Potential Usefulness of Lifetime Globotriaosylsphingosine Exposure at Diagnosis and Baseline Modified Disease Severity Score in Early-Diagnosed Patients With Fabry Disease.

BACKGROUND: Fabry disease (FD) is a lysosomal storage disease caused by a deficit of α-galactosidase A (GAL). Recently, plasma globotriaosylsphingosine (lyso-Gb3), a pathogenic analog of a substrate of GAL, has been suggested as a potential biomarker for FD, and disease severity scores, such as the Mainz Severity Score Index (MSSI), the Disease Severity Scoring System (DS3), and FASTEX (FAbry STabilization indEX), are useful tools for evaluating the severity of signs and symptoms in symptomatic FD patients. However, a more useful method of evaluating disease severity in early-diagnosed FD patients such as children, adult females, and asymptomatic patients is needed. Here, we proposed modified MSSI and DS3 scores to which we added phenotype, urinary mulberry bodies, and history of past pain attacks and examined the clinical usefulness of lyso-Gb3 and modified scores for early-diagnosed FD patients. RESULT: In 13 early-diagnosed FD patients, we developed modified MSSI and DS3 scores and examined the correlation of lifetime lyso-Gb3 exposure at diagnosis with the conventional or modified scores. Lifetime lyso-Gb3 exposure was positively correlated only with the modified DS3 score. Additionally, we examined the long-term changes in plasma lyso-Gb3 concentration and in conventional MSSI, DS3, and FASTEX. In males, plasma lyso-Gb3 concentration decreased more rapidly than in females. In all patients, the severity scores were mild and remained nearly stable throughout the follow-up period. CONCLUSION: Our data suggest that lifetime lyso-Gb3 exposure and the modified DS3 score are useful in early-diagnosed patients.

Incidence and potential risk factors of human cytomegalovirus infection in patients with severe and critical coronavirus disease 2019.

BACKGROUND: Human cytomegalovirus (HCMV) infection occurs in immunosuppressed individuals and is known to increase mortality. Patients with coronavirus disease 2019 (COVID-19) are often treated with steroids, require intensive care unit (ICU) treatment, and may therefore be at risk for HCMV infection. However, which factors predispose severely ill patients with COVID-19 to HCMV infection and the prognostic value of such infections remain largely unexplored. This study aimed to examine the incidence and potential risk factors of HCMV infection in patients with severe or critical COVID-19 and evaluate the relationship between HCMV infection and mortality. METHODS AND FINDINGS: We used administrative claims data from advanced treatment hospitals in Japan to identify and analyze patients with severe or critical COVID-19. We explored potential risk factors for HCMV infection using multivariable regression models and its contribution to mortality in patients with COVID-19. Overall, 33,151 patients who progressed to severe or critical COVID-19 illness were identified. The incidence of HCMV infection was 0.3-1.7 % depending on the definition of HCMV infection. Steroids, immunosuppressants, ICU admission, and blood transfusion were strongly associated with HCMV infection. Furthermore, HCMV infection was associated with patient mortality independent of the observed risk factors for death. CONCLUSIONS: HCMV infection is a notable complication in patients with severe or critical COVID-19 who are admitted to the ICU or receive steroids, immunosuppressants, and blood transfusion and can significantly increase mortality risk.

Epidemiology and Risk Factors of Eosinophilic Esophagitis in Japan: A Population-Based Study.

BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) has been increasingly diagnosed globally. However, there have been few general population-based studies in Asia. The aim of this study was to investigate EoE epidemiology in the Japanese general population. METHODS: We analyzed an employer-based health insurance claim database from January 2005 to September 2022. EoE cases were identified on the basis of the International Statistical Classification of Diseases and Health-related Problems, 10th Revision code, K20.0. We calculated the incidence and prevalence of EoE using Poisson regression and binomial distribution, respectively. Using 10 matched controls for each EoE case, a nested case-control study was performed to identify potential risk factors for EoE. RESULTS: Of 15,200,895 individuals, 1010 EoE cases were identified. The incidence and prevalence of EoE were 2.82 (95% confidence interval [CI], 2.44-3.26) per 100,000 person-years and 10.68 (95% CI, 10.01-11.37) per 100,000 people in 2022, nearly 3 and 8 times as high as those in 2017, respectively. Smoking was associated with decreased risk of EoE (odds ratio [OR], 0.45, 0.36-0.56, P < .001), whereas alcohol consumption (OR, 1.51, 1.21-1.88, P < .001) was associated with increased risk of EoE along with several allergic conditions and psychiatric disorders. EoE was not related to either body mass index or lifestyle-related diseases such as hypertension, diabetes mellitus, hyperuricemia, and dyslipidemia. CONCLUSIONS: The incidence and prevalence of EoE in Japan have steadily increased over the past 2 decades. Nevertheless, EoE remains less common in Japan compared with the United States and Western Europe. Factors contributing to the epidemiology of EoE on a global basis may improve our understanding of the contribution of genetic and environmental risk factors.

