A randomized phase II trial of ridaforolimus,dalotuzumab, and exemestane compared with ridaforolimus and exemestane in patients with advanced breast cancer

Purpose

To evaluate whether adding humanized monoclonal insulin growth factor-1 receptor (IGF-1R) antibody (dalotuzumab) to mammalian target of rapamycin (mTOR) inhibitor (ridaforolimus) plus aromatase inhibitor (exemestane) improves outcomes in patients with estrogen receptor (ER)-positive advanced/metastatic breast cancer.

Methods

This randomized, open-label, phase II trial enrolled 80 postmenopausal women with high-proliferation (Ki67 index staining ≥15%), ER-positive breast cancer that progressed after a non-steroidal aromatase inhibitor (NCT01605396). Randomly assigned patients were given oral ridaforolimus 10 mg QD 5 ×/week, intravenous dalotuzumab 10 mg/kg/week, and oral exemestane 25 mg/day (R/D/E, n = 40), or ridaforolimus 30 mg QD 5 ×/week and exemestane 25 mg/day (R/E; n = 40). Primary end point was progression-free survival (PFS).

Results

Median PFS was 23.3 weeks for R/D/E versus 31.9 weeks for R/E (hazard ratio 1.18; 80% CI 0.81–1.72; P = 0.565). Grade 3–5 adverse events were reported in 67.5% of patients in the R/E arm and 59.0% in the R/D/E arm. Stomatitis (95.0 vs. 76.9%; P = 0.021) and pneumonitis (22.5 vs. 5.1%; P = 0.027) occurred more frequently in the R/E than the R/D/E arm; hyperglycemia (27.5 vs. 28.2%) occurred at a similar rate.

Conclusions

R/D/E did not improve PFS compared with R/E. Because the PFS reported for R/E was similar to that reported for everolimus plus exemestane in patients with advanced breast cancer, it is possible that lower-dose ridaforolimus in the R/D/E arm (from overlapping toxicities with IGF1R inhibitor) contributed to lack of improved PFS.

     

Myocardial Revascularization in Patients With Ischemic Cardiomyopathy: Functional Observations

Objective. A prospective angiographic study was undertaken to investigate, with an objective analysis, the global and regional wall response to myocardial revascularization.

Methods. Thirty-one patients (30 men and 1 woman, mean age, 61 years) with a left ventricular ejection fraction of less than 0.30 were admitted to our institution between 1992 and 1995 for two- or three-vessel coronary artery disease requiring myocardial revascularization. All patients underwent isolated coronary artery bypass grafting and were studied 3 months later with angiography. Preoperative and postoperative wall motion were analyzed using special software that computed a segmental left ventricular ejection fraction, generating a segmental score. Computerized analysis allowed us to distinguish patients with diffuse hypokinesis and a symmetric contraction pattern from patients with akinesis involving at least two segments and an asymmetric contraction pattern.

Results. There were no operative deaths and no patient required intraaortic balloon counterpulsation. One patient had postoperative enzymatic evidence of myocardial infarction. Postoperative angiography showed a graft patency rate of 84%. Global analysis showed a small but significant rise in the left ventricular ejection fraction (0.25 ± 0.51 to 0.31 ± 0.70, p < 0.001) and a fall in the left ventricular end-diastolic pressure (23.7 ± 10 to 16.5 ± 9 mm Hg, p < 0.01). Mean scores always have been lower after the operation than before it, with the best results obtained for the apex and the worst for the anterobasal segment. The group with a symmetric contraction pattern showed a trend toward a better hemodynamic response than the group with an asymmetric contraction pattern. Regression analysis revealed two important predictors of segmental functional improvement: (1) the absence of an echocardiographic scar, and (2) the presence of a collateral circulation.

Conclusions. Coronary artery bypass grafting produced a small but substantial improvement in patients with ischemic cardiomyopathy. The greater benefit occurred in patients with a symmetric contraction pattern. The absence of an echocardiographic scar and the presence of a collateral circulation predicted segmental functional improvement.     

