Significant Improvement In Survival Research Articles

Exploring Regorafenib Responsiveness and Uncovering Molecular Mechanisms in Recurrent Glioblastoma Tumors through Longitudinal In Vitro Sampling.

Glioblastoma, a deadly brain tumor, shows limited response to standard therapies like temozolomide (TMZ). Recent findings from the REGOMA trial underscore a significant survival improvement offered by Regorafenib (REGO) in recurrent glioblastoma. Our study aimed to propose a 3D ex vivo drug response precision medicine approach to investigate recurrent glioblastoma sensitivity to REGO and elucidate the underlying molecular mechanisms involved in tumor resistance or responsiveness to treatment. Three-dimensional glioblastoma organoids (GB-EXPs) obtained from 18 patients' resected recurrent glioblastoma tumors were treated with TMZ and REGO. Drug responses were evaluated using NAD(P)H FLIM, stratifying tumors as responders (Resp) or non-responders (NRs). Whole-exome sequencing was performed on 16 tissue samples, and whole-transcriptome analysis on 13 GB-EXPs treated and untreated. We found 35% (n = 9) and 77% (n = 20) of tumors responded to TMZ and REGO, respectively, with no instances of TMZ-Resp being REGO-NRs. Exome analysis revealed a unique mutational profile in REGO-Resp tumors compared to NR tumors. Transcriptome analysis identified distinct expression patterns in Resp and NR tumors, impacting Rho GTPase and NOTCH signaling, known to be involved in drug response. In conclusion, recurrent glioblastoma tumors were more responsive to REGO compared to TMZ treatment. Importantly, our approach enables a comprehensive longitudinal exploration of the molecular changes induced by treatment, unveiling promising biomarkers indicative of drug response.

Nusinersen therapy changed the natural course of spinal muscular atrophy type 1: What about spine and hip?

Spinal muscular atrophy type 1 has a devastating natural course and presents a severe course marked by scoliosis and hip subluxation in nonambulatory patients. Nusinersen, Food and Drug Administration-approved spinal muscular atrophy therapy, extends survival and enhances motor function. However, its influence on spinal and hip deformities remains unclear. In a retrospective study, 29 spinal muscular atrophy type 1 patients born between 2017 and 2021, confirmed by genetic testing, treated with intrathecal nusinersen, and had registered to the national electronic health database were included. Demographics, age at the first nusinersen dose, total administrations, and Children's of Philadelphia Infant Test of Neuromuscular Disorders scores were collected. Radiological assessments included parasol rib deformity, scoliosis, pelvic obliquity, and hip subluxation. Mean age was 3.7 ± 1.1 (range, 2-6), and average number of intrathecal nusinersen administration was 8.9 ± 2.9 (range, 4-19). There was a significant correlation between Children's of Philadelphia Infant Test of Neuromuscular Disorders score and the number of nusinersen administration (r = 0.539, p = 0.05). The correlation between Children's of Philadelphia Infant Test of Neuromuscular Disorders score and patient age (r = 0.361) or the time of first nusinersen dose (r = 0.39) was not significant (p = 0.076 and p = 0.054, respectively). While 93.1% had scoliosis, 69% had pelvic obliquity, and 60.7% had hip subluxation, these conditions showed no significant association with patient age, total nusinersen administrations, age at the first dose, or Children's of Philadelphia Infant Test of Neuromuscular Disorders scores. Disease-modifying therapy provides significant improvements in overall survival and motor function in spinal muscular atrophy type 1. However, progressive spine deformity and hip subluxation still remain significant problems in the majority of cases which would potentially need to be addressed.

Therapeutically targeting the unique disease landscape of pediatric high-grade gliomas.

Pediatric high-grade gliomas (pHGG) are a rare yet devastating malignancy of the central nervous system's glial support cells, affecting children, adolescents, and young adults. Tumors of the central nervous system account for the leading cause of pediatric mortality of which high-grade gliomas present a significantly grim prognosis. While the past few decades have seen many pediatric cancers experiencing significant improvements in overall survival, the prospect of survival for patients diagnosed with pHGGs has conversely remained unchanged. This can be attributed in part to tumor heterogeneity and the existence of the blood-brain barrier. Advances in discovery research have substantiated the existence of unique subgroups of pHGGs displaying alternate responses to different therapeutics and varying degrees of overall survival. This highlights a necessity to approach discovery research and clinical management of the disease in an alternative subtype-dependent manner. This review covers traditional approaches to the therapeutic management of pHGGs, limitations of such methods and emerging alternatives. Novel mutations which predominate the pHGG landscape are highlighted and the therapeutic potential of targeting them in a subtype specific manner discussed. Collectively, this provides an insight into issues in need of transformative progress which arise during the management of pHGGs.

