Search Results (37)

Chronic diseases, particularly those with progressive neurological impairment, present a significant challenge in healthcare due to their impact on millions globally and the limited availability of effective therapies. Addressing this challenge requires innovative approaches, such as leveraging individuals’ genetic features for early intervention and treatment strategies. Due to the irregular intervals of patient visits, clinical data typically appear as censored, necessitating advanced analytical methods. Thus, this study introduces GTsurvival, a novel network architecture that combines graph convolutional networks (GCN) with a neural decision tree, providing promising advancements in disease prediction. GTsurvival utilizes restricted mean survival time (RMST) as pseudo-observations and directly connects them with baseline variables. Through the joint simulation of RMST, GTsurvival can effectively utilize shared information and enhance its predictive ability for patients’ future survival status. Firstly, GTsurvival is introduced to handle complex censored data, emphasizing the crucial role of graphs utilized in GCNs for processing related information among samples. Secondly, the neural decision tree within GTsurvival enhances decision-making by mitigating uncertainty at split nodes, effectively minimizing the global loss function and optimizing survival analysis in high-dimensional datasets. Thirdly, evaluations on simulated datasets and a real-world neurodegenerative disease cohort verify that the proposed GTsurvival method surpasses existing approaches. This superiority is partly attributed to the inclusion of a generalized score test during feature selection, which helps capture variants associated with disease progression. Full article

Background/Objectives: The purpose of this study is to assess whether the addition of an oxymetazoline (OXY) hemostatic solution, which can be used to manage pulpal bleeding, maintains higher MTA survivability than pulpotomies treated with FS. Methods: In this retrospective cross-sectional study, patient data (n = 75) were used to assess radiographic and clinical signs and symptoms of pathosis in primary molars treated with a pulpotomy and a stainless-steel crown. Pulpotomies treated with FS (Group 1) were compared to those treated with MTA with OXY-induced hemostasis (Group 2). Restricted mean survival times (RMSTs) were calculated for the two groups, and Cox proportional hazards regression was used to analyze the effects of patient and practice level covariates on radiographic and clinical pathosis. Results: Cox proportional-hazard regression identified three potential covariates (age, pulpotomy groups, and procedure location) that predicted radiographic pathosis. The adjusted hazard ratio for Group 2 was 0.30 (95% CI: 0.11–0.82), indicating improved radiographic outcomes compared with Group 1 (p = 0.02). The 36-month RMST for Group 2 was 30.1 months (95% CI: 26.5–33.7) compared to 24.7 months (21.6–27.8) for Group 1 (p = 0.025). Conclusions: A pulpotomy utilizing OXY hemostasis prior to MTA placement led to a higher chance of pulpotomy survival than FS. Full article

Background/Objectives: This study explored the epidemiology of Status Epilepticus (SE) in Kazakhstan. Methods: Utilizing data from the National Health System from 2014 to 2023, we investigated the age-standardized incidence rate (ASIR) of SE. The authors employed restricted mean survival time (RMST) models to evaluate how sex, older age, epilepsy, history of cerebrovascular diseases (CVD), central nervous system (CNS) infections, brain tumors, and cancer affected survival during 30 days through the fifth year following hospital admission for SE. Results: This study included 14,010 patients. The ASIR per 100,000 increased threefold, from 4.15 (95% CI: 3.85; 4.46) in 2014 to 12.12 (95% CI: 11.64; 17.59) in 2023, with a sharp increase during the COVID-19 pandemic. The 30-day and 5-year mortality were 2.10% and 8.85%, respectively. The RMST identified that all-cause mortality was driven by elderly age, brain tumors, and cancer, where the difference in survival increased from one day at baseline to over a year by the fifth year. The effects of CVD, CNS infections, and sex on survival were substantially lower. However, epilepsy was associated with a better prognosis. Conclusions: We observed an incremental increase in the SE incidence over a decade. Our findings warrant actions to resolve issues related to rescue medicines to improve SE outcomes in both country and region. It may be a priority for elderly patients and those with systemic tumors. Further research is needed to understand the role of epilepsy in SE epidemiology, with emphasis on design-related biases. Full article

