Concurrent RB1 Loss and BRCA-Deficiency Predicts Enhanced Immunological Response and Long-Term Survival in Tubo-Ovarian High-Grade Serous Carcinoma.

PURPOSE: To evaluate RB1 expression and survival across ovarian carcinoma histotypes, and how co-occurrence of BRCA1 or BRCA2 (BRCA) alterations and RB1 loss influences survival in tubo-ovarian high-grade serous carcinoma (HGSC). EXPERIMENTAL DESIGN: RB1 protein expression was classified by immunohistochemistry in ovarian carcinomas of 7436 patients from the Ovarian Tumor Tissue Analysis consortium. We examined RB1 expression and germline BRCA status in a subset of 1134 HGSC, and related genotype to overall survival (OS), tumor-infiltrating CD8+ lymphocytes and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cells with and without BRCA1 alterations to model co-loss with treatment response. We performed whole-genome and transcriptome data analyses on 126 primary HGSC to characterize tumors with concurrent BRCA-deficiency and RB1 loss. RESULTS: RB1 loss was associated with longer OS in HGSC, but with poorer prognosis in endometrioid ovarian carcinoma. Patients with HGSC harboring both RB1 loss and pathogenic germline BRCA variants had superior OS compared to patients with either alteration alone, and their median OS was three times longer than those without pathogenic BRCA variants and retained RB1 expression (9.3 vs. 3.1 years). Enhanced sensitivity to cisplatin and paclitaxel was seen in BRCA1-altered cells with RB1 knockout. Combined RB1 loss and BRCA-deficiency correlated with transcriptional markers of enhanced interferon response, cell-cycle deregulation, and reduced epithelial-mesenchymal transition. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1. CONCLUSIONS: Co-occurrence of RB1 loss and BRCA-deficiency was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.

A prospective study of dietary patterns and the incidence of endometriosis diagnosis.

BACKGROUND: Although endometriosis is a common condition-affecting ∼10% of premenopausal individuals-its etiology is unknown. Diet receives a lot of attention from patients, but studies of the role of diet are limited. Examining dietary patterns is essential to provide new insight. OBJECTIVE: We sought to determine whether dietary patterns are associated with laparoscopically-confirmed endometriosis diagnosis. STUDY DESIGN: We conducted a prospective cohort study among 81,997 premenopausal participants of the Nurses' Health Study II, who were followed from 1991-2015. Diet was assessed with validated food frequency questionnaires every 4 years. We examined 6 dietary patterns: Western, Prudent, Alternative Healthy Eating Index, Dietary Approaches to Stop Hypertension, an estrogen-associated pattern, and a proinflammatory pattern. Cox proportional hazard ratios and 95% confidence intervals were used to quantify the association between each of these patterns and laparoscopically-confirmed endometriosis diagnosis. RESULTS: Three thousand eight hundred ten incident cases of endometriosis were diagnosed during 24 years of follow-up. Adherence to the Alternative Healthy Eating Index, reflecting a healthier dietary pattern, was associated with a 13% lower risk of endometriosis diagnosis (fifth vs first quintile 95% confidence interval, 0.78-0.96; Ptrend=.02). Participants in the highest quintile of the Western dietary pattern, characterized by high intake of red meat, processed meat, refined grains, and desserts, had a 27% higher risk of endometriosis diagnosis than those in the lowest quintile (95% confidence interval, 1.09-1.47; Ptrend=.004). The Prudent, Dietary Approaches to Stop Hypertension, and estrogen-associated dietary patterns did not demonstrate clear associations with endometriosis risk, and there was the suggestion of a higher risk of endometriosis diagnosis among those with a higher proinflammatory diet score (hazard ratio for fifth vs first quintile, 1.10 [95% confidence interval, 0.99-1.23]; Ptrend=.01). CONCLUSION: Our results suggest that consuming a dietary pattern that adheres to the Alternative Healthy Eating Index-2010 recommendations lowers the risk of endometriosis diagnosis, potentially through a beneficial impact on pelvic pain. In addition, consuming a less healthy diet high in red/processed meats and refined grains may have a detrimental impact on endometriosis symptoms.

Racial and ethnic differences in epithelial ovarian cancer risk: an analysis from the Ovarian Cancer Association Consortium.

