In Vitro and In Vivo Efficacy of a Stroma-Targeted, Tumor Microenvironment Responsive Oncolytic Adenovirus in Different Preclinical Models of Cancer.

More than one million women are diagnosed annually worldwide with a gynecological cancer. Most gynecological cancers are diagnosed at a late stage, either because a lack of symptoms, such as in ovarian cancer or limited accessibility to primary prevention in low-resource countries, such as in cervical cancer. Here, we extend the studies of AR2011, a stroma-targeted and tumor microenvironment responsive oncolytic adenovirus (OAdV), whose replication is driven by a triple hybrid promoter. We show that AR2011 was able to replicate and lyse in vitro fresh explants obtained from human ovarian cancer, uterine cancer, and cervical cancer. AR2011 was also able to strongly inhibit the in vitro growth of ovarian malignant cells obtained from human ascites fluid. The virus could synergize in vitro with cisplatin even on ascites-derived cells obtained from patients heavily pretreated with neoadjuvant chemotherapy. AR2011(h404), a dual transcriptionally targeted derived virus armed with hCD40L and h41BBL under the regulation of the hTERT promoter, showed a strong efficacy in vivo both on subcutaneous and intraperitoneally established human ovarian cancer in nude mice. Preliminary studies in an immunocompetent murine tumor model showed that AR2011(m404) expressing the murine cytokines was able to induce an abscopal effect. The present studies suggest that AR2011(h404) is a likely candidate as a novel medicine for intraperitoneal disseminated ovarian cancer.

Polity's Enduring Effect on Infant Health Outcomes.

OBJECTIVES: How a nation's style of governance (polity) affects infant health is not fully understood. Here, the effects of polity on infant mortality rates (IMRs) is evaluated across 164 nations over a 28-year period. METHODS: Variation in 2018 IMRs was examined in relation to Polity Scores from 1990 to 2017 that quantify autocratic-to-democratic propensities of governments. Regression coefficients of effect, adjusted for national differences in economic prosperity, income equity and gender parity are reported. RESULTS: IMRs and polity was inversely related and more strongly associated with greater time between measurements. 2018 IMRs decreased by 0.12 deaths for a unitary increase in 2017 Polity Scores and 0.84 deaths when 1990 Polity Scores were examined. A similar, but more intense pattern was found when Polity Scores were aggregated to represent Autocratic, Anocratic and Democratic governance. CONCLUSIONS FOR PRACTICE: Beyond risks associated with birthright, behavior and physical environments, a nation's form of government has a real, enduring effect on infant health. A full measure of that association requires extended time for proper evaluation.

Serious adverse events in African-American cancer patients with sickle cell trait and inherited haemoglobinopathies in a SEER-Medicare claims cohort.

African-American (AA) cancer patients have long-experienced worse outcomes compared to non-Hispanic whites (NHW). No studies to date have evaluated the prognostic impact of sickle cell trait (SCT) and other inherited haemoglobinopathies, of which several are disproportionately high in the AA population. In a cohort analysis of treated patients diagnosed with breast or prostate cancer in the linked SEER-Medicare database, the relative risk (RR) for ≥1 serious adverse events (AEs), defined as hospitalisations or emergency department visits, was estimated for 371 AA patients with a haemoglobinopathy (AA+) compared to patients without haemoglobinopathies (17,303 AA-; 144,863 NHW-). AA+ patients had significantly increased risk for ≥1 AEs compared to AA- (RR = 1.19; 95% CI 1.11-1.27) and NHW- (RR = 1.23; 95% CI 1.15-1.31) patients. The magnitude of effect was similar by cancer type, and in analyses of AA+ with SCT only. Our findings suggest a novel hypothesis for disparities in cancer outcomes.

Dysphagia and Oral Morbidities in Chemoradiation-Treated Head and Neck Cancer Patients.

