Gray Competing Risk Regression Research Articles

Identifying the optimal measurement timing and hemodynamic targets of portal pressure gradient after TIPS in patients with cirrhosis and variceal bleeding

The optimal timing of measurement and hemodynamic targets of portacaval pressure gradient (PPG) after transjugular intrahepatic portosystemic shunt (TIPS) placement remain unclear. This study aimed to identify the ideal moment for hemodynamic measurements and the optimal target of PPG in patients undergoing covered TIPS for variceal bleeding. Between May 2018 and December 2021, 466 consecutive patients with recurrent variceal bleeding treated with covered TIPS were prospectively included. Post-TIPS PPG was measured immediately (immediate PPG), 24-72 hours (early PPG), and again 1 month (late PPG) after TIPS placement. The agreement among PPGs measured at different time points was assessed by intra-class correlation coefficient (ICC) and Bland-Altman method. The unadjusted and confounder-adjusted effects of PPGs on clinical outcomes (portal hypertensive complications [PHCs], overt hepatic encephalopathy [OHE], further decompensation, and death) were assessed using Fine and Gray competing risk regression models. The agreement between early PPG and late PPG (ICC: 0.34) was better than that between immediate PPG and late PPG (ICC: 0.23, p <0.001). Early PPG revealed an excellent predictive value for PHCs (early PPG≥ vs. <12mmHg: adjusted hazard ratio 2.17, 95% CI 1.33-3.55, p= 0.002) and OHE (0.40, 95% CI 0.17-0.91, p= 0.030), while immediate PPG did not. Late PPG showed a predictive value for PHC risk but not OHE. By targeting the lowest risk of further decompensation, we identified an optimal hemodynamic target with early PPG ranging from 11 to 14mmHg that was associated with a decreased risk of OHE and effective prevention of PHC. PPG measured 24 to 72 hours after TIPS correlates with long-term PPG and clinical outcomes, and a hemodynamic target PPG of 11-14mmHg is associated with reduced encephalopathy but not compromised clinical efficacy. The optimal timing of measurement and hemodynamic targets of portacaval pressure gradient (PPG) after transjugular intrahepatic portosystemic shunt (TIPS) remain unclear. Here we show that post-TIPS PPG measured at least 24 hours but not immediately after the procedure correlated with long-term PPG and clinical events. Thus, PPG measurements taken at least 24 hours after TIPS should be used to guide decision making in order to improve clinical outcomes. Targeting a post-TIPS PPG of 11-14mmHg or a 20%-50% relative reduction from pre-TIPS baseline measured 24-72 hours after the procedure was associated with reduced encephalopathy but not compromised clinical efficacy. Thus, these criteria could be used to guide TIPS creation and revision in patients with cirrhosis and variceal bleeding undergoing covered TIPS. ClinicalTrials.gov, ID: NCT03590288.

Aryl hydrocarbon receptor repressor (AHRR) methylation predicts risk of vascular disease: A cohort study of the general population.

Smoking is a risk factor for cardiovascular disease, but there is currently no clinically established biomarker for its cardiovascular damage. We aimed to investigate the hypothesis that aryl hydrocarbon receptor repressor (AHHR) methylation at CpG site cg05575921, a biomarker of smoking behavior, is associated with the risk of peripheral artery disease (PAD) and aortic aneurysm (AA) in the general population. In this prospective cohort study of the general population, we measured AHRR methylation in individuals from three visits of the Copenhagen City Heart Study. Information on risk factors were collected at visits with ten years intervals; visit 1 (1991-94), visit 2 (2001-03), and visit 3 (2011-15). Individuals were followed up in the Danish National Patient Register for PAD and AA until December 2018. Subhazard ratios were calculated using Fine and Gray competing risk regression. In 11,332 individuals from visit 1 (n=9,234), visit 2 (n=5,384), and visit 3 (n=4,387) there were 613 and 219 events of PAD and AA during up to 26.5 years of follow-up. AHRR hypomethylation was associated with higher risk of PAD and AA with multivariable adjusted subhazard ratios of 2.82 (1.91; 4.15) for PAD and 2.88 (1.42; 5.88) for AA in individuals within the lowest versus highest methylation quintile. We found that AHRR methylation, a strong biomarker for smoking, was associated with risk of PAD and AA. AHRR methylation could be a useful tool in more personalized risk prediction of PAD and AA.

Systemic inflammatory biomarkers are novel predictors of all-cause and cardiovascular mortality in individuals with osteoarthritis: a prospective cohort study using data from the NHANES

BackgroundChronic inflammation may contribute to increased mortality risk in individuals with osteoarthritis (OA), but research on the prognostic value of inflammatory biomarkers is limited. We aimed to evaluate the associations of the systemic immune–inflammation index (SII) and systemic inflammation response index (SIRI) with all-cause and cardiovascular mortality among US adults with OA.MethodsThis cohort study included 3545 adults with OA aged ≥ 20 years from the National Health and Nutrition Examination Survey 1999–2020. The SII and SIRI were calculated using complete blood cell count data. Participants were categorized as having a higher or lower SII and SIRI using cutoff points derived by the maximally selected rank statistics method. Cox proportional hazards models, Fine–Gray competing risk regression models and time-dependent receiver operating characteristic (ROC) analysis were used to evaluate the associations between the SII/SIRI and mortality in OA patients.ResultsOver a median follow-up of 5.08 (3.42–9.92) years, 636 (17.94%) deaths occurred, including 149 (4.20%) cardiovascular deaths. According to multivariable-adjusted models involving demographic, socioeconomic, and health factors, OA patients with a higher SII had a twofold greater risk of all-cause mortality than patients with a lower SII (HR 2.01; 95% CI: 1.50–2.68). Similarly, a higher SIRI was associated with an 86% increased risk of all-cause mortality relative to a lower SIRI (HR 1.86; 95% CI: 1.46–2.38). Similar to the trend found with all-cause mortality, patients with an elevated SII and SIRI had a 88% and 67% increased risk of cardiovascular mortality, respectively, compared to patients with a lower SII (HR 1.88; 95% CI: 1.16–3.03) and SIRI (HR 1.67; 95% CI: 1.14–2.44). Time-dependent ROC curves showed that both the SII and SIRI have moderate and valid performance in predicting short- and long-term mortality in patients with OA.ConclusionsHigher SII and SIRI values were associated with greater all-cause and cardiovascular mortality among US adults with OA.