BACKGROUND: Limited estimates exist on risk factors for epithelial ovarian cancer (EOC) in Asian, Hispanic, and Native Hawaiian/Pacific Islander (NHPI) women. METHODS: Participants included 1734 Asian (785 cases, 949 controls), 266 NHPI (99 cases, 167 controls), 1149 Hispanic (505 cases, 644 controls), and 24,189 White (9,981 cases, 14,208 controls) women from 11 studies in the Ovarian Cancer Association Consortium. Logistic regression models estimated odds ratios (ORs) and 95% confidence intervals (CIs) for risk associations by race and ethnicity. RESULTS: Heterogeneity in EOC risk associations by race and ethnicity (p ≤ 0.02) was observed for oral contraceptive (OC) use, parity, tubal ligation and smoking. We observed inverse associations with EOC risk for OC use and parity across all groups; associations were strongest in NHPI and Asian women. The inverse association for tubal ligation with risk was most pronounced for NHPI participants (OR=0.25, 95% CI 0.13-0.48), versus Asian and White participants, respectively (OR=0.68, 95% CI 0.51-0.90; OR=0.78, 95% CI 0.73-0.85). CONCLUSIONS: Differences in EOC risk factor associations were observed across racial and ethnic groups, which could in part be due to varying prevalence of EOC histotypes. Inclusion of greater diversity in future studies is essential to inform prevention strategies.

Concurrent RB1 loss and BRCA-deficiency predicts enhanced immunological response and long-term survival in tubo-ovarian high-grade serous carcinoma.

Background: Somatic loss of the tumour suppressor RB1 is a common event in tubo-ovarian high-grade serous carcinoma (HGSC), which frequently co-occurs with alterations in homologous recombination DNA repair genes including BRCA1 and BRCA2 (BRCA). We examined whether tumour expression of RB1 was associated with survival across ovarian cancer histotypes (HGSC, endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous carcinoma (LGSC)), and how co-occurrence of germline BRCA pathogenic variants and RB1 loss influences long-term survival in a large series of HGSC. Patients and methods: RB1 protein expression patterns were classified by immunohistochemistry in epithelial ovarian carcinomas of 7436 patients from 20 studies participating in the Ovarian Tumor Tissue Analysis consortium and assessed for associations with overall survival (OS), accounting for patient age at diagnosis and FIGO stage. We examined RB1 expression and germline BRCA status in a subset of 1134 HGSC, and related genotype to survival, tumour infiltrating CD8+ lymphocyte counts and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cell lines with and without BRCA1 mutations to model co-loss with treatment response. We also performed genomic analyses on 126 primary HGSC to explore the molecular characteristics of concurrent homologous recombination deficiency and RB1 loss. Results: RB1 protein loss was most frequent in HGSC (16.4%) and was highly correlated with RB1 mRNA expression. RB1 loss was associated with longer OS in HGSC (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.66-0.83, P = 6.8 ×10-7), but with poorer prognosis in ENOC (HR 2.17, 95% CI 1.17-4.03, P = 0.0140). Germline BRCA mutations and RB1 loss co-occurred in HGSC (P < 0.0001). Patients with both RB1 loss and germline BRCA mutations had a superior OS (HR 0.38, 95% CI 0.25-0.58, P = 5.2 ×10-6) compared to patients with either alteration alone, and their median OS was three times longer than non-carriers whose tumours retained RB1 expression (9.3 years vs. 3.1 years). Enhanced sensitivity to cisplatin (P < 0.01) and paclitaxel (P < 0.05) was seen in BRCA1 mutated cell lines with RB1 knockout. Among 126 patients with whole-genome and transcriptome sequence data, combined RB1 loss and genomic evidence of homologous recombination deficiency was correlated with transcriptional markers of enhanced interferon response, cell cycle deregulation, and reduced epithelial-mesenchymal transition in primary HGSC. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1. Conclusions: Co-occurrence of RB1 loss and BRCA mutation was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.

Characteristics of Adolescents Who Use Secure Messaging on a Health System's Patient Portal.

