Improvement In Survival Research Articles

Conditional survival estimates for ependymomas reveal the dynamic nature of prognostication

BackgroundTraditional survival analysis is frequently used to assess the prognosis of ependymomas (EPNs); however, it may not provide additional survival insights for patients who have survived for several years. Thus, the conditional survival (CS) pattern of this disease is yet to be further investigated. This study aimed to evaluate the improvement of survival over time using CS analysis and develop a CS-based nomogram model for real-time dynamic survival estimation for EPN patients.MethodsData on patients with EPN were collected from the Surveillance, Epidemiology, and End Results (SEER) database. In order to construct and validate the model effectively, the selected patients were randomly divided at 7:3 ratio. CS is defined as the probability of surviving for a specified time period (y years) after initial diagnosis, given that the patient has survived x years. The CS pattern of EPN patients were explored. Then, the least absolute shrinkage and selection operator (LASSO) regression method with tenfold cross-validation was employed to identify prognostic predictors. Multivariate Cox regression was employed to develop a CS-based nomogram model, and we used this model to quantify EPN patient risk. Finally, the performance of the prediction model was also evaluated and verified.ResultsIn total, 1829 patients diagnosed with EPN were included in the study, with 1280 and 549 patients in the training and validation cohorts, respectively. The CS analysis demonstrated that patients' OS saw gradual improvements over time. With each additional year of survival post-diagnosis, the 10-year survival rate of EPN patients saw an increase, updating from 74% initially to 79%, 82%, 85%, 87%, 89%, 91%, 93%, 96%, and 98% (after surviving for 1–9 years, respectively). The LASSO regression model, which implements tenfold cross-validation, identified 7 significant predictors (age, tumor grade, tumor site, tumor extension, tumor size, surgery and radiotherapy) to develop a CS-based nomogram model. And further risk stratification was conducted based on nomogram model for these patients. Furthermore, this survival prediction model was successfully validated.ConclusionThis study described the CS pattern of EPN patients and highlighted the gradual improvement of survival observed over time for long-term survivors. We also developed the first novel CS-nomogram model that enabled individualized and real-time prognosis prediction. But patients must be counselled that individual circumstances may not always accurately reflect the findings of the nomogram.

Malaria Rapid Tests, Febrile Illness Management, and Child Mortality Across Sub-Saharan African Countries.

A prompt malaria diagnosis is crucial for the management of children with febrile illness in sub-Saharan African countries, where malaria remains a leading cause of mortality among children younger than 5 years of age. The development and distribution of point-of-care rapid diagnostic tests (RDTs) for malaria has transformed practice, but limited systematic evidence exists on how malaria RDTs have affected the management of febrile illness and mortality for children younger than 5 years of age across sub-Saharan Africa countries. To evaluate the association between the distribution of malaria RDTs and the management of febrile illness and mortality among children younger than 5 years of age in sub-Saharan African countries. This quasi-experimental study used a novel dataset linking malaria RDT distribution to 165 nationally representative household surveys across 35 sub-Saharan African countries with mortality data. The sample comprised approximately 3.9 million child-year observations and approximately 260 000 febrile illness episodes in children younger than 5 years of age between 2000 and 2019. Fixed-effects linear probability models were used to analyze the association between variation in malaria RDTs distributed per child younger than 5 years of age (by country per year) and blood testing, antimalarial drug use, antibiotic use, use of symptomatic treatments, and mortality rates. Variation in the effects of testing and treatment was also assessed across the sub-Saharan African countries that had varying prevalence of malaria. The mortality sample included 1 317 866 children and the fever sample included 256 292 children. The mean age of the children with febrile illness was 2.4 years (SD, 1.3 years) and 49% were female. Each additional malaria RDT distributed per child younger than 5 years of age was associated with an increase of 3.5 percentage points (95% CI, 3.2-3.8 percentage points) in blood testing, an increase of 1.5 percentage points (95% CI, 1.2-1.8 percentage points) in the use of antimalarial drugs, an increase of 0.4 percentage points (95% CI, 0.1-0.6 percentage points) in antibiotic use, and a decrease of 0.4 percentage points (95% CI, 0.1-0.8 percentage points) in the use of treatments for symptoms. Each additional malaria RDT distributed per child younger than 5 years of age was associated with a reduction in child mortality of 0.34 deaths per 1000 child-years (95% CI, 0.15-0.52 deaths per 1000 child-years). The effects of malaria RDT distribution on medication use and child mortality varied across prevalence settings (low vs high) for malaria; there were survival improvements only in areas that had a high prevalence of malaria. Increasing distribution of malaria RDTs was associated with increased blood testing, increased use of antimalarial drugs, and modestly improved survival in children younger than 5 years of age in sub-Saharan African countries. However, malaria RDTs were associated with increases in the rates of antibiotic use that were already high, suggesting that more comprehensive approaches to case management of febrile illness are needed.