Treatment response of advanced HNSCC towards immune checkpoint inhibition is associated with an activated effector memory T cell phenotype.

Locally advanced or metastatic head and neck squamous cell carcinoma (HNSCC) is associated with a poor prognosis. The introduction of PD-1 inhibitors has led to a significant improvement in survival, but only a subpopulation of patients responds to therapy. Current biomarkers cannot reliably identify these patients. The identification of biomarkers for the prediction and monitoring of immunotherapy is therefore of great importance. In this study, we characterized lymphocyte subsets in the peripheral blood of HNSCC patients under PD-1 inhibition. Patients with primary response (n=11) to PD-1 inhibition showed an increase of the CD3+ effector memory (CD3/EM) population and an elevated expression of the activation marker CD69 in CD3+ T cells, particularly in the CD3/EM subpopulation at 3 months when treatment response was assessed. In contrast, patients with primary treatment failure and progressive disease (n=9) despite PD-1 inhibition had lower absolute lymphocyte counts and an increased expression of CTLA-4 in CD3+ T cells at the time of treatment failure compared with baseline, particularly in CD4+ and CD8+ effector memory populations. Our results demonstrate that HNSCC patients' response to immune checkpoint inhibition shows a distinct immune signature in peripheral blood, which could help identify refractory patients earlier. Furthermore, strategies to overcome primary therapy failure by inducing a beneficial T cell phenotype or adding alternative immune checkpoint inhibitors could improve response rates and survival of HNSCC patients.

Two intestinal microbiota-derived metabolites, deoxycholic acid and butyrate, synergize to enhance host defense peptide synthesis and alleviate necrotic enteritis

BackgroundNecrotic enteritis (NE) is a major enteric disease in poultry, yet effective mitigation strategies remain elusive. Deoxycholic acid (DCA) and butyrate, two major metabolites derived from the intestinal microbiota, have independently been shown to induce host defense peptide (HDP) synthesis. However, the potential synergy between these two compounds remains unexplored.MethodsTo investigate the possible synergistic effect between DCA and butyrate in regulating HDP synthesis and barrier function, we treated chicken HD11 macrophage cells and jejunal explants with DCA and sodium butyrate (NaB), either individually or in combination, for 24 h. Subsequently, we performed RNA isolation and reverse transcription-quantitative PCR to analyze HDP genes as well as the major genes associated with barrier function. To further determine the synergy between DCA and NaB in enhancing NE resistance, we conducted two independent trials with Cobb broiler chicks. In each trial, the diet was supplemented with DCA or NaB on the day-of-hatch, followed by NE induction through sequential challenges with Eimeria maxima and Clostridium perfringens on d 10 and 14, respectively. We recorded animal mortality after infection and assessed intestinal lesions on d 17. The impact of DCA and NaB on the microbiota in the ileum and cecum was evaluated through bacterial 16S rRNA gene sequencing.ResultsWe found that the combination of DCA and NaB synergistically induced multiple HDP genes in both chicken HD11 cells and jejunal explants. Additionally, the gene for claudin-1, a major tight junction protein, also exhibited synergistic induction in response to DCA and NaB. Furthermore, dietary supplementation with a combination of 0.75 g/kg DCA and 1 g/kg NaB led to a significant improvement in animal survival and a reduction in intestinal lesions compared to either compound alone in a chicken model of NE. Notably, the cecal microbiota of NE-infected chickens showed a marked decrease in SCFA-producing bacteria such as Bacteroides, Faecalibacterium, and Cuneatibacter, with lactobacilli becoming the most dominant species. However, supplementation with DCA and NaB largely restored the intestinal microbiota to healthy levels.ConclusionsDCA synergizes with NaB to induce HDP and claudin-1 expression and enhance NE resistance, with potential for further development as cost-effective antibiotic alternatives.

Treatment of Stage III Resectable Melanoma-Adjuvant and Neoadjuvant Approaches.