This study prospectively evaluated relationships between oral morbidities and swallowing ability in head/neck cancer patients following chemoradiation therapy (CRT) and at 3 months following CRT. Thirty patients with confirmed head/neck cancer undergoing chemoradiation were assessed with a battery of swallowing measures and measures of oral morbidities related to chemoradiation (xerostomia, mucositis, pain, taste/smell, oral moisture). All measures were completed at baseline (within the first week of CRT), at 6 weeks (end of treatment), and at 3 months following chemoradiation. Descriptive and univariate statistics were used to depict change over time in swallowing and each oral morbidity. Correlation analyses evaluated relationships between swallowing function and oral morbidities at each time point. Most measures demonstrated significant negative change at 6 weeks with incomplete recovery at 3 months. At 6 weeks, mucositis ratings, xerostomia, and retronasal smell intensity demonstrated significant inverse relationships with swallowing function. In addition, oral moisture levels demonstrated significant positive relationships with swallowing function. At 3 months, mucositis ratings maintained a significant, inverse relationship with swallow function. Taste and both orthonasal and retronasal smell intensity ratings demonstrated inverse relationships with measures of swallow function. Swallow functions and oral morbidities deteriorate significantly following CRT with incomplete recovery at 3 months post treatment. Furthermore, different patterns of relationships between swallow function measures and oral morbidities were obtained at the 6-week versus the 3-month assessment point suggesting that different mechanisms may contribute to the development versus the maintenance of dysphagia over the trajectory of treatment in these patients.

Neuregulin-1 promotes functional improvement by enhancing collateral sprouting in SOD1(G93A) ALS mice and after partial muscle denervation.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration of motoneurons, which is preceded by loss of neuromuscular connections in a "dying back" process. Neuregulin-1 (Nrg1) is a neurotrophic factor essential for the development and maintenance of neuromuscular junctions, and Nrg1 receptor ErbB4 loss-of-function mutations have been reported as causative for ALS. Our main goal was to investigate the role of Nrg1 type I (Nrg1-I) in SOD1(G93A) mice muscles. We overexpressed Nrg1-I by means of an adeno-associated viral (AAV) vector, and investigated its effect by means of neurophysiological techniques assessing neuromuscular function, as well as molecular approaches (RT-PCR, western blot, immunohistochemistry, ELISA) to determine the mechanisms underlying Nrg1-I action. AAV-Nrg1-I intramuscular administration promoted motor axon collateral sprouting by acting on terminal Schwann cells, preventing denervation of the injected muscles through Akt and ERK1/2 pathways. We further used a model of muscle partial denervation by transecting the L4 spinal nerve. AAV-Nrg1-I intramuscular injection enhanced muscle reinnervation by collateral sprouting, whereas administration of lapatinib (ErbB receptor inhibitor) completely blocked it. We demonstrated that Nrg1-I plays a crucial role in the collateral reinnervation process, opening a new window for developing novel ALS therapies for functional recovery rather than preservation.

Mortality risk from comorbidities independent of triple-negative breast cancer status: NCI-SEER-based cohort analysis.

PURPOSE: A comparatively high prevalence of comorbidities among African-American/Blacks (AA/B) has been implicated in disparate survival in breast cancer. There is a scarcity of data, however, if this effect persists when accounting for the adverse triple-negative breast cancer (TNBC) subtype which occurs at threefold the rate in AA/B compared to white breast cancer patients. METHODS: We reviewed charts of 214 white and 202 AA/B breast cancer patients in the NCI-SEER Connecticut Tumor Registry who were diagnosed in 2000-2007. We employed the Charlson Co-Morbidity Index (CCI), a weighted 17-item tool to predict risk of death in cancer populations. Cox survival analyses estimated hazard ratios (HRs) for all-cause mortality in relation to TNBC and CCI adjusting for clinicopathological factors. RESULTS: Among patients with SEER local stage, TNBC increased the risk of death (HR 2.18, 95 % CI 1.14-4.16), which was attenuated when the CCI score was added to the model (Adj. HR 1.50, 95 % CI 0.74-3.01). Conversely, the adverse impact of the CCI score persisted when controlling for TNBC (Adj. HR 1.49, 95 % CI 1.29-1.71; per one point increase). Similar patterns were observed in SEER regional stage, but estimated HRs were lower. AA/B patients with a CCI score of ≥3 had a significantly higher risk of death compared to AA/B patients without comorbidities (Adj. HR 5.65, 95 % CI 2.90-11.02). A lower and nonsignificant effect was observed for whites with a CCI of ≥3 (Adj. HR 1.90, 95 % CI 0.68-5.29). CONCLUSIONS: comorbidities at diagnosis increase risk of death independent of TNBC, and AA/B patients may be disproportionately at risk.