OBJECTIVES: To determine adolescent characteristics associated with patient portal secure messaging use within a health system. METHODS: This study analyzed monthly data from individuals aged 13 to 17 who met study eligibility criteria from 2019 to 2021. The primary outcome was any secure messages sent from an adolescent's account during each observed month. Unadjusted and adjusted associations between adolescent characteristics and secure messaging use were assessed using generalized estimating equations with log link and binomial variance. RESULTS: Of 667 678 observed months, 50.8% occurred among males who were not transgender, 51.5% among those identifying as non-Hispanic white, and 83.3% among the privately insured. The adjusted relative risks of secure messaging use were significantly higher for individuals with female sex and transgender identities (female sex, not transgender: adjusted relative risk [aRR] 1.41, 95% confidence interval [CI] 1.31-1.52; male sex, transgender: aRR 2.39, CI 1.98-2.90, female sex, transgender: aRR 3.01, 95% CI 2.63-3.46; referent male sex, not transgender), those with prior portal use (aRR 22.06, 95% CI 20.48-23.77; referent no use) and those with a recent preventive care visit (aRR 1.09, 95% CI 1.02-1.16; referent no recent visits). The adjusted relative risks of portal secure messaging use were significantly lower among those with public insurance (aRR 0.58, 95% CI 0.50-0.67; referent private). CONCLUSIONS: Adolescents who sent patient portal secure messages differed from those who did not. Interventions to encourage secure messaging use may require tailoring based on patient characteristics.

Understanding the Relationship Between Social Risk Factors and COVID-19 Contacts.

Introduction Social risks are associated with increased risk of COVID-19 transmission by limiting patients' ability to practice precautions and access care. Researchers need to understand the prevalence of patients' social risk factors during the pandemic and recognize how social risks may exacerbate COVID-19. Methods The authors conducted a national survey among Kaiser Permanente members between January and September 2020 and restricted analyses to those who responded to a set of COVID-19 items. The survey asked if they experienced social risks, knew of people with COVID-19, and if COVID-19 affected their emotional and mental health, and their preferred type of assistance. Results Social risks were reported by 62% of respondents, with 38% reporting having 2 or more social risks. Respondents most commonly reported financial strain (45%). One or more contact types with COVID-19 were reported by one-third of the respondents. Those with 2 or more COVID-19 contact types reported higher housing instability, financial strain, food insecurity, and social isolation than those with fewer contacts. Overall, 50% of respondents reported that COVID-19 negatively affected their emotional, mental health, and 19% noted that it affected their ability to maintain a job. Discussion People with any COVID-19 contacts reported more social risks compared to those who did not know anyone with COVID-19. This suggests that those with higher social risks during this time may have faced higher risk for COVID-19, or the converse may be true. Conclusion These findings highlight patients' social health during the pandemic and suggest that health systems develop interventions to assess social health and link patients to appropriate resources.

p53 and ovarian carcinoma survival: an Ovarian Tumor Tissue Analysis consortium study.

Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi-institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36-3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11-2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC.

Feasibility of delivering survivorship care via lay health educators: A pilot randomized controlled trial among rural cancer survivors.

PURPOSE: We tested the feasibility of survivorship care plan (SCP) delivery with/without a lay health educator (LHE) telephone-delivered information session among rural cancer survivors, and their effects on health-related self-efficacy and knowledge of cancer history. METHODS: Randomized trial of cancer survivors from 3 rural oncology clinics featuring either SCP alone (control) or SCP plus LHE-delivered information session (intervention). Participants completed a questionnaire on health-related self-efficacy and knowledge of cancer-specific medical history. Responses were compared to medical records for accuracy. SCPs were then mailed to participants. Approximately 5 months later, participants completed a follow-up questionnaire. A subset of participants took part in subsequent qualitative interviews about their study experience. FINDINGS: Of 301 survivors approached, 72 (23.9%) were randomized (mean age 66.4 years; 3.1 years from diagnosis; 62.5% female), and 65 (90.3%) completed the study. Global mental and physical health or self-efficacy scores did not change significantly from baseline to follow-up for either group. In exploratory analyses, self-efficacy increased in participants with inadequate/marginal health literacy in the intervention arm (+0.7, 95% CI = 0.1-1.2; P = .01). Accuracy of knowledge did not improve but was high at baseline (mean 76.0±14.5%). 60.1% and 48.4% of control and intervention participants, respectively, found SCPs definitely/somewhat useful. Qualitative data (n = 20) suggested that SCPs were helpful to patients when primary and oncology care were less integrated. CONCLUSIONS: An LHE-delivered informational session was feasible but had limited benefit to rural cancer survivors versus delivery of SCP alone but may be of benefit to patients with low health literacy or with less integrated care.

Lifetime ovulatory years and risk of epithelial ovarian cancer: a multinational pooled analysis.

