Patient preferences and adherence to adjuvant GnRH analogs among premenopausal women with hormone receptor positive breast cancer.

PURPOSE: Adjuvant ovarian function suppression (OFS) in premenopausal hormone receptor (HR) positive breast cancer (BC) improves survival. Adherence to adjuvant gonadotropin-releasing hormone analogs (GnRHa) remains a challenge and is associated with toxicities and inconvenient parenteral administration. The goal of this study was to describe real-world adherence patterns and patient preferences surrounding adjuvant GnRHa. METHODS: We analyzed the medical records of premenopausal women with non-metastatic HR positive BC from January 2000 to December 2017; participants received adjuvant monthly goserelin or leuprolide at The Ohio State University. Data collected included demographics, clinicopathologic characteristics, and OFS adherence/side effects. We defined non-adherence as discontinuation of GnRHa within 3 years for a reason other than switching to an alternate OFS, delay > 7 days from a dose, or a missed dose. Chi-square tests assessed associations between clinical characteristics and outcomes. RESULTS: A total of 325 patients met eligibility. Of these, 119 (37%) patients were non-adherent to GnRHa; 137 (42%) underwent elective bilateral salpingo-oophorectomy after initial GnRHa. Those opting for surgery reported significantly more hot flashes (74% vs 48%, p < 0.001), arthralgias (46% vs 30%, p = 0.003), and vaginal dryness (37% vs 21%, p = 0.001) compared with patients remaining on GnRHa. CONCLUSION: Non-adherence to adjuvant GnRHa occurred in over a third of patients and almost half the patients initiating GnRHa underwent subsequent surgical ablation. These high frequencies highlight real-world patterns of OFS. Additionally, treatment toxicities may impact personal preference of OFS modality. Personalized practices to target predictors of adjuvant GnRHa non-adherence are critical to optimize symptoms, adherence, and survivorship.

CCNA2 Ablation in Aged Mice Results in Abnormal rRNA Granule Accumulation in Hippocampus.

Mounting evidence in the literature suggests that RNA-RNA binding protein aggregations can disturb neuronal homeostasis and lead to symptoms associated with normal aging as well as dementia. The specific ablation of cyclin A2 in adult neurons results in neuronal polyribosome aggregations and learning and memory deficits. Detailed histologic and ultrastructural assays of aged mice revealed that post-mitotic hippocampal pyramidal neurons maintain cyclin A2 expression and that proliferative cells in the dentate subgranular zone express cyclin A2. Cyclin A2 loss early during neural development inhibited hippocampal development through canonical/cell-cycle mechanisms, including prolonged cell cycle timing in embryonic hippocampal progenitor cells. However, in mature neurons, cyclin A2 colocalized with dendritic rRNA. Cyclin A2 ablation in adult hippocampus resulted in decreased synaptic density in the hippocampus as well as in accumulation of rRNA granules in dendrite shafts. We conclude that cyclin A2 functions in a noncanonical/non-cell cycle regulatory role to maintain adult pyramidal neuron ribostasis.

Efficacy of different dosing schedules of capecitabine for metastatic breast cancer: a single-institution experience.

Purpose Capecitabine is widely used as a single agent on a 21-day cycle in the management of metastatic breast cancer (MBC). Our primary objective was to compare the standard dosing of capecitabine (Arm A: days 1-14 on 21-day cycle) to biweekly dosing (Arm B: days 1-7 and 15-21 on 28-day cycle) using retrospective data analysis. Methods 166 patients with MBC treated with single agent capecitabine at The Ohio State University from 2002 to 2014 were considered eligible. Median time to treatment failure (TTF) and overall survival (OS) were estimated using Kaplan-Meier (KM) methods. KM curves were compared using log-rank tests with Holm's correction for multiplicity. Results Patients were grouped by dose schedule into one of three arms: Arm A (21-day cycle; capecitabine given at 1000 mg/m2 orally, twice daily on days 1-14 of 21-day cycle); Arm B (28-day cycle; capecitabine given at 1000 mg/m2 orally, twice daily on days 1-7 and 15-21 of 28-day cycle); and Arm C (changeover regimen where patients started on the 21-day cycle, but changed to a 28-day cycle for tolerability). No difference was found in TTF or OS for patients with MBC between those who received capecitabine on either standard dosing (Arm A) and those on a biweekly cycle (Arm B or C). Overall, 41% of patients required dose reduction. Conclusions Our single institution experience showed that alternate dosing of capecitabine (biweekly, 28-day cycle) may be a reasonable alternative to standard 21-day cycle with similar efficacy and fewer dose reductions.