Adverse events in cancer patients with sickle cell trait or disease: case reports.

PURPOSE: Given the relatively high prevalence of sickle cell trait and disease among African Americans and established racial disparities in cancer outcomes, we reviewed the literature regarding adverse events in cancer patients with these hematologic genotypes. Erythrocyte sickling can result from extreme hypoxia and other physiologic stressors, as might occur during cancer therapy. Further, tumoral hypoxia, a poor prognostic and predictive factor, could lead to a cycle of local sickling and increased hypoxia. METHODS: A search of PubMed produced 150 publications, most of which were excluded because of incidental relevance. Eleven case reports of patients diagnosed from 1993 to 2013 were reviewed. RESULTS: Two reports of patients with sickle cell trait describe an abundance of sickled erythrocytes within tumors, and a third report describes sickling-related events requiring multiday hospitalization. Eight reports of patients with sickle cell disease delineated multiorgan failure, vaso-occlusive crises, and rapid renal deterioration. Hypothesized triggers are delayed clearance of anticancer agents attributable to baseline kidney damage, activation of vasoadherent neutrophils from treatment to counter chemotherapy-induced neutropenia, hypoxia from general anesthesia, and intratumoral hypoxia. CONCLUSION: Clinical implications include pretreatment genotyping for prophylaxis, dose adjustment, and enhanced patient monitoring. With the current lack of high-quality evidence, however, the scope of poor outcomes remains unknown.

Secular trends, race, and geographic disparity of early-stage breast cancer incidence: 25 years of surveillance in Connecticut.

OBJECTIVES: We considered changes in the geographic distribution of early stage breast cancer among White and non-White women while secular trends in lifestyle and health care were under way. METHODS: We aggregated tumor registry and census data by age, race, place of residence, and year of diagnosis to evaluate rate variation across Connecticut census tracts between 1985 and 2009. Global and local cluster detection tests were completed. RESULTS: Age-adjusted incidence rates increased by 2.71% and 0.44% per year for White and non-White women, respectively. Significant global clustering was identified during surveillance of these populations, but the elements of clustering differed between groups. Among White women, fewer local clusters were detected after 1985 to 1989, whereas clustering increased over time among non-White women. CONCLUSIONS: Small-area variation of breast cancer incidence rates across time periods proved to be dynamic and race-specific. Incidence rates might have been affected by secular trends in lifestyle or health care. Single cross-sectional analyses might have confused our understanding of disease occurrence by not accounting for the social context in which patient preferences or provider capacity influence the numbers and locations of diagnosed cases. Serial analyses are recommended to identify "hot spots" where persistent geographic disparities in incidence occur.

Outcomes in chronic lymphocytic leukemia patients on novel agents in the US Veterans Health Administration System.

The US veteran population has a high proportion of chronic lymphocytic leukemia (CLL) risk factors. Using the Veterans Health Administration (VHA) population, we conducted a retrospective chart review of 1205 CLL patients who initiated treatment with a novel oral agent. For 1L ibrutinib, 33% (n = 107) discontinued therapy during the study, of which 64% discontinued due to adverse events (AEs). For relapsed/refractory (R/R) ibrutinib, 35% (n = 262) discontinued therapy, of which 63% discontinued due to AEs. For R/R venetoclax, 31% (n = 27) discontinued therapy, of which 41% were due to AEs. For idelalisib, 84% (n = 41) discontinued therapy, of which 54% were due to AEs. This real-world study suggests that AEs play an important role in dose reductions and discontinuations; however, physician inexperience in using these drugs when they were first introduced could be part of what is leading to these negative outcomes.

Who's assessing tobacco use in cancer clinical trials?

