Persistence to extended adjuvant endocrine therapy following Breast Cancer Index (BCI) testing in women with early-stage hormone receptor-positive (HR +) breast cancer.

PURPOSE: Extending adjuvant endocrine therapy (ET) beyond the standard 5 years offers added protection against late breast cancer recurrences in women with early-stage hormone receptor-positive (HR +) breast cancer. Little is known about treatment persistence to extended ET (EET) and the role that genomic assays may play. In this study, we evaluated persistence to EET in women who had Breast Cancer Index (BCI) testing. METHODS: Women with stage I-III HR + breast cancer who had BCI testing after at least 3.5 years of adjuvant ET and ≥ 7 years of follow-up after diagnosis were included (n = 240). Data on medication persistence was based on prescriptions in the electronic health record. RESULTS: BCI predicted 146 (61%) patients to have low - BCI (H/I)-low - and 94 (39%) patients to have high likelihood of benefit from EET (BCI (H/I)-high). Continuation of ET after BCI occurred in 76 (81%) (H/I)-high and 39 (27%) (H/I)-low patients. Non-persistence rates were 19% in the (H/I)-high and 38% in the (H/I)-low group. The most common reason for non-persistence was intolerable side effects. Patients on EET underwent more DXA bone density scans than those who stopped ET at 5 years (mean 2.09 versus 1.27; p < 0.001). At a median follow-up of 10 years from diagnosis, there were 6 metastatic recurrences. CONCLUSIONS: In patients who continued ET after BCI testing, the rates of persistence to EET were high, particularly in patients with predicted high likelihood of benefit from EET. Use of EET is associated with increased use of DXA scans.

Combined Systemic Disruption of MET and Epidermal Growth Factor Receptor Signaling Causes Liver Failure in Normal Mice.

MET and epidermal growth factor receptor (EGFR) tyrosine kinases are crucial for liver regeneration and normal hepatocyte function. Recently, we demonstrated that in mice, combined inhibition of these two signaling pathways abolished liver regeneration after hepatectomy, with subsequent hepatic failure and death at 15 to 18 days after resection. Morbidity was associated with distinct and specific alterations in important downstream signaling pathways that led to decreased hepatocyte volume, reduced proliferation, and shutdown of many essential hepatocyte functions, such as fatty acid synthesis, urea cycle, and mitochondrial functions. Herein, we explore the role of MET and EGFR signaling in resting mouse livers that are not subjected to hepatectomy. Mice with combined disruption of MET and EGFR signaling were noticeably sick by 10 days and died at 12 to 14 days. Mice with combined disruption of MET and EGFR signaling mice showed decreased liver/body weight ratios, increased apoptosis in nonparenchymal cells, impaired liver metabolic functions, and activation of distinct downstream signaling pathways related to inflammation, cell death, and survival. The present study demonstrates that, in addition to controlling the regenerative response, MET and EGFR synergistically control baseline liver homeostasis in normal mice in such a way that their combined disruption leads to liver failure and death.

Acute Myeloid Leukemia Following Gynecologic Cancer in the Era of Platinum-Based Chemotherapy.

OBJECTIVE: The aim of the present study was to estimate the risk of therapy-related acute myeloid leukemia (t-AML) in patients with gynecologic malignancies receiving chemotherapy using a population-based database. METHODS: The National Cancer Institute's Surveillance, Epidemiology, and End Results database was accessed, and a cohort of women diagnosed with a primary ovarian, uterine, or cervical malignancy between January 1, 1992, and December 31, 2014, who received chemotherapy was selected. Those who subsequently developed AML were identified. Standardized incidence ratio (SIR) with 95% confidence intervals (CIs) and excess risk (ER) per 10,000 persons were calculated. Median overall survival of women with t-AML was calculated following generation of Kaplan-Meier curves. RESULTS: We identified 60,130 women who met the inclusion criteria; 56.4%, 19.4%, and 24.2% were diagnosed with ovarian, cervical, and uterine cancer, respectively. A total of 79 patients (0.13%) developed t-AML. The calculated SIR was 4.41 (95% CI, 3.49-5.50). For women with ovarian, cervical, and uterine cancer, the SIRs were 4.25 (95% CI, 3.13-5.66), 5.33 (95% CI, 2.92-8.95), and 4.26, (95% CI, 2.52-6.73), respectively. The highest risk was observed among women younger than 50 years (SIR, 11.69; 95% CI, 7.56-17.25). Median interval between gynecologic cancer and t-AML diagnosis was 40 months (range, 3-218 months), whereas median OS following the diagnosis of t-AML was 4 months (95% CI, 1.52-6.48 months). CONCLUSIONS: Therapy-related AML following chemotherapy treatment for a gynecologic malignancy is a very rare late treatment-related event associated with a poor prognosis.

