Survival Of Patients Research Articles

#2677 A propensity score-matched analysis of kidney replacement therapy outcomes for older adults stratified by frailty severity

Abstract Background and Aims Older people living with frailty who receive kidney replacement therapy (KRT) experience higher mortality and hospital readmission compared to their non-frail counterparts [1–3]. Shared decision making with older people regarding the optimal KRT modality (haemodialysis [HD], peritoneal dialysis [PD], or kidney transplant [TX]) can present challenges due to the lack of research comparing KRT modalities stratified by frailty severity. The Hospital Frailty Risk Score (HFRS), which uses routinely collected clinical data to categorise frailty severity, has been shown to predict outcomes in advanced chronic kidney disease (CKD) [4]. However, the HFRS has not been used to compare outcomes across KRT modalities. This single-centre project aims to explore outcomes between KRT modalities for older people stratified by HFRS frailty severity. Method Adults aged 60 years or older starting KRT at our institution between December 2012 and January 2022 were included. HFRS was calculated at first estimated glomerular filtration rate (eGFR) result below 15 mL/min/1.73 m2 and at start of KRT. Patients were stratified by KRT modality and their frailty severity (categorized as low, intermediate, or high according to their HFRS score). TX patients were then matched to 1:2 to HD patients and 1:1 to PD patients, based on patient age, HFRS category, and Charlson Comorbidity Index (CCI) at KRT start. Outcomes of interest were hospital readmission and mortality, both overall and within 1 year of KRT initiation. Descriptive statistics compared HD, PD, and TX groups. Results Twenty TX, 20 PD, and 40 HD matched patients were included. Age (HD vs PD vs TX: 68.5 vs 67.6 vs 68.3 years, p = 0.50), proportion of males (57.5% vs 70.0% vs 55.0%, p = 0.66), and CCI (15.0 vs 13.0 vs 13.0, p = 0.95) were similar between cohorts. Frailty, as assessed by the HFRS, worsened or remained the same for most patients in all 3 cohorts between first eGFR < 15 and KRT start (81.0% vs 93.0% vs 83.0%, p = 0.61). All patients were either of low (85.0% vs 80.0% vs 85.0%) or intermediate (15.0% vs 20.0% vs 15.0%) frailty status at time of KRT start and the proportion of patients in each category did not vary with modality (p = 0.92). Re-hospitalization within 1 year of starting KRT was similar between groups (32.5% vs 25.0% vs 10.0%, p = 0.12). Kaplan-Meier survival analyses also demonstrated similar survival among groups at 1 year (75.0% vs 95.0% vs 90.0%, log-rank p = 0.09), but better survival among TX patients overall (0.0% vs 66.1% vs 79.4%, log-rank p = 0.02). Overall and 1 year Kaplan-Meier survival for patients stratified by KRT modality and HFRS are shown in Fig. 1. Conclusion TX may optimize longer term survival for older people with low and intermediate frailty status and kidney failure. Furthermore, the HFRS appears to be a useful prognostic tool that could inform shared decision making with older patients regarding KRT modality choice.

