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Microsatellite instability (MSI) and deficiency of mismatch repair (dMMR) are key markers for predicting the response of immune checkpoint inhibitors (ICIs) and screening for Lynch syndrome (LS). This study examined the incidences of and factors associated with the concordance of MSI and MMR in human cancers. A total of 518 formalin-fixed cancer tissues were analyzed for MSI and MMR immunohistochemistry (IHC). MSI was analyzed by a PCR-based method using Promega markers. Concordance with MMR expression and factors associated with concordance were analyzed. In 2 colorectal cancer samples, MMR IHC failed due to inadequate staining conditions. In the remaining 516 cancers, a high level of MSI (MSI-H) was identified in 113 cases, and dMMR was identified in 112. The concordance of MSI and MMR IHC was 98.3%. Only 9 cases (4 pancreatobiliary, 3 colorectal, and 2 endometrial cancers) were discordant. Of the 113 MSI-H cases, 4 (3.5%) were proficient MMR (pMMR); of the 403 microsatellite stability (MSS) cases, 5 (1.2%) were dMMR. The independent factors associated with MSI-H/dMMR included meeting Amsterdam II criteria, assay purpose, and sampling method. Multivariate analysis revealed that cancer type (gastrointestinal cancers or others) was associated with concordance of MSI and MMR IHC. Three LS cases with pancreatic or endometrial cancer demonstrated MSS and dMMR, and one biliary cancer showed MSI-H and pMMR. Discordance between MSI and MMR IHC occasionally occurs in pancreaticobiliary and endometrial cancers. When suspected, both MSI and MMR IHC should be done to judge the ICI indication and screen for LS.

The presence of J waves in cases of ventricular fibrillation (VF) is known to be a risk for sudden cardiac death. Recently, the effectiveness of radiofrequency catheter ablation (RFCA) for early repolarization syndrome (ERS) has been reported. The patient is a 30-year-old male with elevated J waves of 0.1 mV in the inferior leads, who had previously developed VF and undergone implantable cardioverter defibrillator (ICD) implantation. Because the VF from short coupled premature ventricular contraction (PVC) was presented, the RFCA of the triggered PVC was attempted. But it was unsuccessful due to no inducibility of the triggered PVC. After that, despite anti-arrythmia drug treatment, appropriate ICD shock for VF was observed. Although we decided to do a second ablation and evaluated epicardial arrhythmia substrate, no specific findings of early repolarization syndrome were found in the electrophysiological study. Finally, we considered that the cause of VF was short-coupled variant of Torsade de Pointes, and PVC ablation was performed. VF has not occurred since. We consider that this is a rare case to evaluate the epicardial arrhythmogenic substrate of J wave. LEARNING OBJECTIVE: Ablation of the epicardial arrhythmogenic substrate in patients with early repolarization syndrome (ERS) has been shown to be effective, but the relationship between abnormal epicardial potentials and the pathophysiology is unclear. In this case, J-wave and epicardial delayed potentials were not considered to represent obvious arrhythmogenic substrates. Ablation of the triggered premature ventricular contraction may be effective in ERS without apparent abnormal potentials.

BackgroundPneumonia is common among older adults and often recurrent. Several studies have been conducted on the risk factors for pneumonia; however, little is known about the risk factors for recurrent pneumonia. This study aimed to identify the risk factors for developing recurrent pneumonia among older adults and to investigate methods of prevention.MethodsWe analysed the data of 256 patients aged 75 years or older who were admitted for pneumonia between June 2014 and May 2017. Moreover, we reviewed the medical records for the subsequent 3 years and defined the readmission caused by pneumonia as recurrent pneumonia. Risk factors for recurrent pneumonia were analysed using multivariable logistic regression analysis. Differences in the recurrence rate based on the types and use of hypnotics were also evaluated.ResultsOf the 256 patients, 90 (35.2%) experienced recurrent pneumonia. A low body mass index (OR: 0.91; 95% CI: 0.83‒0.99), history of pneumonia (OR: 2.71; 95% CI: 1.23‒6.13), lung disease as a comorbidity (OR: 4.73; 95% CI: 2.13‒11.60), taking hypnotics (OR: 2.16; 95% CI: 1.18‒4.01) and taking histamine-1 receptor antagonist (H1RA) (OR: 2.38; 95% CI: 1.07‒5.39) were risk factors. Patients taking benzodiazepine as hypnotics were more likely to experience recurrent pneumonia than patients not taking hypnotics (OR: 2.29; 95% CI: 1.25–4.18).ConclusionWe identified several risk factors for recurrent pneumonia. Among them, restricting the use of H1RA and hypnotics, in particular benzodiazepines, may be useful in preventing the recurrence of pneumonia in adults aged 75 years or older.