Background/Objectives: Acute Kidney Injury (AKI) requiring continuous renal replacement therapy (CRRT) has historically been a contraindication for left ventricular assist device (LVAD) implantation. However, advancements in magnetically levitated (MagLev) LVADs warrant reevaluation. Methods: A retrospective review of adult LVAD recipients at a tertiary center (2009–2024) was performed. Patients were stratified by preoperative CRRT status and LVAD type. Baseline characteristics and perioperative morbidity, Kaplan–Meier survival estimates, restrictive mean survival time (RMST), and Cox proportional hazards models were assessed. Results: Among 312 MagLev LVAD recipients, 22 (7.1%) required preoperative CRRT. Compared to non-CRRT patients, the CRRT group had higher illness severity (INTERMACS 1 or 2: 95% vs. 71%, p = 0.019). Despite this, preoperative CRRT was not associated with worse mortality within the MagLev cohort at 30 days (9.1% vs. 7.9%), 1 year (18.2% vs. 17.9%), or 2 years (31.8% vs. 20.7%; p = 0.31). RMST at 1 year was also similar (305 vs. 311 days; p = 0.85). In contrast, patients on CRRT receiving non-MagLev devices had significantly worse outcomes, with 30-day, 1-year, and 2-year mortality rates of 57.1%, 71.4%, and 78.6%, respectively. RMST analysis showed a 170-day survival advantage at 1 year for MagLev vs. non-MagLev CRRT patients (p < 0.01). Conclusions: In this single-center cohort, preoperative CRRT was not associated with higher mortality among MagLev LVAD recipients and may challenge traditional contraindications against LVAD therapy. Further investigations using larger cohorts are necessary to further evaluate these findings and delineate patient subgroups that may derive the greatest clinical benefit. Full article

Background: Cardiovascular disease (CVD) is a common cause of death among colorectal cancer (CRC) patients. We examined whether neighborhood disadvantage is associated with CVD mortality in CRC patients. Methods: Data were obtained from the Surveillance, Epidemiology, and End Results (SEER) program for primary CRC patients diagnosed between 2006 and 2017. Neighborhood disadvantage was measured using the quintiles of the Yost Index, a socioeconomic composite measure. Cause-specific mortality (CVD-specific and CRC-specific mortality) was evaluated using a competing risk cause-specific hazard model, controlling for demographic and clinical covariates. Cumulative incidence function (CIF) and restricted mean survival time (RMST) analyses were performed to provide complementary estimates of absolute risk and survival differences. Results: The study included 316,549 patients with CRC. Cancer-specific mortality was the leading cause of death (62.1%), while CVD accounted for 9.6% of deaths. Multivariable competing risk Cox regression showed that the lowest-SES neighborhoods (Group 1) had a higher CVD-specific mortality (HR, 1.39; 95% CI, 1.30–1.48; p < 0.001) compared to the highest-SES neighborhoods (Group 5). RMST and CIF analyses revealed a similar dose–response pattern, with progressively higher CVD mortality associated with increasing levels of neighborhood disadvantage. Effect modification analyses indicated stronger associations in older patients and men, but no modifications by race. Conclusions: Among CRC patients, residing in disadvantaged neighborhoods was independently associated with higher CVD mortality, suggesting the importance of addressing cardiovascular risk in disadvantaged populations. Full article

Background: Poly (ADP-ribose) polymerase inhibitors (PARPi) are the standard of care for first-line maintenance in advanced ovarian cancer, but their benefit varies by BRCA and homologous recombination deficiency (HRD) status, and no head-to-head comparisons are available. Methods: We conducted an indirect comparison of PARPi regimens using reconstructed individual patient data (IPD) from Kaplan–Meier curves of phase III randomized trials (SOLO1, PRIMA, PAOLA1, ATHENA, FLAMES). Progression-free survival (PFS) was the primary endpoint; overall survival (OS) was exploratory. Subgroups were defined as BRCA−mutated (BRCA+), BRCA−/HRD+, and BRCA−/HRD−. Safety outcomes were assessed through a network meta-analysis of adverse drug reactions (ADRs). Results: In BRCA+ patients, olaparib + bevacizumab achieved the largest PFS improvement (HR = 0.27; 95%CI: 0.19–0.39), followed by olaparib monotherapy, while niraparib performed significantly worse. In BRCA−/HRD+, olaparib + bevacizumab was superior to niraparib and rucaparib, with restricted mean survival time (RMST) gains of 3–4 months. In BRCA−/HRD−, PARPi produced only a modest benefit, with no advantage over bevacizumab monotherapy. Exploratory OS analysis confirmed long-term survival with olaparib in BRCA+ but not in the other subgroups. Safety analysis indicated olaparib had the most favorable hematological profile, while niraparib was associated with the highest rates of severe anemia, thrombocytopenia, and neutropenia, despite showing lower gastrointestinal toxicity and fatigue incidence. Conclusions: PARPi efficacy depends strongly on BRCA and HRD status. Olaparib-based regimens provide the greatest clinical benefit with acceptable safety in BRCA+ and HRD+ disease, whereas PARPi appear to be of limited value in HRD-negative ovarian cancer. Full article

