The majority of high-grade serous ovarian cancers (HGSCs) are deficient in homologous recombination (HR) DNA repair, most commonly due to mutations or hypermethylation of the BRCA1/2 genes. We aimed ...to discover how BRCA1/2 mutations shape the cellular phenotypes and spatial interactions of the tumor microenvironment. Using a highly multiplex immunofluorescence and image analysis we generate spatial proteomic data for 21 markers in 124,623 single cells from 112 tumor cores originating from 31 tumors with BRCA1/2 mutation (BRCA1/2mut), and from 13 tumors without alterations in HR genes. We identify a phenotypically distinct tumor microenvironment in the BRCA1/2mut tumors with evidence of increased immunosurveillance. Importantly, we report a prognostic role of a proliferative tumor-cell subpopulation, which associates with enhanced spatial tumor-immune interactions by CD8+ and CD4 + T-cells in the BRCA1/2mut tumors. The single-cell spatial landscapes indicate distinct patterns of spatial immunosurveillance with the potential to improve immunotherapeutic strategies and patient stratification in HGSC.
Abstract Objective Epithelioid trophoblastic tumor (ETT) is a rare form of gestational trophoblastic neoplasm which is distinct based on its development from intermediate trophoblast cells and ...nodular growth pattern. The aim of this study is to describe a case series from a single institution with a review of the literature to better understand the clinical characteristics and outcomes for patients with ETT. Methods A retrospective review was performed using the IRB approved New England Trophoblastic Disease Center (NETDC) database from 1998 to 2014. Eight patients were identified of which seven had complete records. Follow-up data was obtained from the longitudinal medical records. Results Four (57.1%) patients presented with vaginal bleeding and two (28.6%) patients were asymptomatic at presentation. Three (42.9%) patients had extrauterine disease. All three patients with extrauterine disease who received chemotherapy had stable or progressive disease at follow-up. Only two (29%) patients who presented with non-metastatic disease and underwent hysterectomy were alive with no evidence of disease. The mean interval following antecedent pregnancy was 104 months. All patients with an interval > 4 years demonstrated stable or progressive disease despite intensive chemotherapy. Two patients with non-metastatic disease who declined hysterectomy developed stable or progressive disease despite chemotherapy. Conclusions This series highlights several features of ETT including the potential for asymptomatic presentation of extrauterine disease. The series also demonstrates chemoresistance, even with multi-agent therapy and a poor prognosis with extrauterine disease and an interval greater than 4 years following the antecedent pregnancy suggesting that surgery remains critical in disease control.
Whether endometrial carcinoma (EC) should be considered part of the
associated hereditary breast and ovarian cancer (HBOC) syndrome is topic of debate. We sought to assess whether ECs occurring in
...carriers are enriched for clinicopathologic and molecular characteristics, thereby supporting a causal relationship.
Thirty-eight
carriers that developed EC were selected from the nationwide cohort study on hereditary breast and ovarian cancer in the Netherlands (HEBON), and these were supplemented with four institutional cases. Tumor tissue was retrieved via PALGA (Dutch Pathology Registry). Nineteen morphologic features were scored and histotype was determined by three expert gynecologic pathologists, blinded for molecular analyses (UCM-OncoPlus Assay including 1213 genes). ECs with LOH of the
-wild-type allele (
/LOHpos) were defined "
-associated," those without LOH (
/LOHneg) were defined "sporadic."
LOH could be assessed for 40 ECs (30
, 10
), of which 60% were
/LOHpos.
/LOHpos ECs were more frequently of nonendometrioid (58%,
= 0.001) and grade 3 histology (79%,
< 0.001). All but two were in the
-mutated TCGA-subgroup (91.7%,
< 0.001). In contrast,
/LOHneg ECs were mainly grade 1 endometrioid EC (94%) and showed a more heterogeneous distribution of TCGA-molecular subgroups:
-mutated (6.3%), MSI-high (25%), NSMP (62.5%), and
-mutated (6.3%).
We provide novel evidence in favor of EC being part of the
-associated HBOC-syndrome.
-associated ECs are enriched for EC subtypes associated with unfavorable clinical outcome. These findings have profound therapeutic consequences as these patients may benefit from treatment strategies such as PARP inhibitors. In addition, it should influence counseling and surveillance of
carriers.