Acute kidney injury development is associated with mortality in Japanese patients with cirrhosis: impact of amino acid imbalance

BackgroundAcute kidney injury (AKI) is a serious complication of cirrhosis. This study analyzed the prognostic effect of AKI in patients with cirrhosis and its risk factors, particularly in relation to amino acid imbalance.MethodsThis retrospective study reviewed 808 inpatients with cirrhosis at two institutes in Gifu, Japan. AKI was diagnosed according to the recommendations of the International Club of Ascites. Amino acid imbalance was assessed by measuring serum branched-chain amino acid (BCAA) levels, tyrosine levels, and the BCAA-to-tyrosine ratio (BTR). Factors associated with mortality and AKI development were assessed using the Cox proportional hazards regression model with AKI as a time-dependent covariate and the Fine–Gray competing risk regression model, respectively.ResultsOf the 567 eligible patients without AKI at baseline, 27% developed AKI and 25% died during a median follow-up period of 4.7 years. Using a time-dependent covariate, AKI development (hazard ratio [HR], 6.25; 95% confidence interval [CI], 3.98–9.80; p < 0.001) was associated with mortality in patients with cirrhosis independent of potential covariates. In addition, alcohol-associated/-related liver disease, metabolic dysfunction-associated steatohepatitis, Child–Pugh score, and BTR (subdistribution HR 0.78; 95% CI 0.63–0.96; p = 0.022) were independently associated with AKI development in patients with cirrhosis. Similar results were obtained in the multivariate model that included BCAA and tyrosine levels instead of BTR.ConclusionsAKI is common and associated with mortality in Japanese patients with cirrhosis. An amino acid imbalance is strongly associated with the development of AKI in patients with cirrhosis.

Performance of restorations in primary molars over a seven-year period

ObjectiveThe aim of this study was to evaluate the use and reintervention rate of fillings compared to preformed metal crowns in the everyday clinical practice of German dentists. MethodsIn this retrospective, longitudinal analysis, fee codes from the Kassenzahnärztliche Vereinigung Westfalen-Lippe for restorations placed in primary molars between 2012 and 2015 in children until 7 years of age followed for a 7-year period (latest until December 2022) were filtered and analyzed with the Fine and Gray competing risk regression and Cox proportional hazards regression to calculate the risk of reintervention divided into the main outcomes “Successful”, “Minor Failure/Repair” and “Major Failure/Endodontic Treatment/Extraction”. 367,139 primary molars (one-surface fillings: n = 117,721; two-surface fillings n = 198,815; three-surface fillings n = 36,695; more than three-surface fillings n = 8,267 and preformed metal crowns n = 5,641 were included in this study. ResultsTeeth treated with preformed crowns needed significantly less re-interventions. Subdistribution hazard ratio for minor events was 0.117 (95 %-CI: 0.097 to 0.141) and hazard ratio of major events (HR=0.786; 95 %-CI: 0.695 to 0.890) when compared to one-surface fillings in multivariable adjusted analysis. Within 7-year follow-up preformed crowns required less repairs (80.6 % success rate, minor failure 4.4 %, major failure 16.3 %) than the teeth treated with composite fillings (46.2 %–52.6 % success rate, minor failure 27.0 %–39.5 %, major failure 15.5 %–28.4 %, p < 0.001). ConclusionWithin the German healthcare system fillings are the first choice for treating primary molars despite considerably higher reintervention rates. This encourages a discussion on the indication of fillings and the more durable preformed metal crowns to reduce unnecessary reintervention in young children. Clinical significanceThis study gives an unprecedented insight into the German healthcare system regarding the reintervention rates of the most relevant treatment techniques for caries in primary molars.

Preoperative Hepatology and Primary Care Visits Improve Postoperative Outcomes in Patients With Cirrhosis Undergoing Surgery

Background and aimsCirrhosis patients are at increased risk for postoperative complications. It remains unclear whether preoperative nonsurgical clinician visits improve postoperative outcomes. We assessed the impact of preoperative primary care physician (PCP) and/or Gastroenterologist/Hepatologist (GI/Hep) visits on postoperative mortality in cirrhosis patients undergoing surgery and explored differences in medication changes and paracentesis rates as potential mediators. MethodsThis was a retrospective cohort study of cirrhosis patients in the Veterans Health Administration who underwent surgery between 2008 and 2016. We compared 1982 patients with preoperative PCP and/or GI/Hep visits with 1846 propensity matched patients without preoperative visits. We used Cox regression and Fine and Gray competing risk regression to evaluate the association between preoperative visit type and postoperative mortality at 6 months. ResultsPatients with preoperative GI/Hep and PCP visits had a 45% lower hazard of postoperative mortality compared to those without preoperative visits (hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.35-0.87). A smaller effect size was noted with GI/Hep preoperative visit alone (HR, 0.69; 95% CI, 0.48-0.99) or PCP visit alone (HR, 0.70; 95% CI, 0.53-0.93). Patients with preoperative PCP/GI/Hep visits were more likely to have diuretics, spontaneous bacterial peritonitis prophylaxis, and hepatic encephalopathy medications newly initiated and/or dose adjusted and more likely to receive preoperative paracentesis as compared to those without preoperative visits. ConclusionPreoperative PCP/GI/Hep visits are associated with a reduced risk of postoperative mortality with the greatest risk reduction observed in those with both PCP and GI/Hep visits. This synergistic effect highlights the importance of a multidisciplinary approach in the preoperative care of cirrhosis patients.