#1809 Twice against thrice-weekly hemodialysis: the TATH trial

Abstract Background and Aims Frequency of hemodialysis is still a debatable topic. Incremental hemodialysis has gained popularity and requires a smooth increase in dialysis frequency while maintaining a sufficient residual diuresis. In developing countries and some developed countries, a twice-weekly schedule independent of residual kidney function is still performed, sometimes because of lack of resources and some other times because of patients’ resistance to undergo three sessions per week. This study aimed to compare the survival of patients on twice versus thrice-weekly hemodialysis. Method This is a prospective, multicenter, non-randomized trial, that included incident patients on chronic hemodialysis between January 2018 and August 2021. Patients terminally ill were excluded. Patients were divided into two arms: twice-weekly and thrice-weekly hemodialysis. CASTOR eCRF (electronic case report form) was used for data capture. Demographics, comorbidities, laboratory tests, medications, residual diuresis and dialysis prescription were collected from the patients' medical records at dialysis initiation. Patients were followed at 1 month, 3 months, 6 months, one year and two years for their mortality, hospitalisations for pulmonary edema or hyperkalemia, uncontrolled severe hypertension and erythropoietin (EPO) dose requirement. This trial was terminated before reaching the required sample size of 800 because of the pandemic and economic crisis in the country. Missing baseline factors and covariates were imputed using multiple imputation algorithms, then entered in a logistic regression model to estimate propensity scores. A survival analysis with a cox-regression model including propensity score as a covariate assessed the difference between twice-weekly and thrice-weekly dialysis. This trial was registered on Clinicaltrials.gov ID NCT03415776. Results A total of 203 consecutive patients of 10 dialysis units were included, 133 in the thrice-weekly arm and 70 in the twice-weekly. Mean age was 67 ± 15 years, 54.2% were males, 55.5% had diabetes, 53.7% had coronary artery disease. Median eGFR at dialysis initiation was 6 (4, 8) mL/min/1.73 m2. Baseline median 24-hour diuresis was 500 (500, 1000) mL with higher diuresis in patients on twice-weekly (P = 0.051). Baseline mean hemoglobin was 9.6 ± 1.6 g/dL. 41.7% were initiated with AV fistula with more patients in the thrice-weekly initiated with temporary catheter. Median number of dialysis hours per week was 12 (10, 12) and 8 (8, 9) in thrice- and twice-weekly respectively. High-flux membranes with ultrapure dialysate were used in 55% of thrice-weekly and 74.3% of twice-weekly. Mean blood flow was 329 ± 76 mL/min. In univariate analysis, residual diuresis was significantly higher in twice-weekly at 1 month, 3 months (P = .002), 6 months (it dropped at 6 months to a median of 100 (0, 500) in thrice-weekly versus 225 (175, 875) in twice-weekly) and at one year (P = .015). Inter-dialytic weight gain and blood pressure levels were not statistically different at 1, 3, 6 months and one year. 22.5% of patients on thrice-weekly did not need antihypertensive medications at 6 months versus 12.1% in the twice-weekly. Serum potassium was significantly higher in twice-weekly at 3 months and at one year. Cumulative dose of EPO administered during 2 years was significantly higher in twice-weekly with a median of 720000 UI versus 500000 UI in thrice-weekly (P = .001) without a difference in hemoglobin but lower ferritin in twice-weekly (P = .005). There was no difference in hospitalisations' rates between the two arms. A cox regression model including propensity scores as a covariate did not show any survival difference between the two arms (Fig. 1). Conclusion Patients on twice-weekly hemodialysis had a similar survival and hospitalisations' rates at two years as patients on thrice-weekly hemodialysis. However, a twice-weekly schedule was accompanied with higher EPO dose requirements, higher serum potassium levels, more antihypertensive therapy despite more preserved residual diuresis.

#1098 Utilizing a novel individual patient performance score for mortality prediction in hemodialysis patients

Abstract Background and Aims Chronic kidney disease (CKD) management has advanced significantly over recent years, yet mortality rates among hemodialysis (HD) patients remain high. This study aims to assess the impact of changes in an individualized patient performance score (IPPS) on survival in a large cohort of HD patients. Method This multicentre, observational, prospective cohort study included HD patients across 19 countries, starting from January 1st, 2022. We followed these patients for one year, categorizing them based on their survival status at year's end. We calculated the mean IPPS monthly, from June to December 2021, and divided the patients into tertiles based on their December 2021 scores. Subsequently, we formed five groups based on their IPPS dynamics over six months. We used Kaplan-Meier and Cox regression analyses to evaluate survival, presenting the results as hazard ratios (HR) and 95% confidence intervals (95% CI). A p-value below 0.05 was considered statistically significant. The IPPS, ranging from 0 to 100, was calculated based on eight key performance areas, with higher scores indicating better medical performance: Vascular Access (20 points): type of vascular access, episodes of thrombosis and infection); HD adequacy (20 points): eKt/V, blood flow and treatment time; Anemia (20 points): hemoglobin concentration, transferrin saturation, ferritin; Arterial hypertension (10 points): mean arterial pressure; Mineral Bone disease (15 points): iPTH, plasmatic phosphorus and calcium; Fluid status (5 points): percentage of interdialytic fluid gain; Nutrition (5 points): plasmatic albumin and phosphorus and Others (5 points): influenzae vaccination, transplantation status and hospitalization events. The final score is obtained by the weighted sum of positive clinical factors, subtracted from the weighted sum of negative clinical factors and is reported as a number ranging from 0 to 100, with a higher score representing a better medical performance. Results The study included 10 458 HD patients. In the survival analysis, a significant increase in mortality odds was observed in patients with a stable IPPS of 72 or lower, compared to those with a score consistently above 86. Patients transitioning from the lowest to the highest tertile in six months had a mortality HR similar to those consistently in the highest tertile. On the other hand, patients showing a decrease in IPPS score from the highest to the lowest tertile in the same period had a mortality HR similar to the intermediate group (Table 1). Conclusion A lower total IPPS score (<72) was associated with a threefold increase in mortality risk compared to scores above 86. An increase in IPPS from the lowest to the highest tertile correlated with a significant reduction in mortality, equating to the survival rates of patients consistently scoring high. These findings underscore the potential of IPPS as a valuable tool for guiding clinical interventions in the HD population to enhance patient survival.

