The etiology of colorectal cancer (CRC) has been linked to deficiencies in mismatch repair and adenomatous polyposis coli (APC) proteins, diet, inflammatory processes, and gut microbiota. However, ...the mechanism through which the microbiota synergizes with these etiologic factors to promote CRC is not clear. We report that altering the microbiota composition reduces CRC in APCMin/+MSH2−/− mice, and that a diet reduced in carbohydrates phenocopies this effect. Gut microbes did not induce CRC in these mice through an inflammatory response or the production of DNA mutagens but rather by providing carbohydrate-derived metabolites such as butyrate that fuel hyperproliferation of MSH2−/− colon epithelial cells. Further, we provide evidence that the mismatch repair pathway has a role in regulating β-catenin activity and modulating the differentiation of transit-amplifying cells in the colon. These data thereby provide an explanation for the interaction between microbiota, diet, and mismatch repair deficiency in CRC induction.
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•Gut microbiota induce colon cancer in genetically sensitized MSH2-deficient mice•Reduced dietary carbohydrates decreased polyp frequency in APCMin/+MSH2−/− mice•The carbohydrate metabolite butyrate induces colon cancer in APCMin/+MSH2−/− mice•MSH2 regulates β-catenin activity and/or transit-amplifying cell differentiation
Carbohydrate metabolites, produced by gut microbes, can directly induce hyperproliferation and transformation of genetically susceptible colon epithelial cells. This process is independent of inflammation or production of DNA mutagens and provides a mechanism for interaction of microbiota, diet, and mismatch repair deficiency in colorectal cancer induction.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Immune checkpoint inhibitors (ICIs) have transformed the treatment of patients with advanced cancers. However, the majority of patients do not respond or develop early progressive disease. A ...substantial number also develop immune-mediated toxicities that may lead to early treatment discontinuation. Gastrointestinal toxicities in the form of diarrhea and colitis are common and may resemble that observed in patients with inflammatory bowel disease (IBD). Alterations in the gut microbiota are thought to play an important role in mediating the intestinal inflammation that is associated with immune-mediated colitis. In this review, the authors’ objective is to provide an overview of the gastrointestinal and hepatic toxicities that can be seen with ICIs and discuss the interactions between gut microbiota and the immune response. The authors also highlight the potential role for fecal microbial transfer (FMT) as an approach to improve therapeutic efficacy and decrease toxicity.
Background
The relationship between obesity and prognosis of early breast cancer is complex. Increased levels of aromatase present in adipose tissue of obese postmenopausal women may lead to ...suboptimal suppression of systemic estrogens. However, studies have been mixed with respect to the association between use of aromatase inhibitors (AIs) and clinical outcomes in obese women with early breast cancer.
Methods
We conducted a systematic literature review following PRISMA guidelines to examine the impact of obesity on the efficacy of AIs in early-stage hormone receptor-positive breast cancer. Primary outcome measures included disease-free survival, relapse-free survival, distant recurrence-free survival, breast cancer-free survival, and overall survival.
Results
Of 491 studies identified, eight studies met criteria for inclusion: three retrospective cohort studies, one prospective cohort study and four randomized controlled trials. Four studies limited eligibility to postmenopausal women. Percentage of obese patients in studies ranged from 10 to 30%. Two studies examined use of AIs alone while the remainder included patients treated with either AIs or tamoxifen. Five out of seven studies suggested a negative impact of obesity on AI efficacy.
Conclusions
The results of our systematic review highlight a need for further research exploring the optimal endocrine therapies for obese women. There is insufficient evidence at present to recommend tailoring adjuvant endocrine therapy with use of specific AIs or for dosing modifications of AIs in this patient population.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background
Tumor multigene next‐generation sequencing (NGS) is increasingly being offered to cancer patients to guide clinical management and determine eligibility for clinical trials. We undertook a ...review of studies examining the knowledge and attitudes of patients and oncologists regarding the primary results and potential secondary findings of such testing.
Materials and Methods
A search was conducted through the MEDLINE database using the following keywords: “neoplasms” and “molecular sequencing / genome sequencing / tumor profiling / NGS / whole exome sequencing” and “patient / oncologist” and “knowledge / attitudes / satisfaction / experience / evaluation / perspective / practice / preference.” Articles meeting the inclusion criteria and additional relevant articles from their references were selected.
