Response Survival Research Articles

Abstract 6010: BRCA2 reversion alleles confer PARPi resistance via homology-directed repair, not fork protection

Abstract BRCA2 reversion alleles have been identified in relapsed, treatment resistant cancer patients. The reversions restore the open reading frame of the BRCA2 protein often resulting in significant sequence deletions with unknown functional consequences. No reports to date have introduced patient reversion mutations into a BRCA2 null cell model to analyze which BRCA2 functions are re-established and whether all or a subset of activities are required for PARPi resistance. Our study utilized BRCA2 reversion alleles identified through sequencing of circulating tumor DNA (ctDNA) from PARPi resistant ovarian cancer patients. We rigorously evaluated whether altered BRCA2 reversion proteins restore homology-directed repair (HDR), fork protection, or gap suppression to determine the specific activities required for PARPi resistance. We found that reverted BRCA2 proteins are functional for HDR by assessing survival response to PARPi, analyzing RAD51 foci at DSBs, DR-GFP reporter assays, RAD51 binding, and CRISPR/Cas9 gene targeting assays. Surprisingly, using the DNA fibercombing approach to assess replication fork dynamics, we identify two separation-of-function mutants, T1974 and C1654_M1890, which are deficient in fork protection, yet confer PARPi resistance. The mutations are located within the BRC 5-8 domain of BRCA2 proposed to play an important role in RAD51 nucleoprotein filament stability. Biochemical analyses of the purified proteins using single molecule FRET (smFRET) indicate reduced filament stability potentially explaining the deficit in fork protection. In conclusion, these separation-of-function BRCA2 mutations provide new mechanistic insight into the underlying biology of BRCA2 and reveal the specific functions needed to overcome PARPi-mediated cell death. Citation Format: Ryan Jensen, Gemma Moore, Sudipta Lahiri. BRCA2 reversion alleles confer PARPi resistance via homology-directed repair, not fork protection [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 6010.

Survival, immune response and growth of Penaeid shrimp as affected by immunostimulants: A meta-analysis

Immunostimulants represent the most innovative approach for combating shrimp diseases. They are molecules that effectively enhance the host's nonspecific defenses against invading microorganisms. However, methodological differences exist among immunostimulants based on the same source. Therefore, conducting a meta-analysis is essential to derive valid conclusions. The effect size value utilized in this study was Hedges' d. Heterogeneity among studies was assessed using the DerSimonian and Laird tests (Q-statistic). Meta-regression analysis was conducted to explore the sources of heterogeneity in treatment effects. In this study, dose served as a covariate because it was the only continuous variable that significantly contributed to the observed heterogeneity. Funnel plots and the fail-safe number were employed to assess publication bias within the datasets. The article collection process followed the PRISMA methodology. Based on the results of the meta-analysis and meta-regression conducted with 83 articles, it can be concluded that immunostimulants have a significant effect, characterized by high category standard mean difference (SMD) values, on the survival, growth, and immune response of Penaeid family shrimp. Among potential immunostimulants options, algae ingredients exhibited the most favorable effects on the survival, growth, and immune response of Penaeid family shrimp. Subgroup analysis outcomes revealed that various extraction methods significantly impacted the efficacy of immunostimulants, with the ethanol solvent method proving to be the most effective. Among different administration methods, no significant effect was observed on immunostimulant efficacy across all parameters, with positive SMD values for all administration methods. Regarding challenged test pathogens, immunostimulants were observed to enhance immune response, survival, and weight gain against various pathogens. Meta-regression results indicated that algal treatments had a lower optimal dose point, leading to decreased efficacy as the dose increased. In contrast, fungi exhibited a higher optimum dose point, resulting in increased efficacy at higher doses.

High-Loading-Dose Colistin with Nebulized Administration for Carbapenem-Resistant Acinetobacter baumannii Pneumonia in Critically Ill Patients: A Retrospective Cohort Study.