Genome-encoded antibiotic resistance (ARE) ATP-binding cassette (ABC) proteins of the F subfamily (ARE-ABCFs) mediate intrinsic resistance in diverse Gram-positive bacteria. The diversity of chromosomally-encoded ARE-ABCFs is far from being fully experimentally explored. Here we characterise phylogenetically diverse genome-encoded ABCFs from Actinomycetia (Ard1 from Streptomyces capreolus, producer of the nucleoside antibiotic A201A), Bacilli (VmlR2 from soil bacterium Neobacillus vireti) and Clostridia (CplR from Clostridium perfringens, Clostridium sporogenes and Clostridioides difficile). We demonstrate that Ard1 is a narrow spectrum ARE-ABCF that specifically mediates self-resistance against nucleoside antibiotics. The single-particle cryo-EM structure of a VmlR2-ribosome complex allows us to rationalise the resistance spectrum of this ARE-ABCF that is equipped with an unusually long antibiotic resistance determinant (ARD) subdomain. We show that CplR contributes to intrinsic pleuromutilin, lincosamide and streptogramin A resistance in Clostridioides, and demonstrate that C. difficile CplR (CDIF630_02847) synergises with the transposon-encoded 23S ribosomal RNA methyltransferase Erm to grant high levels of antibiotic resistance to the C. difficile 630 clinical isolate. Finally, assisted by uORF4u, our novel tool for detection of upstream open reading frames, we dissect the translational attenuation mechanism that controls the induction of cplR expression upon an antibiotic challenge.

Objectives Limited evidence is available regarding alternative therapeutic agents to vancomycin in treating glycopeptide-susceptible Enterococcus faecium (GSEF) bacteraemia. This study assessed the effectiveness and safety of teicoplanin compared with vancomycin for treating GSEF bacteraemia. Patients and methods This was a retrospective, non-inferiority cohort study. Patients aged ≥18 years who developed GSEF bacteraemia and received either teicoplanin or vancomycin were included. The primary effectiveness outcome was the clinical success at the end of treatment, with a generalized linear model using the propensity score for selecting the agent as a covariate. We used an absolute difference of 20% in clinical success as the non-inferiority margin. Using multivariable logistic regression, the primary safety outcome was the incidence of acute kidney injury (AKI). Results In total, 164 patients (74 and 90 in the teicoplanin and vancomycin groups, respectively) were included. Overall, 64.9% (48/74) and 48.9% (44/90) of patients in the teicoplanin and vancomycin groups, respectively, achieved the primary effectiveness outcome. A generalized linear analysis showed an adjusted effectiveness difference of 9.9% (95% CI, −0.9% to 20.0%; P = 0.07), indicating non-inferiority of teicoplanin versus vancomycin. The incidence of AKI was 8.1% (6/74) and 24.4% (22/90) in the teicoplanin and vancomycin groups, respectively, with an adjusted OR of 0.242 (95% CI, 0.068 to 0.864; P = 0.029), indicating significantly lower AKI risk in the teicoplanin than in the vancomycin group. Conclusions Teicoplanin is a safe and useful alternative therapeutic agent for treating GSEF bacteraemia.

