Expert Review of Anticancer Therapy最新文献

Background: The post-surgical prognosis for Pulmonary Large Cell Neuroendocrine Carcinoma (PLCNEC) patients remains largely unexplored. Developing a precise prognostic model is vital to assist clinicians in patient counseling and creating effective treatment strategies.

Research design and methods: This retrospective study utilized the Surveillance, Epidemiology, and End Results database from 2000 to 2018 to identify key prognostic features for Overall Survival (OS) in PLCNEC using Boruta analysis. Predictive models employing XGBoost, Random Forest, Decision Trees, Elastic Net, and Support Vector Machine were constructed and evaluated based on Area Under the Receiver Operating Characteristic Curve (AUC), calibration plots, Brier scores, and Decision Curve Analysis (DCA).

Results: Analysis of 604 patients revealed eight significant predictors of OS. The Random Forest model outperformed others, with AUC values of 0.765 and 0.756 for 3 and 5-year survival predictions in the training set, and 0.739 and 0.706 in the validation set, respectively. Its superior validation cohort performance was confirmed by its AUC, calibration, and DCA metrics.

Conclusions: This study introduces a novel machine learning-based prognostic model with a supportive web-based platform, offering valuable tools for healthcare professionals. These advancements facilitate more personalized clinical decision-making for PLCNEC patients following primary tumor resection.

Introduction: Although meningiomas are the most common primary brain tumor, there are limited treatment options for recurrent or aggressive lesions. Compared to other brain tumors, meningiomas may be uniquely amenable to immunotherapy by virtue of their location outside the blood-brain barrier.

Areas covered: This review describes our current understanding of the immunology of the meninges, as well as immune cell infiltration and immune signaling in meningioma. Current literature on meningioma immunology and immunotherapy was comprehensively reviewed and summarized by a comprehensive search of MEDLINE (1/1/1990-6/1/2024). Further, we describe the current state of immunotherapeutic approaches, as well as potential future targets. Potential immunotherapeutic approaches include immune checkpoint inhibition, CAR-T approaches, tumor vaccine therapy, and immunogenic molecular markers.

Expert opinion: Meningioma immunotherapy is in early stages, as no immunotherapies are currently included in treatment guidelines. There is substantial heterogeneity in immune cell infiltration, immunogenicity, and immune escape across tumors, even within tumor grade. Furthering our understanding of meningioma immunology and tumor classification will allow for careful selection of tumors and patient populations that may benefit from primary or adjunctive immunotherapy for meningioma.

Introduction: Poly(ADP-ribose) polymerase 1 (PARP1) inhibition has become a major target in anticancer therapy. While PARP inhibitors (PARPi) are approved for homologous recombination (HR) deficient cancers, therapeutic resistance is a challenge and PARPi are now being investigated in cancers lacking HR deficiencies. This creates a need to develop molecular and imaging biomarkers of PARPi response to improve patient selection and circumvent therapeutic resistance.

Areas covered: PubMed and clinicaltrials.gov were queried for studies on PARPi resistance and imaging. This review summarizes established and emerging resistance mechanisms to PARPi, and the current state of imaging and theragnostic probes for PARPi, including fluorescently labeled and radiolabeled probes.

Expert opinion: While progress has been made in understanding PARPi therapeutic resistance, clinical evidence remains lacking and relatively little is known regarding PARPi response outside of HR deficiencies. Continued research will clarify the importance of known biomarkers and resistance mechanisms in patient cohorts and the broader utility of PARPi. Progress has also been made in PARPi imaging, particularly with radiolabeled probes, and both imaging and theragnostic probes have now reached clinical validation. Reducing abdominal background signal from probe clearance will broaden their applicability, and improvements to molecular synthesis and radiation delivery will increase their utility.

Introduction: In the era of chemo-immunotherapy, high-risk factors unequivocally predicted inferior outcomes for patients with CLL. The widespread adoption of BTK inhibitors has challenged the practical implications of such testing, as many patients have improved outcomes despite the presence of high-risk features. The impact of adverse prognostic factors, such as unmutated IGHV, on survival has been ameliorated by continuous treatment with BTK inhibitors, but not by finite-duration therapy with venetoclax-based combinations. Furthermore, TP53 abnormalities continue to be associated with worse outcomes in the era of novel agents. New treatment modalities, such as pirtobrutinib, lisocabtagene maraleucel, and ongoing studies combining BTK inhibitors with venetoclax, raise new questions on the significance of prognostic factors of survival for patients with CLL.

Areas covered: Herein, we summarized the available literature on patients with CLL harboring high-risk biomarkers, with a focus on data from key clinical trials.

Expert opinion: Testing for prognostic biomarkers will remain relevant to identify patients who may have increased benefit from novel therapeutic strategies, such as combination therapies and novel agents. Patients with high-risk disease should be encouraged to participate in clinical trials.

Introduction: Anticancer treatments have significantly contributed to increasing cure rates of breast cancer in the last years; however, they can also lead to short- and long-term side effects, including gonadotoxicity, and compromised fertility in young women. Oncofertility is a crucial issue for young patients who have not yet completed their family planning at the time of cancer diagnosis.