#1869 Acute kidney injury is associated with long-term liver-related outcomes in patients with hepatitis B virus infection

Abstract Background and Aims Hepatitis B virus (HBV) infection presents a global health burden. Despite notable advancements over recent decades, it still accounts for 42% of liver cirrhosis, 40% of hepatocellular carcinoma (HCC) and 60% of viral hepatitis-related deaths. Acute kidney injury (AKI) is prevalent in this vulnerable population, linked to increased in-hospital deaths. However, while renohepatic crosstalk in AKI being recognized, there is a scarcity of data regarding the association of AKI with the long-term liver-related mortality and complications among patients with HBV infection. The study aimed to evaluate the association between AKI with long-term liver-related mortality and complications in patients with HBV infection. Method Adult patients with hepatitis B surface antigen-positive HBV infection and without cirrhosis or HCC were identified using the China Renal Data System (2000-2022), a database compromising electronic health records data from 24 central hospitals across China. All participants were traced by the national electronic cause-of-death reporting system of the China Center for Disease Control and Prevention (CDC) to capture the dates and causes of deaths. The main exposure was AKI, detected by a well-endorsed algorithm based on SCr. In detail, at any time point t when an SCr was measured, a baseline SCr was dynamically defined as the mean of SCr levels within the 7 days before t, and each of the available SCr data within 7 days after t was compared with this baseline. AKI was defined as according to the Kidney Disease Improving Global Outcomes criteria. The primary outcome was post-discharge liver-related mortality, recorded by China CDC. The secondary outcome was a composite of new-onset liver cirrhosis and HCC, defined by diagnoses data. Only patients with at least 90 days follow-up were retained for the secondary analyses. The index date was the discharge date of patients. Fine and Gray competing risks regression was employed for the analyses. Results Of the 86 204 inpatients with HBV infection and without liver cancer or cirrhosis at baseline, 4 407 experienced AKI. During a mean follow-up of 5.0 years, 334 (0.4%) patients died of liver-related events. The cumulative incidence of liver-related mortality in patients with AKI was higher than those without AKI (0.9% vs. 0.4%). After adjustment, AKI during hospitalization was significantly associated with a higher risk of liver-related mortality after discharge (adjusted HR, 1.78; 95% CI, 1.26-2.51, P = 0.001). When reclassified AKI into stage 1 and stage 2/3, patients with more severe AKI (stage 2 or 3 AKI) had a HR of 3.21 (95% CI, 2.01-5.11) for liver-related deaths compared to those patients with non-AKI. Among 42 012 patients with at least one medical visit after 90 days of discharge, the adjusted HR of AKI associated with new-onset HCC or cirrhosis was 1.33 (95% CI, 1.10-1.60, P = 0.004). In subgroup analysis, the associations between AKI with liver-related mortality and complications remained consistent across different subgroups (all P for interaction &amp;gt; 0.05). Conclusion In conclusion, our study highlights the potential role of AKI as a risk factor for liver-related mortality and incident liver-related complications in patients with HBV infection. Physicians should be aware of the poor prognosis associated with AKI in this population. Intensive monitoring and early intervention for AKI are warranted to improve patient outcomes.

Association of diabetic retinopathy on all-cause and cause-specific mortality in older adults with diabetes: National Health and Nutrition Examination Survey, 2005–2008

To evaluate the effect of diabetic retinopathy (DR) status or severity on all-cause and cause-specific mortality among diabetic older adults in the United States using the most recent National Health and Nutrition Examination Survey (NHANES) follow-up mortality data. The severity of DR was graded according to the Early Treatment Diabetic Retinopathy Study (ETDRS) grading scale. Multiple covariate-adjusted Cox proportional hazards regression models, Fine and Gray competing risk regression models, and propensity score matching (PSM) methods were used to assess the risk of all-cause and cause-specific mortality in individuals with diabetes. All analyses adopted the weighted data and complex stratified design approach proposed by the NHANES guidelines. Time to death was calculated based on the time between baseline and date of death or December 31, 2019, whichever came first. Ultimately 1077 participants, representing 3,025,316 US non-hospitalized individuals with diabetes, were included in the final analysis. After a median follow-up of 12.24 years (IQR, 11.16–13.49), 379 participants were considered deceased from all-causes, with 43.90% suffering from DR, including mild DR (41.50%), moderate to severe DR (46.77%), and proliferative DR (PDR) (67.21%). DR was associated with increased all-cause, cardiovascular disease (CVD) and diabetes mellitus (DM)-specific mortality, which remained consistent after propensity score matching (PSM). Results of DR grading assessment suggested that the presence of mild, moderate to severe NPDR was significantly associated with increased risk of all-cause and CVD-specific mortality, while the presence and severity of any DR was associated with increased DM-specific mortality, with a positive trend. The presence of DR in elderly individuals with diabetes is significantly associated with the elevated all-cause and CVD mortality. The grading or severity of DR may reflect the severity of cardiovascular disease status and overall mortality risk in patients with diabetes.