Inhibition of Insulin-like Growth Factor 1 Receptor/Insulin Receptor Signaling by Small-Molecule Inhibitor BMS-754807 Leads to Improved Survival in Experimental Esophageal Adenocarcinoma

The insulin-like growth factor-1 (IGF-1) and insulin axes are upregulated in obesity and obesity-associated esophageal adenocarcinoma (EAC). Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is a contemporary nanotechnology-based paclitaxel (PT) bound to human albumin, ensuring its solubility in water rather than a toxic solvent. Here, we examined the benefits of inhibiting insulin-like growth factor-1 receptor/insulin receptor (IGF-1/IR) signaling and the enhancement of nab-paclitaxel effects by inclusion of the small-molecule inhibitor BMS-754807 using both in vitro and in vivo models of EAC. Using multiple EAC cell lines, BMS-754807 and nab-paclitaxel were evaluated as mono and combination therapies for in vitro effects on cell proliferation, cell death, and cell movement. We then analyzed the in vivo anticancer potency with survival improvement with BMS-754807 and nab-paclitaxel mono and combination therapies. BMS-754807 monotherapy suppressed in vitro cell proliferation and wound healing while increasing apoptosis. BMS-754807, when combined with nab-paclitaxel, enhanced those effects on the inhibition of cell proliferation, increment in cell apoptosis, and inhibition of wound healing. BMS-754807 with nab-paclitaxel produced substantially greater antitumor effects by increasing in vivo apoptosis, leading to increased mice survival compared to those of BMS-754807 or nab-paclitaxel monotherapy. Our outcomes support the use of BMS-754807, alone and in combination with nab-paclitaxel, as an efficient and innovative treatment choice for EAC.

Worldwide CTEPH Registry: Long-Term Outcomes With Pulmonary Endarterectomy, Balloon Pulmonary Angioplasty, and Medical Therapy.

The European Chronic Thromboembolic Pulmonary Hypertension registry (CTEPH), conducted between 2007 and 2012, reported the major impact of pulmonary endarterectomy (PEA) on the long-term survival of patients with CTEPH. Since then, 2 additional treatments for inoperable CTEPH have become available: balloon pulmonary angioplasty (BPA), and an approved oral drug therapy with the guanylate cyclase stimulator riociguat. The current registry aimed to evaluate the effect of these new therapeutic approaches in a worldwide context. Participation in this international global registry included 34 centers in 20 countries. Between February 2015 and September 2016, 1009 newly diagnosed, consecutive patients were included and followed until September 2019. Overall, 605 patients (60%) underwent PEA and 185 (18%) underwent BPA; 76% of the 219 remaining patients not receiving mechanical intervention (ie, neither PEA nor BPA) were treated with pulmonary hypertension drugs. Oof patients undergoing PEA and BPA, 38% and 78% also received drugs for pulmonary hypertension, respectively. Median age at diagnosis was higher in the BPA and No PEA/BPA groups than in the PEA group: 66 and 69, respectively, versus 60 years. Pulmonary vascular resistance (PVR) was similar in all groups, with an average of 643 dynes/(s·cm-5). During an observation period (>3 years; ≤5.6 years), death was reported in 7%, 11%, and 27% of patients treated by PEA and BPA, and those receiving no mechanical intervention (P<0.001). In Kaplan-Meier analysis, 3-year survival was 94%, 92%, and 71% in the 3 groups, respectively. PEA 3-year survival improved by 5% from that observed between 2007 and 2012. There was no survival difference in patients receiving vitamin K antagonists and non-vitamin K oral anticoagulants (P=0.756). In Cox regression, reduced mortality was associated with: PEA and BPA in the global cohort; history of venous thromboembolism and lower PVR in the PEA group; lower right atrial pressure in the BPA group; and use of pulmonary hypertension drugs, oxygen therapy, and lower right atrial pressure, as well as functional class in the group receiving no mechanical intervention. This second international CTEPH registry reveals important improvement in patient survival since the introduction of BPA and an approved drug for pulmonary hypertension. The type of anticoagulation regimen did not influence survival. URL https://clinicaltrials.gov; Unique identifier: NCT02656238.

Survival following adjuvant trastuzumab-based treatment among older patients with HER2-positive early invasive breast cancer: A national population-based cohort study using routine data

BackgroundRandomised controlled trials (RCTs) reported adjuvant trastuzumab-based treatment improved overall survival (OS) among patients with HER2-positive early invasive breast cancer (EIBC). Few RCTs included older patients or those with comorbidity/frailty. This study aimed to determine whether the effect of adjuvant trastuzumab-based treatment on survival outcomes varies by patient age and fitness, using national data from routine care. MethodsWomen (50+ years) newly-diagnosed with HER2-positive EIBC between 2014 and 2019 were identified from England Cancer Registry data. Registration records were linked to Systemic Anti-Cancer Therapy data for treatment details and ONS death register for mortality details. A propensity score analysis employing the inverse probability of treatment weighting method was used to balance the patient variables across treatment groups. Cox models were used to evaluate whether the effect of treatment on OS was associated with patient age and fitness; competing risks regression models were used for breast cancer-specific survival (BCSS). Results5238 women initiated adjuvant trastuzumab-based treatment. Median follow-up was 56.7 months. Comparison with 3421 women who did not receive adjuvant trastuzumab highlighted differences at diagnosis in relation to age, fitness, grade, nodal involvement, surgery type and use of radiotherapy. Weighted survival analysis found trastuzumab was associated with improved OS (hazard ratio HR 0.56, 95 %CI: 0.45–0.70) and improved BCSS (subHR 0.62, 95 %CI: 0.47–0.82). We found no evidence of a difference in effect by age or patient fitness for either outcome. ConclusionIn this national dataset, adjuvant trastuzumab was associated with improvements in survival, with an OS effect size similar to RCT evidence. The effect size was not found to vary by patient age or fitness. Chronological age and fitness alone should not be barriers to receipt of effective adjuvant targeted treatment.

