Cardiac toxicity of trastuzumab in elderly patients with breast cancer

Breast cancer (BC) is diagnosed in ≥ 65 year old women in about half of cases. Experts currently recommend that systemic therapy is offered to elderly patients with BC, if, based on their overall conditions and life expectancy, it can be reasonably anticipated that the benefits will outweigh the risks of treatment. Like for young subjects, the monoclonal antibody against human epidermal growth factor receptor-2 (HER-2), trastuzumab, represents a valid therapeutic option when BC over-expresses this receptor. Unfortunately, administration of trastuzumab is associated with the occurrence of left ventricular dysfunction and chronic heart failure (CHF), possibly because of interference with the homeostatic functions of HER-2 in the heart. Registry-based, retrospective analyses have reported an incidence of CHF around 25% in elderly women receiving trastuzumab compared with 10%–15% in those not given any therapy for BC, and the risk of CHF has been estimated to be two-fold higher in > 60–65 year old trastuzumab users vs. non-users. Extremely advanced age and preexisting cardiac disease have been shown to predispose to trastuzumab cardiotoxicity. Therefore, selection of older patients for treatment with trastuzumab should be primarily based on their general status and the presence of comorbidities; previous chemotherapy, especially with anthracyclines, should be also taken into account. Once therapy has started, efforts should be made to ensure regular cardiac surveillance. The role of selected biomarkers, such as cardiac troponin, or new imaging techniques (three-dimension, tissue Doppler echocardiography, magnetic resonance imaging) is promising, but must be further investigated especially in the elderly. Moreover, additional studies are needed in order to better understand the mechanisms by which trastuzumab affects the old heart.     

Basic fibroblast growth factor: effects on matrix remodeling, receptor expression, and transduction pathway in human periosteal fibroblasts with FGFR2 gene mutation.

The Crouzon syndrome, which is associated with fibroblast growth factor receptor (FGFR2) mutations, is characterized by premature fusion of cranial sutures. We used an in vitro model of cultured periosteal fibroblasts from normal subjects and from Crouzon patients with FGFR2 mutation. We analyzed the matrix turnover rate and the effects of adding FGF2 by evaluating fibronectin synthesis and the activity of some proteolytic enzymes. To assess the role of some FGF signaling molecules involved in FGFR2 regulation, we studied Grb2 tyrosine phosphorylation and the phosphotyrosine proteins associated with Grb2. The iodinate FGF binding assay was performed to quantify FGFR expression. Compared with normal fibroblasts, fibronectin synthesis was decreased in Crouzon fibroblasts, and protease activities in cells and medium were enhanced, suggesting that excess fibronectin catabolism is present. Differences were more marked when FGF2 was added. Very few phosphoproteins were visible in anti-Grb2 immunoprecipitations from Crouzon fibroblasts, which showed a significant increase in the number of high-affinity and low-affinity FGF2 receptors. These results suggest that the abnormal genotype and the Crouzon cellular phenotype are related. To compensate the low levels of tyrosine phosphorylation, Crouzon cells might increase the numbers of FGFR2, thus increasing the cell surface binding sites for FGF2.     

Diagnostic accuracy of myocardial perfusion imaging with single photon emission computed tomography and positron emission tomography: a comparison with coronary angiography

Objective The aim of this study was to compare the diagnostic accuracy of myocardial perfusion imaging (MPI) by positron emission tomography (PET) with the diagnostic accuracy of MPI by single photon emission computed tomography (SPECT) in two comparable patient cohorts, using coronary angiography (CA) as the standard of reference. Methods A “SPECT-group” of 80 patients (15 female, 65 male; mean age 60 ± 9 years) and a “PET-group” of 70 patients (14 female, 56 male; mean age 57 ± 10 years) underwent a one day stress/rest examination either with attenuation-corrected ¹³N-ammonia PET or attenuation-corrected ²⁰¹TlCl SPECT or ^99mTc-hexakis-methoxy-isobutyl-isonitril (MIBI) SPECT. PET and SPECT results were semiquantitatively graded using a 6-segment heart model. All patients underwent CA, and stenoses were graded as a diameter reduction ≥50%. Results Coronary findings between both groups did not significantly differ at CA. For the SPECT-group overall sensitivity and specificity for localisation of stenoses was 77% and 84%. Respective values for the PET-group were 97% and 84%. The specificity of MPI by SPECT in the detection of ischemia was 74% and 91% for MPI by PET. The diagnostic accuracy of MPI improves when the individual coronary dominance and previous coronary revascularisations are taken into account. Conclusion MPI by ¹³N-ammonia PET is more sensitive in the detection and localisation of coronary stenoses, and more specific in the detection of ischemia than MPI by ²⁰¹TlCl/^99mMIBI SPECT.     