Combined systemic elimination of MET and epidermal growth factor receptor signaling completely abolishes liver regeneration and leads to liver decompensation.

Receptor tyrosine kinases MET and epidermal growth factor receptor (EGFR) are critically involved in initiation of liver regeneration. Other cytokines and signaling molecules also participate in the early part of the process. Regeneration employs effective redundancy schemes to compensate for the missing signals. Elimination of any single extracellular signaling pathway only delays but does not abolish the process. Our present study, however, shows that combined systemic elimination of MET and EGFR signaling (MET knockout + EGFR-inhibited mice) abolishes liver regeneration, prevents restoration of liver mass, and leads to liver decompensation. MET knockout or simply EGFR-inhibited mice had distinct and signaling-specific alterations in Ser/Thr phosphorylation of mammalian target of rapamycin, AKT, extracellular signal-regulated kinases 1/2, phosphatase and tensin homolog, adenosine monophosphate-activated protein kinase α, etc. In the combined MET and EGFR signaling elimination of MET knockout + EGFR-inhibited mice, however, alterations dependent on either MET or EGFR combined to create shutdown of many programs vital to hepatocytes. These included decrease in expression of enzymes related to fatty acid metabolism, urea cycle, cell replication, and mitochondrial functions and increase in expression of glycolysis enzymes. There was, however, increased expression of genes of plasma proteins. Hepatocyte average volume decreased to 35% of control, with a proportional decrease in the dimensions of the hepatic lobules. Mice died at 15-18 days after hepatectomy with ascites, increased plasma ammonia, and very small livers. CONCLUSION: MET and EGFR separately control many nonoverlapping signaling endpoints, allowing for compensation when only one of the signals is blocked, though the combined elimination of the signals is not tolerated; the results provide critical new information on interactive MET and EGFR signaling and the contribution of their combined absence to regeneration arrest and liver decompensation. (Hepatology 2016;64:1711-1724).

Experimentally-induced maternal hypothyroidism alters crucial enzyme activities in the frontal cortex and hippocampus of the offspring rat.

Thyroid hormone insufficiency during neurodevelopment can result into significant structural and functional changes within the developing central nervous system (CNS), and is associated with the establishment of serious cognitive impairment and neuropsychiatric symptomatology. The aim of the present study was to shed more light on the effects of gestational and/or lactational maternal exposure to propylthiouracil (PTU)-induced hypothyroidism as a multilevel experimental approach to the study of hypothyroidism-induced changes on crucial brain enzyme activities of 21-day-old Wistar rat offspring in a brain region-specific manner. This experimental approach has been recently developed and characterized by the authors based on neurochemical analyses performed on newborn and 21-day-old rat offspring whole brain homogenates; as a continuum to this effort, the current study focused on two CNS regions of major significance for cognitive development: the frontal cortex and the hippocampus. Maternal exposure to PTU in the drinking water during gestation and/or lactation resulted into changes in the activities of acetylcholinesterase and two important adenosinetriphosphatases (Na(+),K(+)- and Mg(2+)-ATPase), that seemed to take place in a CNS-region-specific manner and that were dependent upon the PTU-exposure timeframe followed. As these findings are analyzed and compared to the available literature, they: (i) highlight the variability involved in the changes of the aforementioned enzymatic parameters in the studied CNS regions (attributed to both the different neuroanatomical composition and the thyroid-hormone-dependent neurodevelopmental growth/differentiation patterns of the latter), (ii) reveal important information with regards to the neurochemical mechanisms that could be involved in the way clinical hypothyroidism could affect optimal neurodevelopment and, ultimately, cognitive function, as well as (iii) underline the need for the adoption of more consistent approaches towards the experimental simulation of congenital and early-age-occurring hypothyroidism.

Exposure to ethanol during neurodevelopment modifies crucial offspring rat brain enzyme activities in a region-specific manner.

