Citations

AbstractBackgroundPatients with acute myeloid leukemia (AML) who have tumor protein p53 (TP53) mutations or a complex karyotype have a poor prognosis, and hypomethylating agents are often used. The authors evaluated the efficacy of entospletinib, an oral inhibitor of spleen tyrosine kinase, combined with decitabine in this patient population.MethodsThis was a multicenter, open‐label, phase 2 substudy of the Beat AML Master Trial (ClinicalTrials.gov identifier NCT03013998) using a Simon two‐stage design. Eligible patients aged 60 years or older who had newly diagnosed AML with mutations in TP53 with or without a complex karyotype (cohort A; n = 45) or had a complex karyotype without TP53 mutation (cohort B; n = 13) received entospletinib 400 mg twice daily with decitabine 20 mg/m2 on days 1–10 every 28 days for up to three induction cycles, followed by up to 11 consolidation cycles, in which decitabine was reduced to days 1–5. Entospletinib maintenance was given for up to 2 years. The primary end point was complete remission (CR) and CR with hematologic improvement by up to six cycles of therapy.ResultsThe composite CR rates for cohorts A and B were 13.3% (95% confidence interval, 5.1%–26.8%) and 30.8% (95% confidence interval, 9.1%–61.4%), respectively. The median duration of response was 7.6 and 8.2 months, respectively, and the median overall survival was 6.5 and 11.5 months, respectively. The study was stopped because the futility boundary was crossed in both cohorts.ConclusionsThe combination of entospletinib and decitabine demonstrated activity and was acceptably tolerated in this patient population; however, the CR rates were low, and overall survival was short. Novel treatment strategies for older patients with TP53 mutations and complex karyotype remain an urgent need.

Critically ill patients presenting with acute on chronic liver failure (ACLF) represent a particularly vulnerable population due to various considerations surrounding the syndrome definition, lack of robust prospective evaluation of outcomes, and allocation of resources such as organs for transplantation. Ninety-day mortality related to ACLF is high and patients who do leave the hospital are frequently readmitted. Artificial intelligence (AI), which encompasses various classical and modern machine learning techniques, natural language processing, and other methods of predictive, prognostic, probabilistic, and simulation modeling, has emerged as an effective tool in various areas of healthcare. These methods are now being leveraged to potentially minimize physician and provider cognitive load and impact both short-term and long-term patient outcomes. However, the enthusiasm is tempered by ethical considerations and a current lack of proven benefits. In addition to prognostic applications, AI models can likely help improve the understanding of various mechanisms of morbidity and mortality in ACLF. Their overall impact on patient-centered outcomes and countless other aspects of patient care remains unclear. In this review, we discuss various AI approaches being utilized in healthcare and discuss the recent and expected future impact of AI on patients with ACLF through prognostic modeling and AI-based approaches.

AbstractOur objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high‐grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi‐institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36–3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11–2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC.

AbstractExperimental data suggested activation of yes‐associated protein (YAP‐1) as a critical regulator of liver regeneration (LR). Serotonin (5‐HT) promotes LR in rodent models and has been proposed to act via YAP‐1. How 5‐HT affects LR is incompletely understood. A possible mechanism how 5‐HT affects human LR was explored. Sixty‐one patients were included. Tissue samples prior and 2 h after induction of LR were collected. Circulating levels of 5‐HT and osteopontin (OPN) were assessed. YAP‐1, its phosphorylation states, cytokeratin 19 (CK‐19) and OPN were assessed using immunofluorescence. A mouse model of biliary epithelial cells (BECs) specific deletion of YAP/TAZ was developed. YAP‐1 increased as early as 2 h after induction of LR (p = 0.025) predominantly in BECs. BEC specific deletion of YAP/TAZ reduced LR after 70% partial hepatectomy in mice (Ki67%, p < 0.001). SSRI treatment, depleting intra‐platelet 5‐HT, abolished YAP‐1 and OPN induction upon LR. Portal vein 5‐HT levels correlated with intrahepatic YAP‐1 expression upon LR (R = 0.703, p = 0.035). OPN colocalized with YAP‐1 in BECs and its circulating levels increased in the liver vein 2 h after induction of LR (p = 0.017). In the context of LR tyrosine‐phosphorylated YAP‐1 significantly increased (p = 0.042). Stimulating BECs with 5‐HT resulted in increased YAP‐1 activation via tyrosine‐phosphorylation and subsequently increased OPN expression. BECs YAP‐1 appears to be critical for LR in mice and humans. Our evidence suggests that 5‐HT, at least in part, exerts its pro‐regenerative effects via YAP‐1 tyrosine‐phosphorylation in BECs and subsequent OPN‐dependent paracrine immunomodulation.