Arterial Thromboembolism in Japanese Patients With Cancer: Incidence, Predictors, and Survival Impact

BackgroundThromboembolism is a significant complication for patients with cancer, leading to treatment interruptions and poor outcomes. ObjectivesThe aim of this study was to investigate the incidence of arterial thromboembolism (ATE) within cancer populations, identify the predictors of ATE, and determine its survival impact. MethodsA retrospective multicenter study was performed using data from the Osaka Cancer Registry linked with administrative data from 2010 to 2015. Patients were monitored for 5 years after cancer diagnosis, and ATE incidence was calculated with death as a competing risk. Fine and Gray competing risk regression models and Cox proportional hazards models were used to evaluate the predictors of ATE and the survival impact. Restricted mean survival time (RMST) was used to assess whether antithrombotic therapy after ATE contributed to improved survival. ResultsThe cohort comprised 97,448 patients with cancer (42.3% women, median age 70 years). ATE incidence displayed an annual increase, peaking 1 year after cancer diagnosis (1-, 2-, 3-, 4-, and 5-year cumulative incidences were 1.29%, 1.77%, 2.05%, 2.22%, and 2.32%, respectively). Male sex, advanced age, advanced cancer stage, and hematologic malignancies correlated with a high risk for ATE. Patients with ATE had a 2-fold increased risk for mortality compared with those without ATE. The 90-day and 1-year RMST differences for those on antithrombotic therapy were 13.3 days (95% CI: 10.4-16.2 days; P < 0.001) and 57.8 days (95% CI: 43.1-72.5 days; P < 0.001), favoring the antithrombotic therapy group. The RMST differences varied by cancer stage. ConclusionsThe risk for ATE varies according to sex, age, and cancer progression and type. Antithrombotic therapy after ATE is associated with improved survival among patients with cancer.

Autoimmune diseases in primary sclerosing cholangitis and their first-degree relatives.

Primary sclerosing cholangitis (PSC) is linked to inflammatory bowel disease (IBD). However, there is limited overlap between IBD and PSC risk genes, but a stronger association between PSC and other autoimmune conditions. We aimed to assess the coexistence and familial association of autoimmune disorders in PSC, and the influence of autoimmune comorbidity on severe outcomes. In a matched cohort study, 1378 individuals with PSC and 13,549 general population comparators and their first-degree relatives were evaluated. National registries provided data on diagnoses and outcomes (liver transplantation, hepatobiliary cancer, and liver-related death). The OR of autoimmune disease was estimated by logistic regression. The Fine and Gray competing risk regression estimated HRs for severe outcomes. The prevalence of non-IBD, non-autoimmune hepatitis, and autoimmune disease was 18% in PSC and 11% in comparators, OR: 1.77 (95% CI: 1.53-2.05). Highest odds were seen for celiac disease [OR: 4.36 (95% CI: 2.44-7.49)], sarcoidosis [OR: 2.74 (95% CI: 1.29-5.33)], diabetes type 1 [OR: 2.91 (95% CI: 2.05-4.05)], and autoimmune skin disease [OR: 2.15 (95% CI: 1.52-2.96)]. First-degree relatives of individuals with PSC had higher odds of developing IBD, autoimmune hepatitis, and any autoimmune disease than relatives of the comparators [OR: 3.25 (95% CI: 2.68-3.91); OR: 5.94 (95% CI: 2.82-12.02); OR: 1.34 (95% CI: 1.19-1.50)]. Autoimmune comorbidity in PSC was not associated with poorer outcomes [HR: 0.96 (95% CI: 0.71-1.28)]. Individuals with PSC and their first-degree relatives had higher odds of autoimmune disease compared to matched comparators. This finding provides validation for prior genetic discoveries at a phenotypic level. Autoimmune comorbidity did not impact severe outcomes.

Association between long-term use of calcium channel blockers (CCB) and the risk of breast cancer: a retrospective longitudinal observational study protocol

IntroductionCalcium channel blockers (CCB), a commonly prescribed antihypertensive (AHT) medicine, may be associated with increased risk of breast cancer. The proposed study aims to examine whether long-term CCB use is...

Association between dietary flavonol intake and mortality risk in the U.S. adults from NHANES database