Carbapenem-resistant Acinetobacter baumannii (CRAB) infections pose a serious threat, with high morbidity and mortality rates. This retrospective cohort study, conducted at Nakornping Hospital between January 2015 and October 2022, aimed to evaluate the efficacy and safety of a high loading dose (LD) of colistin combined with nebulized colistin in critically ill patients with CRAB pneumonia. Of the 261 patients included, 95 received LD colistin, and 166 received LD colistin with nebulized colistin. Multivariate Cox regression analysis, adjusted for baseline covariates using inverse probability weighting, showed no significant difference in 30-day survival between patients who received LD colistin and those who received LD colistin with nebulized colistin (adjusted hazard ratio [aHR]: 1.17, 95% confidence interval [CI]: 0.80-1.72, p = 0.418). Likewise, there were no significant differences in clinical response (aHR: 0.93, 95% CI: 0.66-1.31, p = 0.688), microbiological response (aHR: 1.21, 95% CI: 0.85-1.73, p = 0.279), or nephrotoxicity (aHR: 1.14, 95% CI: 0.79-1.64, p = 0.492) between the two treatment groups. No significant adverse events related to nebulized colistin were reported. These findings suggest that the addition of nebulized colistin may not offer additional benefits in terms of 30-day survival, clinical or microbiological response, or nephrotoxicity in these patients.

Intravenous Vitamin C in Cancer Care: Evidence Review and Practical Guidance for Integrative Oncology Practitioners

Intravenous vitamin C (IVC) is a common therapy used by naturopathic doctors and other licensed integrative practitioners. With several proposed mechanisms of action related to cancer care, it is often used in integrative oncology settings. Despite its common use, there are no published evidence-based resources on the efficacy, safety, and procedural considerations for the use of IVC in practice. The objectives of this review are to summarize the evidence on high-dose IVC in supportive cancer care and to provide a resource of practical clinical guidance for IVC application. In cancer care, IVC is most commonly used at doses high enough to achieve a potential cancer cell cytotoxicity. This review focuses on IVC at doses of ≥15 g which we have defined as high-dose. To date, there are 23 published clinical trials evaluating the use of high-dose IVC in cancer support. Based on data from these clinical studies, IVC used concurrently with oxidative therapies, such as chemotherapy and radiotherapy, seems to produce the greatest likelihood for improvements in quality of life and additive anti-tumour effects compared with IVC as monotherapy or with non-oxidative therapies. IVC has shown promise in improving quality of life in patients with breast cancer and advanced pancreatic and ovarian cancers. Limited evidence suggests survival and/or tumour response may be improved with the inclusion of IVC in patients with advanced pancreatic cancer, non-small cell lung cancer, and RAS-mutated colorectal cancer. IVC does not offer curative potential, and further research is needed to explore its effectiveness relevant to mortality outcomes. Practical guidance including assessment, monitoring, dosing, safety, and communication with other healthcare providers is discussed.

Mycobacterium bovis BCG as immunostimulating agent prevents the severe form of chronic experimental Chagas disease.

There is currently no vaccine against Chagas disease (ChD), and the medications available confer multiple side effects. Mycobacterium bovis Bacillus Calmette-Guérin (BCG) produces balanced Th1, Th2, and Th17 modulatory immune responses and has improved efficacy in controlling chronic infections through nonspecific immunity. We aimed to improve the response to infection by inducing a stronger immune response and greater protection against the parasite by trained immunity. BALB/c mice were immunized with BCG subcutaneously, and 60 days later, they were infected with Trypanosoma cruzi intraperitoneally. An evaluation of the progression of the disease from the acute to the chronic stage, analyzing various aspects such as parasitemia, survival, clinical status, and humoral and cellular immune response, as well as the appearance of visceral megas and the histopathological description of target organs, was performed. Vaccination reduced parasitemia by 70%, and 100% survival was achieved in the acute stage; although the presentation of clinical signs was reduced, there was no increase in the antibody titer or in the differential production of the isotypes. Serum cytokine production indicated a proinflammatory response in infected animals, while in those who received BCG, the response was balanced by inducing Th1/Th2-type cytokines, with a better prognosis of the disease in the chronic stage.