Evaluating the association of body mass index with COVID-19 severity and mortality using Japanese administrative claims data.

INTRODUCTION: Obesity is a risk factor for aggravation of and mortality from coronavirus disease 2019 (COVID-19). We aimed to investigate the relationship between COVID-19 and Body Mass Index (BMI) in the Japanese population. METHODS: We used administrative claims data from an advanced treatment hospital in Japan and extracted data from patients hospitalized for COVID-19. The exposure variable was BMI measured at the time of admission, and the study outcomes were progression to critical illness and death. Analyses were performed for each age group. RESULTS: Overall, 58,944 patients met the inclusion criteria. The risk of critical illness increased monotonically with higher BMI. In contrast, the relationship between BMI and mortality follows a J-shaped curve; being underweight and obese are risk factors for mortality. When stratified by age, similar trends were observed for both critical illness and mortality. CONCLUSION: A higher BMI is a risk factor for the progression of COVID-19 severity, whereas both lower and higher BMIs are risk factors for mortality in the Japanese population.

Protocol of a pilot randomized clinical trial to evaluate nutritional support and rehabilitation on prevention of skeletal muscle mass loss during neoadjuvant chemotherapy in patients with esophageal cancer.

BACKGROUND: Subtotal esophagectomy with lymph node dissection followed by neoadjuvant chemotherapy (NAC) is the standard treatment for stage II-III esophageal cancer. Esophagectomy is still associated with high morbidity rates, and reducing these rates remains challenging. Among several complications, postoperative pneumonia (PP) is sometimes fatal, which has been reportedly caused by sarcopenia. Thus, nutritional support and rehabilitation may be promising for preventing skeletal muscle mass loss and reduce the incidence of PP. METHODS: This single-center, randomized, open-label, pilot trial will randomize a total of 40 patients with esophageal cancer in a 1:1 ratio either to ISOCAL Clear + rehabilitation arm or only rehabilitation arm. Although all patients will be educated about rehabilitation by a specialized physician and will be asked to undergo the prespecified rehabilitation program, patients treated with ISOCAL Clear + rehabilitation arm will be supplemented by 400 mL of ISOCAL Clear (Nestlé Japan Ltd, Tokyo, Japan) per day during two courses of NAC with docetaxel, cisplatin, and fluorouracil. Body composition will be assessed using Inbody (Inbody Co., Ltd., Tokyo, Japan) just before starting NAC and surgery. The primary endpoint is the change of skeletal muscle index (SMI) during NAC. Secondary endpoints include (i) body weight, total skeletal muscle mass, appendicular skeletal muscle mass, and lean body mass index changes; (ii) the percentage of ISOCAL Clear continuation; (iii) appetite evaluation; (iv) the percentage of targeted calorie achievement; (v) adverse events of NAC; (vi) postoperative complication rates; and (vii) postoperative hospital stay. DISCUSSION: This prospective trial assesses the efficacy of nutritional support in addition to rehabilitation during NAC for patients with esophageal cancer. The results will be utilized in assessing whether the effects of nutritional support by ISOCAL Clear are promising or not and in planning future larger clinical trials.

Assessment of patients' characteristics associated with the efficacy and safety of oral valganciclovir treatment for infants with symptomatic congenital cytomegalovirus disease.

