Update on the Management of Stage III NSCLC: Navigating a Complex and Heterogeneous Stage of Disease.

BACKGROUND: Stage III nonsmall cell lung cancer (NSCLC) represents a heterogeneous group of patients. Many patients are treated with curative intent multimodality therapy, either surgical resection plus systemic therapy or chemoradiation plus immunotherapy. However, many patients are not suitable for curative intent therapy and are treated with palliative systemic therapy or best supportive care. METHODS: This paper is a review of recent advances in the management of patients with curative intent disease. RESULTS: There have been significant advances in curative intent therapy for patients with stage III NSCLC in recent years. These include both adjuvant and neoadjuvant systemic therapies. For patients with resectable NSCLC, two trials have demonstrated that adjuvant atezolizumab or pembrolizumab, following chemotherapy, significantly improved disease-free survival (DFS). In patients with tumours harbouring a common mutation of the EGFR gene, adjuvant osimertinib therapy was associated with a large improvement in both DFS and overall survival (OS). Five randomized trials have evaluated chemotherapy plus nivolumab, pembrolizumab, durvalumab, or toripalimab, either as neoadjuvant or perioperative (neoadjuvant plus adjuvant) therapy. All five trials show significant improvements in the rate of pathologic complete response (pCR) and event-free survival (EFS). OS data are currently immature. This would now be considered the standard of care for resectable stage III NSCLC. The addition of durvalumab to chemoradiation has also become the standard of care in unresectable stage III NSCLC. One year of consolidation durvalumab following concurrent chemoradiation has demonstrated significant improvements in both progression-free and overall survival. CONCLUSIONS: Immune checkpoint inhibitor (ICI) therapy has become a standard recommendation in curative intent therapy for stage III NSCLC.

Chemo-Immunotherapy in First Line Extensive Stage Small Cell Lung Cancer (ES-SCLC): A Systematic Review and Meta-Analysis.

Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma with early metastatic potential. The standard-of-care treatment has not changed in years. Recent studies report improved progression-free survival (PFS) and overall survival (OS) with combined ICI and chemotherapy in ES-SCLC. We conducted a systematic review and meta-analysis to assess the magnitude of survival benefits. We searched MEDLINE, EMBASE, and Cochrane between 1 January 2010 and 15 July 2022 and conference proceedings from 2018 to 2022, for randomised controlled trials, evaluating chemo-ICI compared with platinum-doublet chemotherapy in untreated ES-SCLC. Outcomes assessed were PFS, OS, objective response rate (ORR), duration of response (DoR), toxicity, and health-related quality of life (HRQoL). The search identified 8061 studies, with 8 (56 publications) included in the final analysis. PFS and OS were significantly improved for patients randomised to chemo-ICI (PFS hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.70-0.80) and (OS HR 0.79, 95% CI 0.73-0.85). Subgroup analysis demonstrated a differential effect between PD-1/PD-L1 and CTLA-4 inhibitors. There was no difference in ORR and DoR. All-grade adverse events (RR 1.06, 95% CI 1.00-1.12) were similar. The addition of ICI to chemotherapy in untreated ES-SCLC results in a 22% risk reduction in death, and a 25% risk reduction in disease progression with a minimal increase in toxicity. These improvements are modest but represent progress beyond the standard of care.

Evaluation of a novel strategy to implement exercise evidence into clinical practice in breast cancer care: protocol for the NEXT-BRCA randomised controlled trial.

INTRODUCTION: The burden of breast cancer in Canada is steadily growing. More women are surviving breast cancer, yet, survivors live with side effects for years after treatments have ended. The benefits of exercise for women with breast cancer are well established and include improvement in treatment-related physical and emotional side effects. Despite these benefits, few survivors meet exercise guidelines. Exercise programmes are needed within the cancer institution in Canada to bridge the current knowledge to practice gap. The purpose of this study is to test the effects of a novel implementation strategy that includes institution-based exercise plus self-management (SM) or SM alone versus usual care in improving exercise level, quality of life, aerobic capacity, muscle strength and use of healthcare services over 12 months for women with breast cancer receiving chemotherapy. METHODS AND ANALYSIS: Participants: Women with stages I-III breast cancer undergoing chemotherapy. Intervention: Group 1: institution-based exercise and SM (8 exercise sessions plus 8 SM modules); Group 2: SM alone; Group 3: usual care. Outcomes: The primary effectiveness outcome is minutes per week of moderate to vigorous physical activity. Secondary outcomes include quality of life, aerobic capacity, muscle strength, and use of healthcare services. Randomisation: Participants will be randomised (1:1:1) to one of the three groups by a blinded statistician and will be stratified based on age of participant (<40, 40-60, and >60 years). Statistical analysis: Outcomes will be measured at baseline, post-intervention, 6-month and 12-month follow-up using an analysis of covariance to test changes between groups over time adjusted for age. ETHICS AND DISSEMINATION: This study addresses a long-standing need to help women with breast cancer undergoing chemotherapy become and stay more active by implementing novel rehabilitation strategies into real-world practice. This is vital in order for this population to minimise the lingering side effects of treatment, improve function and quality of life and prevent cancer recurrence. TRIAL REGISTRATION NUMBER: The study protocol (v1: July 2020) has been registered on ClinicalTrials.gov (NCT04109274).