Results
From 1,142 publications identified by the search and 9 from references, 21 publications were included in the final review. Patients generally had positive attitudes toward tumor NGS despite relatively little knowledge of test‐related genetics concepts, but their expectations often exceeded the reality of low clinical utility. Patients with higher education and greater genetics knowledge had more realistic expectations and a more altruistic view of the role of NGS. Attitudes toward disclosure of secondary findings were highly variable. Oncologists had poor to moderate genomic literacy; they communicated challenges with tempering patient expectations and deciding what information to disclose.
Conclusion
Patients considering undergoing tumor NGS should be provided with easily understandable resources explaining the procedure, goals, and probable outcomes, whenever possible based on evidence‐based guidelines. Continuing medical education programs on this topic for oncology health care professionals should strive to improve their genomic literacy and instruct them on how to optimally present this information to their patients.
Implications for Practice
Oncologists are increasingly offering tumor multigene testing to patients with advanced cancers to guide more “personalized” treatment and/or determine eligibility for clinical trials. However, patients often have inadequate understanding and unrealistic expectations. Oncologists must ensure that they themselves have sufficient knowledge of the benefits and limitations of testing and must provide their patients with appropriate educational resources. Prior to testing, patients should be told the likelihood of finding a mutation in their specific tumor type for which a targeted treatment or clinical trial is available. Patients also need clear information about the possibility and implications of secondary findings.
This review focuses on patient and/or physicians’ knowledge and attitudes regarding tumor multigene next‐generation sequencing with potential therapeutic intent.
The blood-brain barrier (BBB) is an important factor limiting the effectiveness of central nervous system (CNS) therapeutics. MR-guided focused ultrasound (MRgFUS) is a noninvasive, spatially precise ...technology that enhances drug delivery across a temporarily permeable BBB. However, despite promising preclinical data, successful drug delivery has yet to be proven in human patients. In this study, we provide primary evidence of enhanced brain penetration of trastuzumab with MRgFUS in patients with Her2-positive breast cancer and brain metastases (NCT03714243). Four patients with progressive intracranial disease and stable systemic disease were enrolled in a single-arm open-labeled study. Twenty treatments combining transcranial MRgFUS with concomitant standard-of-care intravenous trastuzumab-based therapies were administered as outpatient procedures. The primary outcome was safety, and there were no treatment-related serious adverse events. The efficacy of trastuzumab delivery was demonstrated using
In-BzDTPA-NLS-trastuzumab SPECT imaging. The standardized uptake value ratio (SUVR) of MRgFUS-treated lesions increased, on average, by 101 ± 71%, compared to −18 ± 26% in control lesions. MRgFUS enhanced drug uptake in 87 ± 17% of sonicated voxels (>20% increase in SUVR), with up to a 450% voxel-wise increase detected. Control lesions had 8 ± 8% voxels with >20% increase in SUVR. With treatment, unidimensional tumor measurements decreased by 19 ± 12%. This study provides first-in-human evidence of noninvasive, spatially targeted monoclonal antibody delivery across the BBB using MRgFUS, demonstrating the promise of this technology for a broad range of CNS diseases.
Sustained expression of the estrogen receptor-α (ESR1) drives two-thirds of breast cancer and defines the ESR1-positive subtype. ESR1 engages enhancers upon estrogen stimulation to establish an ...oncogenic expression program. Somatic copy number alterations involving the ESR1 gene occur in approximately 1% of ESR1-positive breast cancers, suggesting that other mechanisms underlie the persistent expression of ESR1. We report significant enrichment of somatic mutations within the set of regulatory elements (SRE) regulating ESR1 in 7% of ESR1-positive breast cancers. These mutations regulate ESR1 expression by modulating transcription factor binding to the DNA. The SRE includes a recurrently mutated enhancer whose activity is also affected by rs9383590, a functional inherited single-nucleotide variant (SNV) that accounts for several breast cancer risk-associated loci. Our work highlights the importance of considering the combinatorial activity of regulatory elements as a single unit to delineate the impact of noncoding genetic alterations on single genes in cancer.
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IJS, NUK, SBMB, UL, UM, UPUK
Single-Cell Gene Expression Profiling Levsky, Jeffrey M.; Shenoy, Shailesh M.; Pezo, Rossanna C. ...
Science (American Association for the Advancement of Science),
08/2002, Volume:
297, Issue:
5582
Journal Article
Peer reviewed
A key goal of biology is to relate the expression of specific genes to a particular cellular phenotype. However, current assays for gene expression destroy the structural context. By combining ...advances in computational fluorescence microscopy with multiplex probe design, we devised technology in which the expression of many genes can be visualized simultaneously inside single cells with high spatial and temporal resolution. Analysis of 11 genes in serum-stimulated cultured cells revealed unique patterns of gene expression within individual cells. Using the nucleus as the substrate for parallel gene analysis, we provide a platform for the fusion of genomics and cell biology: "cellular genomics."