Background: Multiple primary malignant tumors (MPMTs) involving the digestive tract pose diagnostic and therapeutic challenges, with survival differences between synchronous and metachronous forms not well defined. This study assessed predictors of overall survival (OS) in patients in whom at least one tumor originated in the digestive tract or accessory organs. Methods: We retrospectively reviewed 1920 oncology cases (January 2020–June 2023) from St. Nicholas Hospital, Romania. Of 118 patients with MPMTs, 45 had ≥1 digestive tract tumor. They were classified as synchronous (<2 months) or metachronous (>2 months) as per the SEER rules. Clinical, pathological, treatment, and follow-up data were analyzed; OS was evaluated using Kaplan–Meier and Cox regression. Results: Fifteen patients (33%) had synchronous tumors and 30 (67%) had metachronous tumors. Overall, 17 of 45 patients (37.8%) died by the last follow-up. The restricted mean survival time (RMST) was 31.3 months for those with synchronous vs. 68.3 months for those with metachronous tumors (HR = 2.49, 95% CI 0.95–6.50, p = 0.062; log-rank p = 0.053). Curative treatment of the first tumor was associated with markedly improved survival (RMST 58.2 vs. 29.4 months; HR = 20.5, 95% CI 3.68–114, p < 0.001). In the multivariable Cox regression analysis, advanced primary nodal stage (N2–N3) remained independently associated with reduced survival (adjusted HR 3.86, 95% CI 1.04–14.3, p = 0.044). The adjusted effect of synchronous vs. metachronous classification was attenuated (adjusted HR 2.22, 95% CI 0.84–5.86, p = 0.10). Conclusions: In this single-center, hypothesis-generating cohort, synchronous digestive-tract MPMTs were associated with shorter unadjusted survival than metachronous tumors, but advanced nodal stage and limited feasibility of curative therapy were the dominant independent predictors of poor outcome. Given the small sample size and retrospective design, these findings should be interpreted as preliminary and warrant validation in larger, multicenter cohorts. Full article

Background/Objectives: Results from a well-designed trial provide evidence to support approval of truly effective treatments or discontinuation of ineffective treatments. However, the information available at the time of trial design may be limited which may lead to underpowered trials. This work aims to evaluate the impact of design assumption misspecifications on the statistical power of randomized trials with survival outcomes. Methods: The impact of the design assumption misspecifications on statistical power of four different statistical methods was investigated in a simulation study. The methods include the log-rank test, MaxCombo test, the test of difference in survival probability, and test of difference in restricted mean survival time (RMST). The deviations considered include the survival rate in the control arm, the expected treatment effect in terms of magnitude and pattern, accrual rate, and drop-out rate. Results: Deviations in the control arm’s survival distribution have no impact on the power of the log-rank and MaxCombo tests but it affects the trial duration since trials designed with these tests require the total number of events to be met before the final analysis can be conducted. Misspecified treatment effect has similar effect on the statistical power of all four methods. When the proportional hazards assumption is misspecified, the RMST is more robust with a larger early treatment effect, while the survival probability and the MaxCombo tests are more robust with a larger late treatment effect and crossing hazards. Conclusions: Selecting the appropriate statistical tests to design a trial depends on the goal of the trial, the mechanism of action of the experimental treatment, the survival quantity of clinical interest, and the pattern of the expected treatment effect. The final design should be based on assumptions that are as accurate as possible, and the potential impacts of deviations from these assumptions on the trial’s statistical power should be carefully considered. Full article