The significance of risk stratification through nomogram-based assessment in determining postmastectomy radiotherapy for patients diagnosed with pT1 − 2N1M0 breast cancer

ObjectiveTo explore the high-risk factors affecting the prognosis of pT1 − 2N1M0 patients after mastectomy, establish a nomogram prediction model, and screen the radiotherapy benefit population.MethodThe clinical data of 936 patients with pT1 − 2N1M0 who underwent mastectomy in the fourth hospital of Hebei Medical University from 2010 to 2016 were retrospectively analyzed. There were 583 patients received postmastectomy radiotherapy(PMRT), and 325 patients without PMRT. Group imbalances were mitigated using the propensity score matching (PSM) method, and the log-rank test was employed to compare overall survival (OS) and disease-free survival (DFS) between the cohorts. The efficacy of PMRT across various risk groups was evaluated using a nomogram model.ResultThe median follow-up period was 98 months, Patients who received PMRT demonstrated significantly improved 5-year and 8-year OS and DFS compared to those who did not (P < 0.001). Multivariate analysis revealed that age, primary tumor site, positive lymph node, stage, and Ki-67 level independently influenced OS, while age, primary tumor site, and stage independently affected DFS. PMRT drastically enhanced OS in the high-risk group (P = 0.001), but did not confer benefits in the low-risk and intermediate risk groups (P = 0.057, P = 0.099). PMRT led to a significant improvement in disease-free survival (DFS) among patients in the intermediate and high-risk groups (P = 0.036, P = 0.001), whereas the low-risk group did not experience a significant benefit (P = 0.475).ConclusionAge ≤ 40 years, tumor located in the inner quadrant or central area, T2 stage, 2–3 lymph nodes metastasis, and Ki67 > 30% were the high-risk factors affecting the prognosis of this cohort of patients. In OS nomogram, patients with a risk score of 149 or higher who received PMRT exhibited improved OS. Similarly, in DFS nomogram, patients with a risk score of 123 or higher who received PMRT demonstrated enhanced DFS.

Pembrolizumab or placebo with chemoradiotherapy followed by pembrolizumab or placebo for newly diagnosed, high-risk, locally advanced cervical cancer (ENGOT-cx11/GOG-3047/KEYNOTE-A18): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 trial.

At the first interim analysis of the phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 study, the addition of pembrolizumab to chemoradiotherapy provided a statistically significant and clinically meaningful improvement in progression-free survival in patients with locally advanced cervical cancer. We report the overall survival results from the second interim analysis of this study. Eligible patients with newly diagnosed, high-risk (FIGO 2014 stage IB2-IIB with node-positive disease or stage III-IVA regardless of nodal status), locally advanced, histologically confirmed, squamous cell carcinoma, adenocarcinoma, or adenosquamous cervical cancer were randomly assigned 1:1 to receive five cycles of pembrolizumab (200 mg) or placebo every 3 weeks with concurrent chemoradiotherapy, followed by 15 cycles of pembrolizumab (400 mg) or placebo every 6 weeks. Pembrolizumab or placebo and cisplatin were administered intravenously. Patients were stratified at randomisation by planned external beam radiotherapy type (intensity-modulated radiotherapy [IMRT] or volumetric-modulated arc therapy [VMAT] vs non-IMRT or non-VMAT), cervical cancer stage at screening (FIGO 2014 stage IB2-IIB node positive vs III-IVA), and planned total radiotherapy (external beam radiotherapy plus brachytherapy) dose (<70 Gy vs ≥70 Gy [equivalent dose of 2 Gy]). Primary endpoints were progression-free survival per RECIST 1.1 by investigator or by histopathological confirmation of suspected disease progression and overall survival defined as the time from randomisation to death due to any cause. Safety was a secondary endpoint. Between June 9, 2020, and Dec 15, 2022, 1060 patients at 176 sites in 30 countries across Asia, Australia, Europe, North America, and South America were randomly assigned to treatment, with 529 patients in the pembrolizumab-chemoradiotherapy group and 531 patients in the placebo-chemoradiotherapy group. At the protocol-specified second interim analysis (data cutoff Jan 8, 2024), median follow-up was 29·9 months (IQR 23·3-34·3). Median overall survival was not reached in either group; 36-month overall survival was 82·6% (95% CI 78·4-86·1) in the pembrolizumab-chemoradiotherapy group and 74·8% (70·1-78·8) in the placebo-chemoradiotherapy group. The hazard ratio for death was 0·67 (95% CI 0·50-0·90; p=0·0040), meeting the protocol-specified primary objective. 413 (78%) of 528 patients in the pembrolizumab-chemoradiotherapy group and 371 (70%) of 530 in the placebo-chemoradiotherapy group had a grade 3 or higher adverse event, with anaemia, white blood cell count decreased, and neutrophil count decreased being the most common adverse events. Potentially immune-mediated adverse events occurred in 206 (39%) of 528 patients in the pembrolizumab-chemoradiotherapy group and 90 (17%) of 530 patients in the placebo-chemoradiotherapy group. This study is registered with ClinicalTrials.gov, NCT04221945. Pembrolizumab plus chemoradiotherapy significantly improved overall survival in patients with locally advanced cervical cancer These data, together with results from the first interim analysis, support this immuno-chemoradiotherapy strategy as a new standard of care for this population. Merck Sharp & Dohme, a subsidiary of Merck & Co.