INTRODUCTION: Insurance coverage for oral valganciclovir (VGCV) began in Japan in April 2023 on the basis of results, including our clinical trials for symptomatic congenital cytomegalovirus (CMV) disease. The VGCV treatment is available throughout Japan, so clinicians must consider the likelihood of hearing improvement and the possibility of neutropenia before dosing. MATERIALS AND METHODS: We performed a substudy of an investigator-initiated, single-arm, prospective, multicenter, clinical trial in which 24 infants with symptomatic congenital CMV disease were orally administered 16 mg/kg VGCV twice daily for 6 months as an intervention. We examined the infants' baseline characteristics associated with improved hearing impairment or a severely reduced neutrophil count. RESULTS: Of the 24 patients, 4 had normal hearing on assessment of their ear with the best hearing. Hearing impairment improved in 14 patients and did not respond to VGCV treatment in 6 patients at the 6-month hearing assessment. CMV DNA levels in plasma at baseline were higher in patients in whom hearing did not respond to treatment. A neutrophil count <500/mm3 occurred in 5 (21%) patients for the first 6 weeks and in 8 (33%) patients for the first 6 months. A neutrophil count at screening and the lowest neutrophil count over the 6 months showed the highest correlation (r = 0.477, p = 0.019). CONCLUSIONS: Infants with a low plasma viral load at screening tend to have an improvement in hearing impairment. Clinicians should be aware of neutropenia during VGCV treatment particularly in patients with a low neutrophil count during screening.

Effects of ipragliflozin on left ventricular diastolic function in patients with type 2 diabetes: A sub-analysis of the PROTECT trial.

BACKGROUND: We hypothesized that the beneficial effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors on diastolic function might depend on baseline left ventricular (LV) systolic function. METHODS: To investigate the effects of SGLT2 inhibitors on LV diastolic function in patients with type 2 diabetes mellitus (T2DM), we conducted a post-hoc sub-study of the PROTECT trial, stratifying the data according to LV ejection fraction (LVEF) at baseline. After excluding patients without echocardiographic data at baseline or 24 months into the PROTECT trial, 31 and 38 patients with T2DM from the full analysis dataset of the PROTECT trial who received ipragliflozin or no SGLT2 inhibitor (control), respectively, were included. The primary endpoint was a comparison of the changes in echocardiographic parameters and N-terminal pro-brain natriuretic peptide levels from baseline to 24 months between the two groups stratified according to baseline LVEF. RESULTS: Differences in diastolic functional parameters (e' and E/e') were noted between the two groups. Among the subgroups defined according to median LVEF values, those with higher LVEF (≥60 %) who received ipragliflozin appeared to have a higher e' and lower E/e' than did those who received the standard of care with no SGLT2 inhibitor, indicating longitudinal improvements between baseline and follow up (p = 0.001 and 0.016, respectively). CONCLUSIONS: Ipragliflozin generally improved LV diastolic function in patients with type 2 diabetes, the extent of this improvement might appear to vary with LV systolic function.

Immune Checkpoint Inhibitor Is Associated with Improved Survival in Advanced Non-small Cell Lung Cancer Occurring in Patients with Autoimmune Disease.

The use of immune checkpoint inhibitors (ICIs) has revolutionized the treatment of advanced non-small cell lung cancer (NSCLC). However, clinical trials often exclude those with a history of autoimmune diseases (ADs) because of concerns regarding immune-related adverse events. Therefore, the efficacy of ICIs in advanced NSCLC patients with ADs should be evaluated. This study used administrative claims data from advanced treatment centers in Japan and identified patients with advanced NSCLC who began chemotherapy between December 2016 and January 2023. The patients were divided into four groups based on the presence of ADs and types of chemotherapy received. The association between ICI therapy and overall survival in the subgroups with or without ADs, and the association between the presence of AD and overall survival in patients who received ICI therapy and conventional chemotherapy, were analyzed using Cox proportional hazard regression, including therapy and presence of ADs and their interaction as covariates. These results were obtained using the inverse probability of treatment weighting. ICI therapy had a hazard ratio (95% confidence interval) for death in the subgroup of AD and non-AD patients of 0.88 (0.84-0.92) and 0.83 (0.71-0.97), respectively (p = 0.459 for interaction). For some specific ADs, including type 1 diabetes mellitus, the association between ICI therapy and decreased mortality was not observed. In conclusion, our study showed comparable associations between ICI therapy and reduced mortality in AD and non-AD subgroups of patients with advanced NSCLC. However, therapy strategies tailored to each AD type and thorough discussions regarding the risk-benefit profile are crucial.

