Significant Improvement In Survival Research Articles

Abstract 3830: Comparison of individual patient data from real-world experience with the ADAURA study for resected stage IB-IIIA EGFR-mutated non-small cell lung cancer

Abstract Introduction: In recent data of ADAURA study, adjuvant osimertinib demonstrated clinically significant improvement in overall survival in completely resected stage IB-IIIA with epidermal growth factor receptor (EGFR)-mutated NSCLC. Among 205 patients who experienced recurrence in the placebo arm, 89.8% of patients received subsequential treatment and 79.0% of patients in the placebo arm received EGFR-TKI after recurrence. Methods: This study included patients with completely resected EGFR-mutated NSCLC who confirmed to pathologic stage II-IIIA between November 2015 and February 2019 at Samsung Medical Center (SMC data). They did not receive adjuvant EGFR-TKI. To compare overall survival between the SMC data and the ADAURA study, the individual patient data (IPD) approach was applied. We assessed the overall survival of individual patient data from real-world experience in comparison to the ADAURA study. Results: A total of 547 patients were included in this study, with 51.0% at stage IB, 23.8% at stage II, and 25.2% at stage IIIA. The median follow-up duration was 71.4 months (range 1-92). At the time of data lock, 241 patients experienced recurrence in the SMC data. Among them, 230 patients (95.4%) received subsequent treatment, and 214 patients (88.8%) received EGFR-TKI after recurrence. In the stage IB and II, there was no difference of overall survival between the SMC data (reference) and the osimertinib arm of the ADAURA study (HR=0.83, 95% CI, 0.36-1.90, p=0.66 in stage IB; HR=1.08, 95% CI, 0.58-2.03, p=0.81 in stage II). However, in the stage IIIA, the 5-year survival rate was 68% in the SMC data and 85% in the osimertinib arm of the ADAURA study (HR=0.42, 95% CI, 0.24-0.73, p<0.01). In the stage IB-IIIA, the 5-year survival rate was 85% in the SMC data (reference), 78% (HR=1.68, 95% CI, 1.25-2.25, p<0.01) in the placebo arm of the ADAURA study, and 88% (HR=0.81, 95% CI, 0.56-1.16, p=0.24) in the osimertinib arm of the ADAURA study. In the stage II-IIIA, the 5-year survival rate was 77% in the SMC data (reference), 73% (HR=1.29, 95% CI, 0.92-1.82, p=0.14) in the placebo arm of the ADAURA study, and 85% (HR=0.62, 95% CI, 0.41-0.93, p= 0.02) in the osimertinib arm of the ADAURA study. Conclusions: In this study, the majority of patients received EGFR-TKIs after recurrence. The 5-year overall survival in the real-world data demonstrated superiority over the placebo arm of the ADAURA study. In stage IB and II disease, there was no significant difference between the SMC data and the osimertinib arm of the ADAURA study. Consequently, patients with pathologic stage IIIA are considered strong candidates for adjuvant osimertinib. Citation Format: Hyun Ae Jung, Junho Lee, Boram Park, Sehhoon Park, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Myung-Ju Ahn. Comparison of individual patient data from real-world experience with the ADAURA study for resected stage IB-IIIA EGFR-mutated non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3830.

Abstract 3201: Preclinical development of a novel Romidepsin nanoparticle for the treatment of T-Cell lymphoid malignancies