#2231 The efficacy of anti-viral therapies for hepatitis B in kidney transplant recipients

Abstract Background and Aims The efficacy and long-term outcomes of anti-viral therapies used for hepatitis B treatment or prevention continue to be a challenging area in kidney transplantation practice. This study aimed to determine the effectiveness of anti-viral treatment in a hepatitis B kidney transplant cohort and its effect on long-term graft and overall survival. Method We reviewed the data of 589 patients who were followed up on at our clinic between January 1, 2002, and December 31, 2023. Recipients who were AntiHbc IgG positive and received Rituximab and HbsAg negative recipients whose donor was HbsAg positive were included in the prophylaxis group, and recipients who were HbsAg positive were included in the treatment group. Age- and gender-matched recipients who did not use anti-viral treatment constituted the control group. HBV-DNA positivity in the prophylaxis group and an increase in HBV-DNA titers in the treatment group were indicators of treatment ineffectiveness. Anti-viral treatment-related side effects were noted. Graft functions, graft, and overall survival rates were examined at the beginning of treatment and at the last visit. Results A total of 30 patients receiving anti-viral therapy (prophylaxis n = 15, treatment n = 15) were included and compared with 32 control patients. The median age of the prophylaxis group was 49 (13–60) years, the median age of the treatment group was 46 (15–63) years, and the median age of the control group was 44 (22–71) years (p = 0.846). No difference was detected between the groups in terms of gender distribution. Entecavir was used in 17 patients, tenofovir in 7, and lamivudine in 6 patients. Hepatitis B activation was not observed in any patient in the prophylaxis group. An increase in HBV-DNA level was observed in 2 of 5 patients (40%) in the treatment group, followed by lamivudine. No treatment unresponsiveness was observed with other agents. No anti-viral drug-related side effects were reported in any patient. While there was no graft loss in the anti-viral treatment groups during follow-up, overall survival was determined as 100% in the prophylaxis group, 80% in the treatment group, and 90.6% in the control group (log rank p = 0.404). No hepatitis B-related mortality was reported. The findings are summarized in Tables 1 and 2. Conclusion Kidney transplant recipients using anti-viral medications for Hepatitis B, either for treatment or prophylaxis, showed similar graft and patient survival compared to the control group. Entecavir is the most commonly used anti-viral agent. Our findings support that it is advisable to consider alternative anti-viral medications instead of lamivudine, as there is a potential risk of non-response.

#2088 Renal outcome, cardio-vascular events and infections in patients with lupus nephritis: MassiLUP cohort 2001-2022

Abstract Background and Aims Most epidemiological studies in lupus nephritis (LN) report the risk of end-stage kidney disease (ESKD) (10-20% of patients at 10-15 years in developed countries), but less data is available on the long-term risk of chronic kidney disease (CKD), even though CKD is a major risk factor for morbidity and mortality. While immunosuppressive therapy for LN aims to reach and maintain remission in order to prevent CKD, it also exposes patients to cardiovascular, infectious and neoplastic adverse events. We conducted a retrospective cohort study to evaluate survival without CKD and adverse events in patients with LN. Method The MassiLUP cohort comprises all patients who underwent a kidney biopsy for a first flare of LN between 2001 and 2022 in the University Hospital of Marseille, France. We assessed patient survival, renal survival and survival without CKD (defined by an estimated glomerular filtration rate < 60 mL/min/1.73 m2), without cardiovascular event, without severe infection (requiring hospitalization, or zoster), and without cancer. Results A total of 168 patients (82.7% female; mean age 33 years; mean serum creatinine 102 µmol/L at the time of the first kidney biopsy) were included, with a mean follow-up of 9.6 ± 5.7 years. One (0.6%) patient had class I LN (ISN/RPS 2003 classification), 17 (10.1%) class II LN, 45 (26.8%) had class III (± V) LN, 73 (43.5%) had class IV (± V) LN, 29 (17.3%) patients had pure class V LN; 3 biopsies could not be classified. Four patients died during the follow-up (3 of severe infections and 1 of stroke); 41 (24.4%) patients developed CKD, among whom 19 (11.3%) patients reached ESKD; 34 (20.2%) patients presented a cardiovascular event, 59 (35.1%) a severe infection, and 12 (7.1%) a cancer. Survival rates without CKD were 82.9%, 74.6% and 67.3% at 5, 10 and 15 years, respectively. Survival rates without ESKD were 94.4%, 88.6% and 79.9% at 5, 10 and 15 years, respectively. Survival rates without cardiovascular event were 85.7%, 77.3% and 75.5% at 5, 10 and 15 years, respectively. Survival rates without severe infection were 76.3%, 63.8% and 51.8% at 5, 10 and 15 years, respectively. Survival rates without cancer were 96.3%, 92.9% and 85.6% at 5, 10 and 15 years, respectively. Conclusion Despite free access to treatment and care in France, the long-term prognosis of patients with lupus nephritis remains burdened by both a risk of CKD and ESKD, and a significant risk of cardiovascular and infectious events. This calls for continued efforts to improve therapeutic strategies, both in terms of efficacy and toxicity, and to strengthen the therapeutic alliance in the care of patients with LN.

The impact of simulation-based training on medical students' whole blood transfusion abilities.

