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Artificial intelligence (AI)-systems can improve cancer diagnosis, yet their development often relies on subjective histological features as ground truth for training. Here, we developed an AI-model applied to histological whole-slide images (WSIs) using CDH1 bi-allelic mutations, pathognomonic for invasive lobular carcinoma (ILC) in breast neoplasms, as ground truth. The model accurately predicted CDH1 bi-allelic mutations (accuracy=0.95) and diagnosed ILC (accuracy=0.96). A total of 74% of samples classified by the AI-model as having CDH1 bi-allelic mutations but lacking these alterations displayed alternative CDH1 inactivating mechanisms, including a deleterious CDH1 fusion gene and non-coding CDH1 genetic alterations. Analysis of internal and external validation cohorts demonstrated 0.95 and 0.89 accuracy for ILC diagnosis, respectively. The latent features of the AI-model correlated with human-explainable histopathologic features. Taken together, this study reports the construction of an AI-algorithm trained using a genetic rather than histologic ground truth that can robustly classify ILCs and uncover CDH1 inactivating mechanisms, providing the basis for orthogonal ground truth utilization for development of diagnostic AI-models applied to WSI.
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OBJECTIVE: To determine the safety and efficacy of the oral progesterone antagonist onapristone extended release (onapristone-XR) in patients with recurrent progesterone receptor (PR)-positive adult-type granulosa cell tumor (aGCT), low-grade serous ovarian cancer (LGSOC), or endometrioid endometrial cancer (EEC). METHODS: This single-institution phase II study included patients with PR-positive aGCT, LGSOC, or EEC who received ≥1 prior line of chemotherapy. Patients were enrolled from 5/2019-5/2020. PR status was evaluated via immunohistochemistry. Eligible patients had PR expression ≥1% on tissue collected within 3 years of enrollment. Patients received 50 mg of onapristone-XR twice daily until disease progression or treatment discontinuation. Adverse events were graded by Common Terminology Criteria for Adverse Events version 5.0. The primary endpoint was overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors 1.1. Secondary endpoints were response duration, clinical benefit rate (CBR), and safety. RESULTS: Five patients with LGSOC and 1 with EEC enrolled, but both cohorts closed early due to slow accrual. Fourteen patients with aGCT enrolled and completed stage 1 accrual. No responses were observed. Four patients with LGSOC were evaluable, with median PFS of 4.4 months (range, 1.8-NE) and CBR of 50% (range, 6.8%-93.2%). All 14 patients with aGCT were evaluable, with median PFS of 2.8 months (range, 1.6-4.9), 6-month PFS rate of 21.4% (range, 5.2%-44.8%), 12-month PFS rate of 14.3% (range, 2.3%-36.6%), and a CBR of 35.7% (range, 12.8%-64.9%). CONCLUSIONS: The study did not meet its primary endpoint. While onapristone-XR was well tolerated in all 3 arms, no objective responses were observed.
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Whole-genome doubling (WGD) is a critical driver of tumor development and is linked to drug resistance and metastasis in solid malignancies. Here, we demonstrate that WGD is an ongoing mutational process in tumor evolution. Using single-cell whole-genome sequencing, we measured and modeled how WGD events are distributed across cellular populations within tumors and associated WGD dynamics with properties of genome diversification and phenotypic consequences of innate immunity. We studied WGD evolution in 65 high-grade serous ovarian cancer (HGSOC) tissue samples from 40 patients, yielding 29,481 tumor cell genomes. We found near-ubiquitous evidence of WGD as an ongoing mutational process promoting cell-cell diversity, high rates of chromosomal missegregation, and consequent micronucleation. Using a novel mutation-based WGD timing method, doubleTime , we delineated specific modes by which WGD can drive tumor evolution: (i) unitary evolutionary origin followed by significant diversification, (ii) independent WGD events on a pre-existing background of copy number diversity, and (iii) evolutionarily late clonal expansions of WGD populations. Additionally, through integrated single-cell RNA sequencing and high-resolution immunofluorescence microscopy, we found that inflammatory signaling and cGAS-STING pathway activation result from ongoing chromosomal instability and are restricted to tumors that remain predominantly diploid. This contrasted with predominantly WGD tumors, which exhibited significant quiescent and immunosuppressive phenotypic states. Together, these findings establish WGD as an evolutionarily 'active' mutational process that promotes evolvability and dysregulated immunity in late stage ovarian cancer.