Seasonal variations for newly prescribed urate-lowering drugs for asymptomatic hyperuricemia and gout in Japan.

Background: Urate-lowering drugs (ULDs) have been approved for treatment of asymptomatic hyperuricemia and gout in Japan. Although serum urate levels and rates of gout onset are known to have seasonal variations, no survey results regarding the seasonality of ULD prescriptions for asymptomatic hyperuricemia and gout have been reported. Methods: A large-scale database of medical claims in Japan filed between January 2019 and December 2022 was accessed. In addition to total size of the recorded population for each month examined, the numbers of patients every month with newly prescribed ULDs for asymptomatic hyperuricemia and gout were noted, based on the International Classification of Diseases, 10th Revision, codes E79.0 and M10. Results: The results identified 201,008 patients with newly prescribed ULDs (median age 49.0 years, male 95.6%). Of those, 64.0% were prescribed ULDs for asymptomatic hyperuricemia and 36.0% for gout. The proportion of new ULD prescriptions was seasonal, with that significantly (p < 0.001) higher in summer (June-August) [risk ratio (RR) 1.322, 95% CI 1.218 to 1.436] and autumn (September-November) (RR 1.227, 95% CI 1.129-1.335) than in winter (December-February), whereas the proportion in spring (March-May) was not significantly different from winter. There was no significant difference after stratification by drug type (uric acid production inhibitor/uricosuric agent) or size of the medical institution, nor subgrouping by age or sex (p for interaction = 0.739, 0.727, 0.886, and 0.978, respectively). On the other hand, the proportions of new ULD prescriptions for asymptomatic hyperuricemia were significantly lower and for gout significantly higher in spring than winter, while those were similar in summer and autumn for both groups (p for interaction<0.001). Conclusion: The present findings indicate that new prescriptions for ULDs to treat asymptomatic hyperuricemia or gout in Japan show seasonal differences, with higher rates noted in summer and autumn as compared to winter.

Lack of Association Between Immunotherapy and Improvement of Survival for Non-small Cell Lung Cancer Patients With Hemodialysis: A Nationwide Retrospective Cohort Study.

BACKGROUND: The number of patients undergoing hemodialysis continues to increase globally, and the incidence of cancer is high among these patients. Immune checkpoint inhibitors are widely used in patients with advanced cancer, especially non-small cell lung cancer (NSCLC); however, their effectiveness in hemodialysis patients is poorly documented. METHODS: This retrospective cohort study used data from a nationwide database. Patients diagnosed with NSCLC, undergoing hemodialysis, and who started chemotherapy between September 2008 and January 2023 were included. In the intention to treat (ITT) analysis, patients were divided into immune checkpoint inhibitor (ICI) and conventional chemotherapy group, and in the chronological analysis, patients were divided into 2 groups before and after ICI approval. Overall survival (OS) was analyzed using the Kaplan-Meier method with log-rank tests and Cox proportional hazards analyses. A propensity score approach was applied to address confounding factors, and analyses were performed by weighting each patient with the inverse of the estimated propensity score. RESULTS: We identified 322 and 389 patients in the ITT and chronological analyses respectively. In both analyses, there were no notable difference of OS between 2 groups (P values by log-rank test 0.933 and 0.248, respectively). The hazard ratios for OS were 0.980 (95% confidence interval [CI]: 0.678-1.415) in the ITT analysis and 0.805 (95% CI: 0.531-1.219) in the chronological analysis. CONCLUSION: The ICI treatment and approval were not significantly associated with improvement of survival in patients with NSCLC undergoing hemodialysis.

Long-term effects of ipragliflozin on blood pressure in patients with type 2 diabetes: insights from the randomized PROTECT trial.