Lack of HCV infection in malignant cells refutes the hypothesis of a direct transforming action of the virus in the pathogenesis of HCV-associated B-cell NHLs

AIMS AND BACKGROUND: Preliminary evidence suggests that hepatitis C virus (HCV) might play a pathogenetic role in autoimmune-related, non-malignant B-cell lymphoproliferation, as well as in a subset of B-cell non-Hodgkin's lymphomas (NHLs). With regard to the mechanism(s) by which HCV might favor B-cell expansion and malignant transformation, most data support an indirect pathogenetic role of the virus as an exogenous trigger. A direct oncogenetic role of HCV by direct cell infection and deregulation has only been hypothesized on the basis of the lymphotropism of the virus. METHODS: In this study we investigated the possible HCV infection of NHL B cells by means of sensitive and quantitative polymerase chain reaction (PCR) on affinity-purified neoplastic cells, and by HCV-specific immunohistochemistry and in situ hybridization. RESULTS: HCV infection of neoplastic B cells was documented in only three cases, namely the low-grade B-cell NHLs that arose in the course of mixed cryoglobulinemia syndrome (MC). HCV infection, below one viral genome per cell, was detectable only by PCR. All the remaining low-grade (one case) and high-grade B-cell NHLs (two cases) were HCV uninfected. Previous immunoglobulin gene analyses were consistent with an antigen-driven B-cell lymphoproliferation in the studied cases. CONCLUSIONS: Overall, our data are consistent with an indirect oncogenetic role of HCV in B-cell lymphomagenesis as an exogenous trigger. Infection of B cells by HCV appears possible in some NHL subsets, but the implications remain unknown.     

Prevalence of methylenetetrahydrofolate reductase 677T and 1298C alleles and folate status: a comparative study in Mexican, West African, and European populations

BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) 677C-->T polymorphism is heterogeneously distributed worldwide, with the highest and lowest frequencies of the T allele in Mexico and Africa, respectively, and a south-to-north gradient in Europe. Distribution of MTHFR 1298A-->C is less well known. It has been hypothesized that 677T frequency could result in part from gene-nutrient interactions. OBJECTIVE: The objective was to compare the association of 677T and 1298C alleles with plasma concentrations of homocysteine, folate, and vitamin B-12 in geographical areas with contrasting 677T allele frequencies. DESIGN: Healthy young adults (n = 1277) were recruited in Mexico City, the West African countries of Bénin and Togo, France, and Sicily (Italy). Homocysteine, folate, and vitamin B-12 were measured in plasma, and MTHFR polymorphisms were measured in genomic DNA. RESULTS: Mexico City and Sicily reported the highest and Bénin and Togo reported the lowest plasma concentrations of folate. Mexico City had the highest 677T allele prevalence and the lowest influence of 677TT genotype on homocysteine, whereas the opposite was observed in Africa. The prevalence of the 1298C allele was lowest in the Mexicans and Africans and highest in the French. The percentage of the 677T genotype was significantly associated with the folate concentrations in 677CC carriers in a univariate analysis (R = 0.976; 95% CI: 0.797, 0.996; P < 0.0002) and in a multiple regression model that included homocysteine, vitamin B-12, and age (P = 0.0002). CONCLUSION: Our data agree with the hypothesis of a gene-nutrient interaction between MTHFR 677C-->T polymorphism and folate status that may confer a selective advantage of TT-homozygous genotype when dietary intake of folate is adequate, at least in the areas studied.     

Urine testing to monitor adherence to TB preventive therapy

This study examined the validity of the Arkansas urine test. One hundred ninety-four adolescents submitted an unannounced urine specimen monthly (for 6 to 8 months). Duplicate specimens were blindly tested with high agreement (kappa >90%). Sensitivity and specificity were estimated. In 68% of test runs, adolescents recalled taking INH within 24 hr of specimen collection. For recall intervals of 24, 48, and 72 hr, sensitivity was 87, 85, and 83%, respectively. Females were less likely to test positive when INH was taken within the previous 24 hr (sensitivity 84 versus 92% males). Specificity was 57, 91, and 95% at 24, 48, and 72 hr, respectively. The Arkansas urine test was practical to use, and results correlated well with self-reported adherence to INH for treatment of latent tuberculosis infection (LTBI), over several months of follow-up. The test may be useful as part of an adherence-monitoring program when used in conjunction with self-reported measures.     