Lymphatic endothelial cell-mediated accumulation of CD177+Treg cells suppresses antitumor immunity in human esophageal squamous cell carcinoma

ABSTRACT Regulatory T (Treg) cells are critical in shaping an immunosuppressive microenvironment to favor tumor progression and resistance to therapies. However, the heterogeneity and function of Treg cells in esophageal squamous cell carcinoma (ESCC) remain underexplored. We identified CD177 as a tumor-infiltrating Treg cell marker in ESCC. Interestingly, expression levels of CD177 and PD-1 were mutually exclusive in tumor Treg cells. CD177+ Treg cells expressed high levels of IL35, in association with CD8+ T cell exhaustion, whereas PD-1+ Treg cells expressed high levels of IL10. Pan-cancer analysis revealed that CD177+ Treg cells display increased clonal expansion compared to PD-1+ and double-negative (DN) Treg cells, and CD177+ and PD-1+ Treg cells develop from the same DN Treg cell origin. Importantly, we found CD177+ Treg cell infiltration to be associated with poor overall survival and poor response to anti-PD-1 immunotherapy plus chemotherapy in ESCC patients. Finally, we found that lymphatic endothelial cells are associated with CD177+ Treg cell accumulation in ESCC tumors, which are also decreased after anti-PD-1 immunotherapy plus chemotherapy. Our work identifies CD177+ Treg cell as a tumor-specific Treg cell subset and highlights their potential value as a prognostic marker of survival and response to immunotherapy and a therapeutic target in ESCC.

Comparing the Efficacy of Carboplatin plus 5-Fluorouracil, Cisplatin plus 5-Fluorouracil, and Best Supportive Care for Advanced Esophageal Squamous Cell Carcinoma: A Propensity Score Analysis from a Tertiary Hospital in Southern Thailand.

Background: Although cisplatin plus 5-fluorouracil (5-FU) is the standard first-line treatment for advanced-stage esophageal squamous cell carcinoma (ESCC), carboplatin was substituted for cisplatin in cisplatin-ineligible patients. The efficacy of carboplatin plus 5-FU for advanced-stage ESCC remains unreported. Methods: This retrospective study analyzed first-line treatment-carboplatin plus 5-FU, cisplatin plus 5-FU, or best supportive care (BSC)-in advanced-stage ESCC patients at a tertiary hospital in Thailand (2012-2022). Survival was assessed using the Kaplan-Meier method, compared via the log-rank test, and adjusted through propensity score matching. Significance was set at p < 0.05. Results: Of 256 patients, 39.9% received carboplatin plus 5-FU, 27.7% cisplatin plus 5-FU, and 32.4% BSC. Carboplatin was significantly associated with older age, poorer performance status, more comorbidities, chronic kidney disease, and lower creatinine clearance. Median overall survival (OS) for carboplatin plus 5-FU, cisplatin plus 5-FU, and BSC was 8.05 (HR 0.31 [0.23, 0.43] vs. BSC, p < 0.001; HR 1.06 [0.78, 1.44] vs. cisplatin plus 5-FU, p = 0.7), 8.43, and 3.64 months, respectively. No significant OS difference was observed between carboplatin and cisplatin treatments after propensity score matching. Median progression-free survival (PFS) and objective response rates (ORR) showed no significant difference between carboplatin and cisplatin treatments. Conclusions: Despite less favorable baseline characteristics of patients receiving carboplatin plus 5-FU, this combination exhibited comparable OS, PFS, and ORR to cisplatin plus 5-FU in real-world scenarios. Furthermore, it significantly improved OS over BSC. Consequently, carboplatin plus 5-FU should be considered as an alternative regimen, particularly for advanced-stage ESCC patients who are ineligible for cisplatin.

Response of the terrestrial isopod Porcellio scaber to lipopolysaccharide challenge after microplastic and insecticide exposure

The exposure of organisms to microplastics could compromise their ability to cope with other environmental stressors, such as infections. In this context, we investigated the effects of a 14-day exposure of the terrestrial isopod Porcellio scaber to tire particles in soil (1.5 % w w−1 dry weight) on the organisms' response to a secondary exposure, i.e., injection of the bacterial endotoxin lipopolysaccharide. In addition, the insecticide chlorpyrifos (2 mg kg−1 dry weight) was tested as a positive control. The survival and immune response of P. scaber was assessed at the end of the 7- and 14-day primary exposure and two days after the secondary exposure, by analyzing selected haemolymph immune parameters (total haemocyte count, differential haemocyte count, and haemocyte viability). No change in survival was observed after primary exposure of P. scaber to tire particles or chlorpyrifos. However, primary exposure to chlorpyrifos triggered a strong activation of the immune response, which was not the case following exposure to the tire particles. Further injection of lipopolysaccharide into the body did not affect the survival of animals exposed to tire particles or chlorpyrifos, while a strong immunomodulatory change was observed, particularly with chlorpyrifos, and to some extent, tire particles. Based on these results, we conclude that exposure of P. scaber to tire particles or chlorpyrifos has no significant effect on the susceptibility of the organism to lipopolysaccharide in terms of their mortality, but primary exposure to an insecticide significantly modulates the immune response of the organisms to a second stressor. We discuss the “stress on stress” approach for testing low-toxic substances, such as microplastics, where an environmentally realistic exposure is followed by a secondary exposure.