Although previous reports have shown that sodium-glucose cotransporter-2 (SGLT2) inhibitors have a blood pressure (BP) lowering effect, relevant long-term data is limited. This study aimed to evaluate the effect of the SGLT2 inhibitor ipragliflozin on BP, and associations between BP reduction and changes in cardiometabolic variables in diabetic patients. This was a sub-analysis of the PROTECT trial, a multicenter, randomized, open-label study to assess if ipragliflozin delays carotid atherosclerosis in patients with type 2 diabetes. Participants were randomized to ipragliflozin and control groups. The primary endpoint of the present sub-analysis was the trajectory of systolic BP over 24 months. Correlations between systolic BP changes and cardiometabolic variables were also evaluated. A total of 232 eligible participants with well-balanced baseline characteristics were included in each study group. Throughout the 24-month study period, mean systolic BP was lower in the ipragliflozin group. At 24 months, a between-group difference (ipragliflozin minus control) in mean systolic BP change from baseline was -3.6 mmHg (95% confidence interval, -6.2 to -1.0 mmHg), and the reduction in systolic BP in the ipragliflozin group was consistent across subgroups examined. Changes in systolic BP significantly correlated with those in body mass index in the ipragliflozin group, while no significant correlations with other cardiometabolic variables tested were observed. In conclusion, ipragliflozin treatment was associated with BP reduction throughout the 24-month follow-up period as compared to control treatment. BP reduction correlated with weight loss, which might be one of the mechanisms for the BP lowering effect of SGLT2 inhibitors.

Treatment sequencing after failure to alectinib in patients with anaplastic lymphoma kinase-positive non-small-cell lung cancer.

Alectinib is the first-line therapy for anaplastic lymphoma kinase-positive non-small-cell lung cancer. Although some guidelines have recommended using other anaplastic lymphoma kinase inhibitors after alectinib failure, evidence for such regimens in patients who fail to respond to alectinib is limited. This study involved using administrative claims data from acute care hospitals in Japan. We extracted the data of 634 patients diagnosed with lung cancer between September 1, 2014, and January 31, 2023, who received alectinib treatment before treatment with another anaplastic lymphoma kinase inhibitor. We assessed distributions of patients according to their treatment sequencing and prognosis among three periods defined based on the initial marketing dates of lorlatinib and brigatinib. The type of anaplastic lymphoma kinase inhibitors after alectinib failure changed over time. In the most recent period, lorlatinib (58%) and brigatinib (40%) became predominant. Two-year overall survival improved over time (47%-84%), accompanied by an increased 2-year proportion of patients who continuously used anaplastic lymphoma kinase inhibitors after alectinib failure (13%-44%). The times to treatment discontinuation of the regimen between patients treated with lorlatinib and brigatinib were similar, with a hazard ratio of 1.02 (95% confidence interval, 0.64-1.64) in the period after marketing brigatinib. This study provides insights into the evolving treatment landscape for patients with anaplastic lymphoma kinase-positive non-small-cell lung cancer who experience failed alectinib treatment and highlights the need for further studies and data accumulation to determine the optimal treatment strategy.

A Pragmatic Method to Integrate Data From Preexisting Cohort Studies Using the Clinical Data Interchange Standards Consortium (CDISC) Study Data Tabulation Model: Case Study.

Background: In recent years, many researchers have focused on the use of legacy data, such as pooled analyses that collect and reanalyze data from multiple studies. However, the methodology for the integration of preexisting databases whose data were collected for different purposes has not been established. Previously, we developed a tool to efficiently generate Study Data Tabulation Model (SDTM) data from hypothetical clinical trial data using the Clinical Data Interchange Standards Consortium (CDISC) SDTM. Objective: This study aimed to design a practical model for integrating preexisting databases using the CDISC SDTM. Methods: Data integration was performed in three phases: (1) the confirmation of the variables, (2) SDTM mapping, and (3) the generation of the SDTM data. In phase 1, the definitions of the variables in detail were confirmed, and the data sets were converted to a vertical structure. In phase 2, the items derived from the SDTM format were set as mapping items. Three types of metadata (domain name, variable name, and test code), based on the CDISC SDTM, were embedded in the Research Electronic Data Capture (REDCap) field annotation. In phase 3, the data dictionary, including the SDTM metadata, was outputted in the Operational Data Model (ODM) format. Finally, the mapped SDTM data were generated using REDCap2SDTM version 2. Results: SDTM data were generated as a comma-separated values file for each of the 7 domains defined in the metadata. A total of 17 items were commonly mapped to 3 databases. Because the SDTM data were set in each database correctly, we were able to integrate 3 independently preexisting databases into 1 database in the CDISC SDTM format. Conclusions: Our project suggests that the CDISC SDTM is useful for integrating multiple preexisting databases.