Objectives: Chronic Hepatitis B virus (HBV) infection is a significant global health issue, with dialysis patients at increased risk and reduced response to HBV vaccination. The effects of HBV serological status on kidney transplant outcomes, particularly for patients with resolved or inactive HBV infection, needs more data, especially from current era. This study evaluated the impact of chronic and non-active HBV infection on patient and graft survival after kidney transplantation. Methods: Retrospective analysis was conducted of kidney-only transplant recipients at our center from 1 January 1990 to 31 August 2019 (end of observation). Patients were grouped by their HBV serostatus before transplantation into three categories: HBV negative (HBsAg−/Anti-Hbc−), non-active HBV infection (HbsAg−/Anti-Hbc+) and chronic HBV infection (HbsAg+/Anti-Hbc+). Primary outcomes included patient survival, graft survival, and overall graft and patient survival, analyzed using Kaplan–Meier (KM) curves, log-rank tests, Restricted mean survival times (RMST), and Accelerated failure time (AFT) models. Results: Among 2490 patients, 2197 were HBV negative, 218 had non-active HBV, and 75 had chronic HBV. Over a mean follow-up of 8.1 years, mortality and graft failure rates were highest in chronic HBV patients (49% and 37%), followed by non-active HBV (39% and 29%) and HBV-negative patients (30% and 20%). KM analysis revealed significantly lower overall survival rates for chronic HBV and non-active HBV groups compared to HBV-negative patients (p = 0.006). RMST confirmed significant reductions in survival for the non-active group (12.57 vs. 14.17 years, p = 0.007). Cox regression and AFT models identified older recipient/donor age, Hepatitis-C-virus coinfection, and broad antigen mismatches as negative predictors, while living donors improved outcomes. Conclusions: While unadjusted Kaplan–Meier curves and RMST analysis suggested differences in patient and graft survival, further thorough multivariable AFT analysis did not show a significant association between non-active or chronic HBV infection and patient or graft survival after kidney transplantation. Full article

Background/Objectives: Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality globally, especially in limited-resource countries (LRCs) where access to advanced treatments such as targeted therapy and immunotherapy is constrained. Platinum-based chemotherapy remains a cornerstone of first-line therapy. This study aims to identify prognostic factors influencing survival outcomes and evaluate treatment response to chemotherapy in advanced NSCLC patients in LRCs. Methods: A retrospective cohort study was conducted on 200 advanced NSCLC patients treated with first-line platinum-based doublet chemotherapy at Surin Hospital Cancer Center, Thailand. Prognostic factors were assessed through univariate and multivariate Cox regression analyses. Additionally, restricted mean survival time (RMST) was calculated to compare survival outcomes between responders and non-responders. Results: Independent prognostic factors associated with improved survival included good performance status, ECOG 0–1 (HR 0.50, p = 0.012), serum albumin ≥ 3.5 mg/dL (HR 0.60, p = 0.010), and favorable response to chemotherapy (HR 0.57, p = 0.003). Responders demonstrated significantly longer RMST at 12 months (p < 0.001), 24 months (p < 0.001), and 36 months (p = 0.004) compared to non-responders. Conclusions: Identifying prognostic factors and treatment responses is important for improving outcomes in advanced NSCLC patients, particularly in limited-resource settings where access to novel therapies is restricted. Full article

Background: The KRAS G12C mutation, prevalent in various malignancies, including non-small cell lung cancer (NSCLC), represents a unique therapeutic target. Adagrasib and sotorasib, two FDA-approved agents specifically targeting this mutation, have shown promise in clinical trials. This study aims to compare their efficacy in treating KRAS G12C-mutated NSCLC, drawing insights from pivotal clinical trials. Methods: We analyzed data from three key clinical trials: KRYSTAL-1, CodeBreak100, and CodeBreak200. Our methodology involved reconstructing individual patient data from published Kaplan–Meier curves using the IPDfromKM tool (Version 0.1.10). The primary endpoints were progression-free survival (PFS) and overall survival (OS), evaluated through hazard ratios (HRs) and the restricted mean survival time (RMST) method. Results: The HR for PFS favored adagrasib (HR: 0.90 [95% CI: 0.69, 1.19], p = 0.473), suggesting a non-significant trend toward better disease control compared to sotorasib. For OS, the HR was 0.99 [95% CI: 0.75, 1.33] (p = 0.969), indicating no significant difference between the two drugs. RMST analysis supported these findings, with adagrasib showing a consistently higher RMST in PFS at 6, 12, and 18 months. However, OS benefits converged over time, with adagrasib marginally surpassing sotorasib by the 18-month mark. Conclusions: This comprehensive analysis reveals that while adagrasib may offer a slight advantage in PFS, both drugs demonstrate comparable efficacy in OS for KRAS G12C-mutated NSCLC. The subtle differences observed, particularly in PFS, could inform clinical decision-making, emphasizing the need for personalized treatment strategies. Future research should focus on long-term effects and identifying patient subgroups that may benefit more from one drug over the other. Full article