A phase I study of an oral selective gamma secretase (GS) inhibitor RO4929097 in combination with neoadjuvant paclitaxel and carboplatin in triple negative breast cancer.

Upregulation of Notch pathway is associated with poor prognosis in breast cancer. We present the results of a phase I study of an oral selective gamma secretase (GS) inhibitor (critical to Notch signaling), RO4929097 in combination with neoadjuvant chemotherapy for operable triple negative breast cancer. The primary objective was to determine the maximum tolerated dose (MTD) of RO4929097. Secondary objectives were to determine real-time pharmacokinetics of RO4929097 and paclitaxel, safety and pathologic (pCR) complete response to study treatment. Eligible patients, initiated carboplatin at AUC 6 administered intravenously (IV) on day 1, weekly paclitaxel at 80 mg/m2 IV and RO4929097 10 mg daily given orally (PO) on days 1-3, 8-10 and 15-17 for six 21-day cycles. RO4929097 was escalated in 10 mg increments using the 3 + 3 dose escalation design. Two DLTs were observed in 14 patients - Grade (G) 4 thrombocytopenia in dose level 1 (10 mg) and G3 hypertension in dose level 2 (20 mg). Protocol-defined MTD was not determined due to discontinuation of RO4929097 development. However, 4 of 5 patients enrolled to 20 mg dose of RO4929097 required dose reduction to 10 mg due to toxicities (including neutropenia, thrombocytopenia and hypertension) occurring during and beyond the DLT observation period. Thus, 10 mg would have been the likely dose level for further development. G3 or higher hematologic toxicities included neutropenia (N = 8, 57%) and thrombocytopenia (N = 5, 36%) patients. Six (43%) patients had G2-3 neuropathy requiring paclitaxel dose reduction. No signs of drug-drug interaction between paclitaxel and RO4929097 were evident. Five patients (36%) had pCR.

Cervical Cancer Among Older Women: Analyses of Surveillance, Epidemiology and End Results Program Data.

OBJECTIVE: To describe age-specific cervical cancer incidence rates based on demographic and clinical characteristics. METHODS: Women with cervical cancer in the SEER program were grouped into 3 age categories. Demographics, clinical characteristics, and incidence rates were obtained for each age group. RESULTS: Older women (≥65 years) had higher incidence rates of cervical cancer than women <65 years with the highest rates in black women ≥75 years. Older black women had more adverse factors at diagnosis than similarly aged white and younger black women. There was a higher incidence rate of cervical cancer in women with lower socioeconomic status (SES), with the highest rates in older black women. However, the incidence rates were similar for older black women regardless of SES. CONCLUSION: Older black have the highest cervical cancer incidence rates, regardless of SES, suggesting an age and race disparity when compared to younger and white women.

The impact of granulocyte colony-stimulating factor use in patients with metastatic breast cancer treated with palliative chemotherapy: a single-institution retrospective review.

PURPOSE: The goal of chemotherapy for metastatic breast cancer (MBC) is palliation of symptoms while minimizing treatment-related toxicities. It remains unclear whether use of granulocyte colony-stimulating factor (G-CSF) to maintain relative dose intensity of chemotherapy for MBC is associated with improved clinical outcomes. METHODS: The medical records of MBC patients treated with chemotherapy in 1st-3rd-line settings between May 2010 and April 2014 were reviewed. Time to progression (TTP), progression-free survival (PFS), and overall survival (OS) were compared between patients who received G-CSF and those who did not. Antibiotic use, total clinic visits, and pre- and post-treatment Eastern Cooperative Oncology Group (ECOG) performance status were also compared between the groups. RESULTS: Of the 169 patients included, 55 (32.5%) received > 1 G-CSF dose and 114 (67.5%) did not receive any G-CSF. The median TTP was similar between the two groups (5.0 months (95% CI 3.4-7.1) vs. 5.2 months (95% CI 4.8-6.2) respectively; p = 0.998). The median PFS (p = 0.955; 5.0 months (95% CI 3.4-5.9) vs. 5.2 months (95% CI 4.7-6.0), respectively) and OS (14.6 (95% CI 9.0-26.6) vs. 18.5 months (95% CI 15.2-22.0) in G-CSF and non-G-CSF groups, respectively; p = 0.628) were also similar between groups. No significant between-group differences were noted in rate of decline in ECOG performance status, antibiotic use, and number of clinic visits and hospitalizations. CONCLUSION: This retrospective analysis did not find any evidence that the use of G-CSF to maintain chemotherapy dose intensity for the treatment of MBC improves TTP, PFS, and OS or results in improved ECOG performance status compared with lack of G-CSF use in patients with MBC treated in 1st to 3rd-line settings.