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Programmed death-1 (PD-1) inhibitors are approved for therapy of gynecologic cancers with DNA mismatch repair deficiency (dMMR), although predictors of response remain elusive. We conducted a single-arm phase 2 study of nivolumab in 35 patients with dMMR uterine or ovarian cancers. Co-primary endpoints included objective response rate (ORR) and progression-free survival at 24 weeks (PFS24). Secondary endpoints included overall survival (OS), disease control rate (DCR), duration of response (DOR) and safety. Exploratory endpoints included biomarkers and molecular correlates of response. The ORR was 58.8% (97.5% confidence interval (CI): 40.7-100%), and the PFS24 rate was 64.7% (97.5% one-sided CI: 46.5-100%), meeting the pre-specified endpoints. The DCR was 73.5% (95% CI: 55.6-87.1%). At the median follow-up of 42.1 months (range, 8.9-59.8 months), median OS was not reached. One-year OS rate was 79% (95% CI: 60.9-89.4%). Thirty-two patients (91%) had a treatment-related adverse event (TRAE), including arthralgia (n = 10, 29%), fatigue (n = 10, 29%), pain (n = 10, 29%) and pruritis (n = 10, 29%); most were grade 1 or grade 2. Ten patients (29%) reported a grade 3 or grade 4 TRAE; no grade 5 events occurred. Exploratory analyses show that the presence of dysfunctional (CD8+PD-1+) or terminally dysfunctional (CD8+PD-1+TOX+) T cells and their interaction with programmed death ligand-1 (PD-L1)+ cells were independently associated with PFS24. PFS24 was associated with presence of MEGF8 or SETD1B somatic mutations. This trial met its co-primary endpoints (ORR and PFS24) early, and our findings highlight several genetic and tumor microenvironment parameters associated with response to PD-1 blockade in dMMR cancers, generating rationale for their validation in larger cohorts.ClinicalTrials.gov identifier: NCT03241745 .
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Biomarcadores Tumorais , Reparo de Erro de Pareamento de DNA , Nivolumabe , Humanos , Feminino , Pessoa de Meia-Idade , Nivolumabe/uso terapêutico , Nivolumabe/efeitos adversos , Idoso , Adulto , Biomarcadores Tumorais/genética , Reparo de Erro de Pareamento de DNA/genética , Neoplasias dos Genitais Femininos/tratamento farmacológico , Neoplasias dos Genitais Femininos/genética , Neoplasias dos Genitais Femininos/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Intervalo Livre de Progressão , Idoso de 80 Anos ou mais , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Mutação , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antineoplásicos Imunológicos/uso terapêutico , Antineoplásicos Imunológicos/efeitos adversosRESUMO
Background: In India, anemia is widely researched in children and women of reproductive age, however, studies in older populations are lacking. Given the adverse effect of anemia on cognitive function and dementia this older population group warrants further study. The Longitudinal Ageing Study in India - Harmonized Diagnostic Assessment of Dementia (LASI-DAD) dataset contains detailed measures to allow a better understanding of anaemia as a potential risk factor for dementia. Method: 2,758 respondents from the LASI-DAD cohort, aged 60 or older, had a complete blood count measured from venous blood as well as cognitive function tests including episodic memory, executive function and verbal fluency. Linear regression was used to test the associations between blood measures (including anemia and hemoglobin concentration (g/dL)) with 11 cognitive domains. All models were adjusted for age and gender with the full model containing adjustments for rural location, years of education, smoking, region, BMI and population weights.Results from LASI-DAD were validated using the USA-based Health and Retirement Study (HRS) cohort (n=5720) to replicate associations between blood