scaling model. We found an increasing trend of eDNA concentration against the increase in abundance across all species. In the most abundant species, a significant increase in the precision of predicted abundance was achieved by considering confounding factors, such as season and discharge. Although this study successfully determined the relationships between eDNA concentration and fish abundance under lotic field conditions, it also identified several limitations of quantitative eDNA metabarcoding. The relationship between eDNA concentration and fish abundance in rare species showed significant variances in the regression. More sequencing depth may be necessary to detect rare species sufficiently. The eDNA concentration estimation error effect was significant, particularly among the samples that showed the same abundance figures by direct capture estimation. The utilization of quantitative eDNA metabarcoding may be suitable for organisms that are expected to have a substantial variation in their population density. More comparative studies with various conventional methods would be informative, especially in lotic field environments, to overcome these limitations and achieve wider applications of eDNA metabarcoding in future research and monitoring.

Abstract There is no useful biomarker to evaluate treatment response and early relapse in head and neck squamous cell carcinoma (HNSCC). Circulating tumor DNA (ctDNA) is a promising biomarker for detecting minimal residual diseases and monitoring treatment effect. We investigated whether individualized ctDNA analysis could help monitor treatment response and relapse in HNSCC. Mutation analysis of tumor and peripheral blood mononuclear cell (PBMC) DNAs of 26 patients with HNSCC was performed using a custom squamous cell carcinoma (SCC) panel. The identified individualized mutated genes were defined as ctDNA candidates. We investigated whether frequent ctDNA monitoring via digital PCR (dPCR) is clinically valid for HNSCC patients. TP53 was the most frequently mutated gene and was detected in 14 of 24 cases (58.2%), wherein two cases were excluded owing to the absence of tumor‐specific mutations in the SCC panel. Six cases were excluded because of undesignable and unusable primer‐probes for dPCR. Longitudinal ctDNA was monitored in a total of 18 cases. In seven cases, ctDNA tested positive again or did not test negative, and all seven cases relapsed after initial curative treatment. In 11 cases, after initial curative treatment, ctDNA remained negative and patients were alive without recurrence. Patients who remained negative for ctDNA during follow‐up after initial curative treatment (n = 11) had a significantly better prognosis than those who reverted to ctDNA positivity (n = 7; p

Abstract Aims Cancer therapy‐related cardiac dysfunction (CTRCD) is commonly reported, but its histopathology, mechanisms, and risk factors are not known. We aimed to clarify the histopathology and mechanisms of CTRCD to identify risk factors. Methods and results We performed myocardial histopathological studies on 13 endomyocardial biopsies from CTRCD patients, 35 autopsied cancer cases with or without cardiac dysfunction, and controls without cancer (10 biopsies and 9 autopsies). Cardiotoxicity risk scores were calculated based on medication; and patient‐related risk factors, fibrosis, and cardiomyocyte changes were scored; and p53 and H3K27ac histone modification were evaluated by histological score (H‐score). In the biopsy cases, all histopathological changes and the p53 evaluation were significantly higher in the CTRCD group than in the controls [p53 H‐score; 63 (9.109) vs. 33 (5.099), P 4.2 years), cellular abnormalities and p53 trended to a positive correlation and cardiotoxicity risk scores and p53 positively correlated (r = 0.95, P

Abstract Aims/Introduction This study aimed to identify the clinical factors affecting postoperative residual pancreatic β‐cell function, as assessed by the C‐peptide index (CPI), and to investigate the association between perioperative CPI and the status of diabetes management after pancreatectomy. Materials and Methods The associations between perioperative CPI and clinical background, including surgical procedures of pancreatectomy, were analyzed in 47 patients who underwent pancreatectomy, and were assessed for pre‐and postoperative CPI. The association between perioperative CPI and glycemic control after pancreatectomy was investigated. Results The low postoperative CPI group (CPI

Abstract Programmed cell death‐1 (PD‐1) and its ligand (PD‐L1) are significant mediators of immune suppression in the tumor microenvironment. We focused on the immunological impact of PD‐1/PD‐L1 signaling during tumor progression in colorectal carcinoma (CRC) and its association with resistance to neoadjuvant chemoradiotherapy (NCRT) in locally advanced rectal carcinoma (LAd‐RC). Histopathological and immunohistochemical analyses of 100 CRC cases (including 34 RC) without NCRT and 109 NCRT‐treated LAd‐RC cases were performed. Membranous tumoral PD‐L1 expression was identified in 9 of 100 (9%) CRC cases, including 1 of 34 (2.9%) RC cases, but PD‐L1 immunopositivity was not associated with any clinicopathological factors, with the exception of deficient mismatch repair (dMMR) status. In contrast, stromal PD‐L1+ immune cells, which frequently exhibited coexpression of PD‐1 and CD8 markers, were significantly correlated with tumor vessel invasion, nuclear β‐catenin+ tumor budding cancer stem cell (CSC)‐like features, and unfavorable prognosis. In the LAd‐RC cases, stromal CD8+ (but not PD‐L1+) immune cell infiltration in pretreatment‐biopsied samples was significantly and positively associated with therapeutic efficacy. After NCRT, tumoral PD‐L1 expression was observed in only 2 of 83 (2.4%) tumors, independent of dMMR status, whereas high stromal PD‐L1+ and tumoral nuclear β‐catenin positivity were significantly linked to a poor response to NCRT and high tumor budding features. In addition, high stromal PD‐L1 immunoreactivity was significantly associated with poorer overall survival. In conclusion, a combination of stromal PD‐L1+ immune cells and nuclear β‐catenin+ tumor budding may contribute to tumor progression in CRC and resistance to NCRT in LAd‐RC, through formation of niche‐like lesions that exhibit immune resistance and CSC properties.