We describe the wiring technique and evaluate the radiographic and clinical outcomes of treatment with a pin and wire system (PWS) for comminuted patella fractures. From June 2013 to October 2018, 33 patients with comminuted patella fractures were treated using a PWS. Open reduction and internal fixation was performed with multiple pins and a wire. All patients were allowed full weight bearing without a brace. Radiographs were obtained to evaluate bone union, implant breakage, back-out of pins, and intra-articular gaps and step-off. Clinical outcomes and postoperative complications were assessed at final follow-up examination. All fractures were united. Thirteen cable wires in 13 patients were partially broken without displacement of fracture at an average of 7.4 months (range, 1–19 months) postoperatively. The average preoperative, postoperative, and final follow-up intra-articular gap and step-off were 11.7 mm, 0.5 mm, and 0.03 mm and 6.6 mm, 0.4 mm, and 0.2 mm, respectively. The average postoperative pin displacement was 0.1 mm (range, 0–0.8 mm). Deep infection was not observed after the surgery. The implant removal rate was 21% (7 of 33). Among these, the symptomatic implant removal rate was 9% (3 of 33). Additionally, 3 of 7 patients with implant removal had broken wires. The average flexion and extension of knee joints were 139.7° (range, 120°–150°) and −0.9° (range, −10° to 0°), respectively. A PWS prevents back-out of the pins and reduces intra-articular gaps and step-off distances to acceptable levels, even if the cable wire is partially broken. Therefore, a PWS is a good treatment option for comminuted patella fractures. [ Orthopedics . 202x;4x(x):xx–xx.]

Anatomical variations often occur in the anterior communicating artery (AComA) complex, and a careful preoperative evaluation is required before repair of this lesion. We report a case of a fenestrated AComA complex mimicking an unruptured cerebral aneurysm. A 49-year-old woman was referred to our hospital under suspicion of unruptured aneurysms of the AComA and the left middle cerebral artery on magnetic resonance angiography (MRA). Additional three-dimensional computed tomographic angiography (CTA) showed the lesion arising from the AComA complex with a maximum diameter of 4.2 mm. Intraoperative findings showed that the putative aneurysm was actually a fenestrated AComA complex as the blood vessels that formed the AComA complex were dilated and meandering. After the operation, MRA and CTA three-dimensional images were reviewed again but we could still not diagnose the lesion as a fenestrated AComA complex rather than an aneurysm. However, in the MRA source image, a secant line in the lesion was the only finding suggestive of a fenestration. The AComA complex is often associated with various vascular malformations, and it is essential to consider this association in the preoperative evaluation. The interpretation of source images may be helpful for accurate diagnosis and surgical planning.