BACKGROUND: The role of ovulation in epithelial ovarian cancer (EOC) is supported by the consistent protective effects of parity and oral contraceptive use. Whether these factors protect through anovulation alone remains unclear. We explored the association between lifetime ovulatory years (LOY) and EOC. METHODS: LOY was calculated using 12 algorithms. Odds ratios (ORs) and 95% confidence intervals (CIs) estimated the association between LOY or LOY components and EOC among 26 204 control participants and 21 267 case patients from 25 studies. To assess whether LOY components act through ovulation suppression alone, we compared beta coefficients obtained from regression models with expected estimates assuming 1 year of ovulation suppression has the same effect regardless of source. RESULTS: LOY was associated with increased EOC risk (OR per year increase = 1.014, 95% CI = 1.009 to 1.020 to OR per year increase = 1.044, 95% CI = 1.041 to 1.048). Individual LOY components, except age at menarche, also associated with EOC. The estimated model coefficient for oral contraceptive use and pregnancies were 4.45 times and 12- to 15-fold greater than expected, respectively. LOY was associated with high-grade serous, low-grade serous, endometrioid, and clear cell histotypes (ORs per year increase = 1.054, 1.040, 1.065, and 1.098, respectively) but not mucinous tumors. Estimated coefficients of LOY components were close to expected estimates for high-grade serous but larger than expected for low-grade serous, endometrioid, and clear cell histotypes. CONCLUSIONS: LOY is positively associated with nonmucinous EOC. Differences between estimated and expected model coefficients for LOY components suggest factors beyond ovulation underlie the associations between LOY components and EOC in general and for non-HGSOC.

Improving Methods of Identifying Anaphylaxis for Medical Product Safety Surveillance Using Natural Language Processing and Machine Learning.

We sought to determine whether machine learning and natural language processing (NLP) applied to electronic medical records could improve performance of automated health-care claims-based algorithms to identify anaphylaxis events using data on 516 patients with outpatient, emergency department, or inpatient anaphylaxis diagnosis codes during 2015-2019 in 2 integrated health-care institutions in the Northwest United States. We used one site's manually reviewed gold-standard outcomes data for model development and the other's for external validation based on cross-validated area under the receiver operating characteristic curve (AUC), positive predictive value (PPV), and sensitivity. In the development site 154 (64%) of 239 potential events met adjudication criteria for anaphylaxis compared with 180 (65%) of 277 in the validation site. Logistic regression models using only structured claims data achieved a cross-validated AUC of 0.58 (95% CI: 0.54, 0.63). Machine learning improved cross-validated AUC to 0.62 (0.58, 0.66); incorporating NLP-derived covariates further increased cross-validated AUCs to 0.70 (0.66, 0.75) in development and 0.67 (0.63, 0.71) in external validation data. A classification threshold with cross-validated PPV of 79% and cross-validated sensitivity of 66% in development data had cross-validated PPV of 78% and cross-validated sensitivity of 56% in external data. Machine learning and NLP-derived data improved identification of validated anaphylaxis events.

Increased FOXJ1 protein expression is associated with improved overall survival in high-grade serous ovarian carcinoma: an Ovarian Tumor Tissue Analysis Consortium Study.

BACKGROUND: Recently, we showed a >60% difference in 5-year survival for patients with tubo-ovarian high-grade serous carcinoma (HGSC) when stratified by a 101-gene mRNA expression prognostic signature. Given the varied patient outcomes, this study aimed to translate prognostic mRNA markers into protein expression assays by immunohistochemistry and validate their survival association in HGSC. METHODS: Two prognostic genes, FOXJ1 and GMNN, were selected based on high-quality antibodies, correlation with protein expression and variation in immunohistochemical scores in a preliminary cohort (n = 134 and n = 80, respectively). Six thousand four hundred and thirty-four (FOXJ1) and 5470 (GMNN) formalin-fixed, paraffin-embedded ovarian neoplasms (4634 and 4185 HGSC, respectively) represented on tissue microarrays from the Ovarian Tumor Tissue Analysis consortium underwent immunohistochemical staining and scoring, then univariate and multivariate survival analysis. RESULTS: Consistent with mRNA, FOXJ1 protein expression exhibited a linear, increasing association with improved overall survival in HGSC patients. Women with >50% expression had the most favourable outcomes (HR = 0.78, 95% CI 0.67-0.91, p < 0.0001). GMNN protein expression was not significantly associated with overall HSGC patient survival. However, HGSCs with >35% GMNN expression showed a trend for better outcomes, though this was not significant. CONCLUSION: We provide foundational evidence for the prognostic value of FOXJ1 in HGSC, validating the prior mRNA-based prognostic association by immunohistochemistry.

