Investigating the WNT and TGF-beta pathways alterations and tumor mutant burden in young-onset colorectal cancer.

Colorectal cancer (CRC) is the third most common cancer in the United States. Recent epidemiological evidence demonstrates an increasing incidence of young-onset CRC cases, defined as CRC cases in individuals 50 years old or younger. Studies have established that alterations in both the WNT and TGF-Beta signaling pathways have contributed to CRC development. While this is well understood, the comprehensive analysis of WNT and TGF-Beta pathway alterations in young-onset CRC cases has yet to be investigated. Here, we conducted a comprehensive bioinformatics analysis of mutations associated with each of the WNT and TGF-Beta signaling pathways according to age (≤ 50 years old versus > 50 years old) utilizing published genomic data from the cBioPortal. Chi-square results demonstrated no significant difference in WNT alterations between young-onset CRC and those > 50 years old. However, across all age groups, WNT alterations were frequently found in rectal cancers. We also found that WNT alterations were associated with better outcomes. The mutations associated with TGF-beta were observed at a higher rate in older CRC patients when compared to those ≤ 50 years old. Additionally, these mutations were found more frequently in colon primaries.

CDK4/6 inhibitors: The Devil is in the Detail.

PURPOSE OF REVIEW: Update on the most recent clinical evidence on CDK4/6 inhibitors (CDK4/6i) in the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor (HER)2-negative breast cancer. RECENT FINDINGS: Over the past decade, CDK4/6i have become part of the standard of care treatment of patients with both metastatic and high-risk early HR + /HER2- breast cancers. The three available CDK4/6i (palbociclib, ribociclib and abemaciclib) have been extensively studied in combination with endocrine therapy (ET) in metastatic breast cancer (mBC) with consistent prolongation of progression free survival; however, ribociclib has emerged as the preferred first line agent in mBC given overall survival benefit over endocrine monotherapy. In early BC, abemaciclib is the only currently approved agent while ribociclib has early positive clinical trial data. Toxicities and financial burden limit the use of CDK4/6i in all patients and resource-poor settings, and optimal timing of their use in mBC remains unclear. There is considerable evidence for the use of CDK4/6i in metastatic and early HR + /HER2- breast cancer, but knowledge gaps remain, and further research is necessary to better define their optimal use.

The Efficacy of Immune Checkpoint Inhibitors in Microsatellite Stable Colorectal Cancer: A Systematic Review.

The use of immune checkpoint inhibitors (ICIs) has revolutionized cancer care, particularly in immune-inflamed tumors and tumors with a high mutational burden, like microsatellite instable colorectal cancer (CRC). However, their effectiveness in microsatellite stable (MSS) CRC is limited. This systematic review aims to evaluate the efficacy of ICIs in MSS CRC and explore promising combination strategies. A comprehensive search from the Web of Science, Medline, and Embase databases, for studies published until 14 November 2022, identified 53 clinical trials included in the review. ICI monotherapy or ICI-ICI combinations demonstrated limited clinical activity for patients with MSS CRC, with overall response rates below (ORR) 10% in most studies. The ICI and tyrosine kinase inhibitor (TKI) garnered ORRs ranging from 10% to 40% and indicated a higher benefit for patients, particularly those without active liver metastases. The combination of ICIs with anti-VEGF agents showed modest ORRs, especially in the earlier treatment lines and in combination with chemotherapy. While these combinations could lead to modest improvements, well-defined biomarkers for long-term benefit are yet to be delineated. Combinations involving BRAF inhibitors with ICIs were studied, showing promising responses with combination approaches in molecularly defined subgroups. In conclusion, while ICI monotherapy has limited efficacy in MSS CRC, combination strategies hold promise to enhance survival outcomes. Further research is necessary to identify optimal combination approaches, predictive biomarkers for treatment response, as well as enrollment according to tumor molecular characteristics.

Babesiosis as a cause of false-positive HIV serology.

This is a case of a 71-year-old homosexual man who presented with a 4-day history of fever, weakness and headaches, near syncope, nausea and poor oral intake. The patient denied recent travel or sick contacts but had significant tick bites in the last 4 weeks. A peripheral blood smear showed 0.5% parasitaemia with signet ring appearance organisms consistent with Babesia microti. Serology testing for HIV 1 and 2 by ELISA and western blot were positive. Treatment for Babesia was started and the patient improved. Repeat serology testing for HIV was negative. To the best of our knowledge, this is the first case of false-positive HIV serology that is associated with active babesiosis. In this case, the positive HIV serology turned negative after successful treatment of babesiosis.

Cortical surface characteristics among offspring of schizophrenia subjects.

BACKGROUND: A systematic study of cortical surface parameters in adolescent offspring of schizophrenia subjects before clinical manifestation could clarify neurodevelopmental antecedents of increased genetic risk. We examined these measures obtained on structural magnetic resonance imaging (MRI) scans at baseline and one year on a series of offspring of schizophrenia parents and healthy subjects. METHODS: We measured cortical surface area, curvature and thickness using BRAINS2 on structural MRI scans acquired using 1.5 T GE whole body scanner on all subjects. We examined the differences between study groups at baseline using mixed-effects models, and longitudinal trajectory of these measures using linear mixed-effects models. RESULTS: At baseline, offspring of schizophrenia parents showed reduced gyral surface area in the fronto-parietal lobes along with increased sulcal curvature and parietal gyral cortical thinning compared to healthy subjects. Prospective follow up of these subjects for one year showed shrinking of the total surface area, especially in the bilateral frontal and occipital regions along with preservation of cortical thickness among offspring of schizophrenia parents whereas healthy subjects showed preserved or increased surface area and cortical thinning. Correlation of these measures with lobar volumes was not observed at baseline cross-sectional comparisons but was observed in longitudinal examinations. DISCUSSION: Our observations suggest that adolescents with genetically elevated risk for schizophrenia show altered cortical surface measures affecting cortical surface area and thickness differentially suggesting a divergent trajectory of neurodevelopment. Cortical surface measures appear to be more sensitive to genetic liability to schizophrenia compared to volumetric measures.