Introduction One of the complications of laparoscopic surgery is gas embolism, which has low incidence but high mortality. Carbon dioxide embolism diagnosed during robot‐assisted laparoscopic partial nephrectomy has been experienced. Case presentation 77‐year‐old woman with a left renal tumor received robot‐assisted laparoscopic partial nephrectomy. End‐tidal carbon dioxide pressure and oxygen saturation of peripheral artery suddenly decreased 5 min after the start of tumor resection with pneumoperitoneum pressure of 15 mmHg and positive end‐expiratory pressure turned off. Therefore, pulmonary artery gas embolism was diagnosed. The pneumoperitoneum pressure was dropped, and positive end‐expiratory pressure was restarted. These conditions improved and the procedure was completed. Conclusion Carbon dioxide gas embolism during robot‐assisted partial nephrectomy should be focused on because prompt diagnosis and treatment will improve life outcomes. The optimal pneumoperitoneum pressure for each case, rather than making it uniform, should be reconsidered.

Abstract Background and Aim Radiofrequency ablation (RFA) therapy is frequently used as first‐line treatment for small hepatocellular carcinoma (HCC). RFA is often associated with pain; however, no definitive solution has been established for its relief. We retrospectively analyzed the safety and efficacy of the combination of pentazocine and midazolam to relieve pain experienced by HCC patients undergoing RFA. Methods We studied 77 patients with 98 HCCs treated with RFA between January 2015 and August 2019. Patients were divided into two groups: the sedative‐free group, which included those who received pentazocine alone, and the pentazocine–midazolam group, which included those who received a combination of pentazocine and midazolam. The degrees of analgesia and sedation were evaluated using the numerical rating scale (NRS) and the Richmond Agitation‐Sedation Scale (RASS), respectively. Other parameters such as treatment time, awakening time, midazolam dosage, vital signs, local recurrence rate, and time to recurrence were also examined. Results The median NRS score and RASS score were significantly lower in the pentazocine–midazolam group. Ninety‐five percent of patients in the pentazocine–midazolam group had no memory of the RFA session. The treatment time and awakening time were prolonged for the pentazocine–midazolam group. No significant differences in oxygen saturation, recurrence rates, and time to local recurrence were observed between groups. Conclusion A combination of pentazocine and midazolam is safe and effective for pain and anxiety relief experienced by patients undergoing RFA for local treatment of HCC.

Abstract Human small extracellular vesicles (sEVs) derived from adipose‐derived mesenchymal stromal cells (ASC) have been reported to suppress the progression of osteoarthritis (OA) in animal studies and subsequently, translation of this potential to assess their clinical efficacy is anticipated. However, fabrication protocols for sEVs to eliminate potential contamination by culture medium‐derived components need to be established prior to their clinical use. The purpose of the present studies was to elucidate the influence of medium‐derived contaminants on the biological effects of sEVs, and to establish isolation methods for sEVs using a new clinical grade chemically‐defined media (CDM). The quantity and purity of ASC‐derived sEVs cultured in four different CDMs (CDM1, 2, 3 and 4) were evaluated. The concentrates of the four media incubated without cells were used as the background (BG) control for each set of sEVs. The biological effect of sEVs fabricated in the four different CDMs on normal human articular chondrocytes (hACs) were evaluated in vitro using a variety of methodological assessments. Finally, the sEVs with the highest purity were tested for their ability to suppress the progression of knee OA mouse model. Analysis of the BG controls revealed that CDM1‐3 contained detectable particles, while there was no visible contamination of culture media‐derived components detected with CDM4. Accordingly, the sEVs fabricated with CDM4 (CDM4‐sEVs) exhibited the highest purity and yield. Notably, the CDM4‐sEVs were the most efficient in promoting the cellular proliferation, migration, chondrogenic differentiation, and anti‐apoptotic activity of hACs. Furthermore, CDM4‐sEVs significantly suppressed the osteochondral degeneration in vivo model. Small EVs derived from ASCs cultured in a CDM without detectable contaminants demonstrated enhanced biological effects on hACs and the progression of OA. Thus, sEVs isolated with CDM4 most optimally meet the requirements of efficacy and safety for assessment in their future clinical applications.

Key Clinical Message Signet‐ring cell gastric carcinomas presenting as pericardial effusion early in diagnosis are rare and associated with high mortality and a poor prognosis. There are two interesting aspects of this case: primary gastric carcinoma presenting as cardiac tamponade and the metastatic behavior of gastric signet‐ring cell carcinoma. Abstract This report describes an 83‐year‐old man diagnosed to have cardiac tamponade due to massive pericardial effusion. A cytological analysis of the pericardial effusion disclosed adenocarcinoma. The patient was treated with continuous pericardial drainage and the amount of pericardial effusion decreased.