Fruit and vegetable consumption, pesticide residue intake from consumption of fruits and vegetables, and risk of uterine fibroids.

OBJECTIVE: To examine the association between consumption of fruits and vegetables and pesticide residue intake from consumption of fruits and vegetables and risk of ultrasound- or hysterectomy-confirmed fibroids. Only a few studies have evaluated the association of fruit and vegetable intake with uterine fibroids, with inconsistent results. No studies have examined pesticide exposure through fruits and vegetables with fibroid risk. DESIGN: Prospective cohort study. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). SETTING: Not applicable. PATIENT(S): A total of 81,782 premenopausal participants from the Nurses' Health Study II cohort were followed from 1991 to 2009 for fruit and vegetable analysis, and 49,927 participants were followed from 1999 to 2009 for pesticide residue burden analysis. Their diet was assessed every 4 years with a food frequency questionnaire. Fruits and vegetables were classified into high- or low-pesticide residues using a validated method based on surveillance data from the US Department of Agriculture. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Cases of ultrasound- or hysterectomy-confirmed fibroids were identified from self-reports to validated questionnaires. RESULT(S): From 1991 to 2009, 9,706 incident cases of ultrasound- or hysterectomy-confirmed fibroids were reported, and 4,195 incident cases were identified from 1999 to 2009. No association was observed between total fruit and vegetable consumption and uterine fibroid risk. Participants with the highest intake of total fruits (≥4/day) were 10% less likely to develop uterine fibroids compared with participants who consumed <1/day (95% CI = 0.80-1.01). No associations were observed with any other fruit or vegetable groups. An inverse association was observed between intake of high-pesticide-residue fruits and vegetables and fibroid risk (HR for 5th vs. 1st quintile = 0.87; 95% CI = 0.77-0.99), while no association with low-pesticide-residue fruits and vegetables was observed (HR for 5th vs. 1st quintile = 1.08; 95% CI = 0.95-1.23). CONCLUSION(S): Our findings suggest that pesticide residues on fruits and vegetables are not associated with a higher risk of uterine fibroids. Furthermore, our results suggest that intake of fruits may be associated with a lower risk of fibroids. Future research in this area should focus on dietary exposures across the life course as well as assessment of class-specific pesticides.

Profiling the immune landscape in mucinous ovarian carcinoma.

OBJECTIVE: Mucinous ovarian carcinoma (MOC) is a rare histotype of ovarian cancer, with low response rates to standard chemotherapy, and very poor survival for patients diagnosed at advanced stage. There is a limited understanding of the MOC immune landscape, and consequently whether immune checkpoint inhibitors could be considered for a subset of patients. METHODS: We performed multicolor immunohistochemistry (IHC) and immunofluorescence (IF) on tissue microarrays in a cohort of 126 MOC patients. Cell densities were calculated in the epithelial and stromal components for tumor-associated macrophages (CD68+/PD-L1+, CD68+/PD-L1-), T cells (CD3+/CD8-, CD3+/CD8+), putative T-regulatory cells (Tregs, FOXP3+), B cells (CD20+/CD79A+), plasma cells (CD20-/CD79a+), and PD-L1+ and PD-1+ cells, and compared these values with clinical factors. Univariate and multivariable Cox Proportional Hazards assessed overall survival. Unsupervised k-means clustering identified patient subsets with common patterns of immune cell infiltration. RESULTS: Mean densities of PD1+ cells, PD-L1- macrophages, CD4+ and CD8+ T cells, and FOXP3+ Tregs were higher in the stroma compared to the epithelium. Tumors from advanced (Stage III/IV) MOC had greater epithelial infiltration of PD-L1- macrophages, and fewer PD-L1+ macrophages compared with Stage I/II cancers (p = 0.004 and p = 0.014 respectively). Patients with high epithelial density of FOXP3+ cells, CD8+/FOXP3+ cells, or PD-L1- macrophages, had poorer survival, and high epithelial CD79a + plasma cells conferred better survival, all upon univariate analysis only. Clustering showed that most MOC (86%) had an immune depleted (cold) phenotype, with only a small proportion (11/76,14%) considered immune inflamed (hot) based on T cell and PD-L1 infiltrates. CONCLUSION: In summary, MOCs are mostly immunogenically 'cold', suggesting they may have limited response to current immunotherapies.

Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes.

PURPOSE: Advanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features. EXPERIMENTAL DESIGN: Discovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n = 333), mucinous borderline ovarian tumors (MBOT, n = 151), and upper GI (n = 65) and lower GI tumors (n = 55). RESULTS: Infiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77; 95% confidence interval (CI), 1.04-7.41, P = 0.042]. Increased expression of THBS2 and TAGLN was associated with shorter OS in MOC patients (HR, 1.25; 95% CI, 1.04-1.51, P = 0.016) and (HR, 1.21; 95% CI, 1.01-1.45, P = 0.043), respectively. ERBB2 (HER2) amplification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%). CONCLUSIONS: An infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC samples clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies.

Pesticide residue intake from fruit and vegetable consumption and risk of laparoscopically confirmed endometriosis.

OBJECTIVE: To examine the association between the intake of fruits and vegetables with high- vs. low-pesticide residue burden and diagnosis of laparoscopically confirmed endometriosis. The etiology of endometriosis is not well understood, but dietary factors may influence the risk. Pesticides may act as endocrine disruptors, and the intake of pesticide-contaminated food is a common exposure pathway. DESIGN: Prospective cohort study. Hazard ratios and 95% confidence intervals were calculated using multivariable Cox proportional hazard models to evaluate the intake of fruits and vegetables with high- and low-pesticide residues in relation to the diagnosis of laparoscopically confirmed endometriosis. SETTING: Not applicable. PATIENT(S): Premenopausal US women (N = 52,053) of the Nurses' Health Study II, aged 34-53 years at study baseline (1999), were followed until 2013. The diet was assessed every 4 years using a validated food frequency questionnaire. A previously developed and validated pesticide residue burden score (PRBS), on the basis of the US Department of Agriculture Pesticide Data Program, was used to assign fruits and vegetables to pesticide residue groups (high/low). INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Cases of laparoscopically confirmed endometriosis were identified from self-reports to validated questionnaires. RESULT(S): During 14 years of follow-up, 956 incidences of laparoscopically confirmed endometriosis were reported. No association was observed between the intake of high- or low-PRBS fruit and vegetable intake and endometriosis (hazard ratio for 5th vs. 1st quintile: high-PRBS intake = 0.94, 95% confidence interval = 0.73-1.23; low-PRBS intake = 1.07, 95% confidence interval = 0.82-1.40). No associations were observed for high- or low-PRBS fruit and vegetable intake by fertility status. CONCLUSION(S): No clear associations were observed between high- or low-PRBS fruit and vegetable intake and endometriosis risk among premenopausal women. To our knowledge, this is the first study to evaluate the association between dietary pesticide residue intake and endometriosis. Further research is needed, particularly to evaluate this association among a younger population of women (adolescence or early adulthood) and assess the dietary exposure to specific pesticides or chemical families.

Long-term neurocognitive and quality of life outcomes in survivors of pediatric hematopoietic cell transplant.

PURPOSE: Pediatric patients who undergo hematopoietic cell transplant (HCT) are at risk for neurocognitive impairments, which can impact quality of life. Given limited long-term studies, we aimed to characterize the late neurocognitive outcomes in a cohort of pediatric HCT survivors. METHODS: Eligible survivors (HCT at age < 21 year and ≥ 1 year post-HCT) completed a 60-question survey of neurocognitive function and quality of life, which included the Childhood Cancer Survivor Study Neurocognitive Questionnaire (CCSS-NCQ) and the Neuro-Quality of Life Cognitive Function Short Form (Neuro-QoL). Analyses of risk factors included univariate comparisons and multivariable logistic regression. RESULTS: Participants (n = 199, 50.3% female, 53.3% acute leukemia, 87.9% allogeneic transplants) were surveyed at median age of 37.8 years (interquartile range [IQR] 28.5-48.8) at survey and median 27.6 years (IQR 17.0-34.0) from transplant. On the CCSS-NCQ, 18.9-32.5% of survivors reported impairments (Z score > 1.28) in task efficiency, memory, emotional regulation, or organization, compared with expected 10% in the general population (all p < 0.01). In contrast, survivors reported average Neuro-QoL (T score 49.6±0.7) compared with population normative value of 50 (p = 0.52). In multivariable regression, impaired Neuro-QoL (T score < 40) was independently associated with hearing issues (OR 4.97, 95% CI 1.96-12.6), history of stroke or seizure (OR 4.46, 95% CI 1.44-13.8), and sleep disturbances (OR 6.95, 95% CI 2.53-19.1). CONCLUSIONS: Although long-term survivors of pediatric HCT reported higher rates of impairment in specific neurocognitive domains, cognitive quality of life was perceived as similar to the general population. Subsets of survivors with certain co-morbidities had substantially worse neurocognitive outcomes. IMPLICATIONS FOR CANCER SURVIVORS: While the long-term impact of pediatric HCT can include neurocognitive deficits, survivors report average cognitive quality of life.

