A phase II trial of docetaxel and erlotinib as first-line therapy for elderly patients with androgen-independent prostate cancer

Background: Docetaxel is the standard first-line agent for the treatment of androgen-independent prostate cancer (AIPC). The combination of docetaxel with molecularly targeted therapies may offer the potential to increase the efficacy and decrease the toxicity of cytotoxic chemotherapy for prostate cancer. Previous studies demonstrate activation of the human epidermal growth factor receptor (EGFR) in prostate cancer. Erlotinib is a specific inhibitor of the tyrosine-kinase activity of EGFR. The goal of this study is to determine the anti-cancer activity docetaxel combined with erlotinib for the treatment of elderly subjects with AIPC. Methods: This is a multi-institutional Phase II study in patients with histologically confirmed adenocarcinoma of the prostate and age [greater than or equal to] 65 years. Patients were requred to have progressive disease despite androgen-deprivation therapy as determined by: (1) measurable lesions on cross-sectional imaging; (2) metastatic disease by radionucleotide bone imaging; or (3) elevated prostate specific antigen (PSA). Treatment cycles consisted of docetaxel 60 mg/m2 IV on day 1 and erlotinib 150 mg PO days 1-21. Patients with responding or stable disease after 9 cycles were eligible to continue on erlotinib alone as maintenance therapy. Results: Characteristics of 22 patients enrolled included: median age 73.5 years (range, 65-80); median Karnofsky Performance Status 90 (range 70-100); median hemoglobin 12.1 g/dl (range, 10.0-14.3); median PSA 218.3 ng/ml (range, 9-5754). A median of 6 treatment cycles were delivered per patient (range 1-17). No objective responses were observed in 8 patients with measurable lesions (0%, 95% CI 0-31%). Bone scan improvement and PSA decline was seen in 1 patient (5%, 95% CI 0.1-25%). Five of 22 patients experienced [greater than or equal to] 50% decline in PSA (23%, 95% CI 8-45%). Hematologic toxicity included grade 3 neutropenia in 9 patients and neutropenic fever in 2 patients. Common non-hematologic toxicities ([greater than or equal to] grade 3) included fatigue, anorexia, and diarrhea. Conclusion: Docetaxel/erlotinib can be delivered safely in elderly patients with AIPC. Anti-cancer disease activity appears generally comparable to docetaxel when used as monotherapy. Hematologic and nonhematologic toxicity may be increased over docetaxel monotherapy. Prospective randomized studies would be required to determine if the toxicity of docetaxel and erlotinib justifies its use in this setting.This study was supported by NIH Prostate SPORE P50 CA92131 to DBA. Phase One Foundation to MEG and DBA

Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth

AbstractErbB2 is a ligand-less member of the ErbB receptor family that functions as a coreceptor with EGFR, ErbB3, and ErbB4. Here, we describe an approach to target ErbB2's role as a coreceptor using a monoclonal antibody, 2C4, which sterically hinders ErbB2's recruitment into ErbB ligand complexes. Inhibition of ligand-dependent ErbB2 signaling by 2C4 occurs in both low- and high-ErbB2-expressing systems. Since the ErbB3 receptor contains an inactive tyrosine kinase domain, 2C4 is very effective in blocking heregulin-mediated ErbB3-ErbB2 signaling. We demonstrate that the in vitro and in vivo growth of several breast and prostate tumor models is inhibited by 2C4 treatment

Impact of Protein Stability, Cellular Localization, and Abundance on Proteomic Detection of Tumor-Derived Proteins in Plasma