Imaging-guided prognostic score-based approach to assess the benefits of combotherapy versus monotherapy with immune checkpoint inhibitors in metastatic MSI-H colorectal cancer patients

BackgroundThis retrospective study determined survival responses to immune checkpoint inhibitors (ICIs), comparing mono- (mono) and combo-immunotherapy (combo) in patients with microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC) by analyzing quantitative imaging data and clinical factors. MethodsOne hundred fifty patients were included from two centers and divided into training (n = 105) and validation (n = 45) cohorts. Radiologists manually annotated chest-abdomen-pelvis computed tomography and calculated tumor burden. Progression-free survival (PFS) was assessed, and variables were selected through Recursive Feature Elimination. Cutoff values were determined using maximally selected rank statistics to binarize features, forming a risk score with hazard ratio-derived weights. ResultsIn total, 2258 lesions were annotated with excellent reproducibility. Key variables in the training cohort included: total tumor volume (cutoff: 73 cm3), lesion count (cutoff: 20), age (cutoff: 60) and the presence of peritoneal carcinomatosis. Their respective weights were 1.13, 0.96, 0.91, and 0.38, resulting in a risk score cutoff of 1.36. Low-score patients showed similar overall survival and PFS regardless of treatment, while those with a high-score had significantly worse survivals with mono vs combo (P = 0.004 and P = 0.0001). In the validation set, low-score patients exhibited no significant difference in overall survival and PFS with mono or combo. However, patients with a high-score had worse PFS with mono (P = 0.046). ConclusionsA score based on total tumor volume, lesion count, the presence of peritoneal carcinomatosis, and age can guide MSI-H mCRC treatment decisions, allowing oncologists to identify suitable candidates for mono and combo ICI therapies.

A pyrimidine metabolism-related signature for prognostic and immunotherapeutic response prediction in hepatocellular carcinoma by integrating analyses.

Hepatocellular carcinoma (HCC), with discouraging morbidity and mortality, ranks as one of the most prevalent tumors worldwide. Pyrimidine metabolism is a critical process that regulates DNA and RNA synthesis in cells. It is imperative to investigate the significance of pyrimidine metabolism in liver cancer. Transcriptome and clinical data were downloaded from the TCGA database and the GEO database. The genes related to pyrimidine metabolism were sourced from the MSigDB. The pyrimidine metabolism-related signature (PMRS) was constructed through Cox regression and Lasso regression and then verified in the external validation set from the ICGC database. Functional enrichment, immune infiltration analysis, drug sensitivity, and Immunophenoscore (IPS) were further implemented to predict the response to immunotherapy. The role of PMRS in the malignant phenotype of hepatocellular carcinoma was explored by conducting a series of in vitro experiments. Our study developed a four-genes PMRS which demonstrates a substantial correlation with the prognosis of HCC patients, serving as an independent predictor in clinical practice. The result of risk-stratified analysis yielded evidence that low-risk patients experienced more favorable clinical outcomes. The nomogram exhibited remarkable prognostic predictive value. The subsequent results revealed that low-risk patients manifested a more promising response to immunotherapy. Moreover, the results of cell experiments demonstrated that the downregulation of DCK markedly inhibited the malignant phenotype of hepatocellular carcinoma. Our pyrimidine metabolism-centered prognostic signature accurately predicts overall survival, immune status, and treatment response in hepatocellular carcinoma (HCC) patients, offering innovative insights for precise diagnosis, personalized treatment, and improved prognosis.

Integrating and optimizing tonabersat in standard glioblastoma therapy: A preclinical study.