Fractional CO2 laser therapy for genitourinary syndrome of menopause for breast cancer survivors.

PURPOSE: Fractional CO2 laser therapy is an emerging treatment for genitourinary syndrome of menopause (GSM). The objective of this study was to determine the feasibility and preliminary efficacy of fractional CO2 laser therapy in breast cancer survivors. METHODS: This was a single arm feasibility study of breast cancer survivors with dyspareunia and/or vaginal dryness. Participants received three treatments of fractional CO2 laser therapy at 30-day intervals and returned for a 1-month follow-up. Feasibility was defined as treatment completion without serious adverse events (SAE) in 80% of patients. We collected data on the Vaginal Assessment Scale (VAS), the Female Sexual Function Index (FSFI), the Urinary Distress Index (UDI), and SAE. RESULTS: A total of 64 patients participated in the study. The majority of women had Estrogen receptor/Progesterone receptor (ER/PR) positive/Her2neu negative (n = 37; 63%), stage I (n = 32, 54%) or II (n = 19, 32%) breast cancer. Most were receiving endocrine therapy (n = 54, 92%), most commonly aromatase inhibitors (AI; n = 40, 68%). Fifty-nine (88.1%) of those enrolled completed all treatments according to protocol with no reported SAE. No patient withdrew due to SAE. The scores of the VAS (mean Δ - 0.99; 95% CI [- 1.19, - 0.79], p < 0.001)), FSFI (mean Δ 9.67; 95% CI [7.27, 12.1], p < 0.001), and UDI (mean Δ - 8.85; 95% CI [- 12.75, - 4.75], p < 0.001)) improved from baseline to follow-up. CONCLUSION: Fractional CO2 laser treatment for breast cancer survivors is feasible and appears to reduce GSM symptoms across treatment and follow-up.

Incorporation of a patient navigator into a secondary fracture prevention program identifies barriers to patient care.

INTRODUCTION: Patient navigation improves outcomes in various clinical contexts, but has not been evaluated in secondary fracture prevention. METHODS: We retrospectively reviewed charts of patients, age 50 + from April to October, 2016 hospitalized with fragility fracture contacted by a patient navigator. Patients were identified using an electronic tool extracting data from electronic medical records which alerted the patient navigator to contact patients by phone post-discharge to schedule appointments to "High-Risk Osteoporosis Clinic" (HiROC) and Dual-energy X-ray Absorptiometry (DXA) scan. Primary outcome was transition from hospital to HiROC. We also compared completion of DXA, five osteoporosis-associated in-hospital laboratory tests (calcium, 25-hydroxy vitamin D, complete blood count, renal, and liver function), osteoporosis medication prescription and adherence, and other patient characteristics to historical controls (2014-2015) without patient navigation. Comparisons were made using Chi-square, Fisher's Exact, two-sample t test or Wilcoxon Rank Sum test, as appropriate. RESULTS: The proportion of patients transitioning to HiROC with and without patient navigation was not different (53% vs. 48%, p = 0.483), but DXA scan completion was higher (90% vs. 67%, p = 0.006). No difference in medication initiation within 3 months post discharge (73% vs. 65%, p = 0.387) or adherence at 6 months (68% vs. 71%, p = 0.777) was found. Patients attending HiROC lived closer (11 vs. 43 miles, p < 0.001) and more likely to follow-up in surgery clinic (95% vs. 61%, p < 0.001). CONCLUSION: Patient navigation did not improve transition to HiROC. Longer travel distance may be a barrier-unaffected by patient navigation. Identifying barriers may inform best practices for Fracture Liaison Service programs.