INTRODUCTION: Clinical trials that do not collect data on tobacco use/exposure may not adequately assess the efficacy and effectiveness of experimental treatments. METHODS: A cross-sectional study of interventional trials cited on ClinicalTrials.gov was undertaken that inquired of Local Project Directors from Connecticut guiding studies of breast, prostate, or colorectal cancer chemotherapy (N = 68) whether their protocols measured tobacco use by trial participants. Information pertaining to 46 trials (68%) is reported here. All but 1 were multicentered trials enrolling patients around the country. RESULTS: Only 3 trials (7%) reported routine collection of tobacco use information at baseline and no trial reported monitoring tobacco use during treatment follow-up. None of the 3 trials collecting tobacco data reported using exposure information in analysis of treatment effects. Survey respondents suggested that uncertainty about the relevance of tobacco exposure to therapeutic efficacy, ambivalence about how to incorporate such data into analyses, insufficient resources for collecting such information, and uncertainty about the validity of assessment methods might be reasons why tobacco use is not routinely assessed. DISCUSSION: Additional studies that address a fuller range of cancers, therapies, disease states, and clinical environments are needed to fully define the extent of this data lapse. Providing clinicians and trialists with appropriate tools for tobacco use assessment and encouraging them to collect such information about patients during treatment and follow-up may offer a simple cost-effective way to improve the quality and consequences of cancer care for every patient.

Application of a Preventive Training Program Implementation Framework to Youth Soccer and Basketball Organizations.

CONTEXT: Preventive training programs (PTPs) can reduce injury rates and improve neuromuscular control and sport performance. However, PTPs must be implemented correctly and consistently over time for athletes to benefit. Coaches represent the best long-term option for implementing PTPs. Youth athletes are at the optimal age for developing good habits before maturation. Although frameworks have been proposed to guide implementation efforts, little is known regarding the feasibility and real-world context of PTP implementation at the youth sport level. OBJECTIVE: To evaluate the application of the 7-Step framework for promoting implementation of a preseason PTP workshop. DESIGN: Descriptive epidemiology study. SETTING: Youth soccer and basketball organizations. PATIENTS OR OTHER PARTICIPANTS: Organizations with at least 1 team of athletes aged 8 to 14 years were invited to participate in a free preseason coaches' education workshop on PTP implementation. INTERVENTION(S): The 7-Step framework was used to guide PTP education and implementation for each organization. Personnel at organizations that agreed to participate attended a single preseason workshop for coaches. Research staff were available as a resource throughout the season but did not actively implement or monitor the PTPs. MAIN OUTCOME MEASURE(S): Retrospective evaluation of each organization's completion of steps 1 through 5 of the 7-Step framework. RESULTS: A total of 62 youth soccer (n = 40) and basketball (n = 22) organizations were invited to participate. Twelve organizations completed steps 1 through 4 and steps 5a through 5d. The highest drop-off rate occurred during step 1, "Establishing Administrative Support." No organization completed all components of steps 1 through 5. CONCLUSIONS: To better understand how to successfully promote PTP adoption, we must identify the implementation steps that may present the most challenges. Because the highest drop-off rate was seen during the initial step, establishing administrative support and strengthening initial engagement are necessary to improve PTP implementation.

Comparative Validity of the American Speech-Language-Hearing Association's National Outcomes Measurement System, Functional Oral Intake Scale, and G-Codes to Mann Assessment of Swallowing Ability Scores for Dysphagia.