Patients with stage III resectable melanoma carry a high risk of melanoma recurrence that ranges from approximately 40% to 90% at 5 years following surgical management alone. Postoperative systemic adjuvant therapy targets residual micrometastatic disease that could be the source of future recurrence and death from melanoma. Randomized phase III adjuvant trials reported significant improvements in overall survival with high-dose interferon α in 2 of 3 studies (compared with observation and GMK ganglioside vaccine) and with anti-cytotoxic T-lymphocyte antigen 4 ipilimumab at 10 mg/kg compared with placebo and ipilimumab 3 mg/kg compared with high-dose interferon α. In the modern era, more recent phase III trials demonstrated significant recurrence-free survival improvements with anti-programmed cell death protein 1, pembrolizumab, and BRAF-MEK inhibitor combination dabrafenib-trametinib (for BRAF mutant melanoma) versus placebo. Furthermore, anti-programmed cell death protein 1, nivolumab and pembrolizumab have both been shown to significantly improve recurrence-free survival as compared with ipilimumab 10 mg/kg. For melanoma patients with clinically or radiologically detectable locoregionally advanced disease, emerging data support an important role for preoperative systemic neoadjuvant therapy. Importantly, a recent cooperative group trial (S1801) reported superior event-free survival rates with neoadjuvant versus adjuvant therapy. Collectively, current data from neoadjuvant immunotherapy and targeted therapy trials support a future change in clinical practice in favor of neoadjuvant therapy for eligible melanoma patients.

Peg-asparaginase associated toxicities in children with acute lymphoblastic leukemia: A single-center cross-sectional study

BackgroundLeukemia is the most prevalent type of cancer affecting children, representing approximately 35% of cancer diagnoses in Saudi Arabia. Notably, significant improvement in the overall survival and cure rates for pediatrics with acute lymphoblastic leukemia (ALL) has been attributed to adding asparaginase to the chemotherapy regimen. However, the administration of these agents may lead to a multifactorial range of toxicities that often alter treatment outcomes. ObjectiveThe study aimed to characterize the prevalence of common toxicities related to polyethylene glycol (PEG) asparaginase in children aged 0–14 years diagnosed with ALL. Additionally, it assessed the types of toxicities associated with intravenous (IV) and intramuscular (IM) administration of Peg-asparaginase. MethodIt was an observational retrospective cross-sectional study. Data was extracted from the hospital's electronic health record (EPIC). Using EPIC, we reviewed medical charts of all pediatric patients below 14 years old diagnosed with ALL who received at least one dose of PEG-asparaginase between January 2020 and March 2023. The toxicity grading was based on the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE). ResultsOne hundred and ninety-one patients with ALL were included in the study. Overall, 79 toxicity episodes were experienced by the study patients. Anaphylaxis/hypersensitivity (36.7%) and hepatotoxicity (31.6%) were the most prevalent toxicities reported, followed by pancreatitis and hyperglycemia (12.7% each). According to the CTCAE grading, approximately 70% of toxicities were categorized as Grade 3 and 4. Notably, 60% of the events occurred during the induction and consolidation phase of therapy. Interestingly, there was no significant difference in rates of toxicities between patients receiving IV or IM PEG-asparaginase. ConclusionThe distribution of toxicities highlighted in our study aligns with findings from previously published studies. Furthermore, multivariate analysis indicated that patients with high-risk ALL and T-ALL were more likely to develop toxicities compared to other forms of ALL.

Drivers of success: improving implementation research tools for better health outcomes.

A thorough examination of context, and how it influences implementation of evidence-based interventions, is a promising strategy for enhancing child survival initiatives. Spreading approaches that are identified as drivers of successful reduction in under-five mortality from 'exemplar' countries could be pivotal in leading to reductions in other settings facing stagnant mortality rates, in particular for low- and middle-income countries with high disease burden and insufficient programmatic capacity to effectively implement evidence-based interventions at scale. Yet there remains a lack of robust analytic methods to accurately assess mortality and describe the drivers of interventions' implementation success at both national and subnational levels. The field of implementation science and its defining targets and tools is well positioned to address this knowledge gap by integrating qualitative and quantitative research methods into an adaptable evaluation framework that can be tailored to meet the specific needs across varying country contexts. These tools enhance the measurement of population health outcomes and provide crucial evidence on implementation barriers and facilitators that can inform policies that can be adjusted for diverse contexts. This commentary aims to emphasize the role of implementation research in understanding how exemplar countries achieved significant improvements in child survival and in identifying replicable lessons for other settings. Ultimately, all manuscripts underscore the relevance of implementation research in bolstering the reduction of under-five mortality.

