Citations

Abstract Background Obesity is an established risk factor for colorectal cancer (CRC), but the evidence for the association is inconsistent across molecular subtypes of the disease. Methods We pooled data on body mass index (BMI), tumor microsatellite instability status, CpG island methylator phenotype status, BRAF and KRAS mutations, and Jass classification types for 11 872 CRC cases and 11 013 controls from 11 observational studies. We used multinomial logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) adjusted for covariables. Results Higher BMI was associated with increased CRC risk (OR per 5 kg/m2 = 1.18, 95% CI = 1.15 to 1.22). The positive association was stronger for men than women but similar across tumor subtypes defined by individual molecular markers. In analyses by Jass type, higher BMI was associated with elevated CRC risk for types 1-4 cases but not for type 5 CRC cases (considered familial-like/Lynch syndrome microsatellite instability-H, CpG island methylator phenotype-low or negative, BRAF-wild type, KRAS-wild type, OR = 1.04, 95% CI = 0.90 to 1.20). This pattern of associations for BMI and Jass types was consistent by sex and design of contributing studies (cohort or case-control). Conclusions In contrast to previous reports with fewer study participants, we found limited evidence of heterogeneity for the association between BMI and CRC risk according to molecular subtype, suggesting that obesity influences nearly all major pathways involved in colorectal carcinogenesis. The null association observed for the Jass type 5 suggests that BMI is not a risk factor for the development of CRC for individuals with Lynch syndrome.

OBJECTIVE Stereotactic radiosurgery (SRS) is an effective treatment for intracranial metastatic disease, but its role in triple-negative breast cancer requires further study. Herein, the authors report overall survival (OS) and local tumor control in a multiinstitutional cohort with triple-negative breast cancer metastases treated with SRS. METHODS Patients treated from 2010 to 2019 at 9 institutions were included in this retrospective study if they had biopsy-proven triple-negative breast cancer with intracranial metastatic lesions treated with SRS. Patients were excluded if they had undergone prior SRS, whole-brain radiation therapy, or resection of the metastatic lesions. A retrospective chart review was conducted to determine OS, local control, and treatment efficacy. RESULTS Sixty-eight patients with 315 treated lesions were assessed. Patients had a median Karnofsky Performance Status of 80 (IQR 70–90) and age of 57 years (IQR 48–67 years). Most treated patients had 5 or fewer intracranial lesions, with 34% of patients having a single lesion. Treated lesions were small, having a median volume owf 0.11 cm3 (IQR 0.03–0.60 cm3). Patients were treated with a median margin dose of 18 Gy (IQR 18–20 Gy) to the median 71% isodose line (IQR 50%–84%). Overall, patients had a 1-year OS of 43% and 2-year OS of 20%. Most patients (88%) were followed until death, by which time local tumor progression had occurred in only 7% of cases. Furthermore, 76% of the lesions demonstrated regression. Tumor volume was correlated with local tumor progression (p = 0.012). SRS was very well tolerated, and only 3 patients (5%) developed symptomatic radiation necrosis. CONCLUSIONS SRS is a safe and efficacious treatment for well-selected patients with triple-negative breast cancer, especially for those with a favorable performance status and small- to moderate-volume metastatic lesions.

Abstract Understanding the function of non-coding genomic sequence variants represents a challenge for biomedicine. Many diseases are products of gene-by-environment interactions with complex mechanisms. This study addresses these themes by mechanistic characterization of non-coding variants that influence gene expression only after drug or hormone exposure. Using glucocorticoid signaling as a model system, we integrated genomic, transcriptomic, and epigenomic approaches to unravel mechanisms by which variant function could be revealed by hormones or drugs. Specifically, we identified cis-regulatory elements and 3D interactions underlying ligand-dependent associations between variants and gene expression. One-quarter of the glucocorticoid-modulated variants that we identified had already been associated with clinical phenotypes. However, their affected genes were ‘unmasked’ only after glucocorticoid exposure and often with function relevant to the disease phenotypes. These diseases involved glucocorticoids as risk factors or therapeutic agents and included autoimmunity, metabolic and mood disorders, osteoporosis and cancer. For example, we identified a novel breast cancer risk gene, MAST4, with expression that was repressed by glucocorticoids in cells carrying the risk genotype, repression that correlated with MAST4 expression in breast cancer and treatment outcomes. These observations provide a mechanistic framework for understanding non-coding genetic variant-chemical environment interactions and their role in disease risk and drug response.

Abstract BACKGROUND Glioblastoma diagnostic criteria have been redefined with the 5th edition of WHO classification of tumors of the central nervous system. Glioblastomas are defined as IDH wildtype diffuse astrocytic glioma tumors with one of the following features: microvascular proliferation, or necrosis, or TERT promoter mutation, or EGFR gene amplification, or +7/-10 chromosome copy number changes. The aim of this study is to establish the impact of extent of resection in overall survival (OS) and progression free survival (PFS) in glioblastoma, IDH-wildtype (WT), WHO grade 4 (WHO 2021). METHODS Systematic literature search was performed using the following databases: PubMed, Web of Science, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and ClinicalTrials.gov to identify studies comparing OS and PFS after gross total resection (GTR) vs subtotal resection (STR) or biopsy for glioblastoma IDH-WT. Prognostic hazard ratios (HR) for OS and PFS were analyzed using a random-effects model. RESULTS We identified 1439 publications. Nine studies met inclusion/exclusion criteria. 788 patients underwent GTR out of 1818. The meta-analysis showed a significant increase in OS and PFS duration when undergoing GTR for glioblastoma IDH-WT with a median OS of 20 months 95% CI (17-25) compared to 12 months 95% CI (9-15) for STR or biopsy and a median PFS of 11 months 95% CI (9-12) for GTR compared to 7 months 95% CI (5-7) for STR or biopsy respectively. GTR showed a 49% significant reduction of mortality risk HR=0.51 95%CI (0.42-0.59) and a 44% significant reduction of progression risk HR=0.56 95%CI (0.41-0.71) compared to STR or biopsy. CONCLUSIONS This systematic review indicates that GTR may be associated with improved OS and PFS compared to STR or biopsy for Glioblastoma, IDH-WT, WHO grade 4 (WHO 2021). However, this is limited by variable study design and significant clinical and methodological heterogeneity among studies.