What do I do? Developing a competency inventory for postgraduate (residency) program directors

Background: Few new Residency Program Directors (PD) are formally trained for the demands and responsibilities of the leadership aspect of their role. Currently, there are no comprehensive frameworks that describe specific leadership competencies that can inform PD self-reflection or faculty development.

Methods: The authors developed a Postgraduate Program Director Competency Inventory (PPDCI) in order to frame the performance of PDs for a multisource feedback (MSF) program. The development of the PPDCI occurred in five phases which involved: development of an initial inventory, implementation of a key informant survey of national opinion leaders, execution of a validity survey with postgraduate education leaders and committee members and implementation of a further refined inventory with 17 PD and 147 raters as part of a pilot MSF program.

Outcomes: Five distinct domains of leadership competence were identified which included: Communication and relationship management, leadership, professionalism and self-management, environmental engagement, and management skills and knowledge. The content validity of the PPDCI was endorsed by 85% of the key informants. The validity survey indicated strong endorsement of the PPDCI domains and recognition of its utility for both orientation of new PD as well as a frame for self-assessment. The pilot MSF program yielded a further refined and reduced inventory of 26 items of competence as well as recommendations for its utility.

Conclusions: Use of this leadership inventory has the potential to ensure effective leadership of postgraduate programs.     

Accuracy of dual-source CT coronary angiography: first experience in a high pre-test probability population without heart rate control

The aim of this study was to assess the diagnostic accuracy of dual-source computed tomography (DSCT) for evaluation of coronary artery disease (CAD) in a population with extensive coronary calcifications without heart rate control. Thirty patients (24 male, 6 female, mean age 63.1±11.3 years) with a high pre-test probability of CAD underwent DSCT coronary angiography and invasive coronary angiography (ICA) within 14±9 days. No beta-blockers were administered prior to the scan. Two readers independently assessed image quality of all coronary segments with a diameter ≥1.5 mm using a four-point score (1: excellent to 4: not assessable) and qualitatively assessed significant stenoses as narrowing of the luminal diameter >50%. Causes of false-positive (FP) and false-negative (FN) ratings were assigned to calcifications or motion artifacts. ICA was considered the standard of reference. Mean body mass index was 28.3±3.9 kg/m² (range 22.4–36.3 kg/m²), mean heart rate during CT was 70.3±14.2 bpm (range 47–102 bpm), and mean Agatston score was 821±904 (range 0–3,110). Image quality was diagnostic (scores 1–3) in 98.6% (414/420) of segments (mean image quality score 1.68±0.75); six segments in three patients were considered not assessable (1.4%). DSCT correctly identified 54 of 56 significant coronary stenoses. Severe calcifications accounted for false ratings in nine segments (eight FP/one FN) and motion artifacts in two segments (one FP/one FN). Overall sensitivity, specificity, positive and negative predictive value for evaluating CAD were 96.4, 97.5, 85.7, and 99.4%, respectively. First experience indicates that DSCT coronary angiography provides high diagnostic accuracy for assessment of CAD in a high pre-test probability population with extensive coronary calcifications and without heart rate control.     