B cell receptor signaling and associated pathways in the pathogenesis of chronic lymphocytic leukemia.

B cell antigen receptor (BCR) signaling is a key driver of growth and survival in both normal and malignant B cells. Several lines of evidence support an important pathogenic role of the BCR in chronic lymphocytic leukemia (CLL). The significant improvement of CLL patients' survival with the use of various BCR pathway targeting inhibitors, supports a crucial involvement of BCR signaling in the pathogenesis of CLL. Although the treatment landscape of CLL has significantly evolved in recent years, no agent has clearly demonstrated efficacy in patients with treatment-refractory CLL in the long run. To identify new drug targets and mechanisms of drug action in neoplastic B cells, a detailed understanding of the molecular mechanisms of leukemic transformation as well as CLL cell survival is required. In the last decades, studies of genetically modified CLL mouse models in line with CLL patient studies provided a variety of exciting data about BCR and BCR-associated kinases in their role in CLL pathogenesis as well as disease progression. BCR surface expression was identified as a particularly important factor regulating CLL cell survival. Also, BCR-associated kinases were shown to provide a crosstalk of the CLL cells with their tumor microenvironment, which highlights the significance of the cells' milieu in the assessment of disease progression and treatment. In this review, we summarize the major findings of recent CLL mouse as well as patient studies in regard to the BCR signalosome and discuss its relevance in the clinics.

Glioblastoma Therapy: Past, Present and Future.

Glioblastoma (GB) stands out as the most prevalent and lethal form of brain cancer. Although great efforts have been made by clinicians and researchers, no significant improvement in survival has been achieved since the Stupp protocol became the standard of care (SOC) in 2005. Despite multimodality treatments, recurrence is almost universal with survival rates under 2 years after diagnosis. Here, we discuss the recent progress in our understanding of GB pathophysiology, in particular, the importance of glioma stem cells (GSCs), the tumor microenvironment conditions, and epigenetic mechanisms involved in GB growth, aggressiveness and recurrence. The discussion on therapeutic strategies first covers the SOC treatment and targeted therapies that have been shown to interfere with different signaling pathways (pRB/CDK4/RB1/P16ink4, TP53/MDM2/P14arf, PI3k/Akt-PTEN, RAS/RAF/MEK, PARP) involved in GB tumorigenesis, pathophysiology, and treatment resistance acquisition. Below, we analyze several immunotherapeutic approaches (i.e., checkpoint inhibitors, vaccines, CAR-modified NK or T cells, oncolytic virotherapy) that have been used in an attempt to enhance the immune response against GB, and thereby avoid recidivism or increase survival of GB patients. Finally, we present treatment attempts made using nanotherapies (nanometric structures having active anti-GB agents such as antibodies, chemotherapeutic/anti-angiogenic drugs or sensitizers, radionuclides, and molecules that target GB cellular receptors or open the blood-brain barrier) and non-ionizing energies (laser interstitial thermal therapy, high/low intensity focused ultrasounds, photodynamic/sonodynamic therapies and electroporation). The aim of this review is to discuss the advances and limitations of the current therapies and to present novel approaches that are under development or following clinical trials.

The Impact of Initial Tumor Response on Survival Outcomes of Patients With HER2-Positive Advanced Breast Cancer Treated With Docetaxel, Trastuzumab, and Pertuzumab: An Exploratory Analysis of the CLEOPATRA Trial

IntroductionThe CLEOPATRA trial (NCT00567190) established a dual anti-HER2 blockade in combination with docetaxel as the first-line standard of care for patients with metastatic HER2-positive breast cancer. While this treatment is overall associated with significant improvement in progression-free survival (PFS) and overall survival (OS), not all patients respond equally. We hypothesized that a radiological complete response (CR) at week 9 (i.e., first disease re-evaluation) is associated with prolonged OS and PFS compared to radiological partial response (PR) or stable disease (SD). MethodsWe performed an exploratory analysis of the CLEOPATRA study to address this question. ResultsOut of 362 patients treated with docetaxel, trastuzumab, and pertuzumab eligible for our analysis, 46 (12.7%) had radiological CR at week 9, 243 (67.1%) PR, and 73 (20.2%) SD per central RECIST v1.0. Radiological CR at first tumor re-evaluation was associated with a 60% risk reduction for death compared to SD (adjusted HR = 0.40 95% confidence interval (CI) 0.23-0.70), whereas no significant impact on survival was observed for PR (adjusted HR = 0.85 95% CI 0.60-1.20). The same was observed for PFS with adjusted HR = 0.30 (95% CI 0.18-0.48) for the CR subgroup and adjusted HR = 0.81 (95% CI 0.60-1.09) for the PR subgroup. In multivariate analysis, no variables were associated with radiological CR. ConclusionsOur findings suggest that radiological CR at first disease re-evaluation is associated with more prolonged survival; this might result from stronger dependence on HER2 pathway addiction, supporting the need for further translational research.