The NCCN Guidelines for Prostate Cancer Early Detection provide recommendations for individuals with a prostate who opt to participate in an early detection program after receiving the appropriate counseling on the pros and cons. These NCCN Guidelines Insights provide a summary of recent updates to the NCCN Guidelines with regard to the testing protocol, use of multiparametric MRI, and management of negative biopsy results to optimize the detection of clinically significant prostate cancer and minimize the detection of indolent disease.

Abstract Background: Approximately 5% of breast cancer patients carry a deleterious germline BRCA1/2 mutation, which leads malignant cells to be deficient in the repair of DNA double-strand breaks via homologous recombination. The poly(adenosine diphosphate–ribose) polymerase (PARP) enzymes are important on DNA single-strand break repair and PARP inhibitors (PARPi) cause an accumulation of unresolved DNA damage in tumors with BRCA1/2 mutations, resulting in cell death. However, because platinum salts also ultimately cause double-strand DNA breaks and may have overlapping mechanisms of resistance with PARPi, the efficacy of PARPi in patients with prior platinum therapy is unknown. We sought to evaluate the efficacy of PARPi in patients with BRCA1/2-related breast cancer and previous platinum exposure. Methods: We performed a systematic review and meta-analysis of studies that evaluated the efficacy of PARPi in patients with advanced or metastatic breast cancer and germline BRCA1/2 mutations. Two independent investigators identified double-blind, randomized controlled trials (RCTs) that included the subgroup of previous exposure to platinum. PubMed, Embase, and Cochrane databases were searched for papers up to June 26, 2022. Data extraction from published reports and quality assessment were performed under Cochrane recommendations. Hazard ratios (HRs) with a 95% confidence interval (CI) were pooled, and a p-value of &lt; 0.05 was considered statistically significant. The software Review Manager 5.3 was selected for conducting the statistical analysis. The primary endpoint of interest was progression-free survival (PFS). Results: Out of 2069 database results (487 on PubMed; 1376 on Embase; and 206 on Cochrane), 42 studies were selected for full review, and 4 RCTs, with a total of 249 patients, were included in the final investigation. The PARPi included were Olaparib, Talazoparib, Niraparib, and Veliparib. Pooled analysis showed that PARPi improved PFS in breast cancer patients with prior treatment with platinum-based therapy compared to the control group [HR = 0.72; 95% CI, 0.53-0.97; p = 0.03]. In comparison, the population without previous platinum exposure had a similar but slightly greater benefit from PARPi [HR = 0.68; 95% CI, 0.52-0.89; p = 0.005]. A subgroup analysis containing only the three randomized trials with PARPi monotherapy confirmed the central tendency favoring PARPi over physicians’ choice of single-agent chemotherapy in patients with prior platinum-therapy; however, because of small numbers and wide confidence interval it was not statistically significant [HR = 0.72; 95% CI, 0.51-1.01; p = 0.06]. Conclusions: Our findings suggest that PARPi are associated with longer PFS in patients with advanced breast cancer and previous exposure to platinum therapy, decreasing the concerns about cross-resistance between the drug classes. Nonetheless, more extensive studies are still necessary to investigate the efficacy of PARPi in patients with prior platinum exposure and truly platinum-resistant disease. Progression-free survival of included studies Citation Format: Alice D. Marinho, Beatriz Mella S. Pessoa, Gabriela R. Brandao, Caroliny H. Da Silva, Pedro A. Reis, Ana Carolina M. Comini, Felipe Batalini. Efficacy of PARP Inhibitors in Patients With BRCA1/2-related Breast Cancer with Prior Platinum Exposure: A Systematic Review and Meta-Analysis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-08.