Abstract The histone deacetylase inhibitors (HDACi) have long been regarded as an important class of drugs for treating T-cell lymphoid malignancies (TCL). Romidepsin (Romi), a bicyclic peptide, was approved for patients with relapsed or refractory cutaneous (CTCL) and peripheral T-cell lymphomas (PTCL). Unfortunately, the approval of Romi for relapsed/refractory PTCL was withdrawn due to a negative Phase 4 post-marketing requirement. Given its potent activity against Class I HDACs, Romi is considered one of the most effective HDAC inhibitors studied and used in patients with TCL. Herein, we report on a first-in-class nanoparticle of Romi (NanoRomi) with a superior safety and efficacy profile compared to the free drug in preclinical models of PTCL and large granular lymphocyte leukemia (LGLL). We developed a first-in-class NanoRomi using our proprietary amphiphilic di-block copolymer-based nanochemistry platform. NanoRomi was characterized in cell viability, flow cytometry, and western blotting (WB) assays to determine the concentration-effect relationships with regard to the induction of apoptosis and histone acetylation in cell lines representative of TCL and LGLL, as well as primary LGLL patient PBMC samples. In addition, we performed extensive in vivo modeling using murine xenografts of CTCL, including repeated dose toxicity, biodistribution, efficacy, and survival studies. Cytotoxicity assays demonstrated superior/comparable activity of NanoRomi (IC50: 1.1-2.3 nM) compared to free Romi (IC50: 4.8-10.6 nM) across all PTCL and LGLL cell lines studied, while in primary LGLL samples, NanoRomi exhibited superior cytotoxicity (2-fold) compared to Romi. WB analysis showed that NanoRomi induced apoptosis and increased acetylation of histone H3 and H4 in a time and concentration-dependent manner in cell lines representing CTCL, ALK+-ALCL, and LGLL. Repeat dose toxicity studies in CTCL xenografts confirmed that the overall tolerability of NanoRomi was substantially better than Romi. Tracking studies with a fluorescent dye (DiO) in the NanoRomi demonstrated preferential localization of NanoRomi in tumors of mice compared to the normal organs after 6 hours of drug administration. NanoRomi exhibited superior efficacy in the murine CTCL xenograft models, including a significant improvement in overall survival compared to Romi. Collectively, these data show that NanoRomi exhibits markedly superior pharmacokinetics, tolerability, and efficacy in models of TCL. We anticipate that the improved activity and tolerability of NanoRomi relate to the altered pharmacologic profile and superior bioavailability of the drug, which optimizes the effects of the drug for its influence on epigenetic biology. This unique platform offers the prospect of improving the tolerability and efficacy of epigenetic treatment strategies in these challenging diseases. Citation Format: Ipsita Pal, Anuradha Illendula, Andrea Joyner, Tess M. Deddens, Deepthi P. Damera, Todd E. Fox, Marya E. Dunlap-Brown, Kallesh D. Jayappa, Thomas P. Loughran, David J. Feith, Owen A. O'Connor. Preclinical development of a novel Romidepsin nanoparticle for the treatment of T-Cell lymphoid malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3201.

Abstract 6641: Improving response to bladder-sparing therapies by combining radiotherapy to immuno-potentiating agents in immunologically cold models of bladder cancer

Abstract INTRODUCTION: Radiation therapy (RT) is a promising approach for bladder-sparing in muscle-invasive bladder cancer (MIBC). Despite its efficacy, 30% of patients develop radioresistant tumors necessitating salvage surgery. Combining RT with immune checkpoint inhibitor was reported to have synergic effects on anti-tumor immunity. In addition, activation of the STING pathway induces cell death, cancer cell antigens release and presentation, and promote T cells trafficking into tumors. Previous in vivo results from our team using the immunologically ‘hot’ murine tumor model MB49 demonstrated significant improvement of survival and immune cell infiltration upon STING agonist treatment, when combined with RT and anti-PDL1 treatment. Oppositely, treating the ‘cold’ tumor model UPPL with a combination of RT and anti-PDL1 treatment did not improve survival compared to RT alone. Consistently, UPPL tumors present low T cell and high neutrophil infiltration in vivo. Thus, the main objective of the present study is to evaluate whether combining RT, anti-PDL-1 and STING agonist treatments can improve the immunogenicity of UPPL tumors. METHODS: Male C57BL/6 mice were subcutaneously injected with 5.106 UPPL cells then randomized into various treatment combinations of RT, anti-PDL-1 and STING agonist. Midpoint and endpoint tumors were harvested for flow cytometry and IHC and stools for 16S-sequencing. RESULTS: We report that RT-combined treatments delayed tumor growth and prolonged survival in vivo. Neighborhood analyses in tissue revealed that response to RT combinations associated with increased macrophages density in the vicinity of infiltrating CD8+ T cells and with gut enrichment in Faecalibaculum, Bifidobacterium, and Candidatus arthomitus. Network analyses showed strong positive correlations between pro-tumor neutrophil recruitment and beneficial gut microbes in non-responders. Network analyses revealed positive correlations between pro-tumor neutrophil recruitment and dysbiotic gut microbes in non-responders. Conversely, these same neutrophil populations were associated to families associated to gut health in responding mice. CONCLUSIONS: Our results suggest combining RT in cold tumors enhances the TME, boosting T cell function via macrophage support. Furthermore, distal gut microbes may impact local anti-tumor immunity by influencing neutrophil polarization. This study contributes to the limited literature exploring immune modulation in a conventionally 'cold' bladder tumor cell lines, which has implications for treating human resistant tumors. Citation Format: Eva Michaud, Sabina Fehric, Gautier Marcq, JiaMin Huang, Fabio Cury, Madhuri Koti, José Joao Mansure, Ciriaco Piccirillo, Wassim Kassouf. Improving response to bladder-sparing therapies by combining radiotherapy to immuno-potentiating agents in immunologically cold models of bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6641.