Areas covered: This review aims to cover all the latest available evidence in the field of oncofertility, including the gonadotoxicity of currently adopted anticancer therapies in the curative breast cancer setting, the available strategies for fertility preservation and the feasibility of achieving a pregnancy following anticancer treatment completion.

Expert opinion: Over the past years, a significant progress has been made in oncofertility care for young women with breast cancer. In the context of the currently available evidence, every young woman with newly diagnosed breast cancer should receive a proper and complete oncofertility counseling before starting any anticancer treatment to increase her chances of future pregnancies.

Objectives: To screen programmed cell death (PCD)-related genes in esophageal squamous cell carcinoma (ESCC) based on transcriptomic data and to explore its clinical value.

Methods: Differentially expressed PCD genes (DEPCDGs) were screened from ESCC transcriptome and clinical data in TCGA database. Univariate COX and LASSO COX were performed on prognostically DEPCDGs in ESCC to develop prognostic model. Differences in immune cell infiltration in different RiskScore groups were determined by ssGSEA and CIBERSORT. The role of RiskScore in immunotherapy response was explored using Tumor Immune Dysfunction and Exclusion (TIDE) and IMvigor210 cohorts.

Results: Fourteen DEPCDGs associated with prognosis were tapped in ESCC. These DEPCDGs form a RiskScore with good predictive performance for prognosis. RiskScore demonstrated excellent prediction accuracy in three data sets. The abundance of M2 macrophages and Tregs was higher in the high RiskScore group, and the abundance of M1 macrophages was higher in the low RiskScore group. The RiskScore also showed good immunotherapy sensitivity. RT-qPCR analysis showed that AUP1, BCAP31, DYRK2, TAF9 and UBQLN2 were higher expression in KYSE-150 cells. Knockdown BCAP31 inhibited migration and invasion.

Conclusion: A prognostic risk model can predict prognosis of ESCC and may be a useful biomarker for risk stratification and immunotherapy assessment.

Introduction: The androgen receptor (AR) is a critical driver of prostate cancer progression, and the advent of androgen receptor pathway inhibitors (ARPIs) has transformed the treatment landscape of metastatic prostate cancer. However, resistance to ARPIs eventually develops via mutations in AR, AR overexpression, and alternative AR signaling which have required novel approaches to target effectively.

Areas covered: The mechanism of action and early clinical results of proteolysis targeting chimera (PROTAC) agents targeting AR are reviewed. Preclinical and early clinical data for other emerging AR-targeting therapeutics, including dual-action androgen receptor inhibitors (DAARIs) and anitens that target the N-terminal domain of AR, were also identified through literature search for agents which may circumvent resistance through AR splice variants and AR ligand-binding domain mutations. The literature search utilized PubMed to identify articles that were relevant to this review from 2000 to 2024.

Expert opinion: PROTACs, DAARIs, and anitens represent novel and promising AR-targeting therapeutics that may become an important part of prostate cancer treatment in the future. Elucidating mechanisms of resistance, including ability of these agents to target full length AR, may yield further insights into maximal therapeutic efficacy aimed at silencing AR signaling.

Introduction: Aspartame, invented in 1965 by GD-Searle, is an intense artificial sweetener taste approximately 200 times as sweet as sucrose and used as an additive in more than 6,000 products. Aspartame (APM) was submitted for pre-marketing safety evaluation in early 1980. The studies, performed by GD-Searle, produced controversial results.

Areas covered: Because of the great commercial diffusion of aspartame, in 1997 the Ramazzini Institute (RI) started a large experimental project on rodents to test the carcinogenic effects of aspartame following an experimental model with more sensitive characteristics, namely a large number of rat and mice, starting treatment from prenatal life, observation until spontaneous death. Overall, the project included studying 2270 rats and 852 mice. These studies have shown that aspartame is a carcinogenic agent in experimental animals, inducing a significant dose-related increased incidence of several types of malignant tumors and, among them, hematological neoplasia, and liver cancer.

Expert opinion: The results of these studies on aspartame by the Ramazzini Institute opened a real front on the evaluation of artificial sweeteners and their possible health risks. Adequate long-term carcinogenicity bioassays on other diffuse artificial sweeteners such as acesulfame-k, sucralose, saccharin, including their blends, are likewise important for public health.

Introduction: Despite several therapeutic advancements, the proportion of patients with advanced biliary tract cancers (BTC) surviving 5 years from diagnosis remains dismal. The increasing recognition of targetable genetic alterations in BTCs has ushered in a new era in the treatment of these patients. Newer therapeutic agents targeting mutations such as isocitrate dehydrogenase (IDH), fibroblastic growth factor receptor (FGFR), human epidermal growth factor receptor (HER), and so on have established a new standard of care for treatment upon progression on frontline therapy in patients with disease harboring these mutations.

Areas covered: The current review aims to concisely summarize progress with various targeted therapy options for BTC. We also briefly discuss future directions in clinical and translational research for the adoption of a personalized approach for the treatment of unresectable or advanced BTC.

Expert opinion: Several new agents continue to emerge as feasible treatment options for patients with advanced BTC harboring targetable mutations. There is a growing need to identify mechanisms to conquer primary and acquired resistance to these agents. The identification of potential biomarkers that predict response to targeted therapy may be helpful in adopting a more tailored approach. All patients receiving treatment for advanced BTC should undergo tissue genomic profiling at diagnosis.