Loss of RAS Mutations in Liquid Biopsies of Patients With Multi-Treated Metastatic Colorectal Cancer.

BACKGROUND: Liquid biopsy (LB) is a non-invasive tool to evaluate the heterogeneity of tumors. Since RAS mutations (RAS-mut) play a major role in resistance to antiepidermal growth factor receptor inhibitors (EGFR) monoclonal antibodies (Mabs), serial monitoring of RAS-mut with LB may be useful to guide treatment. The main aim of this study was to evaluate the prognostic value of the loss of RAS-mut (NeoRAS-wt) in LB, during the treatment of metastatic colorectal cancer (mCRC). METHODS: A retrospective study was conducted on patients with mCRC between January 2018 and December 2021. RAS-mut were examined in tissue biopsy, at mCRC diagnosis, and with LB, during treatment. RESULTS: Thirty-nine patients with RAS-mut mCRC were studied. LB was performed after a median of 3 lines (0-7) of systemic treatment including anti-vascular endothelial growth factor (anti-VEGF) Mabs. NeoRAS-wt was detected in 13 patients (33.3%); 9 (69.2%) of them received further treatment with anti-EGFR Mabs with a disease control rate of 44.4%. Median overall survival (OS), from the date of LB testing, was 20 months in the NeoRAS-wt group and 9 months in the persistent RAS-mut group (log-rank 2.985; P = .08), with a 12-month OS of 84.6% and 57.7%, respectively. NeoRAS-wt was identified as a predictor of survival (HR = 0.29; P = .007), with an 11-month improvement in median OS and a 71% decrease in risk of death, in heavily pretreated patients. CONCLUSIONS: In conclusion, monitoring clonal evolution in mCRC by LB may provide an additional treatment line for patients with NeoRAS-wt in advanced disease.

Beta-Adrenergic Blockade in Advanced Non-Small Cell Lung Cancer Patients Receiving Immunotherapy: A Multicentric Study.

Introduction The standard treatment of cancer has dramatically improved with immune checkpoint inhibitors (ICIs). Despite their proven advantage, many patients fail to exhibit a meaningful and lasting response. The beta-adrenergic signalling pathway may hold significant promise due to its role in promoting an immunosuppressive milieu within the tumour microenvironment. Inhibiting ß-adrenergic signalling could enhance ICI activity; however, blocking this pathway for this purpose has yielded conflicting results. The primary objective of this study was to evaluate the effect of beta-blocker use on overall survival and progression-free survival during ICI therapy. Methods A multicentric, retrospective, observational study was conducted in four Portuguese institutions. Patients with advanced non-small cell lung cancer treated with ICIs between January 2018 and December 2019 were included. Those using beta blockers for non-oncological reasons were compared with non-users. Results Among the 171 patients included, 36 concomitantly received beta blockers and ICIs. No significant increase was found in progression-free survival among patients who took ß-blockers (HR 0.74, 95% confidence interval (CI) 0.48-1.12, p = 0.151), and no statistically significant difference was found in overall survival. An apparent trend was observed towards better outcomes in the beta-blocker group, with a median overall survival of 9.93 months in the group not taking ß-blockers versus 14.90 months in the ß-blocker group (p = 0.291) and a median progression-free survival of 5.37 in the group not taking ß-blockers versus 10.87 months in the ß-blocker group (p = 0.151). Nine (25%) patients in the beta-blocker group and 16 (12%) in the non-beta-blocker group were progressive disease-free at the end of follow-up. This difference between the two groups is statistically significant (p = 0.047). Conclusion Our study found no statistically significant evidence that beta blockers enhance the effectiveness of immunotherapy. Using adrenergic blockade to modulate the immune system shows promise, warranting the need to develop prospective clinical studies.

Alkaline phosphatase and mortality in stroke patients: a systematic review.

Background: Increased plasma levels of alkaline phosphatase (ALP) have been associated to a worse prognosis in several types of diseases. In the present review, the authors aimed to study the relationship between plasma levels of ALP and overall mortality in patients with stroke. Methods: A systematic review was carried out, searching two databases: Web of Science and Medline/PubMed. Results: A total of nine studies that included data on overall mortality in stroke patients were selected. The selected studies were published between 2010 and 2022 and were predominantly from Asia. The articles reviewed quantified ALP levels through different methods: highest versus lowest quintiles of plasma ALP (three reports); highest versus lowest quartiles of plasma ALP (four reports); and plasma ALP levels in deceased versus in surviving patients (two reports). All selected studies showed an increased mortality associated to elevated ALP levels, irrespective of stroke type and length of follow-up, from a mean of 10 days to 2.5 years. The studies comparing the highest to the lowest ALP quintiles showed an aggregate value of 1.8 times greater risk of mortality for the former, when compared to the latter. Whereas, the studies comparing the highest to the lowest ALP quartiles showed an aggregate value of 2.4 times greater risk of mortality for the former, when compared to the latter. Conclusions: Elevated ALP levels are associated with increased mortality in stroke patients and provide cost effective prognostic indicators of mortality in stroke.