Tumor-derived, circulating proteins are potentially useful as biomarkers for detection of cancer, for monitoring of disease progression, regression and recurrence, and for assessment of therapeutic response. Here we interrogated how a protein's stability, cellular localization, and abundance affect its observability in blood by mass-spectrometry-based proteomics techniques. We performed proteomic profiling on tumors and plasma from two different xenograft mouse models. A statistical analysis of this data revealed protein properties indicative of the detection level in plasma. Though 20% of the proteins identified in plasma were tumor-derived, only 5% of the proteins observed in the tumor tissue were found in plasma. Both intracellular and extracellular tumor proteins were observed in plasma; however, after normalizing for tumor abundance, extracellular proteins were seven times more likely to be detected. Although proteins that were more abundant in the tumor were also more likely to be observed in plasma, the relationship was nonlinear: Doubling the spectral count increased detection rate by only 50%. Many secreted proteins, even those with relatively low spectral count, were observed in plasma, but few low abundance intracellular proteins were observed. Proteins predicted to be stable by dipeptide composition were significantly more likely to be identified in plasma than less stable proteins. The number of tryptic peptides in a protein was not significantly related to the chance of a protein being observed in plasma. Quantitative comparison of large versus small tumors revealed that the abundance of proteins in plasma as measured by spectral count was associated with the tumor size, but the relationship was not one-to-one; a 3-fold decrease in tumor size resulted in a 16-fold decrease in protein abundance in plasma. This study provides quantitative support for a tumor-derived marker prioritization strategy that favors secreted and stable proteins over all but the most abundant intracellular proteins

Demineralized Freeze-Dried Bovine Cortical Bone: Its Potential for Guided Bone Regeneration Membrane

Background. Bovine pericardium collagen membrane (BPCM) had been widely used in guided bone regeneration (GBR) whose manufacturing process usually required chemical cross-linking to prolong its biodegradation. However, cross-linking of collagen fibrils was associated with poorer tissue integration and delayed vascular invasion. Objective.This study evaluated the potential of bovine cortical bone collagen membrane for GBR by evaluating its antigenicity potential, cytotoxicity, immune and tissue response, and biodegradation behaviors. Material and Methods. Antigenicity potential of demineralized freeze-dried bovine cortical bone membrane (DFDBCBM) was done with histology-based anticellularity evaluation, while cytotoxicity was analyzed using MTT Assay. Evaluation of immune response, tissue response, and biodegradation was done by randomly implanting DFDBCBM and BPCM in rat’s subcutaneous dorsum. Samples were collected at 2, 5, and 7 days and 7, 14, 21, and 28 days for biocompatibility and tissue response-biodegradation study, respectively. Result. DFDBCBM, histologically, showed no retained cells; however, it showed some level of in vitro cytotoxicity. In vivo study exhibited increased immune response toDFDBCBMin early healing phase; however, normal tissue response and degradation rate were observed up to 4 weeks after DFDBCBM implantation. Conclusion. Demineralized freeze-dried bovine cortical bone membrane showed potential for clinical application; however, it needs to be optimized in its biocompatibility to fulfill all requirements for GBR membrane

A Glycemia Risk Index (GRI) of Hypoglycemia and Hyperglycemia for Continuous Glucose Monitoring Validated by Clinician Ratings

BackgroundA composite metric for the quality of glycemia from continuous glucose monitor (CGM) tracings could be useful for assisting with basic clinical interpretation of CGM data.MethodsWe assembled a data set of 14-day CGM tracings from 225 insulin-treated adults with diabetes. Using a balanced incomplete block design, 330 clinicians who were highly experienced with CGM analysis and interpretation ranked the CGM tracings from best to worst quality of glycemia. We used principal component analysis and multiple regressions to develop a model to predict the clinician ranking based on seven standard metrics in an Ambulatory Glucose Profile: very low-glucose and low-glucose hypoglycemia; very high-glucose and high-glucose hyperglycemia; time in range; mean glucose; and coefficient of variation.ResultsThe analysis showed that clinician rankings depend on two components, one related to hypoglycemia that gives more weight to very low-glucose than to low-glucose and the other related to hyperglycemia that likewise gives greater weight to very high-glucose than to high-glucose. These two components should be calculated and displayed separately, but they can also be combined into a single Glycemia Risk Index (GRI) that corresponds closely to the clinician rankings of the overall quality of glycemia (r = 0.95). The GRI can be displayed graphically on a GRI Grid with the hypoglycemia component on the horizontal axis and the hyperglycemia component on the vertical axis. Diagonal lines divide the graph into five zones (quintiles) corresponding to the best (0th to 20th percentile) to worst (81st to 100th percentile) overall quality of glycemia. The GRI Grid enables users to track sequential changes within an individual over time and compare groups of individuals.ConclusionThe GRI is a single-number summary of the quality of glycemia. Its hypoglycemia and hyperglycemia components provide actionable scores and a graphical display (the GRI Grid) that can be used by clinicians and researchers to determine the glycemic effects of prescribed and investigational treatments