Whole blood transfusion has been found to increase the likelihood of patient survival within both military and civilian medicine contexts. However, no whole blood transfusion training curriculum currently exists within undergraduate or graduate medical education in the United States. The purpose of our study was to: (1) determine the impact of simulation-based training on medical students' abilities to conduct whole blood transfusions; and (2) determine the impact of simulation-based training on medical students' confidence in conducting whole blood transfusions. We assessed 157 third-year military medical students' ability to conduct whole blood transfusion before and after Operation Gunpowder, a 2-day high-fidelity prolonged casualty care simulation. We conducted a paired samples t-test to compare the students' pre- and post-simulation performance scores as well as self-reported confidence and stress ratings. There was a significant difference in students' scores at the beginning of the course (M = 20.469, SD 6.40675) compared to their scores at the end of the course (M = 30.361, SD = 2.10053); t(155) = -18.833, p < .001. The effect size for this analysis (d = 6.56) was large. There was a significant difference (p < .001) between the pre- and post-ratings for all self-reported confidence and stress survey items. Our results suggest that simulation-based training is an effective means of training medical students to conduct whole blood transfusiontraining in a limited resource simulated environment where blood inventories may be limited.

#620 Remaining life expectancy of Korean hemodialysis patients: how much longer can they live?

Abstract Background and Aims Hemodialysis (HD) patients have a higher mortality rate compared to general population. However, no study has investigated life expectancy in Korean HD patients so far. Therefore, this study aimed to calculate the remaining life expectancy among Korean maintenance HD patients and compare it to those of general population as well as HD patients from other countries. Method Baseline data were retrieved from HD quality assessment data from October to December 2015. Among the total number of patients who were alive at the beginning of 2016 (20,537 men and 14,404 women), a total of 22,439 (12,848 men and 9,591 women) were still alive at the end of 2021 while 12,502 (7,689 men and 4,813 women) were deceased during 6 years of follow-up. We used the life table method to calculate the expected remaining years of life in two-year increments. Results The mean age of the patients was 60.5 ± 12.4 years, and 58.7% were male. The average duration of HD was 5.63 ± 5.11 years. The most common cause of end-stage kidney disease was diabetes mellitus (42.0%), followed by hypertension (27.1%) and glomerulonephritis (10.9%). The remaining life expectancy for 60-year-old patients were 11.64 years for men and 14.64 years for women. The average remaining lifetimes of the HD population were only about a half of the general population (Fig.). Diabetic patients demonstrated shorter life expectancy compared to the patients with hypertension or glomerulonephritis. The remaining life expectancy of Korean HD patients was similar to that of Japanese and was almost double that of HD patients in Western countries such as Europe and United States. Conclusion HD population showed shorter life expectancy compared to the general population. Asian HD population seemed to demonstrate better patient survival compared to other countries. Longitudinal analysis should be warranted to analyze the effect of advanced dialysis technology upon improved survival rate among HD population.

#1578 Left ventricular ejection fraction: association with risk of mortality and the incidence of AVF dysfunction

Abstract Background and Aims Ejection fraction (EF) and chronic heart failure (HF) are often considered as criteria for the possibility of arteriovenous fistula (AVF) creation in relation to an increased risk of death, without sufficient evidence for this. There is, however, rare but compelling evidence that low EF increases the risk of AVF dysfunction. Aims: to evaluate the association between EF at the time of AVF creation and the incidence of adverse cardiovascular events, all-cause mortality, as well as AVF dysfunction Method This retrospective cohort study included 962 adult patients who had a first-time created functioning AVF. Only patients with a more than three months period after AVF creation and within a five-year period were included. The mean follow-up period was 34 ± 13 months. Four groups were identified based on EF and the presence of HF at the time of AVF creation (transthoracic echocardiogram): HF with reduced EF (rEF) &amp;lt;40%, with mid-range (mrEF) of 40-49%, or with preserved EF (pEF) ≥50% + HF, and a “no HF” group with EF ≥50% and no HF. Results In the univariate analysis, a reduced EF was associated with an increased risk of mortality, with the hazard ratios (HRs) of 2.706 [95% CI 1.330; 5.507], p = 0.006 for mrEF and 8.250 [95% CI 2.621; 25.97], p &amp;lt; 0.001 for rEF, compared to the “no HF” group (here and thereafter)—Fig. 1. However, after adjusting for age, sex, and Charlson Comorbidity Index (CCI), the EF was not significantly associated with the risk of death. Only the CCI score remained a significant factor (HR = 1.748 [95% CI 1.482; 2.063], p &amp;lt; 0.001). A decreased EF was associated with the incidence of AVF dysfunction both in the univariate analysis and after adjustments. In the univariate analysis, the incidence rate ratios (IRRs) of 6.88 [95% CI 3.88; 12.1], p &amp;lt; 0.001 for mrEF, and 19.9 [95% CI 8. 64; 41.6], p &amp;lt; 0.001 for rEF, were shown. After adjusting for age, sex, and CCI, the IRR for mrEF was 8.96 [95% CI 5.81; 13.7], p &amp;lt; 0.001, and for rEF it was 23.4 [95% CI 13.8; 38.6], p &amp;lt; 0.001. Even in the presence of polycystic kidney disease and diabetes mellitus in the fully adjusted model, the association between EF and the incidence of AVF dysfunction remained statistically significant: the IRR was 8.61 [95% CI 5.61; 13.1], p &amp;lt; 0.001 for mrEF, and 33.4 [95% CI 19.5; 56.2], p &amp;lt; 0.001 for rEF. The findings were confirmed in a sensitivity analysis that included adjustments for unplanned onset of dialysis and competing risks survival analysis (death—outcome of interest, conversion of HD to PD or kidney transplantation and conversion of AVF to CVC—competing events). According to our results patients with EF&amp;lt;40% will inevitably lose AVF function for various reasons within 3.5 years—Fig. 2. Meanwhile, this approach will give the patient additional time of HD via AVF, but not CVC, without increasing the risk of death, subject to Qa monitoring. Conclusion In patients with CKD 5 who are initiating treatment with maintenance hemodialysis, a decreased EF is associated to a greater extent with a higher risk of AVF dysfunction than with an increased risk of mortality. The burden of comorbidities, rather than a standalone assessment of EF, is one of the major risk factors determining patient survival.

