Targeting the subtypes of breast cancer: rethinking investigational drugs

INTRODUCTION: The choice of adjuvant treatments for women with breast cancer is based on several features that take into account the heterogeneity of the disease. Questions raised during the decision process include the following: i) What leads to the use of endocrine therapy? ii) What leads to the use of anti-HER2 therapy? iii) What justifies the use of chemotherapy? AREAS COVERED: Choices of adjuvant treatment are based on parameters defined by molecular characterization of breast cancer subtypes or by approximations to this classification using traditional clinical-pathological features. Clinicians should consider cases within the various distinct subpopulation in order to properly select the most 'personalized' adjuvant therapeutic approach. Sensitivity to chemotherapy and/or targeted agents in subtypes of breast cancers are predictable based on gene pathway alterations and associated gene products. This review covers several clinical data on several investigational agents for early-stage breast cancer molecular subtypes. We selected from literature data prospective Phase I, II and III clinical trials of chemotherapy (weekly or daily schedules), including indicators of activity and toxicity and data on survival/mortality. EXPERT OPINION: The future of many investigational therapeutics in breast cancer is linked to our ability to identify the most druggable target in each subtype.     

Use of non-steroidal anti-inflammatory drugs in pregnancy: impact on the fetus and newborn

Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed in pregnancy to treat fever, pain and inflammation. Indications for chronic use of these agents during pregnancy are inflammatory bowel or chronic rheumatic diseases. Since the seventies, NSAIDs have been used as effective tocolytic agents: indomethacin has been the reference drug, delaying delivery for at least 48 hours and up to 7-10 days. Additionally, self-medication with NSAIDs is practiced by pregnant women. NSAIDs given to pregnant women cross the placenta and may cause embryo-fetal and neonatal adverse effects, depending on the type of agent, the dose and duration of therapy, the period of gestation, and the time elapsed between maternal NSAID administration and delivery. These effects derive from the action mechanisms of NSAIDs (mainly inhibition of prostanoid activity) and from the physiological changes in drug pharmacokinetics occurring during pregnancy. Increased risks of miscarriage and malformations are associated with NSAID use in early pregnancy. Conversely, exposure to NSAIDs after 30 weeks' gestation is associated with an increased risk of premature closure of the fetal ductus arteriosus and oligohydramnios. Fetal and neonatal adverse effects affecting the brain, kidney, lung, skeleton, gastrointestinal tract and cardiovascular system have also been reported after prenatal exposure to NSAIDs. NSAIDs should be given in pregnancy only if the maternal benefits outweigh the potential fetal risks, at the lowest effective dose and for the shortest duration possible. This article discusses in detail the placental transfer and metabolism of NSAIDs, and the adverse impact of prenatal NSAID exposure on the offspring.     

HE4 and epithelial ovarian cancer: comparison and clinical evaluation of two immunoassays and a combination algorithm

BackgroundTwo commercial immunoassays for HE4 have been compared and the diagnostic accuracy of HE4, CA 125 and the combinatory ROMA algorithm for epithelial ovarian cancer (EOC) has been evaluated.MethodsHE4 and CA125 were measured on sera obtained from 259 women (73 healthy, 90 with benign ovarian or adnexal diseases, 96 with EOC). The ARCHITECT CMIA HE4 assay was compared with the Fujirebio EIA HE4, and the risk for EOC by the combinatory ROMA algorithm (HE4 + CA 125) was assessed with both HE4 assays.ResultsThe CMIA HE4 assay showed a good linearity (r > 0.9998) and precision (interassay and total CVs < 4%). The correlation with EIA HE4 was linear (r = 0.994), with an average bias of 0.4%. By ROC curve analysis, the sensitivity for EOC at a fixed specificity of 90%, 95% and 99% was 89.6%, 84.4% and 79.2% by CMIA HE4, 84.4%, 83.3% and 79.2% by EIA HE4, 86.5%, 76.0% and 59.4% by CMIA CA125. The accuracy of the ROMA algorithm determined by CMIA or EIA HE4 was very similar (AUC 87.1% vs. 87.6%; p = n.s.) and greater in menopause.ConclusionsThe two HE4 assays showed a good correlation and similar clinical value, with a greater precision for CMIA. HE4 was more specific and accurate than CA125, supporting its use in addition to clinical and imaging criteria for the discrimination of benign from malignant ovarian lesions. The ROMA algorithm showed a good accuracy for discriminating women at high risk for EOC.     

A follow‐up case–control association study of tractable (druggable) genes in recurrent major depression

The High‐Throughput Disease‐specific target Identification Program (HiTDIP) aimed to study case–control association samples for 18 common diseases. Here we present the results of a follow‐up case–control association study of HiTDIP in major depressive disorder (MDD). The HiTDIP in MDD was conducted in a sample of 974 cases of recurrent MDD of white German origin collected at the Max‐Planck Institute (MP‐GSK) and 968 ethnically matched controls screened for lifetime absence of depression. Six genes were identified as of interest for a follow‐up, based on the strength of the association and based on the interest as potential candidate target for developing new treatment for depression: Solute Carrier Family 4 Member 10 (SLC4A10), Dipeptidyl Peptidase IV (DPP4), Dopamine Receptor D3 (DRD3), Zinc Finger Protein 80 (ZNF80), Nitric Oxide Synthase 2A (NOS2A) and Peroxisome Proliferator‐Activated Receptor‐Gamma, Coactivator 1, Alpha (PPARGC1A). Within the current study, we attempted to follow‐up these findings in a sample from the UK, the Depression Case Control (DeCC) sample consisting of 1,196 cases and 842 screened controls, phenotyped using exactly the same methods as the MP‐GSK sample. Performing Cochran–Mantel–Haenzel statistics to test for genotypic and/or allelic differences between the DeCC and MP‐GSK samples, we found no significant differences, thus being able to combine the two samples for association testing. In the combined sample of 2,170 MDD cases and 1,810 controls, there were positive findings in the Nitric Oxide Synthase 2A (NOS2A) gene both using single SNP analysis and haplotype analysis. © 2011 Wiley‐Liss, Inc.     