cell measures and global cognition. Results: In LASI-DAD, we showed an association between anemia and poor memory (p=0.0054). We found a positive association between hemoglobin concentration and ten cognitive domains tested (ß=0.041-0.071, p<0.05). The strongest association with hemoglobin was identified for memory-based tests (immediate episodic, delayed episodic and broad domain memory, ß=0.061-0.071, p<0.005). Positive associations were also shown between the general cognitive score and the other red blood count tests including mean corpuscular hemoglobin concentration (MCHC, ß=0.06, p=0.0001) and red cell distribution width (RDW, ß =-0.11, p<0.0001). In the HRS cohort, positive associations were replicated between general cognitive score and other blood count tests (Red Blood Cell, MCHC and RDW, p<0.05). Conclusion: We have established in a large South Asian population that low hemoglobin and anaemia are associated with low cognitive function, therefore indicating that anaemia could be an important modifiable risk factor. We have validated this result in an external cohort demonstrating both the variability of this risk factor cross-nationally and its generalizable association with cognitive outcomes.
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CDH1 (E-cadherin) bi-allelic inactivation is the hallmark alteration of breast invasive lobular carcinoma (ILC), resulting in its discohesive phenotype. A subset of ILCs, however, lack CDH1 genetic/epigenetic inactivation, and their genetic underpinning is unknown. Through clinical targeted sequencing data reanalysis of 364 primary ILCs, we identified 25 ILCs lacking CDH1 bi-allelic genetic alterations. CDH1 promoter methylation was frequent (63%) in these cases. Targeted sequencing reanalysis revealed 3 ILCs harboring AXIN2 deleterious fusions (n = 2) or loss-of-function mutation (n = 1). Whole-genome sequencing of 3 cases lacking bi-allelic CDH1 genetic/epigenetic inactivation confirmed the AXIN2 mutation and no other cell-cell adhesion genetic alterations but revealed a new CTNND1 (p120) deleterious fusion. AXIN2 knock-out in MCF7 cells resulted in lobular-like features, including increased cellular migration and resistance to anoikis. Taken together, ILCs lacking CDH1 genetic/epigenetic alterations are driven by inactivating alterations in other cell adhesion genes (CTNND1 or AXIN2), endorsing a convergent phenotype in ILC.
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Cell-intrinsic mechanisms of immunogenicity in ovarian cancer (OC) are not well understood. The presence of damaging mutations in the SWI/SNF chromatin remodeling complex, such as the SMARCA4 (BRG1) catalytic subunit, has been associated with improved response to ICB, however the mechanism by which this occurs is unclear. The aim of this current study was to examine the alterations in tumor cell-intrinsic and extrinsic immune signaling caused by SMARCA4 loss. Using OC models with loss-of-function mutations in SMARCA4 , we found that SMARCA4 loss resulted in increased cancer cell-intrinsic immunogenicity, characterized by upregulation of long-terminal RNA repeats such as endogenous retroviruses, increased expression of interferon-stimulated genes, and upregulation of antigen presentation machinery. Notably, this response was dependent on IRF3 signaling, but was independent of the type I interferon receptor. Mice inoculated with cancer cells bearing SMARCA4 loss demonstrated increased activation of cytotoxic T cells and NK cells in the tumor microenvironment as well as increased infiltration with activated dendritic cells. These results were recapitulated when animals bearing SMARCA4- proficient tumors were treated with a BRG1 inhibitor, suggesting that modulation of chromatin remodeling through targeting SMARCA4 may serve as a strategy to reverse immune evasion in OC.