#1756 Development and internal validation of machine learning algorithms for mortality prediction model of people with DM and CKD

Abstract Background and Aims Diabetes Mellitus (DM) and Chronic Kidney Disease (CKD) are leading causes of morbidity and mortality, presenting challenges in patient management. The aim of this study is to develop a machine learning-based predictive model for mortality in DM and CKD patients, improving early intervention and treatment personalization. Method 3,637 participants with DM and CKD from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018 were included. All-cause mortality was ascertained by linkage to National Death Index records through 31 December 2019 in NHANES. The dataset included clinical profiles, demographic details, and laboratory results of patients with DM and CKD. We performed 100 random groupings, dividing the data into a 75% training set and a 25% validation set each time. We then visualized the results of 100 AUC measurements using a boxplot. The objective was to forecast patient survival over 1, 3, 5, and 10-year horizons using a variety of machine learning algorithms. The algorithms tested included Logistic Regression (LR), Decision Tree (DT), Random Forest (RF), K-Nearest Neighbors (KNN), Gaussian Naive Bayes (GNB), Multinomial Naive Bayes (MNB), Bayesian Network Classifier (BNC), AdaBoost (Ada), Gradient Boosting (Gradient), and Extreme Gradient Boosting (XG). The performance of each algorithm was evaluated based on the Area Under the Receiver Operating Characteristic (ROC) Curve (AUC), with the results visualized in boxplot format. Results Upon result shown as the boxplots, it becomes evident that the Random Forest (RF) algorithm consistently exhibits one of the highest AUCs on average across all prediction intervals, suggesting a strong and stable predictive capacity. In the 1-year survival prediction, the RF algorithm demonstrates a highest AUC, implying consistent performance. The 3 and 5-year predictions reveal a slight dip in AUC for most models, including RF, but it still remains one of the top-performing algorithms with fewer outliers than XG and Gradient Boosting. The mean AUC of RF is particularly noteworthy at the 10-year mark, where most algorithms struggle with prediction accuracy, as indicated by lower median AUCs and greater variability. Notably, the RF algorithm identified six major factors for 1-year survival prediction: systolic blood pressure, uric acid, blood urea nitrogen, lactate dehydrogenase, lymphocyte count and total cholesterol, as well as three major factors for 10-year survival prediction: age, lymphocyte and gamma-glutamyl transferase. Conclusion Overall, the study indicates that while machine learning can be a powerful tool for survival prediction in patients with DM and CKD, the choice of algorithm is crucial, with RF standing out for its consistent and reliable performance.

Cisternal and intraventricular irrigation in subarachnoid and intraventricular haemorrhage

BackgroundSubarachnoid haemorrhage (SAH) and intraventricular haemorrhage (IVH) are associated with poor patient outcomes. Intraventricular fibrinolysis is effective in clearing IVH and improving patient survival and neurological outcome. By similar rationale,...