Assessment of outcomes and novel immune biomarkers in metaplastic breast cancer: a single institution retrospective study.

BACKGROUND: Metaplastic breast cancer remains poorly characterized given its rarity and heterogeneity. The majority of metaplastic breast cancers demonstrate a phenotype of triple-negative breast cancer; however, differences in clinical outcomes between metaplastic breast cancer and triple-negative breast cancer in the era of third-generation chemotherapy remain unclear. METHODS: We compared the clinical outcomes between women with metaplastic breast cancer and women with triple-negative breast cancer diagnosed between 1994 and 2014. Metaplastic breast cancer patients were matched 1:3 to triple-negative breast cancer patients by stage and age at diagnosis. Distant disease-free survival (DDFS) and overall survival (OS) were estimated using Kaplan Meier methods and Cox proportional hazard regression models. Immune checkpoint markers were characterized by immunohistochemistry in a subset of samples. RESULTS: Forty-four metaplastic breast cancer patients (stage I 14%; stage II 73%; stage III 11%; stage IV 2%) with an average age of 55.4 (± 13.9) years at diagnosis. Median follow-up for the included metaplastic breast cancer and triple-negative breast cancer patients (n = 174) was 2.8 (0.1-19.0) years. The DDFS and OS between matched metaplastic breast cancer and triple-negative breast cancer patients were similar, even when adjusting for clinical covariates (DDFS: HR = 1.64, p = 0.22; OS: HR = 1.64, p = 0.26). Metaplastic breast cancer samples (n = 27) demonstrated greater amount of CD163 in the stroma (p = 0.05) and PD-L1 in the tumor (p = 0.01) than triple-negative breast cancer samples (n = 119), although more triple-negative breast cancer samples were positive for CD8 in the tumor than metaplastic breast cancer samples (p = 0.02). CONCLUSIONS: Patients with metaplastic breast cancer had similar outcomes to those with triple-negative breast cancer based on DDFS and OS. The immune checkpoint marker profile of metaplastic breast cancers in this study may prove useful in future studies attempting to demonstrate an association between immune profile and survival.

Abrupt involution induces inflammation, estrogenic signaling, and hyperplasia linking lack of breastfeeding with increased risk of breast cancer.

BACKGROUND: A large collaborative analysis of data from 47 epidemiological studies concluded that longer duration of breastfeeding reduces the risk of developing breast cancer. Despite the strong epidemiological evidence, the molecular mechanisms linking prolonged breastfeeding to decreased risk of breast cancer remain poorly understood. METHODS: We modeled two types of breastfeeding behaviors in wild type FVB/N mice: (1) normal or gradual involution of breast tissue following prolonged breastfeeding and (2) forced or abrupt involution following short-term breastfeeding. To accomplish this, pups were gradually weaned between 28 and 31 days (gradual involution) or abruptly at 7 days postpartum (abrupt involution). Mammary glands were examined for histological changes, proliferation, and inflammatory markers by immunohistochemistry. Fluorescence-activated cell sorting was used to quantify mammary epithelial subpopulations. Gene set enrichment analysis was used to analyze gene expression data from mouse mammary luminal progenitor cells. Similar analysis was done using gene expression data generated from human breast samples obtained from parous women enrolled on a tissue collection study, OSU-2011C0094, and were undergoing reduction mammoplasty without history of breast cancer. RESULTS: Mammary glands from mice that underwent abrupt involution exhibited denser stroma, altered collagen composition, higher inflammation and proliferation, increased estrogen receptor α and progesterone receptor expression compared to those that underwent gradual involution. Importantly, when aged to 4 months postpartum, mice that were in the abrupt involution cohort developed ductal hyperplasia and squamous metaplasia. Abrupt involution also resulted in a significant expansion of the luminal progenitor cell compartment associated with enrichment of Notch and estrogen signaling pathway genes. Breast tissues obtained from healthy women who breastfed for < 6 months vs ≥ 6 months showed significant enrichment of Notch signaling pathway genes, along with a trend for enrichment for luminal progenitor gene signature similar to what is observed in BRCA1 mutation carriers and basal-like breast tumors. CONCLUSIONS: We report here for the first time that forced or abrupt involution of the mammary glands following pregnancy and lack of breastfeeding results in expansion of luminal progenitor cells, higher inflammation, proliferation, and ductal hyperplasia, a known risk factor for developing breast cancer.