A Phase I/II Clinical Trial of Intradermal, Controllable Self-Replicating Ribonucleic Acid Vaccine EXG-5003 against SARS-CoV-2.

mRNA vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have played a key role in reducing morbidity and mortality from coronavirus disease 2019 (COVID-19). We conducted a double-blind, placebo-controlled phase I/II trial to evaluate the safety, tolerability, and immunogenicity of EXG-5003, a two-dose, controllable self-replicating RNA vaccine against SARS-CoV-2. EXG-5003 encodes the receptor binding domain (RBD) of SARS-CoV-2 and was administered intradermally without lipid nanoparticles (LNPs). The participants were followed for 12 months. Forty healthy participants were enrolled in Cohort 1 (5 µg per dose, n = 16; placebo, n = 4) and Cohort 2 (25 µg per dose, n = 16; placebo, n = 4). No safety concerns were observed with EXG-5003 administration. SARS-CoV-2 RBD antibody titers and neutralizing antibody titers were not elevated in either cohort. Elicitation of antigen-specific cellular immunity was observed in the EXG-5003 recipients in Cohort 2. At the 12-month follow-up, participants who had received an approved mRNA vaccine (BNT162b2 or mRNA-1273) >1 month after receiving the second dose of EXG-5003 showed higher cellular responses compared with equivalently vaccinated participants in the placebo group. The findings suggest a priming effect of EXG-5003 on the long-term cellular immunity of approved SARS-CoV-2 mRNA vaccines.

Case Report of Gas Gangrene after Reconstructive Surgery with Anterolateral Thigh Flap for Resection of Oral Cancer.

Necrotizing fasciitis (NF) type I is an acute subcutaneous tissue infection that can promptly disseminate generating crepitus. If not accurately diagnosed and expeditiously treated, it becomes a life-threatening infection. In this report, we present a 65-year-old man who developed a case of NF after a hemiglossectomy resecting a tumor in the dorsal surface of the tongue. A biopsy was performed, and he was pathologically diagnosed with squamous cell carcinoma (T2N1M0). The patient underwent preoperative oral cleaning. Right hemiglossectomy was performed by cervical dissection, pull-through style, with tooth removal on the right mandible and a left anterolateral femoral flap reconstruction. Routine intraoperative lavage was performed with 2000 mL of saline solution. Cefazolin 1gr was administered two times per day postoperatively. Four days after primary surgery, the flap circulation was inadequate; therefore, a computed tomography scan was taken, which indicated gas in the ventral neck area. Tooth extraction was the suspected etiology. Debridement was performed; the abscess was drained and cultured, indicating the presence of Staphylococcus haemolyticus and Escherichia coli. It seems that the abscess was not formed by NF, but rather by leachate reservoir associated with the head and neck tumor. After debridement, re-reconstruction was performed with a deltopectoral flap and pectoralis major myocutaneous flap. When NF is present after a neck dissection, there is a risk of disruption due to the direct invasion and inflammation into the carotid artery. Therefore, it is important to provide adequate oral cleaning care before the surgery and early suspicion of the diagnosis.

Renin-angiotensin-aldosterone system inhibitors are associated with improved paclitaxel-induced peripheral neuropathy in lung cancer: a study using administrative claims data.

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) has been reported to reduce patients' quality of life and impair cancer treatment by causing anticancer drug withdrawal or interruption. However, there are currently no effective methods for the prevention of CIPN. Renin-angiotensin-aldosterone system (RAAS) inhibitors may be associated with a reduced risk of developing oxaliplatin-induced peripheral neuropathy, and it would be valuable to examine whether they have the same effect on CIPN caused by other anticancer drugs. Our study explored the potential preventive effects of RAAS inhibitors on preventing paclitaxel-induced peripheral neuropathy (PIPN). METHODS: An exploratory cohort study was conducted using commercially available administrative claims data on lung cancer patients treated with paclitaxel-based chemotherapy. Cumulative paclitaxel doses, RAAS inhibitor prescriptions, and incidences of PIPN were identified using patient medical records. Fine-Gray analyses with death as a competing risk were performed. A propensity score approach was applied to address the problem of confounding. RESULTS: Patients with lung cancer who received paclitaxel-based chemotherapy were classified into users of RAAS inhibitor (n = 1320) and non-users of RAAS inhibitor (n = 4566). The doses of RAAS inhibitors in our study were similar to those commonly used to treat hypertension. The PIPN incidence was significantly lower in users of RAAS inhibitor than in the non-users of RAAS inhibitor (sub-distribution hazard ratio, 0.842; 95% confidence interval, 0.762-0.929). The result was consistent in various sensitivity analyses and important subgroup analyses. CONCLUSIONS: RAAS inhibitors at doses commonly used for hypertension were associated with a reduced incidence of PIPN in patients with lung cancer.