The cause of death among the majority of epithelial ovarian cancer (EOC) patients involves passive dissemination of cancer cells within the peritoneal cavity and subsequent implantation of cancer ...spheroids into adjacent organs. Thus, it is important to identify the factors that mediate EOC metastasis and implantation, including clearance of the mesothelium. Sushi domain containing 2 (SUSD2) encodes a type I transmembrane protein containing several functional domains inherent to adhesion molecules. Immunohistochemical analysis determined the presence of SUSD2 in several subtypes of EOC, with the strongest staining observed in high-grade serous ovarian carcinomas (HGSOCs). A high-density, clinically annotated HGSOC tissue microarray was stained with an anti-SUSD2 antibody. Patients with tumors that had a low percentage of SUSD2 staining cells had a shorter median survival (31.7 months) compared with patients who had tumors with extensive SUSD2 staining (49.1 months; P-value=0.0083). To investigate the role of SUSD2 in HGSOCs, stable OVCAR3, OVSAHO and KURAMOCHI cell lines were established with knockdown (KD) or non-targeting (NT) of SUSD2. Boyden chamber and wound-healing assays demonstrated that OVCAR3, OVSAHO and KURAMOCHI SUSD2-KD cells migrated at significantly higher rates compared with their SUSD2 NT counterpart cell lines. Quantitative reverse transcription-PCR and western immunoblot analysis indicated an inverse relationship between SUSD2 and well-characterized mesenchymal proteins, including Twist-1, Zeb-1, N-cadherin, STEAP1, AHNAK, Snail-1, COL5A2 and Snail-3 in OVCAR3, OVSAHO and KURAMOCHI cell line models. In addition, OVCAR3 and KURAMOCHI SUSD2-KD spheroids displayed increased mesothelial clearance ability compared with cells that express endogenous levels of SUSD2. These data suggest that SUSD2 has a role in the inhibition of mesothelial clearance, which is required for metastasis. Altogether, our findings indicate that SUSD2 impedes migration, epithelial-to-mesenchymal transitional and mesothelial clearance of HGSOC cells, consistent with prolonged survival of patients with SUSD2-expressing tumors.
Summary Background Exposure to paracetamol during intrauterine life, childhood, and adult life may increase the risk of developing asthma. We studied 6–7-year-old children from Phase Three of the ...International Study of Asthma and Allergies in Childhood (ISAAC) programme to investigate the association between paracetamol consumption and asthma. Methods As part of Phase Three of ISAAC, parents or guardians of children aged 6–7 years completed written questionnaires about symptoms of asthma, rhinoconjunctivitis, and eczema, and several risk factors, including the use of paracetamol for fever in the child's first year of life and the frequency of paracetamol use in the past 12 months. The primary outcome variable was the odds ratio (OR) of asthma symptoms in these children associated with the use of paracetamol for fever in the first year of life, as calculated by logistic regression. Findings 205 487 children aged 6–7 years from 73 centres in 31 countries were included in the analysis. In the multivariate analyses, use of paracetamol for fever in the first year of life was associated with an increased risk of asthma symptoms when aged 6–7 years (OR 1·46 95% CI 1·36–1·56). Current use of paracetamol was associated with a dose-dependent increased risk of asthma symptoms (1·61 1·46–1·77 and 3·23 2·91–3·60 for medium and high use vs no use, respectively). Use of paracetamol was similarly associated with the risk of severe asthma symptoms, with population-attributable risks between 22% and 38%. Paracetamol use, both in the first year of life and in children aged 6–7 years, was also associated with an increased risk of symptoms of rhinoconjunctivitis and eczema. Interpretation Use of paracetamol in the first year of life and in later childhood, is associated with risk of asthma, rhinoconjunctivitis, and eczema at age 6 to 7 years. We suggest that exposure to paracetamol might be a risk factor for the development of asthma in childhood. Funding The BUPA Foundation, the Health Research Council of New Zealand, the Asthma and Respiratory Foundation of New Zealand, the Hawke's Bay Medical Research Foundation, the Waikato Medical Research Foundation, Glaxo Wellcome New Zealand, the New Zealand Lottery Board, Astra Zeneca New Zealand, and Glaxo Wellcome International Medical Affairs.
Some previously described environmental associations for atopic eczema may be due to reverse causation. We explored the role of reverse causation by comparing individual- and school-level results for ...multiple atopic eczema risk factors. The International Study of Asthma and Allergies in Childhood (i.e, ISAAC) Phase Three surveyed children in schools (the sampling unit) regarding atopic eczema symptoms and potential risk factors. We assessed the effect of these risk factors on atopic eczema symptoms using mixed-effect logistic regression models, first with individual-level exposure data and second with school-level exposure prevalence. Overall, 546,348 children from 53 countries were included. At ages 6–7 years, the strongest individual-level associations were with current paracetamol use (odds ratio OR = 1.45, 95% confidence interval CI = 1.37–1.54), which persisted at school-level (OR = 1.55, 95% CI = 1.10–2.21), early-life antibiotics (OR = 1.41, 95% CI = 1.34–1.48), and early-life paracetamol use (OR = 1.28, 95% CI = 1.21–1.36), with the former persisting at the school level, whereas the latter was no longer observed (OR = 1.35, 95% CI = 1.00–1.82 and OR = 0.94, 95% CI = 0.69–1.28, respectively). At ages 13–14 years, the strongest associations at the individual level were with current paracetamol use (OR = 1.57, 95% CI = 1.51–1.63) and open-fire cooking (OR = 1.46, 95% CI = 1.33–1.62); both were stronger at the school level (OR = 2.57, 95% CI = 1.84–3.59 and OR = 2.38, 95% CI = 1.52–3.73, respectively). Association with exposure to heavy traffic (OR = 1.31, 95% CI = 1.27–1.36) also persisted at the school level (OR = 1.40, 95% CI = 1.07–1.82). Most individual- and school-level effects were consistent, tending to exclude reverse causation.