Polymerase ɛ (POLE) mutations in endometrial cancer: clinical outcomes and implications for Lynch syndrome testing.

BACKGROUND: DNA polymerase ɛ (POLE) exonuclease domain mutations characterize a subtype of endometrial cancer (EC) with a markedly increased somatic mutational burden. POLE-mutant tumors were described as a molecular subtype with improved progression-free survival by The Cancer Genome Atlas. In this study, the frequency, spectrum, prognostic significance, and potential clinical application of POLE mutations were investigated in patients with endometrioid EC. METHODS: Polymerase chain reaction amplification and Sanger sequencing were used to test for POLE mutations in 544 tumors. Correlations between demographic, survival, clinicopathologic, and molecular features were investigated. Statistical tests were 2-sided. RESULTS: Thirty POLE mutations (5.6%) were identified. Mutations were associated with younger age (<60 years; P=.001). POLE mutations were detected in tumors with microsatellite stability (MSS) and microsatellite instability (MSI) at similar frequencies (5.9% and 5.2%, respectively) and were most common in tumors with MSI that lacked mutL homolog 1 (MLH1) methylation (P<.001). There was no association with progression-free survival (hazard ratio, 0.22; P=.127). CONCLUSIONS: The discovery that mutations occur with equal frequency in MSS and MSI tumors and are most frequent in MSI tumors lacking MLH1 methylation has implications for Lynch syndrome screening and mutation testing. The current results indicate that POLE mutations are associated with somatic mutation in DNA mismatch repair genes in a subset of tumors. The absence of an association between POLE mutation and progression-free survival indicates that POLE mutation status is unlikely to be a clinically useful prognostic marker. However, POLE testing in MSI ECs could serve as a marker of somatic disease origin. Therefore, POLE tumor testing may be a valuable exclusionary criterion for Lynch syndrome gene testing.

Development of a pediatric-specific clinical probability tool for diagnosis of venous thromboembolism: a feasibility study.

BACKGROUND: Pediatric venous thromboembolism (VTE) is an increasingly common, difficult to diagnose problem. Clinical probability tools (CPT) for adults estimate VTE likelihood, but are not available for children. We hypothesized that a pediatric-specific CPT is feasible. METHODS: Radiology reports were utilized to identify children imaged for suspected VTE. Relevant signs, symptoms, and comorbidity variables, identified from published literature, were extracted from corresponding medical records. Variables associated with pediatric VTE were incorporated into a multivariate logistic regression to create a pilot CPT which was confirmed on a separate cohort. RESULTS: A total of 389 subjects meeting inclusion criteria were identified: 91 with VTE and 298 without. Univariate analysis revealed male gender (odds ratio (OR) = 2.96; P < 0.001), asymmetric extremity (OR = 1.76; P = 0.033), central venous catheter utilization and/or dysfunction (OR = 2.51; P < 0.001), and cancer (OR = 2.35; P = 0.014) as VTE predictive variables. Documentation of an alternate diagnosis was inversely related to VTE (OR = 0.42; P = 0.004). Receiver operating characteristic analysis of the derived CPT demonstrated reasonable ability to discriminate VTE probability in the training cohort (area under the curve (AUC) = 0.73; P < 0.001) and moderate discrimination in a separate validation cohort of 149 children (AUC = 0.64; P = 0.011). CONCLUSION: A pediatric-specific VTE CPT is feasible, would facilitate early diagnosis, and could lead to improved outcomes.

Pten in stromal fibroblasts suppresses mammary epithelial tumours.