Using updated National Health and Nutrition Examination Survey (NHANES) follow-up data, and a large nationwide representative sample of adult U.S. citizens, the aim of this study was to explore the relationship between dietary flavonol intake, all-cause and cause-specific mortality risks. In this prospective cohort study based on NHANES (2007–2008, 2009–2010, and 2017–2018), a total of 11,679 participants aged 20 years and above were evaluated. The amount and type of food taken during a 24-h dietary recall were used to estimate dietary flavonol intake, which includes total flavonol, isorhamnetin, kaempferol, myricetin, and quercetin. Each analysis of the weighted data was dealt with in accordance with the NHANES reporting requirements' intricate stratification design. The Cox proportional risk regression model or Fine and Gray competing risks regression model were applied to evaluate all-cause and cause-specific mortality risks, respectively. The follow-up period was calculated using the time interval between the baseline and the death date or December 31, 2019 (whichever occurs first). Each data analysis was performed between October 1, 2023, and October 22, 2023. Dietary flavonol intake included total flavonol, isorhamnetin, kaempferol, myricetin, and quercetin. Up to December 31, 2019, National Death Index (NDI) mortality data were used to calculate mortality from all causes as well as cause-specific causes. A total of 11,679 individuals, which represents 44,189,487 U.S. non-hospitalized citizens, were included in the study; of these participants, 49.78% were male (n = 5816), 50.22% were female (n = 5, 863); 47.56% were Non-Hispanic White (n = 5554), 18.91% were Non-Hispanic Black (n = 2209), 16.23% were Mexican American (n = 1895), and 17.30% were other ethnicity (n = 2021); The mean [SE] age of the sample was 46.93 [0.36] years, with a median follow-up of 7.80 years (interquartile range, 7.55–8.07 years). After adjusting covariates, Cox proportional hazards models and fine and gray competing risks regression models for specific-cause mortality demonstrated that total flavonol intake was associated with all-cause (HR 0.64, 95% CI 0.54–0.75), cancer-specific (HR 0.45, 95% CI 0.28–0.70) and CVD-specific (HR 0.67, 95% CI 0.47–0.96) mortality risks; isorhamnetin intake was associated with all-cause (HR 0.72, 95% CI 0.60–0.86), and cancer-specific (HR 0.62, 95% CI 0.46–0.83) mortality risks; kaempferol intake was associated with all-cause (HR 0.74, 95% CI 0.63–0.86), and cancer-specific (HR 0.62, 95% CI 0.40–0.97) mortality risks; myricetin intake was associated with all-cause (HR 0.77, 95% CI 0.67–0.88), AD-specific (HR 0.34, 95% CI 0.14–0.85), and CVD-specific (HR 0.61, 95% CI 0.47–0.80) mortality risks; quercetin intake was associated with all-cause (HR 0.66, 95% CI 0.54–0.81), cancer-specific (HR 0.54, 95% CI 0.35–0.84), and CVD-specific (HR 0.61, 95% CI 0.40–0.93) mortality risks; there was no correlation observed between dietary flavonol intake and DM-specific mortality. According to the current study, all-cause, AD, cancer, and CVD mortality risks declined with increased dietary flavonoid intake in the U.S. adults. This finding may be related to the anti-tumor, anti-inflammatory, and anti-oxidative stress properties of flavonol.

Hyperthyroidism and the risk of non-thyroid cancer: a Danish register-based long-term follow-up study.

Cancer is the second most common cause of death worldwide. It is currently debated whether thyroid dysfunction is a modifiable cancer risk factor. Our aim was to evaluate the risk of cancer in patients with hyperthyroidism. This is a register-based nationwide cohort study of individuals with a diagnosis of hyperthyroidism. Each hyperthyroid case was matched with four reference individuals according to age and sex. Using Fine and Gray competing risk regression models, we studied the association of hyperthyroidism and subsequent all-cause cancer diagnoses, adjusted for preexisting morbidity. Sub-analyses were stratified for cause of hyperthyroidism (Graves' disease and toxic nodular goiter, age when diagnosed with hyperthyroidism, sex, and cancer localization (lung, prostate, breast, and colorectal cancer)). The cohort consisted of 95,469 patients with hyperthyroidism (followed for a median of 10.9 years (range: 5.2-17.2)), and 364,494 reference individuals (followed for a median of 11.2 years (range: 5.4-17.4)). Hyperthyroidism was associated with increased all-cause cancer risk (sub-distribution hazard ratio (SHR): 1.12; 95% CI: 1.10-1.14), as well as an increased risk of breast (SHR: 1.07; 95% CI: 1.02-1.13), lung (SHR: 1.20; 95% CI: 1.16-1.26), and prostate cancer (SHR: 1.10; 95% CI: 1.02-1.19), but not colorectal cancer (SHR: 1.04; 95% CI: 0.99-1.09). Sub-analyses stratified for age when diagnosed with hyperthyroidism and cause of hyperthyroidism yielded similar results. In this register-based study, patients with hyperthyroidism had an increased risk of cancer, in particular lung, prostate, and breast cancer. Whether a causal link exists remains to be proven.

Long-term results of percutaneous coronary intervention in no-touch vein grafts are significantly better than in conventional vein grafts.

Conventional vein grafts have a high risk of thrombosis and early atherosclerosis. Percutaneous coronary intervention (PCI) in conventional vein grafts is associated with a higher incidence of late adverse cardiac events. The aim of this study was to evaluate the long-term results after PCI in saphenous vein grafts (SVG) harvested with the no-touch technique compared to the conventional technique. This was a single-center, retrospective, cohort study, based on data from the Swedeheart register. The inclusion criterion was individuals who underwent CABG using different vein graft techniques between January 1992 and July 2020, and who required a PCI in SVGs between January 2006 and July 2020. The primary end point was long-term in-stent restenosis. The secondary endpoints were long-term major adverse cardiac events (MACE) and 1-year re-hospitalization rates. The associations between the graft types and the endpoints were evaluated using the Fine and Gray competing-risk regression analysis. The study included 346 individuals (67 no-touch, 279 conventional). The mean clinical follow-up time was 6.4years with a standard deviation of 3.7years. The long-term in-stent restenosis rate for the no-touch grafts was 3.2% compared to 18.7% for the conventional grafts (p < .01), with a subdistribution hazard ratio (SHR) of 0.16 (p = .010). The long-term MACE rate was 27.0% in the no-touch group and 48.3% in the conventional group (p < .01) with a SHR of 0.53 (p = .017). The short-term results were similar in both groups. Percutaneous coronary intervention in a no-touch vein graft was associated with statistically significantly fewer in-stent restenoses and MACE at long-term follow-up compared to a conventional SVG.

Discontinuation of tenofovir disoproxil fumarate from initial ART regimens because of renal adverse events: An analysis of data from four multi-country clinical trials.