Adolescent and early adulthood inflammation-associated dietary patterns in relation to premenopausal mammographic density.

BACKGROUND: Adolescence and early adulthood has been identified as a critical time window for establishing breast cancer risk. Mammographic density is an independent risk factor for breast cancer that may be influenced by diet, but there has been limited research conducted on the impact of diet on mammographic density. Thus, we sought to examine the association between adolescent and early adulthood inflammatory dietary patterns, which have previously been associated with breast cancer risk, and premenopausal mammographic density among women in the Nurses' Health Study II (NHSII). METHODS: This study included control participants with premenopausal mammograms from an existing breast cancer case-control study nested within the NHSII who completed a Food Frequency Questionnaire in 1998 about their diet during high school (HS-FFQ) (n = 685) and/or a Food Frequency Questionnaire in 1991 (Adult-FFQ) when they were 27-44 years old (n = 1068). Digitized analog film mammograms were used to calculate the percent density, absolute dense, and non-dense areas. Generalized linear models were fit to evaluate the associations of a pro-inflammatory dietary pattern and the Alternative Healthy Eating Index (AHEI, an anti-inflammatory dietary pattern) with each breast density measure. RESULTS: Significant associations were observed between an adolescent pro-inflammatory dietary pattern and mammographic density in some age-adjusted models; however, these associations did not remain after adjustment for BMI and other breast cancer risk factors. No associations were observed with the pro-inflammatory pattern or with the AHEI pattern in adolescence or early adulthood in fully adjusted models. CONCLUSIONS: To our knowledge, this is the first study to evaluate the dietary patterns during adolescence and early adulthood in relation to mammographic density phenotypes. Our findings do not support an association between adolescent and early adulthood diet and breast density in mid-adulthood that is independent of BMI or other breast cancer risk factors.

Late Kidney Morbidity and Mortality in Hematopoietic Cell Transplant Survivors.

Increasing numbers of patients are undergoing hematopoietic cell transplantation (HCT); however, further characterization of late kidney outcomes in HCT recipients is needed. This study investigated long-term kidney outcomes in HCT survivors and compared the risk of late kidney morbidity/mortality in these survivors with that in non-HCT cancer survivors and the general population. A cohort of long-term (≥2 years) allogeneic and autologous HCT survivors treated for cancer at our institution between 1992 and 2009 (n = 1792) was compared with a non-HCT cancer cohort selected from the state cancer registry (n = 5455) matched on diagnosis, sex, and age at year of cancer diagnosis/HCT (index date). Additional comparisons were made with a matched general population sample drawn from state driver's licensing files (DOL; n = 16,340). Statewide hospital discharge codes and death registry codes (International Classification of Diseases 9/10) were used to identify cases of acute kidney failure (AKF) and chronic kidney disease (CKD) occurring ≥2 years after the index date. Cumulative incidence rates and hazard ratios (HRs; according to multivariable proportional hazard models) estimated the absolute and relative risks of AKF and CKD. Among HCT survivors, we examined the influence of additional characteristics including estimated glomerular filtration rate (eGFR) at 1-year post-HCT. The cumulative incidence rates of late kidney complications were slightly greater in the HCT survivors versus the non-HCT cancer survivors at 10 years after the index date. Both groups were more likely to experience late AKF or CKD morbidity/mortality compared with the general population (AKF: HCT, 9.4%; non-HCT, 7.7%; DOL, 1.8%; CKD: HCT, 5.7%; non-HCT, 5.0%; DOL, 1.2%). Differences between HCT survivors and non-HCT survivors were seen primarily starting 5 years after the index date, with increased hazards for late AKF (HR, 1.4; 95% confidence interval [CI], 1.1 to 1.9) and CKD (HR, 1.9; 95% CI, 1.3 to 2.8). Among allogeneic HCT survivors, the presence of hypertension at <2 years post-HCT was significantly associated with subsequent AKF (HR, 2.9; 95% CI, 1.7 to 5.0) and CKD (HR, 5.2; 95% CI, 2.7 to 10.0) at 2 to 10 years post-HCT, with similar associations seen for autologous HCT survivors. Low eGFR (<60 mL/min/1.73 m2) at 1 year post-HCT was associated with late AKF morbidity/mortality for both allogeneic (HR, 5.3; 95% CI, 2.1 to 13.2) and autologous HCT (HR, 2.7; 95% CI, 1.2 to 6.3) compared with survivors with normal eGFR (>90 mL/min/1.73 m2). Overall, the risk for hospitalization or death from AKF or CKD continued to increase with time from HCT and exceeded that of non-HCT cancer survivors at >5 years after treatment. Appropriate screening and early intervention with medication adjustments or lifestyle modifications in those with hypertension or evidence of abnormal eGFR post-HCT could potentially mitigate this risk.