Results from the randomized KEYNOTE-355 study of pembrolizumab plus chemotherapy for Asian patients with advanced TNBC

In the phase 3 KEYNOTE-355 study (NCT02819518), pembrolizumab plus chemotherapy demonstrated statistically significant and clinically meaningful improvements in progression-free survival (PFS) and overall survival (OS) versus placebo plus chemotherapy among patients with previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) and programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥ 10 tumors. We analyzed outcomes for the subgroup of patients enrolled in Asia in KEYNOTE-355. Patients received pembrolizumab 200 mg or placebo (2:1 randomization) every 3 weeks for 35 cycles plus investigator’s choice chemotherapy. Primary endpoints were PFS per Response Evaluation Criteria in Solid Tumors version 1.1 and OS. Among patients enrolled in Hong Kong, Japan, Korea, Malaysia and Taiwan (pembrolizumab plus chemotherapy, n = 113; placebo plus chemotherapy, n = 47), 117 (73.1%) had PD-L1 CPS ≥ 1 and 56 (35.0%) had PD-L1 CPS ≥ 10. Median time from randomization to data cutoff (June 15, 2021) was 43.8 (range, 36.8‒53.2) months (intent-to-treat [ITT] population). Hazard ratios (HRs [95% CI]) for PFS in the CPS ≥ 10, CPS ≥ 1, and ITT populations were 0.48 (0.24‒0.98), 0.58 (0.37‒0.91), and 0.66 (0.44‒0.99), respectively. Corresponding HRs (95% CI) for OS were 0.54 (0.28‒1.04), 0.62 (0.40‒0.97), and 0.57 (0.39‒0.84). Grade 3/4 treatment-related adverse events (AEs) occurred in 77.9% versus 78.7% of patients with pembrolizumab plus chemotherapy versus placebo plus chemotherapy. No grade 5 AEs occurred. Clinically meaningful improvement in PFS and OS with manageable toxicity were observed with pembrolizumab plus chemotherapy versus placebo plus chemotherapy in patients enrolled in Asia with previously untreated, inoperable or metastatic TNBC.Trial registration: ClinicalTrials.gov, NCT02819518.

Enhanced Disease-Specific Survival Among Individuals With Malignant Adnexal Tumors of the Skin Treated With Mohs Surgery: A National Database Study.

Malignant adnexal tumors of the skin are a rare group of tumors that can be locally aggressive and require surgical excision with strict margin control to achieve clearance. Given the rarity of these tumors, there is a limited understanding within the medical community regarding optimal treatment approaches. To examine surgical management trends and outcomes for patients diagnosed with cutaneous adnexal tumors from 2000 to 2020. The Surveillance, Epidemiology, and End Results database was queried to identify biopsy-proven cases of cutaneous adnexal tumors between 2000 and 2020. Clinical and disease characteristics were examined, and disease-specific survivals were compared between surgical approaches using Kaplan-Meier curves and Cox proportional hazards models. Mohs surgery demonstrated a significant increase in utilization from 2000 to 2020 (+447.1%) and improvements in disease-specific survival (mean 231.7 months; p < .001) compared with no surgery; wide local excision exhibited no improved disease-specific survival (227.7 months; p = .070). Multivariable Cox regression further highlighted that only Mohs surgery exhibited a reduced disease-specific mortality risk compared with no surgery (adjusted HR 0.49; p = .011). Given the enhanced disease-specific survival coupled with tissue preservation strategies, Mohs surgery emerges as a promising surgical approach for the treatment of malignant adnexal tumors of the skin.

Osimertinib after definitive chemoradiotherapy in unresectable stage III epidermal growth factor receptor-mutated non-small-cell lung cancer: analyses of central nervous system efficacy and distant progression from the phase III LAURA study.