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BACKGROUND: Community-based, mobile HIV counselling and testing (HCT) and screening for non-communicable diseases (NCDs) may improve early diagnosis and referral for care in underserved populations. We evaluated HCT/NCD data and described population characteristics of those visiting a mobile clinic in high HIV disease burden settings in Cape Town, South Africa, between 2008 and 2016. METHODS: Trained counsellors registered patients ≥12 years old at a mobile clinic, which offered HCT and blood pressure, diabetes (glucose testing) and obesity (body mass index) screening. A nurse referred patients who required HIV treatment or NCD care. Using multivariable logistic regression, we estimated correlates of new HIV diagnoses adjusting for gender, age and year. RESULTS: Overall, 43,938 individuals (50% male; 29% <25 years; median age = 31 years) tested for HIV at the mobile clinic, where 27% of patients (66% of males, 34% of females) reported being debut HIV testers. Males not previously tested for HIV had higher rates of HIV positivity (11%) than females (7%). Over half (55%, n = 1,343) of those previously diagnosed HIV-positive had not initiated ART. More than one-quarter (26%) of patients screened positive for hypertension (males 28%, females 24%, p<0.001). Females were more likely overweight (25% vs 20%) or obese (43% vs 9%) and presented with more diabetes symptoms than males (8% vs 4%). Females (3%) reported more symptoms of STIs than males (1%). Reporting symptoms of sexually transmitted infections (aOR = 3.45, 95% CI = 2.84, 4.20), diabetes symptoms (aOR = 1.61, 95% 1.35, 1.92), and TB symptoms (aOR = 4.40, 95% CI = 3.85, 5.01) were associated with higher odds of a new HIV diagnosis after adjusting for covariates. CONCLUSION: Findings demonstrate that mobile clinics providing integrated HCT and NCD screening may offer the opportunity of early diagnosis and referral for care for those who delay screening, including men living with HIV not previously tested.
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Serviços de Saúde Comunitária/métodos , Prestação Integrada de Cuidados de Saúde/métodos , Infecções por HIV/diagnóstico , Programas de Rastreamento/métodos , Populações Vulneráveis , Adolescente , Adulto , Criança , Doença Crônica/epidemiologia , Aconselhamento/métodos , Diagnóstico Precoce , Feminino , Infecções por HIV/epidemiologia , Infecções por HIV/prevenção & controle , Humanos , Masculino , Pessoa de Meia-Idade , África do SulRESUMO
Curable sexually transmitted infections (STIs) including Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), and Trichomonas vaginalis (TV) are associated with adverse pregnancy outcomes. Partner notification is an important component of STI control as it has been shown to prevent re-infection and reduce infectious burden. Between October 2017 and February 2019, we conducted a cohort study of women attending antenatal care in Cape Town, South Africa. Self-collected vulvovaginal swabs were tested for CT, NG, and TV using Xpert® assays at first antenatal visit, during the third trimester, and postpartum. At the visit following a positive diagnosis, women were asked if they notified their partner and if their partner was treated. Among 242 participants, 97% reported being willing to notify partners if they tested positive and 78% thought their partner would be willing to treat the STI. Of the 73 women who were diagnosed with one or more STIs and reported having a sex partner, 93% reported notifying their partner and 63% reported their partner was treated. Younger maternal age was associated with partner notification and treatment (OR = 3.82; 95%CI = 1.34-10.90). Acceptability of partner notification was high in pregnant women, but partner treatment was low. Future interventions to improve partner notification and treatment are needed.