Nutritional Status as a Prognostic Factor for Survival in Palliative Care: A Retrospective Observational Analysis of Home Parenteral Nutrition in Cancer Patients with Inoperable Malignant Bowel Obstruction

Palliative care patients with malignant bowel obstruction are particularly at risk of developing malnutrition, which in turn directly shortens survival time and worsens quality of life (QoL). According to the available data, the survival time in this patient group is often less than three months. To avoid further complications related to malnutrition and poor outcomes in oncological therapy, nutritional therapy such as home parenteral nutrition (HPN) is offered. The aim of this study was to investigate whether nutritional status is a prognostic factor for survival in palliative care patients with malignant inoperable bowel obstruction qualified for home parenteral nutrition and which nutritional assessment tool has the most accurate prognostic value. This retrospective observational analysis included 200 patients with malignant bowel obstruction referred for home parenteral nutrition between January 2018 and August 2023. The analysis included laboratory test results, body mass index (BMI), Subjective Global Assessment (SGA), Nutritional Risk Index (NRI), Geriatric Nutritional Risk Index (GNRI), Prognostic Nutritional Index (PNI) and malnutrition as defined by the Global Leadership Initiative on Malnutrition (GLIM). The average survival time of the patients was 75 days. Patients with higher NRI and PNI scores were more likely to survive (NRI: p &lt; 0.001; PNI: p &lt; 0.001). The GLIM criteria, SGA scores and BMI values did not prove to be good prognostic factors for survival (GLIM p = 0.922, SGA p = 0.083, BMI p = 0.092). The results suggest that the use of NRI and PNI may be helpful in prognosing survival in these patients and that prevention of the development of malnutrition through earlier nutritional assessment and intervention should be considered in this patient group.

Radiotherapy for pediatric low-grade glioma.

Radiotherapy is a highly effective treatment for pediatric low-grade glioma, serving as the standard for evaluating progression-free and overall survival, as well as vision preservation. Despite its proven efficacy, concerns about treatment complications have led to increased use of chemotherapy and targeted therapy, which are associated with poorer progression-free survival outcomes. This review by Indu Bansal and Thomas E. Merchant examines the indications, timing, and results of radiotherapy for pediatric low-grade glioma. The authors provide a comprehensive analysis of clinical management strategies, addressing the controversies surrounding the use and timing of radiotherapy compared to other therapies. The review highlights that while radiotherapy is essential for certain patients, particularly those who are not candidates for complete resection due to the tumor's infiltrative nature or location, it is often deferred in favor of systemic therapies. This deferral can lead to significant morbidity, including poor visual outcomes. Reports indicate that systemic therapy negatively impacts progression-free survival in patients who eventually undergo radiotherapy. Newer radiotherapy techniques have been developed to minimize complications, offering potential benefits over traditional methods. The evolving clinical management of pediatric low-grade glioma involves balancing the benefits of radiotherapy with concerns about its side effects. Although systemic therapies are increasingly favored, their associated inferior progression-free survival and potential for significant morbidity underscore the need for careful consideration of radiotherapy, particularly in older children, adolescents, or those with progressive disease post-systemic therapy. The emerging role of targeted therapy presents additional challenges, including uncertainties about long-term side effects and its interaction with radiotherapy. Further research is needed to optimize treatment strategies and improve outcomes for pediatric patients with low-grade glioma.

USP44 overexpression drives a MYC-like gene expression program in neuroblastoma through epigenetic reprogramming.

Neuroblastoma is an embryonic cancer that contributes disproportionately to death in young children. Sequencing data have uncovered few recurrently mutated genes in this cancer, although epigenetic pathways have been implicated in disease pathogenesis. We used an expression-based computational screen that examined the impact of deubiquitinating enzymes on patient survival to identify potential new targets. We identified the histone H2B deubiquitinating enzyme USP44 as the enzyme with the greatest impact on survival in patients with neuroblastoma. High levels of USP44 significantly correlate with metastatic disease, unfavorable histology, advanced patient age, and MYCN-amplification. The subset of patients with tumors expressing high levels of USP44 had a significantly worse survival, including those with tumors lacking MYCN amplification. We showed experimentally that USP44 regulates neuroblastoma cell proliferation, migration, invasion, and neuronal development. Depletion of the histone H2B ubiquitin ligase subunit RNF20 resulted in similar findings, strongly implicating this histone mark as the target of USP44 activity in this disease. Integration of transcriptome and epigenome in analyses demonstrates a distinct set of genes that is regulated by USP44, including those in Hallmark MYC target genes in both murine embryonic fibroblasts and the SH-SY5Y neuroblastoma cell line. We conclude that USP44 is a novel epigenetic regulator that promotes aggressive features and may be a novel target in neuroblastoma. Implications: This study identifies a new genetic marker of aggressive neuroblastoma and identifies the mechanisms by which its overactivity contributes to pathophysiology in this disease.

Comprehensive landscape of junctional genes and their association with overall survival of patients with lung adenocarcinoma

Comprehensive landscape of junctional genes and their association with overall survival of patients with lung adenocarcinoma

Survival benefit of nephroureterectomy in systemic therapy exposed metastatic upper tract urinary urothelial carcinoma patients.