The tumour stroma is believed to contribute to some of the most malignant characteristics of epithelial tumours. However, signalling between stromal and tumour cells is complex and remains poorly understood. Here we show that the genetic inactivation of Pten in stromal fibroblasts of mouse mammary glands accelerated the initiation, progression and malignant transformation of mammary epithelial tumours. This was associated with the massive remodelling of the extracellular matrix (ECM), innate immune cell infiltration and increased angiogenesis. Loss of Pten in stromal fibroblasts led to increased expression, phosphorylation (T72) and recruitment of Ets2 to target promoters known to be involved in these processes. Remarkably, Ets2 inactivation in Pten stroma-deleted tumours ameliorated disruption of the tumour microenvironment and was sufficient to decrease tumour growth and progression. Global gene expression profiling of mammary stromal cells identified a Pten-specific signature that was highly represented in the tumour stroma of patients with breast cancer. These findings identify the Pten-Ets2 axis as a critical stroma-specific signalling pathway that suppresses mammary epithelial tumours.

Analysis of factors contributing to severity of breast cancer-related lymphedema.

BACKGROUND: Upper extremity lymphedema is a well-described complication of breast cancer treatment. Risk factors for lymphedema development include axillary lymph node dissection (ALND), obesity, increasing age, radiation, and postoperative complications. In this study, we seek to evaluate a cohort of patients who have either self-referred or been referred to the Department of Physical Therapy for lymphedema treatment. Our goal is to evaluate specific risk factors associated with the severity of lymphedema in this patient population. METHODS: All patients who presented to the Wexner Medical Center at the Ohio State University between January 1, 2009, and December 31, 2010, with a chief complaint of upper extremity lymphedema after breast cancer treatment were reviewed retrospectively. Upper extremity lymphedema index (UELI) was used as a severity indicator and patient factors including demographics and breast cancer treatments were evaluated. Univariate and multivariate statistical analyses were performed. RESULTS: Fifty (4.5%) patients presented for upper extremity lymphedema treatment after breast cancer treatment (total of 1106 patients treated surgically for breast cancer). Greater UELIs were found in patients 50 years and older, those with ALND, radiation, chemotherapy, pathologic stage greater than 3, and an International Society of Lymphology lymphedema stage II (P < 0.05). The multivariate model showed age older than 50 years and pathologic stage greater than 3 were significant predictors of higher UELI (P < 0.05). CONCLUSIONS: In this study, we report that in patients who present for lymphedema treatment, increased UELI is significantly related to ALND, radiation therapy, chemotherapy, age, and pathologic stage. An improved understanding of the patient population referred for lymphedema treatment will allow for the identification of patients who may be candidates for therapeutic intervention.

Comprehensive evaluation of caspase-14 in vulvar neoplasia: an opportunity for treatment with black raspberry extract.

OBJECTIVE: The aim of this study is to determine the expression of caspase-14, a key protein in maturation of squamous epithelia, in archival malignant and premalignant vulvar squamous lesions and examine in-vitro effects of a black raspberry extract (BRB-E) on a vulvar squamous cell carcinoma (VSCC) cell line. METHODS: VSCC cell cultures were exposed to different BRB-E concentrations and used to create cell blocks. Immunohistochemistry for caspase-14 was performed on cell block sections, whole tissue sections, and a tissue microarray consisting of normal vulvar skin, lichen sclerosus (LS), classic and differentiated vulvar intraepithelial neoplasia (cVIN and dVIN respectively), and VSCC. RESULTS: LS demonstrated abnormal full thickness (5/11) or absent (1/11) caspase-14 staining. dVIN often showed markedly reduced expression (4/7), and cVIN occasionally demonstrated either absent or reduced caspase-14 (6/22). VSCC predominantly had absent or markedly reduced caspase-14 (26/28). VSCC cell cultures demonstrated a significant increase in caspase-14 (p=0.013) after BRB-E treatment: 7.3% (±2.0%) of untreated cells showed caspase-14 positivity, while 21.3% (±8.9%), 21.7% (±4.8%), and 22.6% (±5.3%) of cells were positive for caspase-14 after treatment with 200, 400, and 800 µg/mL BRB-E, respectively. Pair-wise comparisons between the treatment groups and the control demonstrated significant differences between no treatment with BRB-E and each of these treatment concentrations (Dunnett's adjusted p-values: 0.024, 0.021, and 0.014, respectively). CONCLUSIONS: Caspase-14 is frequently decreased in premalignant and malignant vulvar squamous lesions, and is upregulated in VSCC cell culture by BRB-E. BRB-E should be further explored and may ultimately be incorporated in topical preparations.