Glioblastoma (GB), a highly aggressive primary brain tumor, presents a poor prognosis despite the current standard therapy, including radiotherapy and temozolomide (TMZ) chemotherapy. Tumor microtubes involving connexin 43 (Cx43) contribute to glioma progression and therapy resistance, suggesting Cx43 inhibition as a potential treatment strategy. This research aims to explore the adjuvant potential of tonabersat, a Cx43 gap junction modulator and blood-brain barrier-penetrating compound, in combination with the standard of care for GB. In addition, different administration schedules and timings to optimize tonabersat's therapeutic window are investigated. The F98 Fischer rat model will be utilized to investigate tonabersat's impact in a clinically relevant setting, by incorporating fractionated radiotherapy (three fractions of 9 Gy) and TMZ chemotherapy (29 mg/kg). This study will evaluate tonabersat's impact on tumor growth, survival, and treatment response through advanced imaging (CE T1-w MRI) and histological analysis. Results show extended survival in rats receiving tonabersat with standard care, highlighting its adjuvant potential. Daily tonabersat administration, both preceding and following radiotherapy, emerges as a promising approach for maximizing survival outcomes. The study suggests tonabersat's potential to reduce tumor invasiveness, providing a new avenue for GB treatment. In conclusion, this preclinical investigation highlights tonabersat's potential as an effective adjuvant treatment for GB, and its established safety profile from clinical trials in migraine treatment presents a promising foundation for further exploration.

Humoral complementomics – exploration of noninvasive complement biomarkers as predictors of renal cancer progression

ABSTRACT Despite the progress of anti-cancer treatment, the prognosis of many patients with solid tumors is still dismal. Reliable noninvasive biomarkers are needed to predict patient survival and therapy response. Here, we propose a Humoral Complementomics approach: a work-up of assays to comprehensively evaluate complement proteins, activation fragments, and autoantibodies targeting complement proteins in plasma, which we correlated with the intratumoral complement activation, and/or local production, focusing on localized and metastatic clear cell renal cell carcinoma (ccRCC). In two prospective ccRCC cohorts, plasma C2, C5, Factor D and properdin were elevated compared to healthy controls, reflecting an inflammatory phenotype that correlated with plasma calprotectin levels but did not associate with CRP or with patient prognosis. Conversely, autoantibodies against the complement C3 and the reduced form of FH (a tumor neo-epitope reported in lung cancer) correlated with a favorable outcome. Our findings pointed to a specific group of patients with elevated plasma C4d and C1s-C1INH complexes, indicating the initiation of the classical pathway, along with elevated Ba and Bb, indicating alternative pathway activation. Boostrapped Lasso regularized Cox regression revealed that the most predictive complement biomarkers were elevated plasma C4d and Bb levels at the time of surgery, which correlated with poor prognosis. In conclusion, we propose Humoral Complementomics as an unbiased approach to study the global state of the complement system in any pathological plasma sample and disease context. Its implementation for ccRCC revealed that elevated C4d and Bb in plasma are promising prognostic biomarkers, correlating with shorter progression-free survival.

Efficacy of cytoreductive radical cystectomy in metastatic urothelial bladder cancer based on site and number of metastases

BackgroundRecent studies have highlighted the overall survival (OS) benefit of cytoreductive radical cystectomy (CRC) in metastatic bladder cancer (mBCa). Cytoreductive surgery has been established in other urologic cancers. However, the efficacy of CRC and optimal criteria for patient selection in mBCa is unclear. This study investigated the oncologic efficacy of CRC, particularly emphasizing the location and number of metastasis sites as a predictor of survival and treatment response. MethodsA retrospective analysis of cT2-4N0-3M1 mBCa patients treated with multiagent chemotherapy between 2004 and 2019 was conducted using the National Cancer Database. Patients were classified by additional treatment with CRC or conservative local treatment (CLT), consisting of transurethral resection of bladder tumor, radiation, or no local treatment and propensity score (PS) matched. Kaplan-Meier analysis and multivariate Cox Proportional Hazards model assessed the effect of CRC or CLT on OS within the matched cohort and in four subgroups (1) patients with only distant lymph node (LN) metastasis vs. any organ metastasis, (2) patients with single metastasis vs. multiple metastases. Sensitivity analysis estimated the influence of unmeasured confounders on CRC OS benefit. ResultsPropensity matching yielded 247 and 251 patients treated with CRC and CLT, respectively. Median OS in patients who received CRC was greater than that of patients treated with CLT (20.4 months vs. 12.0 months, P < 0.001). CRC was associated with reduced mortality risk in patients with only distant LN metastases (HR = 0.545, P = 0.039), any organ metastasis (HR = 0.421, P < 0.001), and single visceral metastasis (HR = 0.483, P = 0.002). However, CRC did not significantly improve OS in patients with multiple metastases (HR = 0.501, P = 0.064). ConclusionThese findings demonstrate an OS benefit of CRC with multiagent chemotherapy and pinpoint multiple visceral metastases as a potential contraindication for CRC. Although limited by the influence of unmeasured confounders, these findings may inform future prospective investigations into CRC.