Effects of the angiotensin II receptor blocker losartan on the monocyte expression of biglycan in hypertensive patients

1. Recently, we demonstrated that biglycan (BGN) is increased in circulating monocyte cells from hypertensive patients and that angiotensin (Ang) II is able to increase BGN expression. The present study was designed to investigate the effects of treatment with the angiotensin AT₁ receptor antagonist losartan on monocyte BGN mRNA and protein expression in essential hypertension. 2. One hundred and twenty‐six newly diagnosed hypertensive patients without additional risk factors for atherosclerosis and cardiovascular disease were treated with 100 mg losartan once daily for 6 months. Biglycan mRNA and protein expression was determined in monocytes isolated from peripheral blood before (T₀) and after (T₁) therapy. Plasma levels of interleukin (IL)‐6, tumour necrosis factor (TNF)‐α and high sensitivity C‐reactive protein (hs‐CRP) were also determined. In addition, BGN mRNA and protein expression was determined after the ex vivo addition of 1 μmol/L AngII to monocytes isolated from 20 randomly selected hypertensive patients. 3. Biglycan mRNA and protein expression, blood pressure and plasma levels of fibrinogen, IL‐6, TNF‐α and CRP were significantly lower at T₁ than at T₀. Variations in BGN expression were associated with inflammatory markers, but not directly with blood pressure. In AngII‐stimulated monocytes, BGN mRNA and protein expression was significantly lower at T₁ that at T₀. Moreover, mean BGN mRNA expression in AngII‐stimulated monocytes isolated from losartan‐treated patients was similar to baseline expression in unstimulated monocytes from untreated patients. 4. The results of the present study show that losartan can reduce BGN expression in monocytes from hypertensive patients, without any linear association with blood pressure, suggesting that the effects of AngII on BGN expression in monocytes may be modulated, in part, by an AT₁ receptor blocker.     

Pregnancy and calving rates following transfer of in-vitro-produced river and F1 (river x swamp) buffalo (Bubalus bubalis) embryos in recipients on natural oestrus or synchronised for ovulation

The main objective of this study was to compare pregnancy and calving rates following transfer of in-vitro-produced fresh river and F1 (river x swamp) buffalo embryos in recipients synchronised by Ovsynch protocol or following natural oestrus. River embryos were produced from cumulus-oocyte complexes (COCs) derived by ovum pick up (OPU) on 40 Murrah and Nili-Ravi donor buffaloes over a twice-weekly collection schedule for 120 single OPUs. F1 embryos were produced by fertilisation of swamp COCs recovered from abattoir ovaries coincubated with river sperm cells. Both groups of embryos were produced following the same protocol for in vitro production. With regard to the OPU source of COCs, 923 antral follicles were punctured and 647 COCs were recovered (70%). From 462 selected COCs for IVM, 257 (55.6%) cleaved zygotes were recorded leading to 93 blastocysts (20.1%). In total, 590 swamp COCs were aspirated from abattoir ovaries and 476 were selected for IVM leading to 270 (56.7%) cleaved zygotes and resulting in 137 blastocysts (28.8%). River and F1 embryos were transferred between Day 6 to 7 of in vitro development, corresponding to blastocyst-expanding blastocyst, into F1 recipients synchronised by Ovsynch and swamp buffaloes following natural oestrus, respectively, each of them receiving two embryos. According to palpation per rectum of the ovaries at the time of embryo transfer, 26 of the 47 (55.3%) F1 recipients synchronised by Ovsynch were considered suitable for transfer, resulting in seven pregnancies (26.9%) and four calvings (15.3%) owing to three abortions occurring between 2 and 3 months of pregnancy. In total, 29 swamp recipients following natural oestrus were judged suitable as recipients, resulting in 12 pregnancies (41.4%) and 10 calvings (34.5%) owing to two abortions at 2 and 3 months of gestation respectively. Pregnancy and calving rates following transfer of river and F1 embryos were similar. Likewise, weight at birth of calves derived from transfer of river and F1 embryos was not different: 30.5 +/- 1.4 and 32.9 +/- 2.4 respectively. Pregnancy and calving rates following AI in a group of river and swamp buffaloes considered for reference in this study were similar to recipients carrying in-vitro-produced embryos. Collectively, no apparent postnatal complications were recorded in resulting live calves.     

DNA minor groove binders: an overview on molecular modeling and QSAR approaches

Molecular recognition of DNA by small molecules and proteins is a fundamental problem in structural biology and drug design. Understanding of recognition in both sequence-selective and sequence neutral ways at the level of successful prediction of binding modes and site selectivity will be instrumental for improvements in the design and synthesis of new molecules as potent and selective gene-regulatory drugs. Minor groove is the target of a large number of non-covalent binding agents. DNA binding with specific sequences, mostly AT, takes place by means of a combination of directed hydrogen bonding to base pair edges, van der Waals interactions with the minor groove walls and generalized electrostatic interactions. These factors are also responsible for protein-DNA recognition, and a number of unifying rules governing the interactions have been elucidated although it has been realized that the earlier goal of a simple recognition code between amino acids and bases is not attainable. At present relatively little is understood about the mode of action at the molecular level of the majority of minor groove-interacting drugs, although there is increasing evidence that they may act by directly blocking or inhibiting protein-DNA recognition. The present review has the aim to focus on interactions between minor groove binders and DNA through a variety of techniques that are commonly used to analyze the DNA binding properties of small molecules. In fact in the last years several articles dealing with in silico techniques on DNA minor groove binders (molecular modeling, molecular dynamics, QSAR) have been published. All these studies can be considered a support in defining valid predictive models. For this reason a compendium of all matter could be an useful support for future developments.     