Diabetes with Hypertension as Risk Factors for Adult Dengue Hemorrhagic Fever in a Predominantly Dengue Serotype 2 Epidemic: A Case Control Study

Dengue is a major vector borne disease in the tropical and subtropical regions. An estimated 50 million infections occur per annum in over 100 countries. A severe form of dengue, characterized by bleeding and plasma leakage, known as dengue hemorrhagic fever (DHF) is estimated to occur in 1–5% of hospitalized cases. It can be fatal if unrecognized and not treated in a timely manner. Previous studies had found a number of risk factors for DHF. However, screening and clinical management strategies based on these risk factors may not be applicable to all populations and epidemics of different serotypes. In this study, we found significant association between DHF and diabetes mellitus and diabetes mellitus with hypertension during the epidemic of predominantly serotype 2 (year 2007 and 2008), but not during the epidemic of predominantly serotype 1 (year 2006). Diabetes mellitus and hypertension are prevalent in Singapore and most parts of South-East Asia, where dengue is endemic. Therefore, it is important to address the risk effect of these co-morbidities on the development of DHF so as to reduce morbidity and mortality. Our findings may have impact on screening and clinical management of dengue patients, when confirmed in more studies

Mapping child growth failure across low- and middle-income countries

Child growth failure (CGF), manifested as stunting, wasting, and underweight, is associated with high 5 mortality and increased risks of cognitive, physical, and metabolic impairments. Children in low- and middle-income countries (LMICs) face the highest levels of CGF globally. Here we illustrate national and subnational variation of under-5 CGF indicators across LMICs, providing 2000–2017 annual estimates mapped at a high spatial resolution and aggregated to policy-relevant administrative units and national levels. Despite remarkable declines over the study period, many LMICs remain far from the World Health 10 Organization’s ambitious Global Nutrition Targets to reduce stunting by 40% and wasting to less than 5% by 2025. Large disparities in prevalence and rates of progress exist across regions, countries, and within countries; our maps identify areas where high prevalence persists even within nations otherwise succeeding in reducing overall CGF prevalence. By highlighting where subnational disparities exist and the highest-need populations reside, these geospatial estimates can support policy-makers in planning locally 15 tailored interventions and efficient directing of resources to accelerate progress in reducing CGF and its health implications

Mapping 123 million neonatal, infant and child deaths between 2000 and 2017

Since 2000, many countries have achieved considerable success in improving child survival, but localized progress remains unclear. To inform efforts towards United Nations Sustainable Development Goal 3.2—to end preventable child deaths by 2030—we need consistently estimated data at the subnational level regarding child mortality rates and trends. Here we quantified, for the period 2000–2017, the subnational variation in mortality rates and number of deaths of neonates, infants and children under 5 years of age within 99 low- and middle-income countries using a geostatistical survival model. We estimated that 32% of children under 5 in these countries lived in districts that had attained rates of 25 or fewer child deaths per 1,000 live births by 2017, and that 58% of child deaths between 2000 and 2017 in these countries could have been averted in the absence of geographical inequality. This study enables the identification of high-mortality clusters, patterns of progress and geographical inequalities to inform appropriate investments and implementations that will help to improve the health of all populations