Decreased intracellular degradation and increased secretion of apo B-100 in Hep G2 cells after inhibition of cholesteryl ester synthesis

Control of apolipoprotein B (apo B) secretion in hepatocytes occurs partly at the post-translational level. The key step in this process appears to be intracellular degradation of newly synthesized apo B. The aim of this paper was to investigate the mechanisms that regulate apo B secretion by Hep G2 cells, in response to the inhibition of Acyl-CoA Acyltransferase (ACAT) by the compound Sandoz 58035 (S-58035). S-58035 (20 μM) reduced cholesteryl ester synthesis from [¹⁴C]oleate by 95%, and increased significantly, in a dose-dependent manner, (2–100 μM) apo B secretion, either in control conditions (from 78±4.3 to 126±6.1 ng apo B-100/mg cell protein/4 h) or upon stimulation of apo B secretion by oleate (from 134±4.23 to 177±4.3 ng apo B/mg cell protein/4 h). This increased secretion of newly synthesized apo B-100 was confirmed by pulse experiments and by gradient ultracentrifugation of the media. Moreover pulse-chase experiments showed that the addition of S-58035 reduced intracellular degradation of apo B-100, both in control conditions and in the presence of oleate. S-58035 (20 μM) did not affect total cellular cholesterol content, but free cholesterol increased with a concomitant decrease of cholesteryl ester (−20%). S-58035 increased cellular triglyceride mass, which was observed in basal conditions (from 12.8±1.09 to 22.7±2.7 μg TG/mg cellular protein) and also in presence of oleate (from 48±0.53 to 59±6.3 μg TG/mg cellular protein). This effect is due to a stimulation of triglyceride synthesis, as determined by incorporation of [³H]glycerol into cellular triglycerides. From these data we conclude that, under our experimental conditions, triglyceride synthesis and/or availability is likely to control intracellular degradation of apo B.     

Retroperitoneal leiomyosarcoma: clinical case

The Authors have reported a case of retroperitoneal leiomyosarcoma. The retroperitoneal localization is quite unusual and early diagnosis is difficult. Only surgery operation and radio-chemotherapy can improve the prognosis. Tumor size is the major prognostic factor.     

Modulation of gastric emptying and gastrointestinal transit in rats through intestinal cannabinoid CB(1) receptors

We studied the delay in gastric emptying and gastrointestinal transit induced by the cannabinoid receptor agonists (+)-WIN 55,212-2 (R(+)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-yl]-(1-naphthalenyl)methanone mesylate) and CP 55,940 ((-)-cis-3[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol), as prevented by the selective cannabinoid CB(1)-receptor antagonist SR141716 ((N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide)) in rats after systemic or central drug administration. Oral SR141716 showed comparable potency (ID(50) range 1.0-3.9 mg/kg) in antagonizing gastric emptying and gastrointestinal transit delay by (+)-WIN 55,212-2 or CP 55,940. Gastric emptying and gastrointestinal transit delay after intracerebroventricular (i.c.v.) (+)-WIN 55,212-2 was prevented by oral or i.c.v. SR141716, but i.c.v. SR141716 did not significantly reduce the effect of i.p. (+)-WIN 55,212-2. Pertussis toxin prevented the delaying action of i.c.v. (+)-WIN 55,212-2 on both gastric emptying and gastrointestinal transit, but had no effect on (+)-WIN 55,212-2 i.p. These findings are consistent with a primary role of peripheral cannabinoid CB(1) receptor mechanisms in gastrointestinal transit delay by specific agonists.     

Parenchymal sparing operations for bronchogenic carcinoma

By the end of the 1950s, the principles of tracheobronchial and pulmonary artery (PA) reconstruction had been established, and their successful clinical application had taken place. It was not until very recently, however, that these techniques aroused widespread interest among thoracic surgeons as a means to achieve complete cancer resection while preserving functioning lung parenchyma. At the present time, sleeve resection of the bronchus and/or PA has a definite role in the surgical management of lung cancer. Growing interest in this field is evidenced by an increasing number of technical variations intended to adapt the basic technique to the different anatomical settings. Also pitfalls, complications, and their prevention and treatment are being extensively described. Last but not least, functional and oncological long-term results, comparing favorably with those of more extended resections, are being reported by many groups. This demonstrates that sleeve lobectomy is no longer reserved only for particularly skillful surgeons. Sleeve lobectomy has achieved its rightful position among the techniques commonly used in thoracic surgery after 40 years of improving understanding and alternating enthusiasm and legitimate doubts.