Distant metastases in non-small-cell lung cancer (NSCLC) are a poor prognostic factor that negatively impact quality of life. The central nervous system (CNS) is a common site of distant progression in epidermal growth factor receptor-mutated (EGFRm) NSCLC. Osimertinib is a third-generation EGFR-tyrosine kinase inhibitor recommended for advanced EGFRm NSCLC and as adjuvant treatment for resected EGFRm NSCLC. In LAURA (NCT03521154), osimertinib demonstrated statistically significant improvement in progression-free survival (PFS) versus placebo in unresectable stage III EGFRm NSCLC without progression during/following chemoradiotherapy (CRT). CNS efficacy and time to death or distant metastases (TTDM) analyses are reported here. Patients without progression during/following definitive platinum-based CRT were randomised 2 : 1 to receive osimertinib (80 mg daily) or placebo until progression [by blinded independent central review (BICR)] or discontinuation. The primary endpoint was PFS by BICR. CNS PFS by neuroradiologist BICR and TTDM by BICR were secondary endpoints. Overall, 216 patients were randomised (143 osimertinib, 73 placebo). Median CNS PFS by neuroradiologist BICR was not reached [95% confidence interval (CI) not calculable (NC)-NC] with osimertinib versus 14.9 months (95% CI 7.4 months-NC) with placebo; hazard ratio (HR) for CNS PFS: 0.17 (95% CI 0.09-0.32). CNS PFS analysis by investigator assessment was consistent with BICR assessment. The cumulative incidence of CNS progression at 12 months was 9% (95% CI 5% to 14%) with osimertinib and 36% (95% CI 24% to 47%) with placebo. There was clinically meaningful improvement in TTDM with osimertinib versus placebo; HR for TTDM: 0.21 (95% CI 0.11-0.38). The cumulative incidence of distant metastases at 12 months was 11% (95% CI 6% to 17%) with osimertinib and 37% (95% CI 26% to 48%) with placebo. Osimertinib demonstrated clinically meaningful improvements in CNS PFS and TTDM versus placebo, supporting osimertinib post-CRT as the standard of care in unresectable stage III EGFRm NSCLC.

Pathological complete response of locally advanced triple-negative breast cancer: case report

Background. Triple-negative breast cancer is the most aggressive molecular subtype among breast malignancies. Due to the high proliferative activity of tumor cells and the lack of targets for targeted therapy, neoadjuvant chemotherapy plays the main role in complex treatment of this subtype. The optimal time to start neoadjuvant chemotherapy is defined as less than 8 weeks. Delays in time to treatment initiation may adversely affect treatment outcomes, as well as cause local or systemic disease progression. Achieving complete pathological response after neoadjuvant chemotherapy reduces the relative risk of relapse by more than 70 %, which, in turn, leads to a significant improvement in long-term survival of these patients. Description of the clinical case. A 32-year-old woman came to the clinic 15 months after being diagnosed with triple-negative breast cancer. The patient was treated with alternative medicine methods for 15 months, and upon admission to the hospital, the patient had pronounced local tumor growth with massive decay, tumor lysis syndrome and nutritional disorders. We decided to perform neoadjuvant chemotherapy: 12 cycles of weekly paclitaxel + carboplatin, followed by 4 cycles of dose-dense doxorubicin + cyclophosphamide. Chemotherapy resulted in a significant reduction in tumor size and improvement of health status of the patient. There were no clinically significant side effects requiring hospitalization or dose reduction. Upon completion of neoadjuvant treatment, the patient underwent mastectomy. The histological examination revealed a complete pathological response of the primary tumor and regional lymph nodes. The patient underwent adjuvant external beam radiation therapy. The patient is alive 3 years after diagnosis and 1.5 years after treatment completion. She plans delayed breast reconstruction with contralateral breast augmentation. Conclusion. This is a rare case of locally advanced triple-negative breast cancer with pathological complete response to neoadjuvant chemotherapy 15 months after diagnosis.

The 5T's of health disparities in multiple myeloma in Latin America.

Health disparities or inequities, which are defined as differences in the quality of medical and healthcare between populations among racial, ethnic, and socioeconomic groups, have been validated in numerous studies as determinants of survival and quality of life in different diseases, including cancer.Compared to the improvement in overall survival in developed countries in relation to better diagnostic opportunity and novel therapeutic approaches, low and middle-income countries still have significant barriers in accessing these therapies.The potential impact of overcoming these barriers is immense and offers hope for better outcomes. There is great heterogeneity in the diagnostic and therapeutic approach to multiple myeloma among different latitudes. Latin America has been characterized by important limitations in using the best technologies currently available in developed countries. Overcoming health disparities in multiple myeloma in LMICs could help improve survival and quality of life outcomes. Likewise, it is necessary to increase the representation of the Latin population in clinical studies, primarily in our region.