Cellular and clinical impact of protein phosphatase enzyme epigenetic silencing in multiple cancer tissues

BackgroundProtein Phosphatase Enzymes (PPE) and protein kinases simultaneously control phosphorylation mechanisms that tightly regulate intracellular signalling pathways and stimulate cellular responses. In human malignancies, PPE and protein kinases are frequently mutated resulting in uncontrolled kinase activity and PPE suppression, leading to cell proliferation, migration and resistance to anti-cancer therapies. Cancer associated DNA hypermethylation at PPE promoters gives rise to transcriptional silencing (epimutations) and is a hallmark of cancer. Despite recent advances in sequencing technologies, data availability and computational capabilities, only a fraction of PPE have been reported as transcriptionally inactive as a consequence of epimutations.MethodsIn this study, we examined promoter-associated DNA methylation profiles in Protein Phosphatase Enzymes and their Interacting Proteins (PPEIP) in a cohort of 705 cancer patients in five tissues (Large intestine, Oesophagus, Lung, Pancreas and Stomach) in three cell models (primary tumours, cancer cell lines and 3D embedded cancer cell cultures). As a subset of PPEIP are known tumour suppressor genes, we analysed the impact of PPEIP promoter hypermethylation marks on gene expression, cellular networks and in a clinical setting.ResultsHere, we report epimutations in PPEIP are a frequent occurrence in the cancer genome and manifest independent of transcriptional activity. We observed that different tumours have varying susceptibility to epimutations and identify specific cellular signalling networks that are primarily affected by epimutations. Additionally, RNA-seq analysis showed the negative impact of epimutations on most (not all) Protein Tyrosine Phosphatase transcription. Finally, we detected novel clinical biomarkers that inform on patient mortality and anti-cancer treatment sensitivity.ConclusionsWe propose that DNA hypermethylation marks at PPEIP frequently contribute to the pathogenesis of malignancies and within the precision medicine space, hold promise as biomarkers to inform on clinical features such as patient survival and therapeutic response.

Lung cancer, predictive factor and ERCC1

Introduction: Excision repair cross-complementing group 1 (ERCC1) counteracts the cytotoxic effect of cisplatin through its role in DNA repair, and its expression level is a crucial factor for sensitivity to this drug. The objective of this study was to assess the impact of ERCC1 on tumor response and survival in patients with advanced non-small cell lung cancer (NSCLC) treated with a platinum-based regimen. Methods: Analysis of survival and tumor response based on the expression level of ERCC1 (detected by immunohistochemistry) in a cohort of NSCLC patients followed in a standard care setting. Results: Among the 77 cases of NSCLC included, ERCC1 expression was low in 64.9% of cases and high in 35.1% of cases. In the 52 patients treated with cisplatin, survival and tumor response were better in the low-expression group compared to the high-expression group: 14.35 months versus 9.49 months, p=0.022; Objective Response: 42.4% versus 0%, p=0.001. No significant difference was found based on protein expression level in patients treated with carboplatin. Conclusion: ERCC1 overexpression in patients treated with cisplatin predicts a poor tumor response and shorter survival.