The experimental simulation of conditions falling within "the fetal alcohol spectrum disorder" (FASD) requires the maternal exposure to ethanol (EtOH) during crucial neurodevelopmental periods; EtOH has been linked to a number of neurotoxic effects on the fetus, which are dependent upon the extent and the magnitude of the maternal exposure to EtOH and for which very little is known with regard to the exact mechanism(s) involved. The current study has examined the effects of moderate maternal exposure to EtOH (10 % v/v in the drinking water) throughout gestation, or gestation and lactation, on crucial 21-day-old offspring Wistar rat brain parameters, such as the activities of acetylcholinesterase (AChE) and two adenosine triphosphatases (Na(+),K(+)-ATPase and Mg(2+)-ATPase), in major offspring CNS regions (frontal cortex, hippocampus, hypothalamus, cerebellum and pons). The implemented experimental setting has provided a comparative view of the neurotoxic effects of maternal exposure to EtOH between gestation alone and a wider exposure timeframe that better covers the human third trimester-matching CNS neurodevelopment period (gestation and lactation), and has revealed a CNS region-specific susceptibility of the examined crucial neurochemical parameters to the EtOH exposure schemes attempted. Amongst these parameters, of particular importance is the recorded extensive stimulation of Na(+),K(+)-ATPase in the frontal cortex of the EtOH-exposed offspring that seems to be a result of the deleterious effect of EtOH during gestation. Although this stimulation could be inversely related to the observed inhibition of AChE in the same CNS region, its dependency upon the EtOH-induced modulation of other systems of neurotransmission cannot be excluded and must be further clarified in future experimental attempts aiming to simulate and to shed more light on the milder forms of the FASD-related pathophysiology.

Immunotherapy in Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck.

Head and neck cancer is the 6th most common cancer worldwide with the most common histology being squamous cell carcinoma (HNSCC). While the majority of patients present at a stage where curative intent therapy is possible, when patients recur and/or develop metastatic disease, outcomes are generally poor, especially with systemic therapy alone, and they lag behind other solid tumors. Over the last decade immunotherapy has revolutionized the field of oncology, and anti-PD-1-based therapy has changed the standard of care in recurrent/metastatic (R/M) HNSCC as well. With these gains have come new questions to continue to move the field forward. In this review, we discuss the tumor immune microenvironment and predictive biomarkers and current status and future directions for immunotherapy in recurrent/metastatic head and neck cancer.

Von Willebrand disease and gastrointestinal bleeding: A national inpatient sample study.

INTRODUCTION: Gastrointestinal tract bleeding (GIB) is a serious complication of von Willebrand Disease (VWD), but little is known regarding prevalence and risk factors. We, therefore, evaluated correlates of GIB among VWD using a large national database. METHODS: We conducted a retrospective analysis of adult discharges from the National Inpatient Sample (NIS) between 2009 and 2014. International Disease Classification codes were used to identify those with and without VWD with and without GIB. Prevalence estimates were weighted using NIS-provided discharge-level weights to reflect national estimates. Categorical variables were compared by Rao-Scott chi-square test, continuous variables by weighted simple linear regression, and independent factors associated with GIB in VWD were determined by weighted multivariable logistic regression. RESULTS: GIB is more prevalent in VWD, 3.70%, than those without VWD, 1.49%, p < .0001, and is more common in those who are younger, male, or Black than in VWD without GIB, each p < .001. Comorbidities of GIB in VWD include surgery, hypertension, hyperlipidemia, and smoking, each more common than in VWD without GIB, p < .0001. VWD with GIB also have higher length of stay and inpatient mortality, p < .0001. In a multivariable model, variables significantly associated with GIB in VWD were angiodysplasia, diverticulitis, hepatitis C, black race, male gender, and smoking, each p < .001. CONCLUSIONS: GIB is more common in VWD who are young, black, or male, and the most significant predictors of GIB include angiodysplasia, diverticulitis, hepatitis C, and smoking. After a first GIB, such individuals should consider factor prophylaxis to prevent GIB recurrence and associated morbidity.

Prevention and treatment of childhood and adolescent obesity: a systematic review of meta-analyses.

BACKGROUND: The goal of this systematic review is to synthesize the published meta-analyses assessing the role of nutritional, behavioral and physical activity factors/interventions on the prevention or treatment of pediatric and adolescent obesity. METHODS: An online search was conducted in PubMed (end-of-search: September 30, 2015); English-language meta-analyses pooling observational and/or interventional studies examining weight-related indices on children and adolescents were included. RESULTS: Sixty-six meta-analyses corresponding to more than 900,000 children and adolescents were retrieved. The majority of meta-analyses included interventional studies most of which referred to mixed or combined interventions, including components such as diet, physical activity and sedentary behavior reduction. Discrepancies between meta-analyses on observational and interventional studies were noted. Combined interventions including physical activity and nutritional modifications seemed to represent the most effective means for tackling childhood obesity. CONCLUSIONS: Synthesis of interventional or observational evidence may yield discrepant results. The combination of enhanced physical activity and improved nutrition emerged as a promising intervention in the fight against childhood/adolescent obesity. However, further research is needed about the most effective multidimensional prevention strategy.

The Role of Semaphorin 4D in Bone Remodeling and Cancer Metastasis.