Background: Early biologic response to endocrine therapy, such as changes in Ki67 labeling index (LI), has been suggested to predict long-term outcomes in hormone sensitive breast cancer. The addition of a CDK4/6 inhibitor to endocrine therapy has been shown to augment biological response in breast cancer. Pre-operative Endocrine Prognostic Index (PEPI) scores, generated based on post-treatment Ki67 LI, have been shown to predict patient outcomes. EndoPredict® is a multigene assay that predicts the risk of distant recurrence in patients with operable estrogen receptor (ER)-positive HER2-negative breast cancer. This study was conducted to evaluate the efficacy of the neoadjuvant endocrine therapy plus palbociclib versus neoadjuvant endocrine therapy plus placebo. Patients and Methods: This is a phase III randomized, double-blind study of neoadjuvant hormonal therapy plus palbociclib versus neoadjuvant hormonal therapy plus placebo in untreated pre/peri- and post-menopausal women with operable, hormone receptor-positive (ER and/or progesterone receptor), HER2-negative breast cancer. The other major inclusion criteria included tumor size ≥ 15mm, T1c-3N0-1, Ki67 LI ≥14% by central assessment, and no previous history of radiotherapy or systemic therapy for breast cancer. Patients were randomly assigned 1:1 to receive 16 weeks of hormonal therapy plus palbociclib or hormonal therapy plus placebo. Hormonal therapy consisted of letrozole for post-menopausal patients and tamoxifen plus LH-RH agonist for pre/peri-menopausal patients. The co-primary endpoints included PEPI score and EPclin Risk Score, a score combining EndoPredict® molecular score with clinical factors. These scores were sequentially analyzed on a modified intent-to-treat basis according to the gatekeeping procedure: if statistical significance was detected on the PEPI score, the statistical significance of EPclin Risk Score would be assessed. The sample size was 100 patients in each arm, which was calculated with < 5% type I error rate (two sided) and 80% power. Results: Between 16 July 2019 – 7 July 2021, 141 eligible patients were randomized from 25 participating institutes in Japan, Korea, Taiwan, Hong Kong and Australia. One hundred twenty-six patients completed the treatment duration and surgical samples were collected to evaluate endpoints. All randomized patients were evaluable for safety assessment. Randomization was well-balanced in terms of age, menopausal status and cancer stage. The proportion of patients who had a low, moderate, or high PEPI score was 15.2%, 50.0% and 34.8% in the hormonal therapy plus palbociclib arm and 13.3%, 55.0% and 31.7% in the hormonal therapy plus placebo arm, respectively. There was no statistically significant difference in PEPI score between two arms (one-sided p-value=0.563). The proportion of patients who had a high risk EPclin Risk Score seemed lower in the palbociclib arm than in the placebo arm (62.1% vs 68.3%) although hypothesis testing was not performed on EPclin Risk Score because statistical significance was not detected on the PEPI score. No new safety signals were found in the study. Permanent discontinuation from the study in association with adverse events was reported for 7 (9.7%) patients in the hormonal therapy plus palbociclib arm and for 0 patients in the hormonal therapy plus placebo arm. Conclusions: The addition of palbociclib to neoadjuvant hormonal therapy did not improve efficacy measured by PEPI score. In palbociclib arm, the rate of patients who had a high risk EPclin Risk Score after treatment was lower than in placebo arm. Translational researches are ongoing to analyze molecular changes by treatments. The role of chemotherapy after neoadjuvant therapy is under investigation. Clinical trial identification: NCT03969121 Funding: Pfizer Inc. Citation Format: Takayuki Ueno, Louis W.C. Chow, Wonshik Han, Chiun Sheng Huang, G Bruce Mann, Satoshi Morita, Hironori Haga, Elham Fakhrejahani, Takayuki Kobayashi, Kenichi Inoue, Mariko Tokiwa, Hirofumi Suwa, Tomoyuki Aruga, Sachiko Minamiguchi, Yosuke Yamada, Yuko Tanabe, Masahiro Takada, Toshinari Yamashita, Hiroji Iwata, Chi-Feng Chung, Sachiko Takahara, Eriko Tokunaga, Shigeru Imoto, Eun Sook Lee, Yasuaki Sagara, Jee Hyun Kim, Richard H DeBoer, Hyun-Ah Kim, Hung Wen Lai, Ming-Feng Hou, Michelle White, Yoshiko Umeyama. Neoadjuvant hormonal therapy plus palbociclib versus hormonal therapy plus placebo in women with operable, hormone sensitive and HER2-negative primary breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-09-01.

In recent years, the southern African region has experienced repeated incursions of highly pathogenic avian influenza viruses (HPAIVs), with wild migratory birds being implicated in the spread. To understand the profile of avian influenza viruses (AIVs) circulating in Zambia, we surveyed wild waterfowl for AIVs and phylogenetically characterised the isolates detected in 2015, 2020, and 2021. A total of 2,851 faecal samples of wild waterfowl were collected from Lochinvar National Park in the Southern Province of Zambia. During the study period, 85 (3.0%) low pathogenicity AIVs belonging to various subtypes were isolated, with H2N9, H8N4, and H10N8 being reported for the first time in avian species in Africa. The majority of the isolates were detected from glossy ibis (order Pelecaniformes) making it the first report of AIV from these birds in Zambia. Phylogenetic analysis of all eight gene segments of the 30 full genomes obtained in this study revealed that all the isolates belonged to the Eurasian lineage with their closest relatives being viruses isolated from wild and/or domestic birds in Bangladesh, Belgium, Egypt, Georgia, Mongolia, the Netherlands, and South Africa. Additionally, the Zambian viruses were grouped into distinct clusters based on the year of isolation. While no notifiable AIVs of the H5 or H7 subtypes were detected in wild birds in Zambia, viral internal protein genes of some viruses were closely related to H7 low pathogenicity AIVs. This study shows that periodically, a considerable diversity of AIV subtypes are introduced into the Zambian ecosystem by wild migratory waterfowl. The findings highlight the importance of continuous surveillance and monitoring of AIVs in wild waterfowl, including birds traditionally not considered to be major AIV reservoirs, for a better understanding of the eco-epidemiology and evolutionary dynamics of AIVs in Africa.