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Busca de Comunicante/estatística & dados numéricos , Complicações Infecciosas na Gravidez/epidemiologia , Gestantes , Parceiros Sexuais , Infecções Sexualmente Transmissíveis/diagnóstico , Infecções Sexualmente Transmissíveis/prevenção & controle , Adulto , Infecções por Chlamydia/epidemiologia , Chlamydia trachomatis , Busca de Comunicante/métodos , Feminino , Gonorreia/epidemiologia , Humanos , Neisseria gonorrhoeae , Gravidez , Infecções Sexualmente Transmissíveis/epidemiologia , Infecções Sexualmente Transmissíveis/microbiologia , África do Sul , Vaginite por Trichomonas/epidemiologia , Trichomonas vaginalis , Adulto JovemRESUMO
BACKGROUND: Extreme heat events have been consistently associated with an increased risk of hospitalization for various hospital diagnoses. Classifying heat events is particularly relevant for identifying the criteria to activate early warning systems. Heat event classifications may also differ due to heterogeneity in climates among different geographic regions, which may occur at a small scale. Using local meteorological data, we identified heat waves and extreme heat events that were associated with the highest burden of excess hospitalizations within the County of San Diego and quantified discrepancies using county-level meteorological criteria. METHODS: Eighteen event classifications were created using various combinations of temperature metric, percentile, and duration for both county-level and climate zone level meteorological data within San Diego County. Propensity score matching and Poisson regressions were utilized to ascertain the association between heat wave exposure and risk of hospitalization for heat-related illness and dehydration for the 1999-2013 period. We estimated both relative and absolute risks for each heat event classification in order to identify optimal definitions of heat waves and extreme heat events for the whole city and in each climate zone to target health impacts. RESULTS: Heat-related illness differs vastly by level (county or zone-specific), definition, and risk measure. We found the county-level definitions to be systematically biased when compared to climate zone definitions with the largest discrepancy of 56 attributable hospitalizations. The relative and attributable risks were often minimally correlated, which exemplified that relative risks alone are not adequate to optimize heat waves definitions. CONCLUSIONS: Definitions based on county-level defined thresholds do not provide an accurate picture of the observed health effects and will fail to maximize the potential effectiveness of heat warning systems. Absolute rather than relative risks are a more appropriate measure to define the set of criteria to activate early warnings systems and thus maximize public health benefits.
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OBJECTIVE: Mycoplasma genitalium (MG) is a sexually transmitted organism associated with cervicitis and pelvic inflammatory disease in women and has been shown to increase the risk of HIV acquisition and transmission. Little is known about the prevalence and incidence of MG in pregnant women. Our study sought to evaluate the prevalence and incidence of MG infection in HIV-infected and HIV-uninfected pregnant women. METHODS: We conducted a cohort study of 197 women ≥18 years receiving antenatal care in South Africa from November 2017 to February 2019. We over-recruited HIV-infected pregnant women to compare MG by HIV infection status. Self-collected vaginal swabs, performed at the first antenatal visit, third trimester and within 1 week post partum, were tested for MG using the Aptima assay (Hologic, USA). We report on the prevalence and incidence of MG and used multivariable logistic regression to describe correlates of MG and adverse pregnancy and birth outcomes (preterm delivery, miscarriage and vertical HIV transmission), adjusting for maternal age and HIV infection status. RESULTS: At first antenatal visit, the median age was 29 years (IQR=24-34) and the gestational age was 19 weeks (IQR=14-23); 47% of women enrolled in the study were HIV-infected. MG prevalence was 24% (95% CI 16% to 34%, n=22) in HIV-infected and 12% (95% CI 6.8% to 20%, n=13) in HIV-uninfected pregnant women. MG incidence during pregnancy and early post partum was 4.7 infections per 100 woman-years (95% CI 1.2 to 12.9) or 3.9 per 1000 woman-months (95% CI 1.0 to 10.7). Adjusting for maternal age, HIV-infected women had over three times the odds of being infected with MG (adjusted OR=3.09, 95% CI 1.36 to 7.06). CONCLUSION: We found a high prevalence and incidence of MG in pregnant women. Younger maternal age and HIV infection were associated with MG infection in pregnancy. Further research into birth outcomes of women infected with MG, including vertical transmission of HIV infection, is needed.