Tenofovir disoproxil fumarate (TDF), a potent and commonly used antiretroviral drug, is associated with renal tubular dysfunction and renal adverse events. We evaluated the frequency of, time to, and baseline risk factors for discontinuing TDF from initial antiretroviral therapy (ART) regimens because of renal adverse events from presumed tenofovir renal toxicity. We conducted an observational cohort study as a secondary analysis of data from four clinical trials conducted mainly in low- and middle-income countries. We included ART naïve participants living with HIV who started TDF-containing ART regimens in the trials. Participants had to have estimated creatinine clearance (eCrCl) equal to or greater than 60ml/min before starting ART. The primary outcome was the first instance of discontinuing TDF because of renal adverse events attributed to tenofovir renal toxicity during the first 48 weeks after starting ART. We evaluated the cumulative incidence of discontinuing TDF and associated risk factors using Fine and Gray competing risk regression models with a backward elimination variable selection strategy. There were 2802 ART-naïve participants who started TDF-containing ART from the four clinical trials were included in the analysis. Fifty-eight percent were female, the median age was 34 years, and 87% had CD4 cell counts less than 200 cells/μl. Sixty-four participants (2.4%, 95% CI 1.7%-2.8%) discontinued TDF due to renal adverse events. Among the 64 participants, the median time to discontinue TDF was 9.4 weeks (IQR: 3.4-20.7 weeks). From multivariable Fine and Gray regression models, risk factors for discontinuing TDF were older age, CD4 cell count <200 cells/μl, presence and severity of anemia, and eCrCl <90 ml/min. The risk of discontinuing TDF because of renal adverse events was low in participants initiating TDF-containing ART with advanced HIV and normal renal function, attesting to the tolerability of TDF in ART in low- and middle-income countries.

Association of long-term aspirin use with kidney disease progression.

Chronic microinflammation contributes to the progression of chronic kidney disease (CKD). Aspirin (ASA) has been used to treat inflammation for centuries. The effects of long-term low-dose ASA on CKD progression are unclear. We examined the association of long-term use of newly initiated low-dose ASA (50-200 mg/day) with all-cause mortality using Cox proportional hazard models; with cardiovascular/cerebrovascular (CV) mortality and with end stage kidney disease (ESKD) using Fine and Gray competing risk regression models; with progression of CKD defined as patients' eGFR slopes steeper than -5 mL/min/1.73m2/year using logistic regression models in a nationwide cohort of US Veterans with incident CKD. Among 831,963 patients, we identified 385,457 who either initiated ASA (N = 21,228) within 1 year of CKD diagnosis or never received ASA (N = 364,229). We used propensity score matching to account for differences in key characteristics, yielding 29,480 patients (14,740 in each group). In the matched cohort, over a 4.9-year median follow-up period, 11,846 (40.2%) patients (6,017 vs. 5,829 ASA users vs. non-users) died with 25.8% CV deaths, and 934 (3.2%) patients (476 vs. 458) reached ESKD. ASA users had a higher risk of faster decline of kidney functions, i.e., steeper slopes (OR 1.30 [95%CI: 1.18, 1.44], p < 0.01), but did not have apparent benefits on mortality (HR 0.97 [95%CI: 0.94, 1.01], p = 0.17), CV mortality (Sub-Hazard Ratio [SHR]1.06 [95%CI: 0.99-1.14], p = 0.11), or ESKD (SHR1.00 [95%CI: 0.88, 1.13], p = 0.95). Chronic low-dose ASA use was associated with faster kidney function deterioration, and no association was observed with mortality or risk of ESKD.

Retrospective Study of Allogeneic Hematopoietic Stem Cell Transplantation for Relapse or Refractory Peripheral T-Cell Lymphoma at Toranomon Hospital and Toranomon Hospital Kajigaya