Mismatch repair protein expression in 1049 endometrial carcinomas, associations with body mass index, and other clinicopathologic variables.

OBJECTIVE: Links between obesity, with its attendant estrogen abnormalities, and the endometrial carcinoma (EC) DNA Mismatch Repair Protein (MMR) system have recently been proposed. We investigated relationships between body mass index (BMI) and clinicopathological correlates including MMR expression in a large single institution EC cohort. METHODS: Clinical and pathological databases from 2007 to 2012 were used to identify consecutive hysterectomy specimens with EC. Univariate and multivariate analyses were used to explore relationships between BMI, age, stage, tumor type and immunohistochemical results for MLH1, PMS2, MSH2 and MSH6. RESULTS: 1049 EC were identified. Overall, BMI was higher amongst women with normal MMR (p=0.002). However, when stratified by age and specific MMR, statistically significant differences localized exclusively to women <50years old with loss of MSH2 and/or MSH6 (p=0.003 and p=0.005 respectively). Higher BMI correlated with endometrioid FIGO 1 and 2 tumors (p<0.001) and with stage 1a (p<0.001). Conversely, MMR abnormalities did not show significant associations with stage (p=0.302) or histologic grade (p=0.097). CONCLUSIONS: BMI showed statistically significant associations with MMR expression, tumor grade and stage amongst 1049 consecutive EC. Obesity correlates with lower grade and stage EC. A link between BMI and maintenance of the MMR system is not supported by our data because the only statistically significant association occurred in women <50years old with MSH2 and/or MSH6 abnormalities where Lynch syndrome related cases are expected to cluster.

Innate immune dysfunction is associated with enhanced disease severity in infants with severe respiratory syncytial virus bronchiolitis.

BACKGROUND: Most patients with respiratory syncytial virus (RSV) bronchiolitis requiring admission to the pediatric intensive care unit (PICU) have no risk factors for severe disease. We sought to investigate the relationship between serum cytokine concentrations, innate immune responsiveness, and RSV disease severity. METHODS: Previously healthy infants (median age, 2.6 months) with RSV bronchiolitis (PICU, n = 20; floor, n = 46) and healthy matched controls (n = 14) were enrolled, and blood samples were obtained within 24 hours of admission to measure plasma tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), interleukin 8 (IL-8), and interleukin 10 (IL-10) concentrations and, whole blood lipopolysaccharide-stimulated cytokine production capacity. RESULTS: Plasma IL-6, IL-8, and IL-10 concentrations were comparable between PICU and floor patients, but higher than in healthy controls (P < .05). In contrast, TNF-α, IL-6, and IL-8 production capacity was significantly decreased in PICU compared with both floor patients and healthy controls. In adjusted analyses, only impaired TNF-α and IL-8 production capacity were associated with longer length of stay (P = .035) and greater disease severity scores (P = .001). CONCLUSIONS: Infants with severe RSV bronchiolitis had increased plasma cytokine concentrations and yet impaired innate immunity cytokine production capacity, which predicted worse disease outcomes. Immune monitoring of otherwise healthy infants with RSV lower respiratory tract infection could help identify patients at risk for severe disease at the time of hospitalization.

Testing the feasibility of mobile ecological momentary assessment for symptom burden and management among metastatic cancer patients.