Deciphering the multidimensional impact of IGFBP1 expression on cancer prognosis, genetic alterations, and cellular functionality: A comprehensive Pan-cancer analysis

ObjectivesIGF-binding protein 1 (IGFBP1) is a key regulator of insulin-like growth factors, impacting biological processes, including cancer progression and prognosis. Materials and methodsThis study investigates genetic alterations affecting IGFBP1 expression in tumors using data from The Cancer Genome Atlas (TCGA) PanCancer Atlas via cBioPortal. We analyzed samples from 32 cancer types for mutation sites, including deep deletions, amplifications, and mutations. RNA-seq data were normalized using log2(value + 1). Statistical analyses, including survival outcomes, were conducted using R packages like ggplot2, stats, and car. Kaplan-Meier survival curves and log-rank tests assessed overall survival (OS) and progression-free survival (PFS). Univariate Cox regression was used to develop nomogram models for OS. Functional consequences of IGFBP1 mutations were explored through protein structure, stability, and IGF interaction analyses. Protein-protein interaction networks and functional enrichment were analyzed using GEPIA2, STRING, and Cytoscape. Gene Ontology (GO), KEGG, and Gene Set Enrichment Analysis (GSEA) provided insights into affected biological pathways. ResultsPan-cancer analysis revealed diverse expression patterns, including significant upregulation in cutaneous melanoma (SKCM) and downregulation in lung adenocarcinoma (LUAD) and stomach adenocarcinoma (STAD). Specifically, elevated IGFBP1 expression in SKCM patients led to a 25 % improvement in 5-year survival. In contrast, higher IGFBP1 levels in LUAD and OV patients resulted in a 30 % and 20 % decrease in survival, respectively. Elevated IGFBP1 levels are significantly linked to advanced tumor stage and grade in OV and LUAD, affecting prognostic outcomes. Nomogram models for OV, SKCM, LUAD, and STAD showed IGFBP1's predictive strength with AUC values ranging from 0.70 to 0.85, indicating its diagnostic potential. Genetic analyses revealed mutations in IGFBP1 in 12 % of STAD cases and 10 % of UCEC cases, indicating significant genetic variation. Immune analysis showed that high IGFBP1 expression significantly influenced immune cell infiltration, particularly macrophages and CD8+ T cells, thereby affecting survival in LUAD and OV. Functional enrichment and gene set enrichment analysis identified IGFBP1 involvement in crucial pathways, such as cell cycle regulation, immune response, and PD-1 signaling, highlighting its biological impact. Additionally, IGFBP1 expression delineates distinct molecular and immune subtypes, correlating with specific cancer behaviors and immune patterns. ConclusionsThese findings highlight IGFBP1's potential as a biomarker and therapeutic target, particularly for immunoregulation and cancer subtype stratification.

Use of menopausal hormone therapy before and after diagnosis and ovarian cancer survival-A prospective cohort study in Australia.

Menopausal hormone therapy (MHT) use before ovarian cancer diagnosis has been associated with improved survival but whether the association varies by type and duration of use is inconclusive; data on MHT use after treatment, particularly the effect on health-related quality of life (HRQOL), are scarce. We investigated survival in women with ovarian cancer according to MHT use before and after diagnosis, and post-treatment MHT use and its association with HRQOL in a prospective nationwide cohort in Australia. We used Cox proportional hazards regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) and propensity scores to reduce confounding by indication. Among 690 women who were peri-/postmenopausal at diagnosis, pre-diagnosis MHT use was associated with a significant 26% improvement in ovarian cancer-specific survival; with a slightly stronger association for high-grade serous carcinoma (HGSC, HR = 0.69, 95%CI 0.54-0.87). The associations did not differ by recency or duration of use. Among women with HGSC who were pre-/perimenopausal or aged ≤55 years at diagnosis (n = 259), MHT use after treatment was not associated with a difference in survival (HR = 1.04, 95%CI 0.48-2.22). Compared to non-users, women who started MHT after treatment reported poorer overall HRQOL before starting MHT and this difference was still seen 1-3 months after starting MHT. In conclusion, pre-diagnosis MHT use was associated with improved survival, particularly in HGSC. Among women ≤55 years, use of MHT following treatment was not associated with poorer survival for HGSC. Further large-scale studies are needed to understand menopause-specific HRQOL issues in ovarian cancer.

Current developments in prehabilitation in urologic oncology.

Prehabilitation describes interventions that are undertaken prior to a major surgical or medical intervention with the objective of improving functional capability with the goal of improving candidacy for therapy, bolstering one's ability to withstand treatment-associated toxicity, functional decline, and facilitating accelerated recovery. The objective of this review is to detail the key tenets of prehabilitation, synthesize contemporary advances in prehabilitation science within Urologic Oncology, and discuss key methodologic trial design considerations salient to future prehabilitation investigations. Contemporary prehabilitation clinical trials have primarily evaluated unimodal interventions aiming to improve functional capacity across the domains of physical exercise, nutrition, and cognition with heightened interest in evaluating multimodal interventions addressing two or more domains. Recent investigations have have demonstrated variable improvements in strength, balance, physical function, and quality of life with preoperative exercise. Although presurgical immunonutrition showed promise in other fields, initial results in uro-oncology have not demonstrated reductions in complications nor improvements in early survival. Emerging data supports the potential of multimodal prehabilitation programs to offer more comprehensive benefits, improving functional outcomes, reducing length of stay, and supporting improved recovery. To date, early prehabilitation studies in patients undergoing surgery for genitourinary malignancies have demonstrated variable ability to facilitate gains in functional capacity and perioperative outcomes. Key issues have arisen including the need to ensure that interventions are pragmatic, scalable, feasible, and acceptable in these populations that often also have a high prevalence of coincident multimorbidity, frailty, and mental health concerns that can increase risk of adverse outcomes after surgery. The integration of personalized prehabilitation strategies as extensions of perioperative enhanced recovery after surgery protocols, supportive care and survivorship paradigms offers of promise to further engage patients in their care, enhance patient resilience and outcomes, while reducing treatment burden in urologic oncology.