Significance of micro-EGFR T790M mutations on EGFR-tyrosine kinase inhibitor efficacy in non-small cell lung cancer.

Small amounts of epidermal growth factor receptor (EGFR) T790M mutation (micro-T790M), which is detected using droplet digital PCR (ddPCR) but not conventional PCR, in formalin-fixed and paraffin-embedded (FFPE) samples have been investigated as a predictive factor for the efficacy of EGFR-tyrosine kinase inhibitors (TKIs). However, the predictive value of micro-T790M remains controversial, possibly owing to the failure to examine artificial T790M in FFPE specimens. Therefore, we examined the predictive value of micro-T790M in first-generation (1G), second-generation (2G), and third-generation (3G) EGFR-TKI efficacy using a new method to exclude FFPE-derived artificial mutations in our retrospective cohort. The primary objective was time to treatment failure (TTF) of 1G, 2G, and 3G EGFR-TKIs according to micro-T790M status. In total, 315 patients with EGFR-positive non-small cell lung cancer treated with 1G, 2G, and 3G EGFR-TKIs were included in this study. The proportion of patients positive for micro-T790M in the 1G, 2G, and 3G EGFR-TKI groups was 48.2%, 47.1%, and 47.6%, respectively. In the micro-T790M-positive group, the TTF was significantly longer in the 2G and 3G EGFR-TKI groups than in the 1G TKI group. No differences in the micro-T790M-negative group were observed. Micro-T790M status detected using ddPCR, eliminating false positives, may be a valuable predictor of EGFR-TKI efficacy.

Employment Status of Patients With Colorectal Cancer After Surgery: A Multicenter Prospective Cohort Study in Japan.