Multiple myeloma (MM) is a cancer characterized by the expansion of plasma cells in the bone marrow. Survival times of patients with MM have increased due to the development of novel therapeutic agents. We herein highlight three MM cases that had a poor prognosis despite treatment with novel therapeutic agents. Of note, all patients presented with hyperammonemia that led to a consciousness disorder. The outcome for patients with MM showing high levels of serum ammonia continues to be poor, even with the use of novel therapies. For such patients showing a consciousness disorder, hyperammonemia should be considered as a possible cause.

[Introduction] Proliferative lesions in the breast have been implicated in the development of breast cancer. Previous studies showed that some proliferative lesions and adjacent breast cancers shared common genetic alterations, suggesting that these originated from the same ancestral cell. However, the clonal structure of normal epithelia and their clonal history during evolution to cancer are poorly understood. In this study, we analyzed genetic profiles of normal epithelia and proliferative lesions in the cancer-borne breast to illustrate the clonal evolution of cancer from a normal epithelial cell. [Methods] Single cell-derived organoids (n=47) were established from breast milk of 4 healthy women aged 22–36 and normal breast tissue of 15 breast cancer patients aged 29–83 to evaluate somatic mutation rate in normal epithelial cells. Multiple normal lobules and proliferative lesions together with cancer lesions were collected using laser-capture micro-dissection (LCM) from fresh frozen (n=3) or formalin-fixed paraffin-embedded (n=5) surgical specimens in 9 premenopausal breast cancer patients. Somatic mutations and copy number alterations were evaluated using whole-genome sequencing. [Results] The mutation profile of single cell-derived organoids suggests that somatic mutations accumulate in normal mammary epithelial cells at a constant rate of 19.4/genome/year before menopause, and the mutation rate decreases to 6.9/genome/year after menopause. Parity was negatively associated with mutation number (-49.3 per life birth). In total, we analyzed 143 LCM samples, including those from 72 normal lobules, 43 proliferative lesions, and 19 non-invasive and 9 invasive cancer samples. Five cases showed a large expansion of proliferative lesions sharing a substantial number of somatic mutations with cancer. These lesions expanded over a distance of 35-90 mm, sharing tens to hundreds of mutations including those in breast cancer-related driver genes, such as PIK3CA, AKT1, GATA3, CBFB and PTEN, while harboring private mutations or copy number alterations of their own. Of interest, the cancers in 4 out of these 5 cases was luminal-A type invasive ducal carcinoma or ER-positive HER2-negative ductal carcinoma in situ, and characterized in common by the presence of der(1;16), concurrent whole-arm 1q gain and 16q loss, in both cancer and proliferative lesions. Phylogenetic analysis adapted with the mutation rate in normal cells predicted that der(1;16) had been acquired between puberty and early 20’s, and the common ancestors of non-cancerous and cancerous lesions emerged by early 30’s, >10 years earlier than at the time of cancer diagnosis. By contrast, analysis of non-cancerous lobules unrelated to cancer showed that der(1;16)-negative non-cancer clones that had emerged after puberty stayed within a single lobule or spatially confined to adjacent lobules and rarely expanded to a large area as observed for those carrying der(1;16), even if the clones had acquired mutations in driver genes such as PIK3CA and PIK3R1, which highlighted the role of der(1;16) in wide clonal expansion. [Conclusions] Our results suggest that in some breast cancer cases, particularly in those with der(1;16), a highly recurrent translocation accounting for the major subset of Luminal A breast cancer, the clones with the funder driver alterations expanded macroscopically long before the onset of cancer, in which further clonal evolutions recursively occur multi-focally, giving rise to multiple proliferative lesions and ultimately, invasive cancers. Our findings provide new insight into the early development of breast cancer. Citation Format: Tomomi Nishimura, Nobuyuki Kakiuchi, Kenichi Yoshida, Takaki Sakurai, Tatsuki R. Kataoka, Eiji Kondoh, Yoshitsugu Chigusa, Masahiko Kawai, Morio Sawada, Takuya Inoue, Yasuhide Takeuchi, Hirona Maeda, Satoko Baba, Yusuke Shiozawa, Ryunosuke Saiki, Masahiro M. Nakagawa, Yasuhito Nannya, Yotaro Ochi, Tomonori Hirano, Yukiko Inagaki-Kawata, Kosuke Aoki, Masahiro Hirata, Eiji Suzuki, Masahiro Takada, Masahiro Kawashima, Kosuke Kawaguchi, Kenichi Chiba, Yuichi Shiraishi, Junko Takita, Satoru Miyano, Masaki Mandai, Kengo Takeuchi, Hironori Haga, Masakazu Toi, Seishi Ogawa. Clonal evolution of mammary epithelial cells into breast cancers [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-13-04.