Prognostic value of extravascular lung water index in critically ill children with acute respiratory failure

Purpose

In critically ill adults, a reduction in the extravascular lung water index (EVLWi) decreases time on mechanical ventilation and improves survival. The purpose of this study is to assess the prognostic value of EVLWi in critically ill children with acute respiratory failure and investigate its relationships with PaO₂, PaO₂/FiO₂ ratio, A-aDO₂, oxygenation index (OI), mean airway pressure, cardiac index, pulmonary permeability, and percent fluid overload.

Methods

Twenty-seven children admitted to PICU with acute respiratory failure received volumetric hemodynamic and blood gas monitoring following initial stabilization and every 4?h thereafter, until discharge from PICU or death. All patients are grouped in two categories: nonsurvivors and survivors.

Results

Children with a fatal outcome had higher values of EVLWi on admission to PICU, as well as higher A-aDO₂ and OI, and lower PaO₂ and PaO₂/FIO₂ ratio. After 24?h EVLWi decreased significantly only in survivors. As a survival indicator, EVLWi has good sensitivity and good specificity. Changes in EVLWi, OI, and mean airway pressure had a time-dependent influence on survival that proved significant according to the Cox test. Survivors spent fewer hours on mechanical ventilation. We detected a correlation of EVLWi with percent fluid overload and pulmonary permeability.

Conclusions

Like OI and mean airway pressure, EVLWi on admission to PICU is predictive of survival and of time needed on mechanical ventilation.     

The Italian Registry of Therapeutic Apheresis: granulocyte-monocyte apheresis in the treatment of inflammatory bowel disease. A multicentric study

Leukocytes are thought to play an important role in the pathogenesis of inflammatory bowel diseases; granulocyte-monocyte adsorptive (GMA) apheresis, an extracorporeal technique aimed at removing activated circulating leukocytes from the blood, may represent a safe and effective therapeutic tool in these patients. The Italian Registry of Therapeutic Apheresis performed an observational, multicentric study involving 24 Gastroenterology Units. In this study, laboratory data and clinical outcomes of 230 patients (148 males, mean age 43.5 years) affected with ulcerative colitis (UC, n = 194) or Crohn's disease (CD, n = 36) who underwent one or more cycles of GMA were analyzed. Each cycle consisted of five GMA treatments. The patients were followed up for a mean of 8.7 (min. 3 to max. 12) months. At 3 months, positive outcome was achieved in 77.7% of UC patients (72.0% remission, 5.7% clinical response) and 61.3% of CD patients (54.8% remission, 6.5% clinical response). The cumulative proportion of positive outcome at 12 months was 87.1% for UC patients (83.7% remission, 3.4% clinical response) and 77.4% for CD patients (74.2% remission, 3.2% clinical response). No single clinical or laboratory parameter among those analyzed (age, sex, disease characteristics, history of smoking, medication history, baseline values of clinical activity index (CAI)/Crohn's disease activity index (CDAI), hemoglobin, white blood cells count, and erythrocyte sedimentation rate) was independently associated with clinical outcome. The procedure was well tolerated with no significant adverse effects registered.     

A study on erm(B)-mediated MLS resistance in Streptococcus pyogenes clinical isolates

The constitutive or inducible macrolide-lincosamide-streptogramin (MLS) phenotype of 30 erm(B)-positive Streptococcus pyogenes isolates was determined by different methods and under various growth conditions and correlated to the sequence of the 5'-untranslated regions of erm(B). The MLS phenotype of one-third of the isolates could not be classified. In liquid medium, some of these isolates responded to induction only during the logarithmic phase of growth, while others expressed clindamycin resistance even under noninducing conditions. By increasing the growth rate, we observed a shift from a constitutive towards an inducible pattern of resistance. All data were confirmed by analysis of the 23S rRNA methylation level. The erm(B)-5'-untranslated region was 99% similar in sequence. In erm(B)-positive S. pyogenes, the MLS phenotype is strongly influenced by culture conditions and control of its expression does not depend exclusively on the sequence of the erm(B)-5'-untranslated region.     

Troubleshooting fine-tuning procedures for qPCR system design

Quantitative real-time PCR (qPCR) has been improved and optimized over the past decade for a wide range of applications. Design of primers and probes is one of the crucial steps to obtain high system efficiency of qPCR since design pitfalls influence negatively amplification performances. We report the results of some experiments. First, we demonstrate the utility of optimal primer design and concentration in PCR by constructing suboptimal primers, for instance with hairpin and primer-dimers secondarystructures, and quantifying the decrease in efficiency of amplification. Second, we show the adverse effects of the target sequence harboring stable secondary structures on the primer binding sites. Finally, we let see that the mere use of probe-based detection is not enough to ensure robustness of qPCR data, because the eventual detrimental products generated by primers not well designed may influence in any case the PCR efficiency.