[Background] Relapsed or refractory peripheral T-cell lymphoma (R/R PTCL) is known to have a poor prognosis. Although new medications have been introduced in recent years, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment for R/R PTCL. We review the results of allo-HSCT for PTCL at our institution. [Methods] We performed a retrospective analysis of R/R PTCL patients who underwent first allo-HSCT at our hospital from February 2011 and April 2023. The primary endpoint was OS, which was defined as the time from allo-HSCT to death from any cause or the last follow-up. The secondary endpoints included progression-free survival (PFS), relapse/progression incidence (RI) and non- relapse mortality (NRM). PFS was defined as the time from allo-HSCT to relapse/progression, death, or the last follow-up. OS and PFS were estimated by the Kaplan-Meier method and multivariate Cox proportional hazard models. The cumulative incidence of relapse and NRM were investigated with a competing risk analysis using Gray's test and multivariable Fine and Gray competing risk regression. [Results] During the study period, a total of 44 patients received first allo-HSCT for PTCL (ALK positive ALCL: 2, ALK negative ALCL: 2, AITL: 10, PTCL-NOS: 21, CTCL: 7, HSTL: 2). The median follow-up months of survivors was 51.6 (range, 2.6-141.6). The median age of patients at transplantation was 50 years (range, 17-70). Clinical stage I/II at diagnosis was 10 cases, and clinical stage III/IV was 34 cases. Prognostic Index for PTCL(PIT) was score 1 in 20 cases, score 2 in 20 cases and score 3 in 3 cases. Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) ≧ 2 was 21 cases. Performance Status (PS) 0-1 was 32 cases and PS 2-4 was 12 cases. Primary induction failure (PIF) was 28 cases and relapse after first remission (REL) was 16 cases, including 5 cases of relapse after autologous stem cell transplantation. Median number of chemotherapy regimens received before allo-HSCT was 3 (range, 1-8). Clinical stage at transplantation was CR/PR in 23 patients and SD/PD in 21 patients.The majority, thirty-two had received unrelated cord blood transplantation (CBT), six did unrelated bone marrow transplantation (uBMT), and 6 did related peripheral blood stem cell transplantation (rPBSCT). Thirty-two patients received myeloablative conditioning (MAC), eighteen of which included total body irradiation (TBI) and 15 of which included busulfan (BU). Twelve patients received reduced-intensity conditioning (RIC) . Regarding the primary endpoint, the 4-year OS after allo-HSCT was 53.3%. The 4-year PFS, RI and NRM were 50.4%, 20.7% and 28.8%, respectively. The 4-year OS of CBT, uBMT and rPBSCT patients was 55.2%, 66.7% and 33.3%, respectively. The 4-year OS of REL and PIF patients was 79.1% and 39.5%, respectively (p&amp;lt;0.01). The 4-year OS of MAC and RIC was 49.5% and 64.3%, respectively (p=0.58). The 4-year OS of patients with TBI was superior to patients without TBI (71.1% vs 40.3%, p=0.05). The 4-year OS of CR/PR patients at transplant was superior to SD/PD patients (67.1% vs. 42.9%, p=0.05). In the univariate analysis, PS 0-1, HCT-CI 0-1, REL, CR/PR patients at transplant, patients with TBI and patients without BU were favorable prognostic factors. In the multivariable analysis, REL was associated with better OS (p=0.01, HR 0.16; 95% CI: 0.04-0.65). Except for 3 patients who died from transplant complications before engraftment, 41 patients achieved neutrophil engraftment, with a median engraftment date of 19 days (range, 11-31 days) after transplantation. Twenty-seven patients had acute GVHD (Grade I: 3, Grade II: 13, Grade III: 8, Grade IV: 3), and 11 patients had chronic GVHD. Eleven patients relapsed after transplant, and the median time from transplant to relapse was 26.3 months (range, 0.6-87.1 months). Three patients survived at the last follow up, and the median follow-up time of survivors from relapse was 430 days (range, 12-1301). [Conclusion] Our data indicated good results of allo-HSCT for R/R PTCL, and significantly better in relapse after first remission patients.

Comparison of Myeloablative Conditioning with Cyclophosphamide and Total-Body Irradiation (Cy/TBI) Vs. Fludarabine, Melphalan, and Total-Body Irradiation (Flu/Mel/TBI) in Patients Undergoing Allogeneic Stem Cell Transplant for AML/ALL

Background: Cyclophosphamide combined with total-body irradiation (Cy/TBI) has been widely used worldwide as the standard myeloablative conditioning (MAC) for allogeneic stem cell transplantation (allo-HCT), but there are concerns about the antitumor effects of CY, as well as side effects, including cardiotoxicity and mucosal toxicity. A few studies suggest that the addition of an anticancer agent to a Cy/TBI regimen may reduce recurrence rates, but comparative studies of Cy/TBI regimens versus other TBI regimens are scarce. Furthermore, the recent expansion of post-transplant cyclophosphamide as graft-versus-host disease (GVHD) prophylaxis has increased its utility for cyclophosphamide-free conditioning regimens. Our institution has extensive experience with cord blood transplantation for relatively elderly patients with high-risk leukemia and has worked to develop safer and more effective MAC regimens other than Cy/TBI. The purpose of this study is to examine the safety and efficacy of fludarabine and melphalan combined with total-body irradiation (Flu/Mel/TBI) regimen, which is widely used at our institution, compared to Cy/TBI. Methods: We retrospectively analyzed adult acute leukemia patients who underwent allo-HCT between August 1994 to February 2023 at Toranomon Hospital. The inclusion criteria were as follows: a diagnosis of acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL), the first allo-HCT, and Cy (120mg/kg) /TBI (8-12Gy) or Flu (180mg/m 2) /Mel (80-120mg/m 2) /TBI (8-12Gy) as MAC regimen. We excluded patients who underwent haploidentical transplantation with post-transplant cyclophosphamide. The primary endpoint was the 5-year cumulative incidence of relapse, and the secondary endpoints were the 5-year cumulative incidence of non-relapse mortality (NRM), 5-year overall survival (OS), and relapse-free survival (RFS). OS and RFS were estimated by the Kaplan-Meier method and multivariate Cox proportional hazard models. The cumulative incidence of relapse and NRM were investigated with a competing risk analysis using Gray's test and multivariable Fine and Gray competing risk regression. Results: A total of 198 patients were included in this study, comprising 101 patients treated with Cy/TBI and 97 treated with Flu/Mel/TBI. Patients who received Flu/Mel/TBI were of higher age (Median age: Cy/TBI 36 years vs. Flu/Mel/TBI 53 years, p&amp;lt;0.01), higher ECOG PS score (PS≥1: 51.5% vs. 66.0%, p=0.044), fewer AML (49.5% vs. 22.7%, p&amp;lt;0.01), and more frequent CBT (45.5% vs. 76.3%, p&amp;lt;0.01). Disease status at HCT (CR1: 53.5% vs. 43.3%, p=0.154) and HCT-CI scores (HCT-CI≥1: 35.6% vs. 44.3%, p=0.214) were not different between the two regimen groups. Regarding the primary endpoint, the 5-year cumulative incidence of relapse was significantly lower in Flu/Mel/TBI group (36.8% vs. 24.9%, p= 0.035). The cumulative incidence of NRM was not significantly different between the two groups (19.1% vs. 25.2%, p=0.345). In the multivariate analysis, conditioning with Flu/Mel/TBI was significantly associated only with a lower risk of relapse (HR: 2.817; 95%CI: 1.183-6.712; p=0.019). Regarding NRM, only disease status not in CR1 was associated with a higher risk (CR1 vs. non-CR1 HR: 2.21; 95%CI: 1.095-4.468; p=0.027). There was no significant difference in 5-year OS (Cy/TBI 48.1% vs. Flu/Mel/TBI 51.4%, p=0.604) and RFS (44.2% vs. 49.9%, p=0.24). Conclusion: Despite older age and worse PS in the Flu/Mel/TBI group, Flu/Mel/TBI had a significantly lower 5-year cumulative relapse rate than Cy/TBI, with no significant difference in NRM. Our results suggest that Flu/Mel/TBI is a reasonable alternative to CY/TBI and may be a superior TBI-containing MAC regimen.