Background The American Speech-Language-Hearing Association (ASHA) advocates using the National Outcomes Measurement System (NOMS) scales to assist speech-language pathologists (SLPs) in the mandated assigning of "functional limitation levels" and G-Code for Medicare Part B claims. Unfortunately, not all SLPs have access to this tool, and it is unclear how other common outcome measurement scales relate to ASHA NOMS or G-Codes. To explore the utility of other scales in reporting Centers for Medicare & Medicaid Services G-Codes, we conducted a comparative validity study comparing ASHA NOMS Dysphagia Scale, Functional Oral Intake Scale (FOIS), and Mann Assessment of Swallowing Ability to G-Codes on a sample of 105 patients who had stroke. Method Nine SLP student researchers trained to criterion on the NOMS and FOIS blindly and independently scored 105 stroke cases with dysphagia de-identified from a past study. Three graduate SLP clinicians independently assigned G-Codes. Data from the student researchers and Mann Assessment of Swallowing Ability scores were compared for admission and discharge from subacute rehabilitation. Analysis included intraclass correlation for reliability, Spearman correlation for comparative validity, and area under the receiver operating characteristic curve to compare the validity and discriminatory utility of measures in classifying dysphagia. Results Strong correlations (> .6) were noted between all measures at baseline, particularly FOIS and NOMS coding ( r = .919). At discharge, superior performance by the FOIS (area under the receiver operating characteristic curve = 0.819) was demonstrated. Code missingness was higher for the NOMS than the other scales. Discussion All 3 clinical dysphagia tools demonstrate acceptable validity in supporting G-Code designation to stroke cases. The FOIS demonstrated superior validity and utility across time points. The NOMS Dysphagia Scale was significantly affected by data missingness due to the multiconstruct nature of the tool.

Is surgery a risk factor for Creutzfeldt-Jakob disease? Outcome variation by control choice and exposure assessments.

OBJECTIVE: To determine whether methodological differences explain divergent results in case-control studies examining surgery as a risk factor for Creutzfeldt-Jakob disease (CJD). METHODS: After case-control studies were systematically identified using PubMed, we performed a homogeneity analysis and applied models to effect sizes (odds ratio [OR] with 95% confidence interval [CI]) using 2 parameters: type of control subject used and consistency of data ascertainment. The hospitals and communities were located in Europe, Japan, and Australia. Patients were CJD case subjects and age- and sex-matched control subjects in the hospital or community. Because of the natural history of the disease, CJD subjects are not considered reliable sources of information for these studies. Therefore, individuals who are considered close to the subjects and who have knowledge of their medical history, including spouses and relatives, are necessarily identified as proxy informants for the surgical record of the case subjects. RESULTS: Overall, the effect sizes lacked homogeneity (P<.0001). Three studies that used control subjects from the community revealed a significantly elevated risk of CJD for patients who underwent surgery (OR, 1.82; 95% CI, 1.41-2.35 [P<.0001]), whereas 3 investigations that used control subjects from the hospital revealed a significantly reduced risk (OR, 0.69; 95% CI, 0.52-0.90 [P=.0069]). Two studies that used proxy informants to acquire information about case subjects and control subjects (consistent ascertainment) found that the risk of CJD was significantly lower in those subjects who underwent surgery (OR, 0.65; 95% CI, 0.48-0.87 [P=.0043]). Conversely, 4 studies in which proxy informants acted only on behalf of case subjects (inconsistent data ascertainment) found a significant positive association between surgery and CJD (OR, 1.67; 95% CI, 1.32-2.12 [P<.0001]). Both models fit the data very well, leaving no remaining variance in effect sizes to explain. CONCLUSION: Variation in the type of control subjects used and in exposure assessment in case-control studies may partially explain conflicting data regarding the association between surgery and CJD. However, there was almost complete confounding of these 2 parameters, making interpretation more difficult. Planning of future investigations must carefully consider these design elements.

Marital status and variability in cortisol excretion in postmenopausal women.

Based on the premise that acute and chronic stresses stimulate and suppress cortisol secretion, respectively, and the hypothesis that marriage provides a buffer to stress, we tested whether extreme values of serum cortisol concentrations would be less likely in married women than in unmarried women. Three hundred women were recruited from two central Connecticut communities. Cortisol was measured in overnight urine samples using liquid chromatography-tandem mass spectrometry. Information on each subject's demographic characteristics, such as income and education level was collected. Mean log urinary cortisol was virtually identical in married and unmarried women, however, as predicted, the variance was significantly larger in the unmarried group (p=0.01). After adjustment for potential confounders, multivariate logistic regression still revealed that absolute deviation of log(10) cortisol from the mean was smaller for married versus unmarried women (p<0.01); deviation from the mean cortisol was also higher for non-working than working women. These results support the idea that marriage and employment reduce the extreme levels of cortisol secretion, and by extension, this may reflect differences in levels of stress in married and in working women compared to unmarried and non-working women.