Development and Validation of the Gene Expression Predictor of High-grade Serous Ovarian Carcinoma Molecular SubTYPE (PrOTYPE).

PURPOSE: Gene expression-based molecular subtypes of high-grade serous tubo-ovarian cancer (HGSOC), demonstrated across multiple studies, may provide improved stratification for molecularly targeted trials. However, evaluation of clinical utility has been hindered by nonstandardized methods, which are not applicable in a clinical setting. We sought to generate a clinical grade minimal gene set assay for classification of individual tumor specimens into HGSOC subtypes and confirm previously reported subtype-associated features. EXPERIMENTAL DESIGN: Adopting two independent approaches, we derived and internally validated algorithms for subtype prediction using published gene expression data from 1,650 tumors. We applied resulting models to NanoString data on 3,829 HGSOCs from the Ovarian Tumor Tissue Analysis consortium. We further developed, confirmed, and validated a reduced, minimal gene set predictor, with methods suitable for a single-patient setting. RESULTS: Gene expression data were used to derive the predictor of high-grade serous ovarian carcinoma molecular subtype (PrOTYPE) assay. We established a de facto standard as a consensus of two parallel approaches. PrOTYPE subtypes are significantly associated with age, stage, residual disease, tumor-infiltrating lymphocytes, and outcome. The locked-down clinical grade PrOTYPE test includes a model with 55 genes that predicted gene expression subtype with >95% accuracy that was maintained in all analytic and biological validations. CONCLUSIONS: We validated the PrOTYPE assay following the Institute of Medicine guidelines for the development of omics-based tests. This fully defined and locked-down clinical grade assay will enable trial design with molecular subtype stratification and allow for objective assessment of the predictive value of HGSOC molecular subtypes in precision medicine applications.See related commentary by McMullen et al., p. 5271.

Late infectious complications in hematopoietic cell transplantation survivors: a population-based study.

Few studies have compared the incidence of infections occurring ≥2 years after hematopoietic cell transplant (HCT) with other cancer patients and the general population. In this study, ≥2-year HCT survivors who were Washington residents treated from 1992 through 2009 (n = 1792; median age, 46 years; 52% allogeneic; 90% hematologic malignancies) were matched to individuals from the state cancer registry (n = 5455, non-HCT) and driver's license files (n = 16 340; Department of Licensing [DOL]). Based on hospital and death registry codes, incidence rate ratios (IRRs; 95% confidence interval [CI]) of infections by organism type and organ system were estimated using Poisson regression. With 7-year median follow-up, the incidence rate (per 1000 person-years) of all infections was 65.4 for HCT survivors vs 39.6 for the non-HCT group (IRR, 1.6; 95% CI, 1.3-1.9) and 7.2 for DOL (IRR, 10.0; 95% CI, 8.3-12.1). Bacterial and fungal infections were each 70% more common in HCT vs non-HCT cancer survivors (IRR, 1.7; P < .01), whereas the risk for viral infection was lower (IRR, 1.4; P = .07). Among potentially vaccine-preventable organisms, the IRR was 3.0 (95% CI, 2.1-4.3) vs the non-HCT group. Although the incidences of all infections decreased with time, the relative risk in almost all categories remained significantly increased in ≥5-year HCT survivors vs other groups. Risk factors for late infection included history of relapse and for some infections, history of chronic graft-versus-host disease. Providers caring for HCT survivors should maintain vigilance for infections and ensure adherence to antimicrobial prophylaxis and vaccination guidelines.