Genetically-determined defects of T cell development.

Genetically determined defects of T-cell development comprise a heterogeneous group of conditions characterized by peripheral T-cell lymphopenia due to impaired intrathymic differentiation of T-cell progenitors. Collectively, these conditions are typically referred to as severe combined immune deficiency (SCID). In some cases (leaky SCID), residual function of the defective gene allows partial T-cell development. The vast majority of SCID disorders are due to genetic defects that affect the T-cell differentiation potential of hematopoietic stem cells, through a variety of mechanisms. However, some forms of SCID reflect impaired development or function of thymic stromal cells. A lack of peripheral T cells leads to increased susceptibility to severe infections since early in life. SCID is inevitably fatal unless immune reconstitution is achieved, most often through hematopoietic cell transplantation. Enzyme replacement therapy, gene therapy, and thymus implantation represent other forms of treatment in selected cases. The availability of newborn screening has greatly facilitated prompt recognition of SCID, which allows statistically significant improvement in survival after hematopoietic cell transplantation.

785. MANAGEMENT OF ESOPHAGEAL CANCER WITH CONCURRENT CERVICAL NODE METASTASIS: A NATIONWIDE POPULATION-BASED COHORT STUDY

Abstract Background In the Netherlands, the standard treatment of locally advanced, resectable esophageal cancer without metastasis is neoadjuvant chemoradiotherapy followed by esophagectomy. There is a small subset of patients that present with concurrent cervical lymph node metastasis (LNM). Historically this was seen as distant metastasis and surgical intervention has usually not been an option for these patients. The contemporary TNM classification now categorizes these lymph node stations as locoregional disease. Our current study aims to describe current treatment paradigms in the Netherlands for patients presenting with esophageal cancer and concurrent cervical LNM. Methods This population-based cohort study utilized data from the Netherlands Cancer Registry (NCR), encompassing patients with locally advanced thoracic esophageal or gastroesophageal junction cancer and concurrent cervical lymph node metastasis. Treatment modalities were categorized into five options: neoadjuvant therapy followed by surgery (Neo + S), definitive chemoradiotherapy (dCRT), chemotherapy with or without radiotherapy &amp;lt; 30 Gray (CT), radiotherapy (RT), and best supportive care (BSC). Overall survival (OS) was assessed using the Kaplan-Meier method and compared via the log-rank test. Hazard rates were computed using Cox proportional hazards regression, with adjustment for confounding achieved through inverse probability of treatment weighting (IPTW). Results Between 2015 and 2021, a cohort of 412 patients was identified from the NCR database. Median survival durations were observed as follows: 24.2 months for Neo + S, 18.0 months for dCRT, 14.5 months for CT, 7.0 months for RT, and 3.2 months for BSC (Figure). A comparison between the Neo + S group and dCRT demonstrated a significant improvement in survival (p=0.02). Further subdivision of the surgical group into neoadjuvant CRT or chemotherapy did not reveal a significant difference in survival (p=0.6). Utilizing IPTW to adjust for confounding factors, Neo + S maintained its survival advantage. Conclusion The retrospective cohort findings suggest that neoadjuvant therapy followed by surgery may represent the optimal approach for managing esophageal cancer patients with cervical LNMs Yet, it's vital to recognize the influence of confounding by indication, which statistical adjustments may not entirely rectify. Furthermore, immortal time bias notably skews results favorably toward surgery. Nevertheless, the results emphasize the importance of considering surgery as a viable option for these patients. These limitations underscore the critical need for a prospective study, prompting the launch of the NODE-II trial.

Molecular profiling METex14+ non-small cell lung cancer (NSCLC): Impact of histology