Semaphorin 4D (Sema4D; CD100) is a transmembrane homodimer 150-kDa glycoprotein member of the Semaphorin family. Semaphorins were first identified as chemorepellants that guide neural axon growth. Sema4D also possesses immune regulatory activity. Recent data suggest other Sema4D functions: inactivation of platelets, stimulation of angiogenesis, and regulation of bone formation. Sema4D is a coupling factor expressed on osteoclasts that inhibits osteoblast differentiation. Blocking Sema4D may, therefore, be anabolic for bone. Sema4D and its receptor Plexin-B1 are commonly dysregulated in cancers, suggesting roles in cancer progression, invasion, tumor angiogenesis, and skeletal metastasis. This review focuses on Sema4D in bone and cancer biology and the molecular pathways involved, particularly Sema4D-Plexin-B1 signaling crosstalk between cancer cells and the bone marrow microenvironment-pertinent areas since a humanized Sema4D-neutralizing antibody is now in early phase clinical trials in cancers and neurological disorders.

Primary Urinary Tract Lymphoma: Rare but Aggressive.

BACKGROUND: Primary urinary tract lymphoma (PUTL) is an uncommon disease with only a few case reports in the literature. MATERIALS AND METHODS: Information about 1,264 patients diagnosed between 1983 and 2013 with PUTL was extracted from the Surveillance, Epidemiology and End Results database. Kaplan-Meier curves and multivariable regression analysis were used to analyze the survival and identify prognostic factors. A comparison of nodal diffuse large B-cell lymphoma (DLBCL) with PUTL DLBCL was performed. In addition, we compared the characteristics of kidney and bladder lymphoma. RESULTS: PUTL incidence was 1 case/1,000,000 people per year. DLBCL was found to be the predominant histology. Five-year overall survival and cancer-specific survival were 49% and 58%, respectively. DLBCL histology, male gender, stage III-IV disease, and advanced age were found to be poor prognostic factors. Surgery may be beneficial. Urinary tract DLBCL has a worse prognosis than nodal DLBCL. CONCLUSION: To our knowledge, this is the largest population-based study of PUTL in the literature. The survival of patients has not improved in the era of modern therapies therefore new treatments are needed.

Risk Factors for Multiple Myeloma: A Systematic Review of Meta-Analyses.

The epidemiology of multiple myeloma (MM) is an increasingly investigated field, with many controversies. This systematic review aims to synthesize meta-analyses examining risk factors for MM so as to provide a comprehensive, parsimonious summary of the current evidence. Eligible meta-analyses were sought in PubMed adopting a predefined algorithm, without any restriction of publication language; end-of-search date was October 10, 2014. The selection of eligible studies and data extraction were performed by working in pairs, independently and blindly to each other; in case of disagreement, consensus with the whole team was reached. Among the 22 ultimately included meta-analyses, 9 examined occupational factors, 4 assessed aspects of lifestyle (smoking, alcohol, body mass index), 5 evaluated the presence of other diseases, and 4 addressed genetic factors as potential risk factors of MM. A vast compendium of significant associations arose, including farming, occupation as a firefighter, occupation as a hairdresser, exposures to chemicals or pesticides, overweight and obesity, patterns of alcohol intake, pernicious anemia, ankylosing spondylitis, gene promoter methylation, and polymorphisms. In conclusion, MM is a multifactorial disease, encompassing a wide variety of risk factors that span numerous life aspects. Further accumulation of evidence through meta-analyses is anticipated in this rapidly growing field.

Effects of experimentally-induced maternal hypothyroidism on crucial offspring rat brain enzyme activities.

Hypothyroidism is known to exert significant structural and functional changes to the developing central nervous system, and can lead to the establishment of serious mental retardation and neurological problems. The aim of the present study was to shed more light on the effects of gestational and/or lactational maternal exposure to propylthiouracil-induced experimental hypothyroidism on crucial brain enzyme activities of Wistar rat offspring, at two time-points of their lives: at birth (day-1) and at 21 days of age (end of lactation). Under all studied experimental conditions, offspring brain acetylcholinesterase (AChE) activity was found to be significantly decreased due to maternal hypothyroidism, in contrast to the two studied adenosinetriphosphatase (Na(+),K(+)-ATPase and Mg(2+)-ATPase) activities that were only found to be significantly altered right after birth (increased and decreased, respectively, following an exposure to gestational maternal hypothyroidism) and were restored to control levels by the end of lactation. As our findings regarding the pattern of effects that maternal hypothyroidism has on the above-mentioned crucial offspring brain enzyme activities are compared to those reported in the literature, several differences are revealed that could be attributed to both the mode of the experimental simulation approach followed as well as to the time-frames examined. These findings could provide the basis for a debate on the need of a more consistent experimental approach to hypothyroidism during neurodevelopment as well as for a further evaluation of the herein presented and discussed neurochemical (and, ultimately, neurodevelopmental) effects of experimentally-induced maternal hypothyroidism, in a brain region-specific manner.