Inhaled delivery of cetuximab-conjugated immunoliposomes loaded with afatinib: A promising strategy for enhanced non-small cell lung cancer treatment.

Afatinib (AT), an FDA-approved aniline-quinazoline derivative, is a first-line treatment for metastatic non-small cell lung cancer (NSCLC). Combining it with cetuximab (CX), a chimeric human-murine derivative immunoglobulin-G1 monoclonal antibody (mAb) targeting the extracellular domain of epidermal growth factor receptor (EGFR), has shown significant improvements in median progression-free survival. Previously, we developed cetuximab-conjugated immunoliposomes loaded with afatinib (AT-MLP) and demonstrated their efficacy against NSCLC cells (A549 and H1975). In this study, we aimed to explore the potential of pulmonary delivery to mitigate adverse effects associated with oral administration and intravenous injection. We formulated AT-MLP dry powders (AT-MLP-DPI) via freeze drying using tert-butanol and mannitol as cryoprotectants in the hydration medium. The physicochemical and aerodynamic properties of dry powders were well analyzed firstly. In vitro cellular uptake and cytotoxicity study revealed concentration- and time-dependent cellular uptake behavior and antitumor efficacy of AT-MLP-DPI, while Transwell assay demonstrated the superior inhibitory effects on NSCLC cell invasion and migration. Furthermore, in vivo pharmacokinetic study showed that pulmonary delivery of AT-MLP-DPI significantly increased bioavailability, prolonged blood circulation time, and exhibited higher lung concentrations compared to alternative administration routes and formulations. The in vivo antitumor efficacy study carried on tumor-bearing nude mice indicated that inhaled AT-MLP-DPI effectively suppressed lung tumor growth.

Improving response time and survival in ward based in-hospital cardiac arrest: A quality improvement initiative

BackgroundSurvival in cardiac arrest is associated with rapid initiation of high-quality cardiopulmonary resuscitation (CPR) and advanced life support. To improve ROSC rates and survival, we identified the need to reduce response times and implement coordinated resuscitation by dedicated cardiac arrest teams (CATs). We aimed to improve ROSC rates by 10% within 6 months, and subsequent survival to hospital discharge. MethodsWe used the Model for Improvement to implement a ward-based cardiac arrest quality improvement (QI) initiative across 3 Plan-Do-Study-Act (PDSA) cycles. QI interventions focused on instituting dedicated CATs and resuscitation equipment, staff training, communications, audit framework, performance feedback, as well as a cardiac arrest documentation form. The primary outcome was the rate of ROSC, and the secondary outcome was survival to hospital discharge. Process measures were call center processing times, CAT response times and CAT nurses’ knowledge and confidence regarding CPR. Balancing measures were the number of non-cardiac arrest activations and the number of cardiac arrest activations in patients with existing do-not-resuscitate orders. ResultsAfter adjustments for possible confounders in the multivariate analysis, there was a significant improvement in ROSC rate post-intervention as compared to the pre-intervention period (OR 2.05 [1.04–4.05], p = 0.04). Median (IQR) call center processing times decreased from 1.8 (1.6–2.0) pre-intervention to 1.4 (1.4–1.6) minutes post-intervention (p = 0.03). Median (IQR) CAT response times decreased from 5.1 (4.5–7.0) pre-intervention to 3.6 (3.4–4.3) minutes post-intervention (p < 0.001). After adjustments for possible confounders in the multivariate analysis, there was no significant improvement in survival to hospital discharge post-intervention as compared to the pre-intervention period (OR 0.71 [0.25–2.06], p = 0.53). ConclusionImplementation of a ward-based cardiac arrest QI initiative resulted in an improvement in ROSC rates, median call center and CAT response times.

Efficacy of Cisplatin-Containing Chemotherapy Regimens in Patients of Pancreatic Ductal Adenocarcinoma: A Systematic Review and Meta-analysis.