Significance of PD-L1 in Metastatic Urothelial Carcinoma Treated With Immune Checkpoint Inhibitors

Immune checkpoint inhibitors (ICIs) have broadened the metastatic urothelial carcinoma (mUC) therapeutic scenario. The association of programmed death ligand 1 (PD-L1) with response and survival in patients treated with ICIs is still controversial. To evaluate the association of PD-L1 with response rate and overall survival among patients with mUC treated with ICIs. PubMed, Embase, American Society of Clinical Oncology and European Society for Medical Oncology Meeting Libraries, and Web of Science were searched up to December 10, 2023. Two authors independently screened the studies. Included studies were randomized and nonrandomized clinical trials enrolling patients with mUC receiving ICIs with available overall survival (OS), progression-free survival (PFS), or overall response rate (ORR) data, separated between patients with PD-L1-positive and -negative tumors. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed. Two reviewers independently extracted data. Fixed- or random-effects models were used depending on the heterogeneity among the studies. Primary outcomes were odds ratios (ORs) for ORR and hazard ratios (HRs) for OS, comparing patients with PD-L1-positive tumors and patients with PD-L1-negative tumors. Secondary outcomes were the PFS HR between patients with PD-L1-positive and -negative tumors and OS HR between ICI arms and non-ICI arms of only randomized clinical trials. A total of 14 studies were selected, comprising 5271 patients treated with ICIs (2625 patients had PD-L1-positive tumors). The ORR was 13.8% to 78.6% in patients with PD-L1-positive tumors and 5.1% to 63.2% in patients with PD-L1-negative tumors, with an association between PD-L1 status and ORR favoring patients with PD-L1-positive tumors (OR, 1.94; 95% CI, 1.47-2.56; P < .001). Median OS ranged from 8.4 to 24.1 months in patients with PD-L1-positive tumors and from 6.0 to 19.1 months in patients with PD-L1-negative tumors. The pooled HR showed a significant reduction for patients with PD-L1-positive tumors compared with those with PD-L1-negative tumors in the risk of death (HR, 0.71; 95% CI, 0.57-0.89; P = .003) and risk of progression (HR, 0.55; 95% CI, 0.44-0.69; P < .001) when ICIs were administered. PD-L1 is not likely to be a predictive biomarker of ICI response. This systematic review and meta-analysis suggests that PD-L1 expression is associated with improved ORR, OS, and PFS for patients with mUC who receive ICIs, but it is unlikely to be useful as a predictive biomarker. Developing predictive biomarkers is essential to select patients most likely to benefit from ICIs and avoid toxic effects and financial burden with these agents.

CA9, CYFIP2 and LGALS3BP-A Novel Biomarker Panel to Aid Prognostication in Glioma.

Brain cancer is a devastating and life-changing disease. Biomarkers are becoming increasingly important in addressing clinical issues, including in monitoring tumour progression and assessing survival and treatment response. The goal of this study was to identify prognostic biomarkers associated with glioma progression. Discovery proteomic analysis was performed on a small cohort of astrocytomas that were diagnosed as low-grade and recurred at a higher grade. Six proteins were chosen to be validated further in a larger cohort. Three proteins, CA9, CYFIP2, and LGALS3BP, were found to be associated with glioma progression and, in univariate analysis, could be used as prognostic markers. However, according to the results of multivariate analysis, these did not remain significant. These three proteins were then combined into a three-protein panel. This panel had a specificity and sensitivity of 0.7459 for distinguishing between long and short survival. In silico data confirmed the prognostic significance of this panel.

Impact of preoperative antiviral therapy on the prognosis of hepatitis B virus-related hepatocellular carcinoma

BackgroundFor chronic hepatitis B virus (HBV) infection patients, increasing evidence has demonstrated the effectiveness of expanding the indications and applicable population for antiviral therapy. However, the expanded indication of antiviral therapy for hepatocellular carcinoma (HCC) remains to be further explored.Methods196 HBV-related HCC patients who received radical hepatectomy and nucleos(t)ide analogues (NAs) therapy at Sichuan Provincial People’s Hospital were enrolled in this study. HCC recurrence, overall survival (OS), early virological (VR) and biochemical responses (BR) of patients were compared between different NAs therapy and the use of anti-programmed cell death protein 1 (PD-1) therapy.ResultsNAs therapy at different timing of surgery was a strong independent risk factor for postoperative recurrence and overall mortality of HBV-related HCC patients. Furthermore, in HCC patients who received postoperative anti-PD-1 therapy, patients with HBV DNA < 1000 copy/mL had significantly better recurrence-free survival (RFS) and OS than those with HBV DNA ≥ 1000 copy/mL (HR: 7.783; P = 0.002; HR: 6.699; P < 0.001). However, the differences of RFS and OS rates between entecavir group and tenofovir disoproxil fumarate group were not statistically significant. Similar results were also observed in the rates of early VR, BR and combined VR and BR.ConclusionTimely and reasonable preoperative NAs therapy showed clinical benefit in improving the prognosis of patients with HBV-related HCC, even in the case of normal alanine aminotransferase (ALT) level and negative hepatitis e antigen (HBeAg). Furthermore, a possible synergistic effect between antiviral therapy and anti-PD-1 therapy was founded and need further verification.