Update on pre-diabetes: Focus on diagnostic criteria and cardiovascular risk

Pre-diabetes, which is typically defined as blood glucose concentrations higher than normal but lower than the diabetes threshold, is a high-risk state for diabetes and cardiovascular disease development. As such, it represents three groups of individuals: Those with impaired fasting glucose (IFG), those with impaired glucose tolerance (IGT) and those with a glycated haemoglobin (HbA_1c) between 39-46 mmol/mol. Several clinical trials have shown the important role of IFG, IGT and HbA_1c-pre-diabetes as predictive tools for the risk of developing type 2 diabetes. Moreover, with regard to cardiovascular disease, pre-diabetes is associated with more advanced vascular damage compared with normoglycaemia, independently of confounding factors. In view of these observations, diagnosis of pre-diabetes is mandatory to prevent or delay the development of the disease and its complications; however, a number of previous studies reported that the concordance between pre-diabetes diagnoses made by IFG, IGT or HbA_1c is scarce and there are conflicting data as to which of these methods best predicts cardiovascular disease. This review highlights recent studies and current controversies in the field. In consideration of the expected increased use of HbA_1c as a screening tool to identify individuals with alteration of glycaemic homeostasis, we focused on the evidence regarding the ability of HbA_1c as a diagnostic tool for pre-diabetes and as a useful marker in identifying patients who have an increased risk for cardiovascular disease. Finally, we reviewed the current evidence regarding non-traditional glycaemic biomarkers and their use as alternatives to or additions to traditional ones.     

Effectiveness of posterior tension band fixation in the thoracolumbar seat-belt type injuries of the young population

The effects of different parameters on the mechanical behaviour of the lumbar spine were in most cases determined deterministically with only one uncertain parameter varied at a time while the others were kept fixed. Thus most parameter combinations were disregarded. The aim of the study was to determine in a probabilistic finite element study how intervertebral rotation, intradiscal pressure, and contact force in the facet joints are affected by the input parameters implant position, implant ball radius, presence of scar tissue, and gap size in the facet joints. An osseoligamentous finite element model of the lumbar spine ranging from L3 vertebra to L5/S1 intervertebral disc was used. An artificial disc with a fixed center of rotation was inserted at level L4/L5. The model was loaded with pure moments of 7.5 Nm to simulate flexion, extension, lateral bending, and axial torsion. In a probabilistic study the implant position in anterior–posterior (ap) and in lateral direction, the radius of the implant ball, and the gap size of the facet joint were varied. After implanting an artificial disc, scar tissue may develop, replacing the anterior longitudinal ligament. Thus presence and absence of scar tissue were also simulated. For each loading case studied, intervertebral rotations, intradiscal pressures and contact forces in the facet joints were calculated for 1,000 randomized input parameter combinations in order to determine the probable range of these output parameters. Intervertebral rotation at implant level varies strongly for different combinations of the input parameters. It is mainly affected by gap size, ap-position and implant ball radius for flexion, by scar tissue and implant ball radius for extension and lateral bending, and by gap size and implant ball radius for axial torsion. For extension, intervertebral rotation at implant level varied between 1.4° and 7.5°. Intradiscal pressure in the adjacent discs is only slightly affected by all input parameters. Contact forces in the facet joints at implant level vary strongly for the different combinations of the input parameters. For flexion, forces are 0 in 63% of the cases, but for small gap sizes and large implant ball radii they reach values of up to 533 N. Similar results are found for extension with a maximum predicted force of 560 N. Here the forces are mainly influenced by gap size, implant ball radius and scar tissue. The forces vary between 0 and 300 N for lateral bending and between 0 and 200 N for axial torsion. The parameters that have the greatest effect in both loading cases are the same as those for extension. Intervertebral rotation and contact force in the facet joints depend strongly on the input parameters studied. The probabilistic study shows a large variation of the results and likelihood of certain values. Clinical studies will be required to show whether or not there is a strong correlation of parameter combinations that cause high facet joint forces and low back pain after total disc replacement.