Approximately, 90% of men with advanced prostate cancer will develop bone metastasis. However, there have been few reports about noninvasive biomarker to detect and predict clinical outcome of bone metastasis (BM) in prostate cancer patients.We examined 1127 patients who underwent prostate biopsy from August 2012 to June 2017. We also investigated bone turnover markers such as bone-specific alkaline phosphatase, type I collagen cross-linked N-terminal telopeptide, C-terminal pyridinoline cross-linked telopeptide of type I collagen, and tartrate-resistant acid phosphatase type 5b (TRACP 5b).A total of 282 patients were diagnosed as prostate cancer with complete clinical data, and 34 patients with bone metastasis. Multivariate analysis revealed C-terminal pyridinoline cross-linked telopeptide of type I collagen, tartrate-resistant acid phosphatase type 5b, and prostate-specific antigen (PSA) were independent biomarkers in detection of BM (p 0.05, respectively). Furthermore, we developed predictive model formula based on tartrate-resistant acid phosphatase type 5b and PSA, for which the area under the curve was 0.95. In patients with bone metastasis, multivariate cox proportional hazards analysis revealed that this model was significantly associated with poor clinical outcome of cancer-specific survival (p 0.05). In validation cohort with 137 patients, we also confirmed the utility of this model for diagnosis of BM (the area under the curve = 0.95).Our developed formula of tartrate-resistant acid phosphatase type 5b in accordance with PSA may serve as the useful tool in diagnosis and prediction of clinical outcome for prostate cancer with bone metastasis.

Lymphatic malformation (LM) that causes inguinoscrotal swelling is extremely rare. Surgery, sclerotherapy and pharmacotherapy have been reported as possible treatment options for LM. Recently, Eppikajutsuto (TJ-28), a traditional Japanese herbal medicine has emerged as therapeutic option for LM. We report the case of a 2-year-old boy who presented with a left inguinoscrotal swelling, which was diagnosed as retroperitoneal LM extending into the left scrotum. The surgical approach was less favourable, given the risk of damaging the testicular vasculature or the spermatic cord. Therefore, the patient received medical treatment with TJ-28. As a result, a volume reduction of 83% was obtained, as well as the unexpected consequence of the left testicle retracting into the inguinal area. Laparoscopic exploration was performed and a small bulge on the internal inguinal ring was detected. The patient’s acquired cryptorchidism was subsequently treated by orchidopexy.