Service learning within the University of Connecticut Master of Public Health Program.

Since 2005, the University of Connecticut Master of Public Health Program has administered its required service-learning practicum through coordinated activities of second-year students assigned to examine a pressing public health issue in Connecticut. The initiative underscores our program's commitment to preparing students for careers as leaders in applied practice and our emphasis on collaboration. Our thematic approach links content across the core curriculum, provides a venue where students demonstrate mastery of academic principles, and affirms values of public responsibility and common purpose. Projects have focused on public health concerns associated with childhood obesity, health literacy, and living with disabilities. Working together and with community-based preceptors, students estimate service needs, assess available program/service capacity, and recommend policy options. Results are compiled within a written report that accompanies a state legislative hearing. This article presents the rationale and organization of our service-learning practicum, and describes how the experience affects the education and personal growth of students and contributes positively to the community at large.

Kernel density analysis reveals a halo pattern of breast cancer incidence in Connecticut.

Breast cancer (BC) incidence rates in Connecticut are among the highest in the United States, and are unevenly distributed within the state. Our goal was to determine whether artificial light at night (ALAN) played a role. Using BC records obtained from the Connecticut Tumor Registry, we applied the double kernel density (DKD) estimator to produce a continuous relative risk surface of a disease throughout the State. A multi-variate analysis compared DKD and census track estimates with population density, fertility rate, percent of non-white population, population below poverty level, and ALAN levels. The analysis identified a "halo" geographic pattern of BC incidence, with the highest rates of the disease observed at distances 5-15 km from the state's major cities. The "halo" was of high-income communities, with high ALAN, located in suburban fringes of the state's main cities.

Place of residence effect on likelihood of surviving prostate cancer.

PURPOSE: To examine geographic variation in survival time of men diagnosed with prostate cancer, adjusted for patient and disease characteristics. METHOD: Survival times for a geographically referenced database of 27,189 incident prostate cancer cases (ICD-O-2: C61.9) from Connecticut, 1984-1998, were evaluated using a newly developed extension of the spatial scan statistic for survival data. RESULTS: Statewide, median survival time was 4.6 years following diagnosis. Age-adjusted survival times across most locales around Connecticut did not differ markedly from the statewide pattern, but our analysis revealed 3 zones with noteworthy differences. Analysis of survival times adjusted for age as well as tumor grade and stage produced only two locations with significant results, and further adjustment for racial composition of cases yielded only one location with significant distinct (lower) survival times. Among cases within that place, the likelihood of dying was estimated to be 1.39-times greater than that of cases different from those diagnosed elsewhere around the state (p = 0.009). CONCLUSION: The prognosis for men with prostate cancer may differ, in part, by virtue of where they live when diagnosed. Measuring geographic differences in survival time should facilitate the targeting of clinical and ancillary services to persons at high risk of poor outcomes.

The National Board of Public Health Examiners: credentialing public health graduates.

The National Board of Public Health Examiners (NBPHE, the Board) is the result of many years of intense discussion about the importance of credentialing within the public health community. The Board is scheduled to begin credentialing graduates of programs and schools of public health accredited by the Council on Education for Public Health (CEPH) in 2008. Among the many activities currently underway to improve public health practice, the Board views credentialing as one pathway to heighten recognition of public health professionals and increase the overall effectiveness of public health practice. The process underway includes developing, preparing, administering, and evaluating a voluntary certification examination that tests whether graduates of CEPH-accredited schools and programs have mastered the core knowledge and skills relevant to contemporary public health practice. This credentialing initiative is occurring at a time of heightened interest in public health education, and an anticipated rapid turnover in the public health workforce. It is fully anticipated that active discussion about the credentialing process will continue as the Board considers the many aspects of this professional transition. The Board wishes to encourage these discussions and welcomes input on any aspects relating to implementation of the credentialing process.