Background: Individuals who have metastatic cancer experience substantial physical and psychological distress (e.g., pain, depression, anxiety) from their disease and its treatment compared to patients with less advanced disease. As the burden of symptoms varies over time, ecological momentary assessment (EMA) may be used to better understand patients' symptom trajectories, complimenting traditional longitudinal data collection methods. However, few have used EMA in patients with metastatic disease. The current study adds to the existing literature by exploring interrelated, common cancer-related symptoms of pain, anxiety, and depression and use of cannabis-based products, opioid medications, other (nonopioid) pain medications, and medications for anxiety or depression. Methods: An eight-day prospective observational feasibility study was conducted among 50 patients with metastatic cancer recruited from seven solid cancer clinics at The Ohio State University Comprehensive Cancer Center. Participants completed a week of interval-contingent mobile EMA, administered daily at 9 a.m., 3 p.m., and 8 p.m., and a comprehensive interviewer-administered questionnaire on Day 8. Participants were queried on their symptom burden and management strategies (i.e., use of medications and cannabis). We considered EMA to be feasible if a priori retention (80%) and adherence goals (75%) were met. Results: Seventy-nine percent of eligible patients contacted enrolled in the study (n = 50 of 63). Among those enrolled, 92% were retained through Day 8 and 80% completed >90% of EMAs, exceeding a priori objectives. Participants' average pain, anxiety, and depressive symptoms across the week of EMA ranged from 1.7 to 1.8 (1 to 5 scale). Symptoms varied little by day or time of administration. On Day 8, significant proportions of participants reported past-week use of medications and cannabis for symptom management. Conclusions: Participants exceeded a priori adherence and retention objectives, indicating that mobile EMA is feasible among metastatic cancer patients, addressing a gap in the existing literature and informing future research. Restricting eligibility to participants with a minimum cutoff of symptom burden may be warranted to increase observations of symptom variability and provide opportunities for future health interventions. Future research is needed to test the acceptability and quality of data over a longer study period in this patient population.

Allele-specific tumor spectrum in pten knockin mice.

Germline mutations in the tumor suppressor gene PTEN (phosphatase and tensin homology deleted on chromosome 10) cause Cowden and Bannayan-Riley-Ruvalcaba (BRR) syndromes, two dominantly inherited disorders characterized by mental retardation, multiple hamartomas, and variable cancer risk. Here, we modeled three sentinel mutant alleles of PTEN identified in patients with Cowden syndrome and show that the nonsense Pten(4-5) and missense Pten(C124R) and Pten(G129E) alleles lacking lipid phosphatase activity cause similar developmental abnormalities but distinct tumor spectra with varying severity and age of onset. Allele-specific differences may be accounted for by loss of function for Pten(4-5), hypomorphic function for Pten(C124R), and gain of function for Pten(G129E). These data demonstrate that the variable tumor phenotypes observed in patients with Cowden and BRR syndromes can be attributed to specific mutations in PTEN that alter protein function through distinct mechanisms.

Factors Related to Human Papillomavirus Positivity among Oral Cavity and Pharynx Cancers from Surveillance, Epidemiology and End Results (SEER) Program Data.

BACKGROUND: As human papillomavirus positive (HPV+) oral cavity and pharynx cancer (OCPC) incidence increases significantly, our objective was to determine whether selected sociodemographic and clinical factors were associated with HPV+ OCPCs overall and by oropharyngeal and non-oropharyngeal sites. METHODS: Surveillance, Epidemiology and End Results (SEER) Program data were used in this study. Specifically, univariate and logistic regression models were used to examine the relationships between HPV+ and HPV- OCPC cases and age, sex, race, ethnicity, marital status, factors of neighborhood socioeconomic status (i.e., nSES/Yost index) and rurality/urbanity, first malignancy status, histology, reporting source, stage at diagnosis, and OCPC anatomic site. The same approach was used to identify risk factors for HPV positivity for oropharyngeal and non-oropharyngeal OCPCs separately. RESULTS: In all OCPCs, cases that were male, <80 years old, lived in the four highest nSES categories, diagnosed with a non-"gum and other mouth" OCPC (ref = hypopharynx), not locally staged at diagnosis, and a first malignancy had higher odds of being HPV+. Cases that were American Indian/Alaska Native and Asian or Pacific Islander (ref = White), Spanish-Hispanic-Latino ethnicity, non-married/partnered, and not reported by a hospital/clinic had lower odds of being HPV+. Associations were maintained in oropharyngeal OCPCs and only age and race remained significant for non-oropharyngeal OCPCs. CONCLUSIONS: Sociodemographic and clinical differences in HPV+ and HPV- OCPC, overall and for (non)oropharyngeal, cases exist. IMPACT: Identification of OCPC and (non)oropharyngeal risk factors for HPV positivity may assist in discovering high-risk groups that should receive enhanced public health efforts to reduce the U.S. OCPC burden.