Immunohistochemical evaluation of the prognostic and predictive power of epidermal growth factor receptor ligand levels in patients with metastatic colorectal cancer.

For patients with metastatic colorectal cancer (mCRC), epidermal growth factor receptor (EGFR) inhibitors are limited to patients with wild-type tumours. Not all patients will benefit from treatment and better predictive biomarkers are needed. Here we investigated the prognostic and predictive impact of the EGFR ligands amphiregulin (AREG) and epiregulin (EREG).

CSK-homologous kinase (CHK/MATK) is a potential colorectal cancer tumour suppressor gene epigenetically silenced by promoter methylation.

Hyperactivation of SRC-family protein kinases (SFKs) contributes to the initiation and progression of human colorectal cancer (CRC). Since oncogenic mutations of SFK genes are rare in human CRC, we investigated if SFK hyperactivation is linked to dysregulation of their upstream inhibitors, C-terminal SRC kinase (CSK) and its homolog CSK-homologous kinase (CHK/MATK). We demonstrate that expression of CHK/MATK but not CSK was significantly downregulated in CRC cell lines and primary tumours compared to normal colonic tissue.

Uptake of hysterectomy and bilateral salpingo-oophorectomy in carriers of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report.

Purpose: This study aimed to report the uptake of hysterectomy and/or bilateral salpingo-oophorectomy (BSO) to prevent gynaecological cancers (risk-reducing surgery [RRS]) in carriers of pathogenic MMR (path_MMR) variants.

Methods: The Prospective Lynch Syndrome Database (PLSD) was used to investigate RRS by a cross-sectional study in 2292 female path_MMR carriers aged 30-69 years.

Results: Overall, 144, 79, and 517 carriers underwent risk-reducing hysterectomy, BSO, or both combined, respectively.

A scoping review of studies using observational data to optimise dynamic treatment regimens.

Background: Dynamic treatment regimens (DTRs) formalise the multi-stage and dynamic decision problems that clinicians often face when treating chronic or progressive medical conditions. Compared to randomised controlled trials, using observational data to optimise DTRs may allow a wider range of treatments to be evaluated at a lower cost. This review aimed to provide an overview of how DTRs are optimised with observational data in practice.

Macrophages provide a transient muscle stem cell niche via NAMPT secretion.

Skeletal muscle regenerates through the activation of resident stem cells. Termed satellite cells, these normally quiescent cells are induced to proliferate by wound-derived signals. Identifying the source and nature of these cues has been hampered by an inability to visualize the complex cell interactions that occur within the wound.

DNA methylation patterns identify subgroups of pancreatic neuroendocrine tumors with clinical association.

Here we report the DNA methylation profile of 84 sporadic pancreatic neuroendocrine tumors (PanNETs) with associated clinical and genomic information. We identified three subgroups of PanNETs, termed T1, T2 and T3, with distinct patterns of methylation. The T1 subgroup was enriched for functional tumors and ATRX, DAXX and MEN1 wild-type genotypes.

Biological Aging Measures Based on Blood DNA Methylation and Risk of Cancer: A Prospective Study.

Background: We previously investigated the association between 5 "first-generation" measures of epigenetic aging and cancer risk in the Melbourne Collaborative Cohort Study. This study assessed cancer risk associations for 3 recently developed methylation-based biomarkers of aging: , , and predicted telomere length.

Methods: We estimated rate ratios (RRs) for the association between these 3 age-adjusted measures and risk of colorectal (N = 813), gastric (N = 165), kidney (N = 139), lung (N = 327), mature B-cell (N = 423), prostate (N = 846), and urothelial (N = 404) cancer using conditional logistic regression models.

Towards Routine Implementation of Liquid Biopsies in Cancer Management: It Is Always Too Early, until Suddenly It Is Too Late.

Blood-based liquid biopsies are considered a new and promising diagnostic and monitoring tool for cancer. As liquid biopsies only require a blood draw, they are non-invasive, potentially more rapid and assumed to be a less costly alternative to genomic analysis of tissue biopsies. A multi-disciplinary workshop ( = 98 registrations) was organized to discuss routine implementation of liquid biopsies in cancer management.

Volatile anaesthesia and peri-operative outcomes related to cancer: a feasibility and pilot study for a large randomised control trial.

Published data suggest that the type of general anaesthesia used during surgical resection for cancer may impact on patient long-term outcome. However, robust prospective clinical evidence is essential to guide a change in clinical practice. We explored the feasibility of conducting a randomised controlled trial to investigate the impact of total intravenous anaesthesia with propofol vs.

Evaluating the utility of tumour mutational signatures for identifying hereditary colorectal cancer and polyposis syndrome carriers.

Objective: Germline pathogenic variants (PVs) in the DNA mismatch repair (MMR) genes and in the base excision repair gene underlie hereditary colorectal cancer (CRC) and polyposis syndromes. We evaluated the robustness and discriminatory potential of tumour mutational signatures in CRCs for identifying germline PV carriers.

Design: Whole-exome sequencing of formalin-fixed paraffin-embedded (FFPE) CRC tissue was performed on 33 MMR germline PV carriers, 12 biallelic germline PV carriers, 25 sporadic methylated MMR-deficient CRCs (MMRd controls) and 160 sporadic MMR-proficient CRCs (MMRp controls) and included 498 TCGA CRC tumours.