Heart Disease Mortality in Cancer Survivors: A Population-Based Study in Japan.

Data on the risk of cardiovascular-related mortality in patients with cancer are limited. This retrospective cohort study used data from the Osaka Cancer Registry and vital statistics in Japan between 1985 and 2013. The causes of death were investigated, and the risk of fatal heart disease was analyzed. Standardized mortality ratios were calculated to compare the risk of fatal heart disease between patients with cancer and the general population. Fine and Gray competing risk regression models were used to assess the risk of fatal heart disease among patients with cancer. In total, 682 886 patients with cancer were included in the analysis, and 335 635 patients died during the study period. Heart disease was the leading cause of noncancer deaths, with 10 686 deaths. Among the patients who died of heart disease, 5017 had ischemic heart disease, 3598 had heart failure, 356 had hypertensive disease, and 1715 had other heart diseases. The standardized mortality ratio for heart disease was 2.80 (95% CI, 2.74-2.85). The standardized mortality ratio for ischemic heart disease, heart failure, and hypertensive disease were 3.26 (95% CI, 3.17-3.35), 2.69 (95% CI, 2.60-2.78), and 5.97 (95% CI, 5.38-6.63), respectively. The risk of fatal heart disease increased over time after cancer diagnosis. Men were more likely to die of heart disease than women (subdistribution hazard ratio, 1.08 [95% CI, 1.02-1.16]). The risk of fatal heart disease among cancer survivors has decreased in recent years. Cancer survivors have a higher risk of fatal heart disease than the general population.

Impact of pharmacological treatment for heart failure after myocardial recovery in arrhythmia-induced cardiomyopathy

Abstract Introduction There is scarce evidence regarding the optimal medical treatment of patients with heart failure and recovered LVEF. To date, no study has analyzed the efficacy of maintaining neurohormonal blockade in patients with arrhythmia-induced cardiomyopathy (AiCM) after LVEF normalization. Purpose The aim of this study is to analyze impact of pharmacological treatment for heart failure in preventing heart failure relapse after myocardial recovery in AiCM. Methods We analyze data from a single-center cohort of 200 patients admitted for heart failure and ventricular dysfunction initially attributed to AiCM between 2008 and 2020. Myocardial recovery was defined as an improvement in LVEF up to &amp;gt; = 50% (complete recovery) or an increase of &amp;gt; = 10% up to a value of LVEF &amp;gt;= 40% (partial recovery). Heart failure relapse was defined as a decrease in LVEF to &amp;lt;50% in those with previous complete recovery or a decrease of &amp;gt; = 10% in patients with partial recovery, unplanned Emergency Department (ED) visit or hospital admission for heart failure. As drug prescriptions are not constant over follow up, changes in medication have been recorded and time varying covariates were used for statistical analysis. A Fine and Gray competing-risk multivariate regression was performed, adjusting for initial LVEF at admission, degree of myocardial recovery (complete or partial), presence of underlying cardiomyopathy and age, considering death as competing risk. Results Over a median of 6.14 years, most of the patients had a complete myocardial recovery (n = 164; 82.0%). 24 patients (12%) had partial recovery and 12 patients (6.0%) did not show significant improvement in ventricular function. At the moment of myocardial recovery, ACEI/ARB/ARNI were prescribed in 160 patients (85.11%); beta-blockers in 170 (90.43%); ARB in 112 (59.57%); iSGLT2 in 8 (4.26%); antiarrhythmic drugs in 75 (39.89%) and Digoxin in 40 (21.28). From 188 patients with initial LVEF recovery, 64 (34.04%) had a relapse of systolic dysfunction. 65 patients (34.57%) required unplanned Emergency Department (ED) visits and 40 patients (21.28%) needed hospital admission for heart failure. Maintenance of ACEI/ARB/ARNI and beta-blockers after myocardial recovery was associated with a significant lower risk of HF relapse [sHR 0.43 (95% CI 0.26 - 0.73), p 0.002 for ACEI/ARB/ARNI]; [sHR 0.52 (95% CI 0.29 - 0.92), p 0.025 for beta-blockers]. ARM was associated with a non-significant lower risk of HF relapse [sHR 0.67 (95% CI 0.42 - 1.09), p 0.093]. Treatment with antiarrhythmic drugs [sHR 0.90 (95% CI 0.54 - 1.51), p 0.696] and Digoxin [sHR 0.90 (95% CI 0.54 - 1.51), p 0.696] did not show benefit in this study. Conclusions Maintenance of ACEI/ARB/ARNI and beta-blockers after myocardial recovery was associated with a significant lower risk of HF relapse after myocardial recovery in patients with AiCM.Risk of HF relapse - ACEI ARB ARNIRisk of HF relapse - BetaBlockers