The relative success of cisplatin-based chemotherapy regimens for PDAC in clinical trials warrants a review of the literature to assess the cumulative results. This study aims to assess the efficacy of cisplatin-containing regimens for PDAC in terms of survival and response outcomes using a systematic review and proportional meta-analysis. In this study, an electronic search was conducted on PubMed, Cochrane Library, Scopus, and Google Scholar to find relevant literature. The random effects model was used to assess pooled overall response rate, stable disease rate, progressive disease rate, 1-year overall survival rate, and their 95% CIs. Publication bias was assessed using funnel plot symmetry and the one-tailed Eggers' test. In all cases, p-value < 0.05 was indicative of significant results. The review is registered with PROSPERO: CRD42023459243. A total of 34 studies consisting of 1599 patients were included in this review. All the included studies were of good quality. In total, 906 patients were male, and the median age of the patients was 58-69years. Overall, 599 patients had cancer of the pancreatic head, 139 had cancer of the pancreatic body, and 102 patients had cancer of the pancreatic tail. The pooled risk ratios (RRs) revealed an overall response rate of 19.2% (95% CI, 14.6-24.2%), a stable disease rate of 42.3% (95% CI, 36.6-48.8), a 1-year overall survival rate of 40% (95% CI, 34.3-45.8), and progressive disease rate of 24.7% (95% CI, 18.8-31.2). Commonly reported adverse events were anemia, thrombocytopenia, abdominal adverse events, neutropenia, fatigue, leukopenia, alopecia, anorexia, mucositis, stomatitis, and hepatobiliary adverse events. Cisplatin-containing regimens have shown moderate efficacy with significant improvement in overall survival at 1year, stable disease rate, and progressive disease rate; however, only a small percentage of patients achieved an overall response rate.

A Meta-Analysis and Review of Radiation Dose Escalation in Definitive Radiation Therapy between Squamous Cell Carcinoma and Adenocarcinoma of Esophageal Cancer

Esophageal cancer, ranked as the eighth most prevalent cancer globally, is characterized by a low survival rate and poor prognosis. Concurrent chemoradiation therapy (CCRT) is the standard therapy in the non-surgical treatment of localized carcinoma of the esophagus. Nevertheless, the radiation doses employed in CCRT remain notably lower compared to the curative definite chemoradiation therapy utilized in the management of other carcinomas. In order to increase the local control rates and enhance the treatment outcomes, several clinical trials have used high-dose radiation to analyze the effect of dose escalation. Despite the integration of technically advanced RT schemes such as intensity-modulated radiation therapy (IMRT), the results of these trials have failed to demonstrate a significant improvement in overall survival or local progression-free survival. In this review, we investigated previous clinical trials to determine the ineffectiveness of radiation dose escalation in the context of CCRT for esophageal cancer. We aim to clarify the factors contributing to the limited efficacy of escalated radiation doses in improving patient outcomes. Furthermore, we delve into recent research endeavors, exploring prospective radiation dose modifications being altered based on the histological characteristics of the carcinoma. The exploration of these recent studies not only sheds light on potential refinements to the existing treatment protocols but also seeks to identify novel approaches that may pave the way for more efficacious and personalized therapeutic strategies for esophageal cancer management.

Prognostic impact of cooccurring mutations in FLT3-ITD pediatric acute myeloid leukemia

AbstractWe sought to define the cooccurring mutational profile of FLT3-ITD–positive (ITDpos) acute myeloid leukemia (AML) in pediatric and young adult patients and to define the prognostic impact of cooperating mutations. We identified 464 patients with FLT3-ITD mutations treated on Children’s Oncology Group trials with available sequencing and outcome data. Overall survival, event-free survival (EFS), and relapse risk were determined according to the presence of cooccurring risk stratifying mutations. Among the cohort, 79% of patients had cooccurring alterations across 239 different genes that were altered through mutations or fusions. Evaluation of the prognostic impact of the cooccurring mutations demonstrated that patients with ITDpos AML experienced significantly different outcomes according to the cooccurring mutational profile. Patients with ITDpos AML harboring a cooccurring favorable-risk mutation of NPM1, CEBPA, t(8;21), or inv(16) experienced a 5-year EFS of 64%, which was significantly superior to of 22.2% for patients with ITDpos AML and poor-risk mutations of WT1, UBTF, or NUP98::NSD1 as well to 40.9% for those who lacked either favorable-risk or poor-risk mutation (ITDpos intermediate; P < .001 for both). Multivariable analysis demonstrated that cooccurring mutations had significant prognostic impact, whereas allelic ratio had no impact. Therapy intensification, specifically consolidation transplant in remission, resulted in significant improvements in survival for ITDpos AML. However, patients with ITDpos/NUP98::NSD1 continued to have poor outcomes with intensified therapy, including sorafenib. Cooccurring mutational profile in ITDpos AML has significant prognostic impacts and is critical to determining risk stratification and therapeutic allocation. These clinical trials were registered at www.clinicaltrials.gov as NCT00002798, NCT00070174, NCT00372593, and NCT01371981.