Comparison of the prognostic value of lymph node yield, lymph node ratio, and number of lymph node metastases in patients with oral squamous cell carcinoma.

The aim of this study was to assess the prognostic significance of lymph node yield (LNY), lymph node ratio (LNR), and the number of lymph node metastases (LNMs) in patients affected by oral squamous cell carcinoma (OSCC). The study included patients who underwent surgical treatment for primary OSCC. Receiver operating characteristic curves were generated to determine the optimal threshold values. Kaplan-Meier curves were employed, along with the log-rank test, for the analysis of survival. To compare the performance in terms of model fit, we computed Akaike's information criterion (AIC). This study enrolled 429 patients. Prognostic thresholds were determined at 22 for LNY, 6.6% for LNR, and 3 for the number of LNMs. The log-rank test revealed a significant improvement in both overall survival and progression-free survival for patients with a LNR of ≤6.6% or a number of LNMs of ≤3 (p < 0.05). Interestingly, LNY did not demonstrate prognostic significance. The AIC analyses indicated that the number of LNMs is a superior prognostic indicator compared to LNY and LNR. Incorporating LNR or the number of LNMs into the TNM classification has the potential to improve the prognostic value, as in other types of cancers. Particularly, the inclusion of the number of LNMs should be contemplated for future N staging.

O93: Calcium channel blockers are associated with improved survival in pancreatic cancer patients undergoing neoadjuvant chemotherapy and resection

Abstract Background Repurposing existing drugs for use in oncology is more safe, efficient and cost-effective than novel drug discovery. Calcium signalling is increasingly recognised to have a key role in chemoresistance and many of the hallmarks of cancer. This study aims to assess the impact of calcium channel blockers (CCB) in pancreatic cancer. Methods Retrospective population study including patients in the SEER-Medicare linked database who underwent resection with curative intent of pancreatic ductal adenocarcinoma diagnosed between 2007 and 2017. Adjusted cox regression models were built to assess the impact on overall survival. As laboratory studies suggest a chemosensitising effect, we assessed the impact of CCB separately in patients receiving chemotherapy. Results 6,223 patients were included, of whom 660 were prescribed CCB. 591 patients received neoadjuvant chemotherapy prior to resection; in this cohort CCB prescription was associated with a significant improvement in overall survival when adjusting for multiple prognostic factors (aHR=0.715, 0.514-0.996, P=0.047). This effect was not observed in patients who did not receive neoadjuvant chemotherapy (aHR=1.082, 0.982-1.191, P=0.112), or in the overall cohort (aHR=1.056, 0.963-1.158, P=0.248), suggesting a chemosensitising effect. Discussion CCB prescription was associated with improved overall survival in patients receiving neoadjuvant chemotherapy prior to pancreatic cancer resection. The association was specific to the group of patients receiving neoadjuvant chemotherapy. This indicates a chemosensitising effect of CCB, which mirrors previous laboratory studies. This study defines those receiving neoadjuvant chemotherapy as a target population for prospective clinical trials of CCB in pancreatic cancer.

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.