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Infecções por HIV/epidemiologia , Infecções por Mycoplasma/epidemiologia , Mycoplasma genitalium , Complicações Infecciosas na Gravidez/epidemiologia , Adulto , Estudos de Coortes , Feminino , Humanos , Incidência , Infecções por Mycoplasma/diagnóstico , Infecções por Mycoplasma/tratamento farmacológico , Mycoplasma genitalium/isolamento & purificação , Gravidez , Resultado da Gravidez , Gestantes , Cuidado Pré-Natal , Prevalência , África do Sul/epidemiologiaRESUMO
Heat waves and high air temperature are associated with increased morbidity and mortality. However, the majority of research conducted on this topic is focused on high income areas of the world. Although heat waves have the most severe impacts on vulnerable populations, relatively few studies have studied their impacts in low and middle income countries (LMICs). The aim of this paper is to review the existing evidence in the literature on the impact of heat on human health in LMICs. We identified peer-reviewed epidemiologic studies published in English between January 1980 and August 2018 investigating potential associations between high ambient temperature or heat waves and mortality or morbidity. We selected studies according to the following criteria: quantitative studies that used primary and/or secondary data and report effect estimates where ambient temperature or heat waves are the main exposure of interest in relation to human morbidity or mortality within LMICs. Of the total 146 studies selected, eighty-two were conducted in China, nine in other countries of East Asia and the Pacific, twelve in South Asia, ten in Sub-Saharan Africa, eight in the Middle East and North Africa, and seven in each of Latin America and Europe. The majority of studies (92.9%) found positive associations between heat and human morbidity/mortality. Additionally, while outcome variables and study design differed greatly, most utilized a time-series study design and examined overall heath related morbidity/mortality impacts in an entire population, although it is notable that the selected studies generally found that the elderly, women, and individuals within the low socioeconomic brackets were the most vulnerable to the effects of high temperature. By highlighting the existing evidence on the impact of extreme heat on health in LMICs, we hope to determine data needs and help direct future studies in addressing this knowledge gap. The focus on LMICs is justified by the lack of studies and data studying the health burden of higher temperatures in these regions even though LMICs have a lower capacity to adapt to high temperatures and thus an increased risk.
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Países em Desenvolvimento , Exposição Ambiental/estatística & dados numéricos , Temperatura Alta , África do Norte , Idoso , Ásia , China , Europa (Continente) , Ásia Oriental , Feminino , Humanos , Oriente Médio , Mortalidade/tendênciasRESUMO
BACKGROUND: Vagus nerve stimulation (VNS) therapy has been used for chronic heart failure and is believed to improve imbalance of autonomic control by increasing parasympathetic activity. Although it is known that there is neural communication between the VN and the cervical sympathetic trunk, there are few data regarding the quantity and/or distribution of the sympathetic components within the vagus nerve (VN). OBJECTIVE: To examine the sympathetic components within the human VN and correlate them with the presence of cardiac and neurologic diseases. METHODS: We performed immunohistochemistry on 31 human cervical and thoracic VNs (total 104 VNs) from autopsies and reviewed the patients' records. We correlated the quantity of sympathetic nerve fibers within the VNs with cardiovascular and neurologic disease states. RESULTS: All 104 VNs contain tyrosine hydroxylase (TH)-positive (sympathetic) nerve fibers; the mean TH-positive areas were 5.47% in the right cervical VN, 3.97% in the left cervical VN, 5.11% in the right thoracic VN, and 4.20% in the left thoracic VN. The distribution of TH-positive nerve fibers varied from case to case: central, peripheral, or scattered throughout nerve bundles. No statistically significant differences in nerve morphology were seen between diseases in which VNS is considered effective (depression and chronic heart failure) and other cardiovascular diseases or neurodegenerative disease. CONCLUSION: Human VNs contain sympathetic nerve fibers. The sympathetic component within the VN could play a role in physiologic effects reported with VNS. The recognition of sympathetic nerve fibers in the VNs may lead to better understanding of the therapeutic mechanisms of VNS.