Approximately 30% of epilepsy patients do not respond to antiepileptic drugs, representing an unmet medical need. There is evidence that neuroinflammation plays a pathogenic role in drug-resistant epilepsy. The high-mobility group box 1 (HMGB1)/TLR4 axis is a key initiator of neuroinflammation following epileptogenic injuries, and its activation contributes to seizure generation in animal models. However, further work is required to understand the role of HMGB1 and its isoforms in epileptogenesis and drug resistance. Using a combination of animal models and sera from clinically well-characterized patients, we have demonstrated that there are dynamic changes in HMGB1 isoforms in the brain and blood of animals undergoing epileptogenesis. The pathologic disulfide HMGB1 isoform progressively increased in blood before epilepsy onset and prospectively identified animals that developed the disease. Consistent with animal data, we observed early expression of disulfide HMGB1 in patients with newly diagnosed epilepsy, and its persistence was associated with subsequent seizures. In contrast with patients with well-controlled epilepsy, patients with chronic, drug-refractory epilepsy persistently expressed the acetylated, disulfide HMGB1 isoforms. Moreover, treatment of animals with antiinflammatory drugs during epileptogenesis prevented both disease progression and blood increase in HMGB1 isoforms. Our data suggest that HMGB1 isoforms are mechanistic biomarkers for epileptogenesis and drug-resistant epilepsy in humans, necessitating evaluation in larger-scale prospective studies.

PD-1 pathway blockade has been shown to promote proatherogenic T-cell responses and destabilization of atherosclerotic plaques. Moreover, preclinical evidence suggests a potential synergy of antiplatelet drugs with immune checkpoint inhibitors (ICIs). We conducted an analysis within a prospective observational protocol (APOLLO study) to investigate the rates, predictors, and prognostic significance of thromboembolic events (TE) and thromboprophylaxis in patients with advanced NSCLC treated with ICIs. Among 217 patients treated between April 2014 and September 2018, 13.8% developed TE events. Current smoking status (HR 3.61 (95% CI 1.52–8.60), p = 0.004) and high (>50%) PD-L1 (HR 2.55 (95% CI 1.05–6.19), p = 0.038) resulted in being independent TE predictors. An increased risk of death following a diagnosis of TE (HR 2.93; 95% CI 1.59–5.42; p = 0.0006) was observed. Patients receiving antiplatelet treatment experienced longer progression-free survival (PFS) (6.4 vs. 3.4 months, HR 0.67 (95% CI 0.48–0.92), p = 0.015) and a trend toward better OS (11.2 vs. 9.6 months, HR 0.78 (95% CI 0.55–1.09), p = 0.14), which were not confirmed in a multivariate model. No impact of anticoagulant treatment on patients’ outcomes was observed. NSCLC patients treated with ICIs bear a consistent risk for thrombotic complications, with a detrimental effect on survival. The impact of antiplatelet drugs on ICIs efficacy deserves further investigation in prospective trials.

Cell-cycle abnormalities are common in estrogen receptor- and/or progesterone receptor-positive, and HER2-non-overexpressing (HR+/HER2-) breast cancer, and have long been considered potential therapeutic targets. Cyclin-dependent kinase (CDK) 4/6 inhibitors have dramatically changed the therapeutic management of HR+/HER2-advanced breast cancer by prolonging progression-free and overall survival when given in combination with endocrine therapy. In this article, available data from PALLAS and monarchE trials regarding the efficacy and toxicity of adjuvant combined therapy with CDK 4/6 inhibitors and endocine therapy in HR+/HER2-early breast cancer are reviewed, and relevant issues including study hypothesis, patient selection, and duration of follow-up are discussed.

Background: The interplay between cancer cells and the immune system is crucial in cancer progression and treatment. In this regard, the tumor immune microenvironment and macroenvironment, marked by systemic inflammation markers and TILs, could be considered key prognostic factors in tumors, including oral and lung squamous cell carcinoma. Methods: We conducted a retrospective clinical study on patients with Oral Squamous Cell Carcinoma (OSCC) and Lung Squamous Cell Carcinoma (LUSCC), examining stages, comorbidities, treatments, and outcomes. We evaluated the prognostic significance of pre-surgical systemic inflammation markers and tumor microenvironment composition. Results: Associations were found between systemic inflammation markers—NLR, MLR, and PLR—and tumor microenvironment factors, such as TILs and CD8+ cell prevalence—elevated inflammation markers correlated with advanced stages. Specifically, NLR was prognostic in OSCC, whereas PLR was prognostic in LUSCC. Using a cutoff value, we divided our tumor samples into two prognostic groups. Moreover, TILs levels >15% of tumor stroma correlated with prolonged overall survival in both OSCC and LUSCC, while increased CD8+ expression was linked to extended disease-free survival in LUSCC. Discussion: Systemic inflammation markers and TILs can be valuable prognostic factors of survival, highlighting the immune response’s role in OSCC and LUSCC. Despite limited clinical integration of the presented cohorts due to a lack of standardization, we concluded that analyzing tumor immune profiles may offer novel prognostic insights. Conclusions: Future integration into cancer classification could improve risk stratification and treatment guidance.

Different de-escalation strategies have been proposed to limit the risk of cumulative toxicity and guarantee quality of life during the treatment trajectory of patients with metastatic colorectal cancer (mCRC). Programmed treatment interruptions, defined as drug holidays (DHs), have been implemented in clinical practice. We evaluated the association between DHs and overall survival (OS). This was a retrospective study, conducted at the University Hospital of Udine and the IRCCS CRO of Aviano. We retrieved records of 608 consecutive patients treated for mCRC from 1 January 2005 to 15 March 2017 and evaluated the impact of different de-escalation strategies (maintenance, DHs, or both) on OS through uni- and multivariate Cox regression analyses. We also looked at attrition rates across treatment lines according to the chosen strategy. In our study, 19.24% of patients received maintenance therapy, 16.12% DHs, and 9.87% both, while 32.07% continued full-intensity first-line treatment up to progression or death. In uni- and multivariate analyses first-line continuous treatment and early discontinuation (treatment for less than 3 months) were associated to worse OS compared to non-continuous strategies (HR, 1.68; 95% CI, 1.22–2.32; p = 0.002 and HR,4.89; 95% CI, 3.33–7.19; p < 0.001, respectively). Attrition rates were 22.8%, 20.61%, and 19.64% for maintenance, DHs, or both, respectively. For continuous therapy and for treatment of less than 3 months it was 21.57% and 49%. De-escalation strategies are safe and effective options. DHs after initial induction chemotherapy may be considered in clinically selected patients with metastatic colorectal cancer.