Background: This retrospective study investigates the impact of various treatment strategies on progression-free survival (PFS) in patients with metastatic colorectal cancer (mCRC), a significant global health issue. Methods: We employed the restricted mean survival time (RMST) to evaluate how different treatments affect PFS over a defined period. The study included 225 patients with mCRC who were treated between 2015 and 2023 at the Oncology Department of Colțea Clinical Hospital in Bucharest. To assign KRAS status, mutation data from exons 2, 3, and 4 of the KRAS gene were required. Eligibility criteria included a confirmed histopathological diagnosis of colorectal adenocarcinoma, a valid RAS mutation test from a solid biopsy, radiological confirmation of stage IV disease by computed tomography, and at least one line of systemic treatment in the metastatic setting. Results: Our analysis revealed a small difference in PFS based on KRAS status, but this difference was not statistically significant. Neither sex nor the urban versus rural environment impacted PFS; however, the data indicated that educational level affected survival outcomes. Conclusions: Consistent with existing literature, our findings showed no survival benefit from locoregional treatments such as surgery of the primary tumor or curative radiotherapy at diagnosis. In contrast, resection of hepatic metastases was associated with improved survival outcomes. Full article

This study investigates novel short-lived long noncoding RNAs (lncRNAs) in mice with altered expression in metabolic dysfunction-associated steatotic liver (MASH) and liver fibrosis. LncRNAs share similarities with mRNAs in their transcription by RNA polymerase II, possession of a 5′ cap structure, and presence of a polyA tail. We identified two lncRNAs, Kcnq1ot1 and Rmst, significantly decreased in both conditions. These lncRNAs showed dramatic expression changes in MASH livers induced by Western diets and CCl₄, and in fibrotic livers induced by CCl₄ alone. The decrease was more pronounced in liver fibrosis, suggesting their potential as biomarkers for disease progression. Our findings are consistent across different fibrosis models, indicating a crucial role for these lncRNAs in MASH and liver fibrosis in mice. With MASH becoming a global health issue and its progression to fibrosis associated with hepatocarcinogenesis and poor prognosis, understanding the underlying mechanisms is critical. This research contributes to elucidating lncRNA functions in murine liver diseases and provides a foundation for developing novel therapeutic strategies targeting lncRNAs in MASH and liver fibrosis, offering new avenues for potential therapeutic interventions. Full article

Background: Neuroendocrine neoplasms (NENs) are increasing in incidence globally. Previous analysis of the UK cancer database (National Cancer Registration and Analysis Service (NCRAS)) showed a notable female survival advantage in most tumour sites. This study aims to compare NCRAS to the Surveillance, Epidemiology, and End Results Program (SEER) to validate these results using the same statistical methods. Methods: A total of 14,834 and 108,399 patients with NENs were extracted from NCRAS and SEER, respectively. Sixty-months survival for both males and females for each anatomical site of NENs were calculated using restricted mean survival time (RMST) and Kaplan–Meier Survival estimates. The sixty-month RMST female survival advantage (FSA) was calculated. Results: FSA was similar in NCRAS and SEER. The highest FSA occurred in lung and stomach NENs. Conclusions: The data from SEER confirm the findings published by NCRAS. Female survival advantage remains unexplained. Full article

Background: For biliary tract cancer (BTC), the addition of immunotherapy (durvalumab or pembrolizumab) to gemcitabine and cisplatin (GemCis) significantly improved overall survival (OS) in phase 3 clinical trials (RCTs). However, the interpretation and magnitude of the treatment effect is challenging because OS Kaplan–Meier curves violate the proportional hazards (PH) assumption. Analysis using restricted mean survival time (RMST) allows quantification of the benefits in the absence of PH. This systematic review and meta-analysis aims to assess the benefit of immunotherapy-based regimens for OS at 24 months using RMST analysis. Methods: A systematic review was conducted using studies published up to 8 November 2023. Only phase 3 RCTs evaluating the use of anti-PD-1/PD-L1 combined with GemCis and reporting OS were included. KM curves for OS were digitized, and the data were reconstructed. A meta-analysis for OS by RMST at 24 months was performed. Results: A total of 1754 participants from the TOPAZ-1 and KEYNOTE-966 trials were included. In TOPAZ-1, RMSTs at 24 months were 13.52 (7.92) and 12.21 (7.22) months with GemCis plus durvalumab and GemCis alone, respectively. In KEYNOTE-966, RMSTs at 24 months were 13.60 (7.76) and 12.45 (7.73) months with GemCis plus pembrolizumab and GemCis alone, respectively. Immunotherapy-based regimens showed a mean OS difference at 24 months by an RMST of 1.21 months [(95% CI: 0.49–1.93), p < 0.001, I² = 0%]. Conclusions: Immunotherapy-based regimens improve OS in advanced BTC. Given this magnitude of benefit, it is essential to weigh up individual patient factors, preferences, and potential risks. RMST analysis provides valuable information to patients and physicians, facilitating decision-making in a value-based medical environment. Full article