It is unknown whether the stage of the primary may influence the survival (OS) of metastatic upper tract urothelial carcinoma (mUTUC) patients treated with nephroureterectomy (NU) and systemic therapy (ST). We tested this hypothesis within a large-scale North American cohort. Within Surveillance Epidemiology and End Results database 2000-2020, all mUTUC patients treated with ST+NU or with ST alone were identified. Kaplan-Maier plots depicted OS. Multivariable Cox regression (MCR) models tested for differences between ST+NU and ST alone predicting overall mortality (OM). All analyses were performed in localized (T1-T2) and then repeated in locally advanced (T3-T4) patients. Of all 728 mUTUC patients, 187 (26%) harbored T1-T2 vs 541 (74%) harbored T3-T4. In T1-T2 patients, the median OS was 20months in ST+NU vs 10months in ST alone. Moreover, in MCR analyses that also relied on 3 months' landmark analyses, the combination of ST+NU independently predicted lower OM (HR 0.37, p < 0.001). Conversely, in T3-T4 patients, the median OS was 12 in ST+NU vs 10months in ST alone. Moreover, in MCR analyses that also relied on 3 months' landmark analyses, the combination of ST+NU was not independently associated with lower OM (HR 0.85, p = 0.1). In mUTUC patients, treated with ST, NU drastically improved survival in T1-T2 patients, even after strict methodological adjustments (multivariable and landmark analyses). However, this survival benefit did not apply to patients with locally more advanced disease (T3-T4).

Survival and inferential analysis in patients with locally advanced breast cancer treated with neoadjuvant chemotherapy and subsequent sentinel lymph node biopsy: prospective single-center study

BackgroundThe lymph node staging is the major prognostic factor in breast cancer patients. Sentinel lymph node biopsy (SLNB) allows an exactly axillar staging in patients with early disease, but not in locally advance breast cancer (LABC). Our aim was to study, the feasibility and accuracy of the SLNB technique with and without axillar lymphadenectomy (LDN) and with lymph node clipping after neoadjuvant chemotherapy (NAC), in patients with LABC.Patients and methodsPatients diagnosed with LABC, scheduled for NAC and subsequent surgery and SLNB. Subsequently the patients were scheduled for adjuvant chemotherapy/hormonotherapy and radiotherapy according with the postsurgical results. Main end points were overall survival (OS) disease-free survival (DFS), mortality, SLNB identification rate (IR), sensitivity, false negative rate (FNR) of SLNB versus LDN, negative predictive value (NPV) and overall accuracy.ResultsOur IR with different techniques was between 89.9 and 100%. OS was between 89 and 97%. DFS was between 89.8 and 96.8%. Sensitivity was between 75 and 100%. NPV was between 89.6 and 100%. FNR was between 0 and 25%; and accuracy was between 66 and 72%. We found that survival was lower (p < 0.05) in patients with triple negative and Luminal B/HER2 intrinsic subtype; with progression or major partial response in Magnetic Resonance Imaging (MRI) results at the end of NAC and in patients with BRCA1/2 mutation.ConclusionsOur study presents excellent results of SLNB alone in patients with LABC with complete nodal response with an OS and DFS > 95%. The FNR is very high in partial responders, so we cannot recommend the SLNB alone in LABC. We recommend, in cN+ patients, axillar clipping, SLNB and LDN because in more than 50% of the patients with axillar clipping, this was not found, and because in 36% of the patients with negative LDN, the SLN (Sentinel Lymph Node) obtained was the only positive node, so these techniques together decrease the FNR and improve the node staging, OS and DFS. This study is the first prospective study that assess OS and DFS in patients with LABC, all submitted to SLNB.

Phase I and Randomized Phase II Study of Ruxolitinib With Frontline Neoadjuvant Therapy in Advanced Ovarian Cancer: An NRG Oncology Group Study.

The interleukin-6/Janus kinase (JAK)/signal transducers and activators of transcription 3 axis is a reported driver of chemotherapy resistance. We hypothesized that adding the JAK1/2 inhibitor ruxolitinib to standard chemotherapy would be tolerable and improve progression-free survival (PFS) in patients with ovarian cancer in the upfront setting. Patients with ovarian/fallopian tube/primary peritoneal carcinoma recommended for neoadjuvant chemotherapy were eligible. In phase I, treatment was initiated with dose-dense paclitaxel (P) 70 mg/m2 once daily on days 1, 8, and 15; carboplatin AUC 5 intravenously day 1; and ruxolitinib 15 mg orally (PO) twice a day, every 21 days (dose level 1). Interval debulking surgery (IDS) was required after cycle 3. Patients then received three additional cycles of chemotherapy/ruxolitinib, followed by maintenance ruxolitinib. In the randomized phase II, patients were randomly assigned to paclitaxel/carboplatin with or without ruxolitinib at 15 mg PO twice a day for three cycles, IDS, followed by another three cycles of chemotherapy/ruxolitinib, without further maintenance ruxolitinib. The primary phase II end point was PFS. Seventeen patients were enrolled in phase I. The maximum tolerated dose and recommended phase II dose were established to be dose level 1. One hundred thirty patients were enrolled in phase II with a median follow-up of 24 months. The regimen was well tolerated, with a trend toward higher grade 3 to 4 anemia (64% v 27%), grade 3 to 4 neutropenia (53% v 37%), and thromboembolic events (12.6% v 2.4%) in the experimental arm. In the randomized phase II, the median PFS in the reference arm was 11.6 versus 14.6 in the experimental, hazard ratio (HR) for PFS was 0.702 (log-rank P = .059). The overall survival HR was 0.785 (P = .24). Ruxolitinib 15 mg PO twice a day was well tolerated with acceptable toxicity in combination with paclitaxel/carboplatin chemotherapy. The primary end point of prolongation of PFS was achieved in the experimental arm, warranting further investigation.