Learning Health System for Breast Cancer: Pilot Project Experience.

PURPOSE: Clinicians need accurate and timely information on the impact of treatments on patient outcomes. The electronic health record (EHR) offers the potential for insight into real-world patient experiences and outcomes, but it is difficult to tap into. Our goal was to apply artificial intelligence technology to the EHR to characterize the clinical course of patients with stage III breast cancer. PATIENTS AND METHODS: Data from patients with stage III breast cancer who presented between 2013 and 2015 were extracted from the EHR, de-identified, and imported into the IBM Cloud. Specialized natural language processing (NLP) annotators were developed to extract medical concepts from unstructured clinical text and transform them to structured attributes. In the validation phase, these annotators were applied to 19 additional patients with stage III breast cancer from the same period. The resulting data were compared with that in the medical chart (gold standard) for nine key indicators. RESULTS: Information was extracted for 50 patients, including tumor stage (94% stage IIIA, 6% stage IIIB), age (28% 50 years or younger, 52% between 51 and 70 years, and 24% older than 70 years), receptor status (84% estrogen receptor positive, 74% progesterone receptor positive), and first treatment (72% surgery, 26% chemotherapy, 2% endocrine). Events in the patient's journey were compiled to create a timeline. For 171 data elements, NLP and the chart disagreed for 41 (24%; 95% CI, 17.8% to 31.1%). With additional manipulation using simple logic, the disagreement was reduced to six elements (3.5%; 95% CI, 1.3% to 7.5%; F1 statistic, 0.9694). CONCLUSION: It is possible to extract, read, and combine data from the EHR to view the patient journey. The agreement between NLP and the gold standard was high, which supports validity.

Regional upregulation of hippocampal melatonin MT2 receptors by valproic acid: therapeutic implications for Alzheimer's disease.

We have reported that clinically relevant concentrations of valproic acid (VPA) upregulate the G protein-coupled melatonin MT1 receptor in rat C6 glioma cells, and both MT1 and MT2 receptors in the rat hippocampus. The melatonin MT2 receptor is relatively enriched in the hippocampus, where it is thought to be involved in modulating synaptic plasticity and cognitive function. Importantly, a significant decrease in MT2 expression has been observed in the hippocampus of Alzheimer's patients. Therefore, we examined whether the global upregulation of this receptor (and also the MT1) by VPA, observed in earlier RT-PCR and real time PCR studies, could be localized to more discrete hippocampal regions, which are involved in cognitive function. In situ hybridization of rat brain slices, following chronic VPA treatment (3mg/mL or 4mg/mL in drinking water), revealed a significant upregulation of the MT2 receptor mRNA in the CA1, CA2, CA3 and dentate gyrus (DG) regions of the rat hippocampus. In contrast, the MT1 receptor was not detected in the hippocampus by in situ hybridization. The significant induction of melatonin MT2 receptor expression by VPA in hippocampal regions involved in learning, memory and/or neural stem cell proliferation, suggests that a combinatorial therapeutic strategy involving VPA together with melatonin or other MT2 agonists, would be beneficial in neurodegenerative disorders such as Alzheimer's disease.

Valproic acid up-regulates melatonin MT1 and MT2 receptors and neurotrophic factors CDNF and MANF in the rat brain.

We have reported that clinically relevant concentrations of valproic acid (VPA) up-regulate the G-protein-coupled melatonin MT1 receptor in rat C6 glioma cells. To determine whether this effect occurs in vivo, the effects of chronic VPA treatment on the expression of both melatonin receptor subtypes, MT1 and MT2, were examined in the rat brain. Reverse transcription-polymerase chain reaction (RT-PCR) and real-time PCR analyses revealed significant increases in MT1 and MT2 mRNA expression in the hippocampus, following VPA (4 mg/ml drinking water) treatment for 17 d. Increases in the mRNA and protein expression of the novel neurotrophic factors, conserved dopamine neurotrophic factor and mesencephalic astrocyte-derived neurotrophic factor, were detected in the hippocampus and/or striatum. In addition, significant changes in persephin, glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor mRNA expression were observed. The robust multi-fold induction of MT1 and MT2 receptors in the hippocampus suggests a role for the melatonergic system in the psychotropic effects of VPA.