BACKGROUND: Because of improved survival rates, patients with colorectal cancer may try to return to work. Many countries, however, have limited knowledge of the employment status of these patients. OBJECTIVE: To explore the employment status of patients with colorectal cancer after surgery in Japan and the risk factors affecting the same. DESIGN: This is a prospective multicenter cohort study that used self-administered questionnaires. Patients were recruited from June 2019 to August 2020 and were followed up for 12 months after surgery. SETTING: Six community hospitals and 1 university hospital in Japan. PATIENTS: Patients with clinical stages I to III colorectal cancer, employed at the time of diagnosis. INTERVENTIONS: Patients who underwent surgical resection between June 2019 and August 2020. MAIN OUTCOME MEASUREMENTS: The time it takes patients to return to work after surgery and the proportion of working patients 12 months after surgery were collected using self-administered questionnaires. RESULTS: A total of 129 patients were included in the analyses. The median time to return-to-work was 1.1 months, and the proportion of working patients at 12 months after surgery was 79%. Risk factors for delayed return-to-work after surgery were an advanced tumor stage, stoma, severe postoperative complications, shorter years of service at the workplace, and lower willingness to return-to-work. Risk factors for not working 12 months after surgery were stoma, lower willingness to return-to-work, nonregular employee status, lower income, national health insurance, and no private medical insurance. LIMITATIONS: This study is limited by its short-term follow-up and small sample size. CONCLUSIONS: This study revealed that Japanese patients with stages I to III colorectal cancer found favorable employment outcomes in the 12 months after surgery. These results may help health care providers better understand the employment status of patients with colorectal cancer and encourage them to consider returning to work after surgery. SITUACIN LABORAL DE LOS PACIENTES CON CNCER COLORRECTAL DESPUS DE LA CIRUGA UN ESTUDIO DE COHORTE PROSPECTIVO MULTICNTRICO EN JAPN: ANTECEDENTES:Debido a las mejores tasas de supervivencia, los pacientes con cáncer colorrectal pueden intentar volver al trabajo. Muchos países, sin embargo, tienen un conocimiento limitado de su situación laboral.OBJETIVO:Explorar la situación laboral de los pacientes con cáncer colorrectal después de la cirugía en Japón y los factores de riesgo que afectan a la misma.DISEÑO:Este es un estudio prospectivo de cohortes multicéntrico que utiliza cuestionarios autoadministrados. Los pacientes fueron reclutados desde junio de 2019 hasta agosto de 2020 y fueron seguidos durante 12 meses después de la cirugía.ENTORNO CLINICO:Seis hospitales comunitarios y un hospital universitario en Japón.PACIENTES:Pacientes con estadios clínicos I-III de cáncer colorrectal, trabajando en el momento del diagnóstico.INTERVENCIONES:Pacientes que recibieron resección quirúrgica desde junio de 2019 hasta agosto de 2020.PRINCIPALES MEDIDAS DE RESULTADO:El tiempo que tardan los pacientes en volver al trabajo después de la cirugía y la proporción de pacientes que trabajan 12 meses después de la cirugía se recogieron mediante cuestionarios autoadministrados.RESULTADOS:Un total de 129 pacientes fueron incluidos en los análisis. La mediana de tiempo de reincorporación al trabajo fue de 1,1 meses y la proporción de pacientes que trabajaban a los 12 meses de la cirugía fue del 79%. Los factores de riesgo para el retraso en el regreso al trabajo después de la cirugía fueron un estadio avanzado del tumor, estoma, complicaciones postoperatorias graves, menos años de servicio en el lugar de trabajo y menor disposición para volver al trabajo. Los factores de riesgo para no trabajar 12 meses después de la cirugía fueron estoma, menor voluntad de volver al trabajo, condición de empleado no regular, ingresos más bajos, seguro nacional de salud y la falta de seguro médico privado.LIMITACIONES:Este estudio está limitado por su seguimiento a corto plazo y tamaño de muestra pequeño.CONCLUSIONES:Este estudio reveló que los pacientes japoneses con cáncer colorrectal en estadios I-III obtuvieron resultados laborales favorables en los 12 meses posteriores a la cirugía. Estos resultados pueden ayudar a los proveedores de atención médica a comprender mejor la situación laboral de los pacientes con cáncer colorrectal y alentarlos a considerar regresar al trabajo después de la cirugía. (Traducción- Dr. Francisco M. Abarca-Rendon ).

Association of plasma xanthine oxidoreductase activity with vascular endothelial function independent of serum uric acid level: MedCity21 health examination registry.

Background: Xanthine oxidoreductase (XOR) inhibitor administration, known to reduce uric acid and reactive oxygen species (ROS) production, also improves vascular endothelial function (VEF). This cross-sectional study examined our hypothesis that XOR contributes to impaired VEF through ROS but not uric acid production. Methods: In 395 subjects (196 males, 199 females) without urate-lowering agent administration who underwent a health examination, plasma XOR activity was determined using our highly sensitive assay based on [13C2,15N2] xanthine and liquid chromatography/triple quadrupole mass spectrometry. For VEF evaluation, flow-mediated dilatation (FMD) in the brachial artery was determined by ultrasound, with physical and laboratory measurements also obtained. Results: The median values for plasma XOR activity, serum uric acid, and FMD were 26.6 pmol/h/mL, 5.4 mg/dL, and 6.2%, respectively. Simple regression analysis showed weak correlations of both log plasma XOR activity and serum uric acid level with FMD (r = -0.213, p < 0.001 and r = -0.139, p = 0.006, respectively). However, multivariable linear regression analyses revealed that log plasma XOR activity but not serum uric acid level remained associated with FMD (ß = -0.116, p = 0.037 and ß = 0.041, p = 0.549, respectively) after adjustments for various clinical parameters, with no remarkable inconsistencies for the association observed in subgroups divided based on sex or uric acid level. Finally, a series of mediation analyses showed that serum uric acid level did not meet the criteria for mediator of the association of plasma XOR activity with FMD (p = 0.538). Conclusions: These findings suggest the possibility that XOR contributes to the pathophysiology of impaired VEF through ROS but not uric acid production.