PARP inhibitors have shown promising clinical activities for patients with BRCA mutations and are changing the landscape of ovarian cancer treatment. However, the therapeutic mechanisms of action for ...PARP inhibition in the interaction of tumors with the tumor microenvironment and the host immune system remain unclear. We find that PARP inhibition by olaparib triggers robust local and systemic antitumor immunity involving both adaptive and innate immune responses through a STING-dependent antitumor immune response in mice bearing Brca1-deficient ovarian tumors. This effect is further augmented when olaparib is combined with PD-1 blockade. Our findings thus provide a molecular mechanism underlying antitumor activity by PARP inhibition and lay a foundation to improve therapeutic outcome for cancer patients.
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•T cell-mediated cytotoxicity is important for therapeutic activity of PARP inhibition•Olaparib-treated Brca1-deficient tumor cells activate the STING pathway in APCs•STING pathway activation is required for the antitumor efficacy of PARP inhibition•PD-1 blockade enhances the antitumor efficacy of olaparib in Brca1-deficient tumors
Ding et al. show that PARP inhibition in Brca1-deficient tumors elicits strong antitumor immunity involving activation of both innate and adaptive immune responses, a process that is dependent on STING pathway activation. In addition, they show that addition of PD-1 blockade augments the therapeutic efficacy of PARP inhibitor treatment.
An ecosystem in freefall, a shrinking water supply for cities and agriculture, an antiquated network of failure-prone levees—this is the Sacramento-San Joaquin Delta, the major hub of California's ...water system. Written by a team of independent water experts, this analysis of the latest data evaluates proposed solutions to the Delta's myriad problems. Through in-depth economic and ecological analysis, the authors find that the current policy of channeling water exports through the Delta is not sustainable for any interest. Employing a peripheral canal-conveying water around the Delta instead of through it—as part of a larger habitat and water management plan appears to be the best strategy to maintain both a high-quality water supply and at the same time improve conditions for native fish and wildlife. This important assessment includes integrated analysis of long term ecosystem and water management options and demonstrates how issues such as climate change and sustainability will shape the future. Published in cooperation with the Public Policy Institute of California
The US Food and Drug Administration (FDA) approved immune checkpoint inhibitor therapy for patients with advanced solid tumors that have DNA mismatch repair defects or high levels of microsatellite ...instability; however, the FDA provided no guidance on which specific clinical assays should be used to determine mismatch repair status.
To develop an evidence-based guideline to identify the optimal clinical laboratory test to identify defects in DNA mismatch repair in patients with solid tumor malignancies who are being considered for immune checkpoint inhibitor therapy.
The College of American Pathologists convened an expert panel to perform a systematic review of the literature and develop recommendations. Using the National Academy of Medicine-endorsed Grading of Recommendations Assessment, Development and Evaluation approach, the recommendations were derived from available evidence, strength of that evidence, open comment feedback, and expert panel consensus. Mismatch repair immunohistochemistry, microsatellite instability derived from both polymerase chain reaction and next-generation sequencing, and tumor mutation burden derived from large panel next-generation sequencing were within scope.
Six recommendations and 3 good practice statements were developed. More evidence and evidence of higher quality were identified for colorectal cancer and other cancers of the gastrointestinal (GI) tract than for cancers arising outside the GI tract.
An optimal assay depends on cancer type. For most cancer types outside of the GI tract and the endometrium, there was insufficient published evidence to recommend a specific clinical assay. Absent published evidence, immunohistochemistry is an acceptable approach readily available in most clinical laboratories.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Summary Background In Phase Three of the International Study of Asthma and Allergies in Childhood (ISAAC), we investigated the relationship between breast feeding in infancy and symptoms of asthma, ...rhinoconjunctivitis and eczema in 6–7 year old children. Methods Parents or guardians of 6–7 year old children completed written questionnaires on current symptoms of asthma, rhinoconjunctivitis and eczema, and on a range of possible asthma risk factors including a history of breast feeding ever. Prevalence odds ratios were estimated using logistic regression, adjusted for gender, region of the world, language, per capita gross national income, and other risk factors. Results In all 206,453 children from 72 centres in 31 countries participated in the study. Reported breast feeding ever was not associated with current wheeze, with an odds ratio (adjusted for gender, region of the world, language, per capita gross national income, and factors encountered in infancy) of 0.99 (95% CI 0.92–1.05), current rhinoconjunctivitis (OR 1.00, 95% CI 0.93–1.08), current eczema (OR 1.05, 95% CI 0.97–1.12), or symptoms of severe asthma (OR 0.95, 95% CI 0.87–1.05). Breast feeding was however associated with a reduced risk of severe rhinoconjunctivitis (OR 0.74, 95% CI 0.59–0.94) and severe eczema (OR 0.79, 95% CI 0.66–0.95). Conclusions There was no consistent association between breast feeding use in the first year of life and either a history or current symptoms of wheezing, rhinoconjunctivitis or eczema in 6–7 year old children, but possibly an effect on severe symptoms of the latter two conditions.
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