Patient-reported outcomes (PROs) with talazoparib (TALA) plus enzalutamide (ENZA) vs. placebo (PBO) plus ENZA in men with metastatic castration-resistant prostate cancer (mCRPC): Subgroup analysis of patients with novel hormonal therapy (NHT) pretreatment in the TALAPRO-2 study.

116 Background: In TALAPRO-2 (NCT03395197), TALA +ENZA vs PBO + ENZA demonstrated significant improvement in radiographic progression-free survival, a manageable adverse event (AE) profile, and a delay in time to definitive clinical meaningful deterioration in global health status (GHS)/quality of life (QoL) overall and across all pre-specified subgroups. This post hoc analysis evaluated PROs in patients with prior NHT treatment. Methods: PROs were assessed on day 1 and scheduled visits (every 4 weeks until week 53 then every 8 weeks) until radiographic progression using the EORTC QLQ-C30 and its prostate cancer module, QLQ-PR25. PRO analyses, performed in NHT-pretreated/ patients for GHS/QoL functional and symptom scales, included on treatment comparison of overall change from baseline (per longitudinal repeated measures mixed-effects model). Results: Of the 805 men randomized and treated, 49 patients were included in this subgroup analysis (TALA + ENZA n= 22, PBO + ENZA n= 27). A statistically significant and clinically meaningful estimated overall change from baseline favored TALA + ENZA in physical functioning (20.5 [95% confidence interval {CI}: 8.8, 32.2]; P=0.0007), role functioning (20.4 [95% CI 4.8, 35.9]; P=0.0103), pain (32.9 [95% CI 50.3, 15.5]; P=0.0002), and constipation (12.5 [24.4, 0.6]; P=0.0399). No significant differences disfavoring TALA + ENZA were observed. Conclusions: In these subgroup analyses of NHT pretreated patients, significant differences in PROs favoring TALA + ENZA were observed. Results should be interpreted with caution given the small sample sizes and exploratory nature of this analysis. Clinical trial information: NCT03395197 .

Canine Parvoviral Enteritis Mortality in Shelter Dogs Receiving Conventional Medical Therapy Compared to Integrative Treatment with the Chinese Herbal Medicine, Zhi Li Tang: A Pilot Study

Canine parvoviral (CPV) enteritis is a contagious infection, which particularly affects young dogs, and is associated with high morbidity and mortality rates in the canine population. This study sought to determine whether including the Chinese herbal medicine formula, Zhi Li Tang (ZLT, Red Back Door), in conjunction with conventional therapy can decrease mortality of shelter dogs with CPV enteritis. Nineteen canine subjects from a shelter population diagnosed with CPV enteritis were randomly assigned to a Control Group which received conventional supportive treatment, or an Integrative Treatment Group which received ZLT along with conventional supportive treatment. Study duration was 14 days unless the subject died, or all clinical signs associated with CPV enteritis had resolved. The outcome measurement was a binary response of mortality within the 14-day trial. In the Control Group, there was a 43% (3/7) mortality rate compared to 0% mortality in the Integrative Treatment Group (12/12, all dogs recovered) within the 14-day study period. All subjects that survived in both study groups had resolution of CPV clinical signs by the end of the study. Despite the small sample size in this pilot study, there was a statistically significant (p=0.036) improvement in survival for the dogs receiving Zhi Li Tang in addition to conventional therapy when compared to the dogs receiving conventional therapy only. The results from this study suggest integrating ZLT with conventional treatment of CPV enteritis could reduce mortality from CPV infections in shelter dogs. Further investigation of these findings with larger studies is needed to confirm study results.

First-line PARP inhibitors (PARPi) with androgen receptor pathway inhibitors (ARPi) in metastatic castration-resistant prostate cancer (mCRPC): A systematic review and meta-analysis.