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
The prevalence of breast cancer amongst older adults in Canada is increasing. This patient population faces unique challenges in the management of breast cancer, as older adults often have distinct ...biological, psychosocial, and treatment-related considerations. This paper presents an expert consensus of the Canadian treatment landscape, focusing on key considerations for optimizing selection of systemic therapy for advanced breast cancer in older adults. This paper aims to provide evidence-based recommendations and practical guidance for healthcare professionals involved in the care of older adults with breast cancer. By recognizing and addressing the specific needs of older adults, healthcare providers can optimize treatment outcomes and improve the overall quality of care for this population.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK, VSZLJ
Activation-induced cytidine deaminase (AID) catalyses the deamination of deoxycytidines to deoxyuracils within immunoglobulin genes to induce somatic hypermutation and class-switch recombination
. ...AID-generated deoxyuracils are recognized and processed by subverted base-excision and mismatch repair pathways that ensure a mutagenic outcome in B cells
. However, why these DNA repair pathways do not accurately repair AID-induced lesions remains unknown. Here, using a genome-wide CRISPR screen, we show that FAM72A is a major determinant for the error-prone processing of deoxyuracils. Fam72a-deficient CH12F3-2 B cells and primary B cells from Fam72a
mice exhibit reduced class-switch recombination and somatic hypermutation frequencies at immunoglobulin and Bcl6 genes, and reduced genome-wide deoxyuracils. The somatic hypermutation spectrum in B cells from Fam72a
mice is opposite to that observed in mice deficient in uracil DNA glycosylase 2 (UNG2)
, which suggests that UNG2 is hyperactive in FAM72A-deficient cells. Indeed, FAM72A binds to UNG2, resulting in reduced levels of UNG2 protein in the G1 phase of the cell cycle, coinciding with peak AID activity. FAM72A therefore causes U·G mispairs to persist into S phase, leading to error-prone processing by mismatch repair. By disabling the DNA repair pathways that normally efficiently remove deoxyuracils from DNA, FAM72A enables AID to exert its full effects on antibody maturation. This work has implications in cancer, as the overexpression of FAM72A that is observed in many cancers
could promote mutagenesis.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
Background
Clinical trial reports often emphasize efficacy over harms, leading to misinterpretation of the risk‐to‐benefit ratio of new therapies. Clear and sufficiently detailed reporting of methods ...and results is especially important in the s of trial reports, as readers often base their assessment of a trial on such information. In this study, we evaluated the quality of adverse event (AE) reporting and quality in phase III randomized controlled trials (RCTs) of systemic therapies in breast and colorectal cancer.
Methods
Medline, EMBASE, Cochrane Database of RCTs, and Cochrane Database of Systematic Reviews were searched from November 2005 to September 2018. Phase III RCTs evaluating systemic therapies in breast or colorectal cancer were included. Each article was independently reviewed by two investigators using a standardized data extraction form based on guidelines developed by the Consolidated Standards of Reporting Trials (CONSORT) group. Descriptive statistics, bivariate analysis, and multivariable linear regression were used to analyze data. All statistical tests were two‐sided.
Results
Of 166 RCTs identified, 99.4% reported harms in the manuscript body, and 59.6% reported harms in the . Reporting was restricted to severe harms in 15.6% of RCTs. Statistical comparison of AE rates went unreported in 59.0% of studies. Information regarding AEs leading to dose reductions, treatment discontinuations, or study withdrawals went unreported in 59.3%, 18.7%, and 86.8% of studies, respectively. Recently published RCTs (P = .009) and those sponsored at least partially by for‐profit companies (P = .003) had higher quality scores.
Conclusions
Breast and colorectal cancer phase III RCTs inadequately report CONSORT‐compliant AE data. Improved guideline adherence and reporting is required to properly weigh benefits and harms of new oncologic therapies.
Systematic Review Registration Number
CRD42019140673.
Clinical trial reports often emphasize efficacy rather than toxicities of investigational agents, leading to misinterpretation of the risk‐to‐benefit ratio of new therapies. Here, we evaluated the quality of adverse event reporting in phase III randomized controlled trials of systemic therapies in breast and colorectal cancer. Our results show that most studies inadequately report adverse event data.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK