Objective The purpose of this study was to assess the uptake and perioperative safety of bilateral salpingectomy (BS) as an ovarian cancer risk-reduction strategy in low-risk women after a regional ...initiative that was aimed at general gynecologists in the province of British Columbia, Canada. Study Design This population-based retrospective cohort study evaluated 43,931 women in British Columbia from 2008-2011 who underwent hysterectomy that was performed with and without BS or bilateral salpingo-oophorectomy or who underwent surgical sterilization by means of BS or tubal ligation. Parameters that were examined include patient age, operating time, surgical approach, indication, length of hospital stay, and perioperative complications. Results There was an increase in the uptake of hysterectomy with BS (5-35%; P < .001) and BS for sterilization (0.5-33%; P < .001) over the study period, particularly in women <50 years old. Minimal additional surgical time is required for hysterectomy with BS (16 minutes; P < .001) and BS for sterilization (10 minutes; P < .001) compared with hysterectomy alone or tubal ligation, respectively. No significant differences were observed in the risks of hospital readmission or blood transfusions in women who underwent hysterectomy with BS (adjusted odds ratio aOR, 0.91; 95% confidence interval CI, 0.75–1.10; and aOR, 0.86; 95% CI, 0.67–1.10, respectively) or BS for sterilization (aOR, 0.8; 95% CI, 0.56–1.21; and aOR, 0.75; 95% CI, 0.32–1.73, respectively). From 2008-2011 the proportion of hysterectomies with BS performed by open laparotomy decreased from 77-44% with uptake in laparoscopic, vaginal, and combined procedures ( P < .001). Conclusion After our 2010 educational initiative, there has been a shift in surgical paradigm in our province. This cancer prevention approach does not increase the risk of operative/perioperative complications and appears both feasible and safe.
OBJECTIVES
To develop an evidence‐based definition of sarcopenia that can facilitate identification of older adults at risk for clinically relevant outcomes (eg, self‐reported mobility limitation, ...falls, fractures, and mortality), the Sarcopenia Definition and Outcomes Consortium (SDOC) crafted a set of position statements informed by a literature review and SDOC's analyses of eight epidemiologic studies, six randomized clinical trials, four cohort studies of special populations, and two nationally representative population‐based studies.
METHODS
Thirteen position statements related to the putative components of a sarcopenia definition, informed by the SDOC analyses and literature synthesis, were reviewed by an independent international expert panel (panel) iteratively and voted on by the panel during the Sarcopenia Position Statement Conference. Four position statements related to grip strength, three to lean mass derived from dual‐energy x‐ray absorptiometry (DXA), and four to gait speed; two were summary statements.
RESULTS
The SDOC analyses identified grip strength, either absolute or scaled to measures of body size, as an important discriminator of slowness. Both low grip strength and low usual gait speed independently predicted falls, self‐reported mobility limitation, hip fractures, and mortality in community‐dwelling older adults. Lean mass measured by DXA was not associated with incident adverse health‐related outcomes in community‐dwelling older adults with or without adjustment for body size.
CONCLUSION
The panel agreed that both weakness defined by low grip strength and slowness defined by low usual gait speed should be included in the definition of sarcopenia. These position statements offer a rational basis for an evidence‐based definition of sarcopenia. The analyses that informed these position statements are summarized in this article and discussed in accompanying articles in this issue of the journal. J Am Geriatr Soc 68:1410‐1418, 2020.
See related editorial by Cesari et al in this issue
Abstract
Background
To drive translational medicine, modern day biobanks need to integrate with other sources of data (clinical, genomics) to support novel data-intensive research. Currently, vast ...amounts of research and clinical data remain in silos, held and managed by individual researchers, operating under different standards and governance structures; a framework that impedes sharing and effective use of data. In this article, we describe the journey of British Columbia’s Gynecological Cancer Research Program (OVCARE) in moving a traditional tumour biobank, outcomes unit, and a collection of data silos, into an integrated data commons to support data standardization and resource sharing under collaborative governance, as a means of providing the gynecologic cancer research community in British Columbia access to tissue samples and associated clinical and molecular data from thousands of patients.
Results
Through several engagements with stakeholders from various research institutions within our research community, we identified priorities and assessed infrastructure needs required to optimize and support data collections, storage and sharing, under three main research domains: (1) biospecimen collections, (2) molecular and genomics data, and (3) clinical data. We further built a governance model and a resource portal to implement protocols and standard operating procedures for seamless collections, management and governance of interoperable data, making genomic, and clinical data available to the broader research community.
Conclusions
Proper infrastructures for data collection, sharing and governance is a translational research imperative. We have consolidated our data holdings into a data commons, along with standardized operating procedures to meet research and ethics requirements of the gynecologic cancer community in British Columbia. The developed infrastructure brings together, diverse data, computing frameworks, as well as tools and applications for managing, analyzing, and sharing data. Our data commons bridges data access gaps and barriers to precision medicine and approaches for diagnostics, treatment and prevention of gynecological cancers, by providing access to large datasets required for data-intensive science.
Germline truncating mutations in DICER1, an endoribonuclease in the RNase III family that is essential for processing microRNAs, have been observed in families with the pleuropulmonary ...blastoma-family tumor and dysplasia syndrome. Mutation carriers are at risk for nonepithelial ovarian tumors, notably sex cord-stromal tumors.
We sequenced the whole transcriptomes or exomes of 14 nonepithelial ovarian tumors and noted closely clustered mutations in the region of DICER1 encoding the RNase IIIb domain of DICER1 in four samples. We then sequenced this region of DICER1 in additional ovarian tumors and in certain other tumors and queried the effect of the mutations on the enzymatic activity of DICER1 using in vitro RNA cleavage assays.
DICER1 mutations in the RNase IIIb domain were found in 30 of 102 nonepithelial ovarian tumors (29%), predominantly in Sertoli-Leydig cell tumors (26 of 43, or 60%), including 4 tumors with additional germline DICER1 mutations. These mutations were restricted to codons encoding metal-binding sites within the RNase IIIb catalytic centers, which are critical for microRNA interaction and cleavage, and were somatic in all 16 samples in which germline DNA was available for testing. We also detected mutations in 1 of 14 nonseminomatous testicular germ-cell tumors, in 2 of 5 embryonal rhabdomyosarcomas, and in 1 of 266 epithelial ovarian and endometrial carcinomas. The mutant DICER1 proteins had reduced RNase IIIb activity but retained RNase IIIa activity.
Somatic missense mutations affecting the RNase IIIb domain of DICER1 are common in nonepithelial ovarian tumors. These mutations do not obliterate DICER1 function but alter it in specific cell types, a novel mechanism through which perturbation of microRNA processing may be oncogenic. (Funded by the Terry Fox Research Institute and others.).
Active neurons exert a mitogenic effect on normal neural precursor and oligodendroglial precursor cells, the putative cellular origins of high-grade glioma (HGG). By using optogenetic control of ...cortical neuronal activity in a patient-derived pediatric glioblastoma xenograft model, we demonstrate that active neurons similarly promote HGG proliferation and growth in vivo. Conditioned medium from optogenetically stimulated cortical slices promoted proliferation of pediatric and adult patient-derived HGG cultures, indicating secretion of activity-regulated mitogen(s). The synaptic protein neuroligin-3 (NLGN3) was identified as the leading candidate mitogen, and soluble NLGN3 was sufficient and necessary to promote robust HGG cell proliferation. NLGN3 induced PI3K-mTOR pathway activity and feedforward expression of NLGN3 in glioma cells. NLGN3 expression levels in human HGG negatively correlated with patient overall survival. These findings indicate the important role of active neurons in the brain tumor microenvironment and identify secreted NLGN3 as an unexpected mechanism promoting neuronal activity-regulated cancer growth.
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•Neuronal activity promotes high-grade glioma (HGG) proliferation and growth•Neuroligin-3 is an activity-regulated secreted glioma mitogen•Neuroligin-3 induces PI3K-mTOR signaling in HGG cells•Neuroligin-3 expression is inversely correlated with survival in human HGG
Neuronal activity promotes the growth of malignant glioma through activity-regulated secretion of the synaptic protein neuroligin-3, which acts as a mitogen, recruiting the PI3K-mTOR pathway to induce glioma cell proliferation.
Diffuse midline gliomas (DMGs) are universally lethal malignancies occurring chiefly during childhood and involving midline structures of the central nervous system, including thalamus, pons, and ...spinal cord. These molecularly related cancers are characterized by high prevalence of the histone H3K27M mutation. In search of effective therapeutic options, we examined multiple DMG cultures in sequential quantitative high-throughput screens (HTS) of 2706 approved and investigational drugs. This effort generated 19,936 single-agent dose responses that inspired a series of HTS-enabled drug combination assessments encompassing 9195 drug-drug examinations. Top combinations were validated across patient-derived cell cultures representing the major DMG genotypes. In vivo testing in patient-derived xenograft models validated the combination of the multi-histone deacetylase (HDAC) inhibitor panobinostat and the proteasome inhibitor marizomib as a promising therapeutic approach. Transcriptional and metabolomic surveys revealed substantial alterations to key metabolic processes and the cellular unfolded protein response after treatment with panobinostat and marizomib. Mitigation of drug-induced cytotoxicity and basal mitochondrial respiration with exogenous application of nicotinamide mononucleotide (NMN) or exacerbation of these phenotypes when blocking nicotinamide adenine dinucleotide (NAD
) production via nicotinamide phosphoribosyltransferase (NAMPT) inhibition demonstrated that metabolic catastrophe drives the combination-induced cytotoxicity. This study provides a comprehensive single-agent and combinatorial drug screen for DMG and identifies concomitant HDAC and proteasome inhibition as a promising therapeutic strategy that underscores underrecognized metabolic vulnerabilities in DMG.
The challenge of linking intergenic mutations to target genes has limited molecular understanding of human diseases. Here we show that H3K27ac HiChIP generates high-resolution contact maps of active ...enhancers and target genes in rare primary human T cell subtypes and coronary artery smooth muscle cells. Differentiation of naive T cells into T helper 17 cells or regulatory T cells creates subtype-specific enhancer-promoter interactions, specifically at regions of shared DNA accessibility. These data provide a principled means of assigning molecular functions to autoimmune and cardiovascular disease risk variants, linking hundreds of noncoding variants to putative gene targets. Target genes identified with HiChIP are further supported by CRISPR interference and activation at linked enhancers, by the presence of expression quantitative trait loci, and by allele-specific enhancer loops in patient-derived primary cells. The majority of disease-associated enhancers contact genes beyond the nearest gene in the linear genome, leading to a fourfold increase in the number of potential target genes for autoimmune and cardiovascular diseases.
Myelination of the central nervous system requires the generation of functionally mature oligodendrocytes from oligodendrocyte precursor cells (OPCs). Electrically active neurons may influence OPC ...function and selectively instruct myelination of an active neural circuit. In this work, we use optogenetic stimulation of the premotor cortex in awake, behaving mice to demonstrate that neuronal activity elicits a mitogenic response of neural progenitor cells and OPCs, promotes oligodendrogenesis, and increases myelination within the deep layers of the premotor cortex and subcortical white matter. We further show that this neuronal activity-regulated oligodendrogenesis and myelination is associated with improved motor function of the corresponding limb. Oligodendrogenesis and myelination appear necessary for the observed functional improvement, as epigenetic blockade of oligodendrocyte differentiation and myelin changes prevents the activity-regulated behavioral improvement.
The presence of increased B-cell tumor infiltrating lymphocytes (TILs) was seen in mouse prostate cancer (PCa) but has not been fully documented in human PCa. We, therefore, investigated the density ...of infiltrating B cells within human PCa utilizing a quantitative computational method.
Archived radical prostatectomy specimens from 53 patients with known clinical outcome and D'Amico risk category were obtained and immunohistochemically (IHC) stained for the B cell marker, CD20. Slides were reviewed by a genitourinary pathologist who manually delineated the tumoral regions of PCa. Slides were digitally scanned and a computer algorithm quantified the area of CD20 stained B-cells as a measure of B cell density within the outlined regions of prostate cancer (intra-tumoral region), versus extra-tumoral prostate tissue. Correlations were analyzed between B-cell density and demographic and clinical variables, including D'Amico risk groups and disease recurrence.
For the entire cohort, the mean intra-tumoral B cell density was higher (3.22 SE = 0.29) than in the extra-tumoral region of each prostatectomy section (2.24, SE = 0.19) (paired t test; P < 0.001). When analyzed according to D'Amico risk group, the intra-tumoral B cell infiltration in low risk (0.0377 vs. 0.0246; p = 0.151) and intermediate risk (0.0260 vs. 0.0214; p = 0.579) patient prostatectomy specimens did not show significantly more B-cells within the PCa tumor. However, patient specimens from the high-risk group (0.0301 vs. 0.0197; p < 0.001) and from those who eventually had PCa recurrence or progression (0.0343 vs. 0.0246; p = 0.019) did show significantly more intra-tumoral CD20+ B-cell staining. Extent of B-cell infiltration in the prostatectomy specimens did not correlate with any other clinical parameters.
Our study shows that higher B-cell infiltration was present within the intra-tumoral PCa regions compared to the extra-tumoral benign prostate tissue regions in prostatectomy sections. For this study we developed a new method to measure B-cells using computer-assisted digitized image analysis. Accurate, consistent quantitation of B-cells in prostatectomy specimens is essential for future clinical trials evaluating the effect of B cell ablating antibodies. The interaction of B-cells and PCa may serve as the basis for new therapeutic targets.
Background
We describe the landscape of cyclin and interactive gene pathway alterations in 190,247 solid tumors.
Methods
Using comprehensive genomic profiling (315 genes, >500× coverage), samples ...were analyzed for alterations in activating/sensitizing cyclin genes (CDK4 amplification, CDK6 amplification, CCND1, CCND2, CCND3, CDKN2B loss, CDKN2A loss, SMARCB1), hormone genes (estrogen receptor 1 ESR1, androgen receptor AR), and co‐alterations in genes leading to cyclin inhibitor therapeutic resistance (RB1 and CCNE1).
Results
Alterations in at least one cyclin activating/sensitizing gene occurred in 24% of malignancies. Tumors that frequently harbored at least one cyclin alteration were brain gliomas (47.1%), esophageal (40.3%) and bladder cancer (37.9%), and mesotheliomas (37.9%). The most frequent alterations included CDKN2A (13.9%) and CDKN2B loss (12.5%). Examples of unique patterns of alterations included CCND1 amplification in breast cancer (17.3%); CDK4 alterations in sarcomas (12%); CCND2 in testicular cancer (23.4%), and SMARCB1 mutations in kidney cancer (3% overall, 90% in malignant rhabdoid tumors). Alterations in resistance genes RB1 and CCNE1 affected 7.2% and 3.6% of samples. Co‐occurrence analysis demonstrated a lower likelihood of concomitant versus isolated alterations in cyclin activating/sensitizing and resistance genes (odds ratio OR, 0.35; p < .001), except in colorectal, cervical, and small intestine cancers. AR and cyclin activating/sensitizing alterations in prostate cancer co‐occurred more frequently (vs. AR alterations and wild‐type cyclin activating/sensitizing alterations) (OR, 1.79; p < .001) as did ESR1 and cyclin activating/sensitizing alterations in breast (OR, 1.62; p < .001) and cervical cancer (OR, 4.08; p = .04) (vs. ESR1 and cyclin wild‐type activating/sensitizing alterations).
Conclusion
Cyclin pathway alterations vary according to tumor type/histology, informing opportunities for targeted therapy, including for rare cancers.
Implications for Practice
Cyclin pathway genomic abnormalities are frequent in human solid tumors, with substantial variation according to tumor site and histology. Opportunities for targeted therapy emerge with comprehensive profiling of this pathway.
This article identifies molecular alterations in genes involved in the cyclin activation/sensitizing pathways and reports coexisting resistance and hormone pathway alterations in 190,247 diverse solid tumors that underwent next‐generation sequencing.
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