ObjectivesMET exon 14 skipping alterations (METex14+) represent a heterogeneous subgroup of non-small cell lung cancer (NSCLC) with distinct biological and genomic features. We characterized this heterogeneity in a large cohort, integrating genomic and transcriptomic profiling with clinical outcomes, to elucidate the histologic and molecular traits and survival patterns of METex14+ NSCLC. Materials and methodsNSCLC tissue samples (n = 28,739) underwent DNA-based next-generation sequencing (592 genes, NextSeq) or whole-exome sequencing (NovaSeq), RNA-sequencing including whole transcriptome sequencing (WTS, NovaSeq), and PD-L1 IHC (Dako 22C3) at Caris Life Sciences. Immune cell fractions were estimated from bulk RNA sequencing (quanTIseq). Real-world survival data (mOS) was calculated from insurance claims. Statistical analyses employed Chi-square, Fisher’s exact, or Mann-Whitney U and log-rank tests, and were corrected for hypothesis testing where applicable. ResultsA total of 711 METex14+ cases were detected. Of 575 cases of defined histology, 77 (13.6 %) were squamous (Sq), 474 (82.3 %) were nSq (non-squamous), and 24 (4.1 %) were adenosquamous. Mutations in POT1 and BRCA2 were enriched, and amplifications in MDM2, HMGA2, CDK4, and MET were common in METex14+. TMB-high and TP53 mutated tumors were reduced in METex14+ independent of histology. KEAP1 (2.1 vs 14.7 %) and STK11 mutations (0.8 vs 17.1 %) were reduced only in METex14+ nSq (vs METex14+ Sq, q < 0.05). While the prevalence of PD-L1 high tumors was enriched in METex14+ independent of histology, T-cell inflamed tumors were enriched only in nSq METex14+. B-cells and CD8+ T-cells (1.07–1.43 fold) were enriched in nSq METex14+ and dendritic cells (0.32 fold) were reduced only in METex14+ Sq. METex14+ tumors had a modest improvement in mOS compared to METex14-tumors (mOS = 22.9 m vs 18.6 m, HR = 0.914, p = 0.04). Moreover, METex14+ tumors who received immunotherapy (IO) had a modest improvement in survival (mOS = 27.5 m vs 21.8 m; HR = 0.803, p = 0.03) compared to those who did not receive IO. METex14+ nSq tumors were associated with improved mOS compared to METex14+ Sq tumors (mOS = 27.7 vs 8.9 m, HR = 0.493, p < 0.0001). ConclusionMETex14+ alterations are a heterogeneous subgroup of NSCLC. Our analysis reveals that METex14+ nSq exhibit improved survival compared to METex14+ Sq. The distinct genomic and transcriptomic variations across histologies warrant clinical consideration.

The Discover In-Hospital Cardiac Arrest (Discover IHCA) Study: An Investigation of Hospital Practices After In-Hospital Cardiac Arrest.

In-hospital cardiac arrest (IHCA) is a significant public health burden. Rates of return of spontaneous circulation (ROSC) have been improving, but the best way to care for patients after the initial resuscitation remains poorly understood, and improvements in survival to discharge are stagnant. Existing North American cardiac arrest databases lack comprehensive data on the post-resuscitation period, and we do not know current post-IHCA practice patterns. To address this gap, we developed the Discover In-Hospital Cardiac Arrest (Discover IHCA) study, which will thoroughly evaluate current post-IHCA care practices across a diverse cohort. Our study collects granular data on post-IHCA treatment practices, focusing on temperature control and prognostication, with the objective of describing variation in current post-IHCA practice. This is a multicenter, prospectively collected, observational cohort study of patients who have suffered IHCA and have been successfully resuscitated (achieved ROSC). There are 24 enrolling hospital systems (23 in the United States) with 69 individual enrolling hospitals (39 in the United States). We developed a standardized data dictionary, and data collection began in October 2023, with a projected 1000 total enrollments. Discover IHCA is endorsed by the Society of Critical Care Medicine. The study collects data on patient characteristics including pre-arrest frailty, arrest characteristics, and detailed information on post-arrest practices and outcomes. Data collection on post-IHCA practice was structured around current American Heart Association and European Resuscitation Council guidelines. Among other data elements, the study captures post-arrest temperature control interventions and post-arrest prognostication methods. Analysis will evaluate variations in practice and their association with mortality and neurologic function. We expect this study, Discover IHCA, to identify variability in practice and outcomes following IHCA, and be a vital resource for future investigations into best-practice for managing patients after IHCA.

Poor outcome despite modern treatments: A retrospective study of 99 patients with primary and secondary plasma cell leukemia.

Plasma cell leukemia (PCL) is a rare monoclonal gammopathy, associated with short survival. Because of its very low incidence, only a few cohorts have been reported and thus, information on this disease is scarce. The goal of this study was to better understand the clinical features, prognostic factors, and efficacy of modern treatments in both primary PCL (pPCL) and secondary PCL (sPCL). We performed a retrospective, multicenter study of patients diagnosed with PCL, defined as circulating plasma cells ≥20% of total leukocytes and/or ≥2 × 109/L. We identified 99 eligible PCL patients, of whom 33 were pPCL and 66 were sPCL. The median progression-free survival (PFS) to frontline treatment and overall survival (OS) were, respectively, 4.8 (95% CI, 0.4-9.2) and 18.3 months (95% CI, 0.0-39.0) for pPCL and 0.8 (95% CI, 0.5-1.1) and 1.2 months (95% CI, 0.9-1.5) for sPCL (both p < 0.001). We observed no improvement in OS over time (2005-2012 vs. 2013-2020, p = 0.629 for pPCL and p = 0.329 for sPCL). Finally, our data suggested that sPCL originates from a high-risk multiple myeloma (MM) population with a short OS (median 30.2 months), early relapse after stem cell transplant (median 11.9 months) and a high proportion of patients with multiple cytogenetic abnormalities (36% with ≥2 abnormalities). This study is one of the largest PCL cohorts reported. We are also the first to investigate characteristics of MM before its transformation into sPCL and demonstrate that high-risk biologic features already present at the time of MM diagnosis. Moreover, our data highlights the lack of improvement in PCL survival in recent years and the urgent need for better treatment options.