A novel tumor-associated neutrophil gene signature for predicting prognosis, tumor immune microenvironment, and therapeutic response in breast cancer

Tumor-associated neutrophils (TANs) can promote tumor progression. This study aimed to investigate the molecular signature that predict the prognosis and immune response of breast cancer (BRCA) based on TAN-related gene (TANRG) expression data. The RNA-seq data of BRCA were gathered from The Cancer Genome Atlas (TCGA) and gene expression omnibus (GEO) datasets. Univariate Cox regression analysis and the least absolute shrinkage and selection operator for selecting prognostic genes. A neo-TAN-related risk signature was constructed by multivariate Cox regression analysis. Time-dependent receiver operating characteristic (ROC) curve analyses and Kaplan–Meier analyses were performed to validate the signature in GEO cohorts and the triple-negative breast cancer (TNBC) subtype. We constructed an independent prognostic factor model with 11 TANRGs. The areas under the ROC curve (AUCs) of the TCGA training cohorts for 3-, 5-, and 7-year overall survival were 0.72, 0.73, and 0.73, respectively. The AUCs of the GEO test cohorts for 3-, 5-, and 7-year overall survival were 0.83, 0.89, and 0.94 (GSE25066) and 0.67, 0.69, and 0.73 (GSE58812), respectively. The proportion of immune subtypes differed among the different risk groups. The IC50 values differed significantly between risk groups and can be used as a guide for systemic therapy. The prognostic model developed by TANRGs has excellent predictive performance in BRCA patients. In addition, this feature is closely related to the prediction of survival, immune activity and treatment response in BRCA patients.

Outcomes in biomarker-selected subgroups from the KESTREL study of durvalumab and tremelimumab in recurrent or metastatic head and neck squamous cell carcinoma

BackgroundSelective biomarkers may improve outcomes in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) treated with immune checkpoint inhibitor therapy. We investigated three independent biomarkers for association with efficacy in the randomized, phase III KESTREL study (NCT02551159) of first-line durvalumab monotherapy or durvalumab plus tremelimumab versus the EXTREME regimen: programmed cell death ligand-1 (PD-L1) immunohistochemistry, blood tumor mutational burden (bTMB) via circulating tumor DNA, and neutrophil-to-lymphocyte ratio (NLR).MethodsTumor or blood samples from patients enrolled in the KESTREL study were analyzed for PD-L1, bTMB, and NLR. Associations with overall survival (OS) or objective response rates (ORRs) were evaluated based on prespecified cut-offs for PD-L1 (tumor cell [TC] ≥ 50%/immune cell ≥ 25% or TC ≥ 25%), bTMB (≥ 16 mutations [mut] per megabase [Mb]), and NLR (≤ 7). Ad hoc analyses of exploratory cut-offs were performed.ResultsPrespecified or exploratory cut-offs for PD-L1 did not enrich for ORR or OS for durvalumab monotherapy or durvalumab plus tremelimumab versus EXTREME. In the bTMB ≥ 16 mut/Mb subgroup, OS hazard ratios (95% confidence interval) for durvalumab monotherapy and durvalumab plus tremelimumab versus EXTREME were 0.90 (0.48–1.72) and 0.69 (0.39–1.25), respectively. Complete response rates were 8.6% with durvalumab plus tremelimumab and 4.3% with EXTREME (≥ 16 mut/Mb subgroup). No improvement in OS was observed for durvalumab monotherapy or durvalumab plus tremelimumab versus EXTREME at prespecified or exploratory NLR cut-offs.ConclusionsbTMB demonstrated potential utility for selecting patients with R/M HNSCC who benefited from durvalumab with or without tremelimumab versus EXTREME.Trial registration ClinicalTrials.gov identifier NCT02551159.