173 Background: The data for combining PARPi and ARPi in mCRPC have shown conflicting results. Here, we report a quantitative summary of benefits by clinically meaningful subgroups (HRR mutation status, BRCA mutation status) to guide the use of PARPi and ARPi combination in mCRPC setting. Methods: MEDLINE, EMBASE, and CENTRAL were systematically searched from each database’s inception through September 7, 2023. Phase III studies comparing PARPi + ARPi with ARPi + placebo in mCRPC were included. Radiographic progression-free survival (rPFS) and overall survival (OS) in patient subgroups based on HRR and BRCA mutation status were assessed. Hazard ratios for rPFS and OS with 95% CI were collected at the level of each trial, and a random-effects meta-analysis was conducted using an inverse variance approach. Subgroup differences were assessed and p-value of interaction &lt;0.1 was considered statistically significant. Results: The literature search identified 4976 studies from which 3 trials (11 references) – TALAPRO2, PROpel and MAGNITUDE met the inclusion criteria. A total of 2254 participants were eligible for analysis. PARPi + ARPi prolonged rPFS in patients with HRR mutations (HR: 0.55, 95%CI: 0.38-0.78) as well as in patients without HRR mutations (HR: 0.74, 95%CI: 0.63-0.88). There is no evidence of treatment interaction by HRR mutation status (p = 0.14). In patients harboring HRR mutations, improved rPFS was observed in those with BRCA mutations (HR: 0.28, 95%CI: 0.13-0.62) as well as those without BRCA mutations (HR: 0.72, 95%CI: 0.59-0.87). However, there is evidence that patients with BRCA mutations derived greater rPFS benefit as compared to patients without BRCA mutations (p =0.02). PARPi + ARPi showed no significant improvement in overall survival either in patients with HRR mutations (HR: 0.79, 95%CI: 0.59-1.05) or in patients without HRR mutations (HR: 0.92, 95%CI: 0.74-1.14). Conclusions: Genomic testing for HRR genes is mandatory to guide clinical decision making in mCRPC patients. Patients harboring BRCA mutations are most likely to derive clinically meaningful benefit from combination PARPi + ARPi treatment. [Table: see text]

Optimal timing of delayed cytoreductive nephrectomy in metastatic renal cell carcinoma during the immunotherapy era.

403 Background: The CARMENA study found no survival benefit from cytoreductive nephrectomy (CN) in poor-risk metastatic renal cell cancer (mRCC) patients treated with first line Sunitinib. Although retrospective studies have reported survival benefits with CN following immunotherapy (IO)-based therapy, the timing remains unclear. We aimed to investigate the ideal timing of CN following IO using the National Cancer Database. Methods: 783 patients with de novo mRCC were diagnosed between 2016 and 2020 who received upfront systemic therapy and underwent CN, 343 patients met our criteria. Patients were categorized into four groups based on the timing of nephrectomy: CN ≤3 months (Group A), 4 to 6 months (Group B), 7 to 9 months (Group C) and ≥ 10 months (Group D) following the initiation of IO-based therapy. Descriptive analysis was performed to examine the demographic and clinical characteristics. Follow up time was measured from the date of surgery to reduce bias. Kaplan-Meier plots were used to analyze survival curves, and a multivariable cox regression analysis was performed to explore associations between timing and survival. Results: 343 patients who received upfront IO -based therapy were divided into four groups: 104 (30%) in A, 114 (33%) in B, 74 (22%) in C and 51 (15%) in D. 71%were male, white (90%), age 40 – 64 (62%), comorbidity index 0 (70%), clear cell histology (69%), sarcomatoid (14%). 54% were treated in academia, 57% had bone metastasis, 50% had lung, 11% had liver, and 7% had brain metastases. 66% received only IO, and 34% received IO + TKI. No significant association between CN timing and survival observed in multivariate cox regression model. (HR 0.87, 95% CI: 0.5- 1.7, p = 0.84). Compared to group A, the HR were 0.96 (95% CI, 0.73 to 1.27; p=0.78), 0.77 (95% CI, 0.53 to 1.13; p=0.19), and 0.66 (95% CI, 0.37 to 1.20; p=0.17) respectively for groups B, C and D. Conclusions: Our study did not find significant survival improvement with an optimal timing of CN following IO-based therapy, while HRs were reduced after 6 months of delay, though insignificant. This could be due to the small sample size or other confounders.