To ensure that highly advanced hepatobiliary-pancreatic surgery (HBPS) is performed safely, the Japanese Society of Hepato-Biliary-Pancreatic Surgery (JSHBPS) board certification system for expert surgeons established a safety committee to monitor surgical safety.We investigated postoperative mortality rates based on summary reports of numbers and outcomes of highly advanced HBPS submitted annually by the board-certified training institutions from 2012 to 2019. We also analyzed summary reports on mortality cases submitted by institutions with high 90-day post-HBPS mortality rates and recommended site visits and surveys as necessary.Highly advanced HBPS was performed in 121 518 patients during the 8-year period. Thirty-day mortality rates from 2012 to 2019 were 0.92%, 0.8%, 0.61%, 0.63%, 0.70%, 0.59%, 0.48%, and 0.52%, respectively (P .001). Ninety-day mortality rates were 2.1%, 1.82%, 1.62%, 1.28%, 1.46%, 1.22%, 1.19%, and 0.98%, respectively (P .001). Summary reports were submitted by 20 hospitals between 2015 and 2019. Mortality rates before and after the start of report submission and audit were 5.72% and 2.79%, respectively (odds ratio 0.690, 95% confidence interval 0.487-0.977; P = .037).Development of a system for designation of board-certified expert surgeons and safety management improved the mortality rate associated with highly advanced HBPS.

We herein report a case of glaucoma with an intraocular pressure (IOP) decrease following total gastrectomy (TG) and anticancer treatment for gastric cancer. A 62-year-old male underwent trabeculectomy of the left and right eyes in August 2011 and July 2012, respectively. During the follow-up, IOP of the right eye was 9-12 mmHg (with bimatoprost, dorzolamide, and timolol maleate), and that of the left eye ranged between 14 and 26 mmHg (with bimatoprost, dorzolamide, timolol maleate, and brimonidine tartrate). In December 2014, TG was performed due to gastric cancer. After surgery, the patient received S-1+CDDP, weekly PAC, and CPT-11 therapies. The patient died on March X, 2017. Before TG, the body mass index (BMI) was 29.5 but decreased to 24.8 before the start of the two courses of weekly PAC therapy. IOP of the right eye was 6 mmHg (with bimatoprost), and that of the left eye was 10 mmHg (with bimatoprost, dorzolamide, and brimonidine tartrate), showing decreases. After the initiation of weekly PAC therapy, BMI was approximately 19. IOP of the right eye ranged between 6 and 10 mmHg until the final ophthalmological examination (January 11, 2017), while that of the left eye ranged between 8 and 15 mmHg. In this patient with glaucoma, IOP was not controlled by eye drop treatment, and TG for gastric cancer and postoperative treatment with anticancer drugs resulted in weight loss and a decrease in IOP.

Uric acid, the end product of purine metabolism in humans, is crucial because of its anti-oxidant activity and a causal relationship with hyperuricemia and gout. Several physiologically important urate transporters regulate this water-soluble metabolite in the human body; however, the existence of latent transporters has been suggested in the literature. We focused on the Escherichia coli urate transporter YgfU, a nucleobase-ascorbate transporter (NAT) family member, to address this issue. Only SLC23A proteins are members of the NAT family in humans. Based on the amino acid sequence similarity to YgfU, we hypothesized that SLC23A1, also known as sodium-dependent vitamin C transporter 1 (SVCT1), might be a urate transporter. First, we identified human SVCT1 and mouse Svct1 as sodium-dependent low-affinity/high-capacity urate transporters using mammalian cell-based transport assays. Next, using the CRISPR-Cas9 system followed by the crossing of mice, we generated Svct1 knockout mice lacking both urate transporter 1 and uricase. In the hyperuricemic mice model, serum urate levels were lower than controls, suggesting that Svct1 disruption could reduce serum urate. Given that Svct1 physiologically functions as a renal vitamin C re-absorber, it could also be involved in urate re-uptake from urine, though additional studies are required to obtain deeper insights into the underlying mechanisms. Our findings regarding the dual-substrate specificity of SVCT1 expand the understanding of urate handling systems and functional evolutionary changes in NAT family proteins.