PARP1-DOT1L transcription axis drives acquired resistance to PARP inhibitor in ovarian cancer.

Poly (ADP-ribose) polymerase inhibitor (PARPi) resistance poses a significant challenge in ovarian carcinoma (OC). While the role of DOT1L in cancer and chemoresistance is acknowledged, its specific role in PARPi resistance remains unclear. This study aims to elucidate the molecular mechanism of DOT1L in PARPi resistance in OC patients. This study analyzed the expression of DOT1L in PARPi-resistant cell lines compared to sensitive ones and correlated it with clinical outcomes in OC patients. Comprehensive in vitro and in vivo functional experiments were conducted using cellular and mouse models. Molecular investigations, including RNA sequencing, chromatin immunoprecipitation (ChIP) and Cleavage Under Targets and Tagmentation (CUT&Tag) assays, were employed to unravel the molecular mechanisms of DOT1L-mediated PARPi resistance. Our investigation revealed a robust correlation between DOT1L expression and clinical PARPi resistance in non-BRCA mutated OC cells. Upregulated DOT1L expression in PARPi-resistant tissues was associated with diminished survival in OC patients. Mechanistically, we identified that PARP1directly binds to the DOT1L gene promoter, promoting transcription independently of its enzyme activity. PARP1 trapping induced by PARPi treatment amplified this binding, enhancing DOT1L transcription and contributing to drug resistance. Sequencing analysis revealed that DOT1L plays a crucial role in the transcriptional regulation of PLCG2 and ABCB1 via H3K79me2. This established the PARP1-DOT1L-PLCG2/ABCB1 axis as a key contributor to PARPi resistance. Furthermore, we discovered that combining a DOT1L inhibitor with PARPi demonstrated a synergistic effect in both cell line-derived xenograft mouse models (CDXs) and patient-derived organoids (PDOs). Our results demonstrate that DOT1L is an independent prognostic marker for OC patients. The PARP1-DOT1L/H3K79me2-PLCG2/ABCB1 axis is identified as a pivotal contributor to PARPi resistance. Targeted inhibition of DOT1L emerges as a promising therapeutic strategy for enhancing PARPi treatment outcomes in OC patients.

Partial Hepatectomy and Ablation for Survival of Early-Stage Hepatocellular Carcinoma Patients: A Bayesian Emulation Analysis

Partial Hepatectomy and Ablation for Survival of Early-Stage Hepatocellular Carcinoma Patients: A Bayesian Emulation Analysis

Association of serum Spp1 levels with disease progression in ALS and SBMA.

In comparison with amyotrophic lateral sclerosis (ALS), the contribution of neuroinflammation in spinobulbar muscular atrophy (SBMA) has been less explored. We investigated the role of neuroinflammation in the pathogenesis of ALS and SBMA by analyzing systemic inflammatory markers and osteopontin (Spp1). This study involved 105 ALS, 77 SBMA, and 55 healthy controls. We measured their systemic inflammatory markers, serum Spp1, and cytokine levels (interferon-γ, interleukin [IL]-1β, IL-6, IL-8, IL-10, tumor necrosis factor-α, and IL-17A), investigated correlations between Spp1 levels and clinical features, and evaluated ALS survival rates according to Spp1 levels. In the ALS group, systemic inflammatory markers were significantly higher than in the control and SBMA groups. Spp1 levels were observed to be higher in ALS patients, but the difference was not statistically significant among the study groups. Cytokine profiles were comparable. In ALS, higher Spp1 levels were correlated with lower ALS Functional Rating Scale-Revised (ALSFRS-R) scores (r = -0.25, p = 0.02) and faster disease progression rate (r = 0.37, p < 0.001). After adjusting for other prognostic indicators, high Spp1 levels were independently associated with shorter survival in ALS patients (hazard ratio 13.65, 95% confidence interval 2.57-72.53, p < 0.01). Neuroinflammation does not appear to be a primary contributor to the pathogenesis of SBMA. Serum Spp1 levels may serve as a reliable biomarker for disease progression and prognosis in ALS. These findings expand our understanding of these two distinct motor neuron disorders and offer a potential biomarker for future studies.