Toward precision immunotherapy using multiplex immunohistochemistry and in silico methods to define the tumor immune microenvironment.

Recent developments in cancer immunotherapy promise better outcomes for cancer patients, although clinical trials for difficult to treat cancers such as malignant brain cancer present special challenges, showing little response to first generation immunotherapies. Reasons for differences in immunotherapy response in some cancer types are likely due to the nature of tumor microenvironment, which harbors multiple cell types which interact with tumor cells to establish immunosuppression. The cell types which appear to hold the key in regulating tumor immunosuppression are the tumor-infiltrating immune cells.

Progastrin production transitions from Bmi1/Prox1 to Lgr5 cells during early intestinal tumorigenesis.

Progastrin is an unprocessed soluble peptide precursor with a well-described tumor-promoting role in colorectal cancer. It is expressed at small levels in the healthy intestinal mucosa, and its expression is enhanced at early stages of intestinal tumor development, with high levels of this peptide in hyperplastic intestinal polyps being associated with poor neoplasm-free survival in patients. Yet, the precise type of progastrin-producing cells in the healthy intestinal mucosa and in early adenomas remains unclear.

Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study.

Background: Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood.

Methods: We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC.

A Combined Proteomics and Mendelian Randomization Approach to Investigate the Effects of Aspirin-Targeted Proteins on Colorectal Cancer.

Background: Evidence for aspirin's chemopreventative properties on colorectal cancer (CRC) is substantial, but its mechanism of action is not well-understood. We combined a proteomic approach with Mendelian randomization (MR) to identify possible new aspirin targets that decrease CRC risk.

Methods: Human colorectal adenoma cells (RG/C2) were treated with aspirin (24 hours) and a stable isotope labeling with amino acids in cell culture (SILAC) based proteomics approach identified altered protein expression.

A thiol-bound drug reservoir enhances APR-246-induced mutant p53 tumor cell death.

The tumor suppressor gene TP53 is the most frequently mutated gene in cancer. The compound APR-246 (PRIMA-1Met/Eprenetapopt) is converted to methylene quinuclidinone (MQ) that targets mutant p53 protein and perturbs cellular antioxidant balance. APR-246 is currently tested in a phase III clinical trial in myelodysplastic syndrome (MDS).

Receipt of infant HIV DNA PCR test results is associated with a reduction in retention of HIV-exposed infants in integrated HIV care and healthcare services: a quantitative sub-study nested within a cluster randomised trial in rural Malawi.

Background: Retention of HIV-infected mothers in integrated HIV and healthcare facilities is effective at reducing mother-to-child-transmission (MTCT) of HIV. In the context of Option B+, we examined maternal and HIV-exposed infant retention across three study arms to 18 months postpartum: mother-and-infant clinics (MIP), MIP with short-messaging service (MIP + SMS) and standard of care (SOC). In particular, we focused on the impact of mothers receiving an infant's HIV PCR test result on maternal and infant study retention.

Cross-Cancer Genome-Wide Association Study of Endometrial Cancer and Epithelial Ovarian Cancer Identifies Genetic Risk Regions Associated with Risk of Both Cancers.

Background: Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers.

Factors Influencing Surgical Outcome in Retrograde Management of Parapelvic Renal Cysts.

To investigate the outcomes of retrograde flexible ureteroscopy in managing parapelvic renal cysts and speculate the factors affecting therapeutic efficacy. Thirty-eight patients with parapelvic renal cysts were recruited and underwent retrograde flexible ureteroscopy using holmium laser. Parapelvic cysts were divided into peripheral type and central type based on the position of cyst convex to the perirenal tissue.

Genetic Variants in the Regulatory T cell-Related Pathway and Colorectal Cancer Prognosis.

Background: High numbers of lymphocytes in tumor tissue, including T regulatory cells (Treg), have been associated with better colorectal cancer survival. Tregs, a subset of CD4 T lymphocytes, are mediators of immunosuppression in cancer, and therefore variants in genes related to Treg differentiation and function could be associated with colorectal cancer prognosis.

Methods: In a prospective German cohort of 3,593 colorectal cancer patients, we assessed the association of 771 single-nucleotide polymorphisms (SNP) in 58 Treg-related genes with overall and colorectal cancer-specific survival using Cox regression models.

Exposure to household air pollution over 10 years is related to asthma and lung function decline.

Introduction: We investigated if long-term household air pollution (HAP) is associated with asthma and lung function decline in middle-aged adults, and whether these associations were modified by glutathione -transferase (GST) gene variants, ventilation and atopy.

Materials And Methods: Prospective data on HAP (heating, cooking, mould and smoking) and asthma were collected in the Tasmanian Longitudinal Health Study (TAHS) at mean ages 43 and 53 years (n=3314). Subsamples had data on lung function (n=897) and GST gene polymorphisms (n=928).

Mendelian randomization analyses suggest a role for cholesterol in the development of endometrial cancer.

Blood lipids have been associated with the development of a range of cancers, including breast, lung and colorectal cancer. For endometrial cancer, observational studies have reported inconsistent associations between blood lipids and cancer risk. To reduce biases from unmeasured confounding, we performed a bidirectional, two-sample Mendelian randomization analysis to investigate the relationship between levels of three blood lipids (low-density lipoprotein [LDL] and high-density lipoprotein [HDL] cholesterol, and triglycerides) and endometrial cancer risk.