The purpose of this study was to compare patency and nonabandonment rates for second percutaneous transluminal angioplasty (PTA) and surgical reconstruction for the treatment of failing vascular access due to restenosis or reocclusion in a short time after initial PTA.Seventy two consecutive patients who underwent second treatment within 90 days after the initial PTA were evaluated retrospectively. The patency (time to corrective procedure) and access abandonment were compared among patients who underwent a second PTA (n = 35) and those who underwent surgical reconstruction (n = 37). Univariate and multivariate analyses were performed to determine independent predictors of patency and access abandonment at 1 year after the treatment.At 1 year after the treatment, the patency rates were 35.1% and 11.4% (P = 0.02) and nonabandonment rates were 64.9% and 77.1% (P = 0.25) for surgical reconstruction and second PTA, respectively. The Kaplan-Meier survival analysis showed that the surgical reconstruction group had better patency probability (P = 0.02), but there was no difference in the nonabandonment probability between the groups (P = 0.29). Shorter time to retreatment was associated with good patency. The female gender was likely to be associated with access abandonment.The access abandonment between the 2 procedures had no difference, although surgical reconstruction provided better patency than second PTA.

Few interventions have shown improved prognosis in patients with heart failure and preserved ejection fraction (HFpEF). Serum chloride levels, which are affected by serum renin secretion, are associated with the prognosis of HFpEF patients. However, the relationship between serum chloride levels and the effects of renin-angiotensin system inhibitors (RASi) in HFpEF patients remains unclear. We investigated whether the prognostic benefit of RASi depends on baseline serum chloride levels in HFpEF patients.This observational study included 506 hospitalized patients with HFpEF (ejection fraction ≥50%) who were discharged. They were divided into two categories based on serum chloride levels at admission (cutoff level: 101 mEq/L) according to previous reports. In each chloride category, all-cause mortality, the primary endpoint, was compared between patients who received RASi and those who did not.Patients who received RASi had a significantly lower mortality rate after discharge than those who did not, but only in the lower chloride category (log-rank, P = 0.001). Multivariable Cox regression analysis confirmed the effect of risk reduction by RASi on all-cause mortality in the lower chloride category (adjusted hazard ratio: 0.31, 95% confidence interval: 0.11-0.84). The prognostic advantages of RASi were evident in the lower chloride category, but not in the higher chloride category, at admission (P for interaction = 0.027).RASi administration was associated with an improved prognosis only in HFpEF patients with a low baseline serum chloride level. Clinicians should consider RASi administration if patients' serum chloride levels are low, to improve the long-term prognosis of HFpEF patients.

Wound infection is the most serious cause of delayed healing for patients with pressure injuries. The wound microbiota, which plays a crucial role in delayed healing, forms by bacterial dissemination from the peri-wound skin. To manage the bioburden, wound and peri-wound skin care has been implemented; however, how the microbiota at these sites contribute to delayed healing is unclear. Therefore, we investigated the relationship between healing status and microbial dissimilarity in wound and peri-wound skin.A prospective cohort study was conducted at a long-term care hospital. The outcome was healing status assessed using the DESIGN-R® tool, a wound assessment tool to monitor the wound healing process. Bacterial DNA was extracted from the wound and peri-wound swabs, and microbiota composition was analyzed using 16S rRNA gene analysis. To evaluate microbial similarity, the weighted UniFrac dissimilarity index between wound and peri-wound microbiota was calculated.Twenty-two pressure injuries (7 deep and 15 superficial wounds) were included in the study. For deep wounds, the predominant bacteria in wound and peri-wound skin were the same in the healing wounds, whereas they were different in all cases of hard-to-heal wounds. Analysis based on the weighted UniFrac dissimilarity index, there was no significant difference for healing wounds (p = 0.639), while a significant difference was found for hard-to-heal wounds (p = 0.047).Delayed healing is possibly associated with formation of wound microbiota that is different in composition from that of the skin commensal microbiota. This study provides a new perspective for assessing wound bioburden.