Patients' preference of trastuzumab administration (subcutaneous versus intravenous) in HER2-positive metastatic breast cancer: Results of the randomised MetaspHer study.

HannaH (NCT00950300) and PrefHer (NCT01401166) studies validated the subcutaneous (H-s.c.) formulation of trastuzumab as effective and safe as intravenous (H-i.v.) and highly preferred by patients in early breast cancer. The present randomised MetaspHer trial (NCT01810393) is the first study assessing patient's preference in metastatic setting. METHODS: Patients with HER2-positive metastatic breast cancer who completed a first line chemotherapy with trastuzumab and achieved a long-term response lasting more than 3 years were randomised to receive 3 cycles of 600-mg fixed-dose adjuvant H-s.c., followed by 3 cycles of standard H-i.v., or the reverse sequence. Primary end-point was overall preference for H-s.c. or H-i.v. at cycle six, assessed by Patient Preference Questionnaire (PPQ). Secondary end-points included healthcare professional (HCP) satisfaction; safety and tolerability; quality of life. RESULTS: Hundred and thirteen patients were randomised and treated. H-s.c. was preferred by 79/92 evaluable intent-to-treat patients (85.9%, 95% confidence interval [CI; 78.8-93.0]; p < 0.001), 13/92 preferred H-i.v. (14.1%, 95% CI [7.0-21.3]). HCPs were most satisfied with H-s.c. (56/88 available data, 63.6%, [53.6-73.7]). On the safety population, adverse events occurred in 73 (67.6%) and 49 (44.1%) patients during the H-s.c. and H-i.v. periods, respectively; 7 (6.5%) and 4 (3.6%) were grade ≥ III, 3 (2.8%) and 2 (1.8%) were serious. CONCLUSION: The safety was consistent with the known H-i.v. and H-s.c. profiles without safety concern raised. Definitively, patients preferred H-s.c. as reported in early stage by PrefHer study.

[A fetal soft marker in obstetric ultrasonography: single umbilical artery]. / Un fetal soft marker nell' ultrasonografia ostetrica: l'arteria ombelicale unica.

The recent advancement in the field of ultrasonography allows for the prenatal precocious diagnosis of an ever increasing number of congenital defects found in various areas of the foetal body. These phenotype variants (markers) and/or morphological anomalies reveal in the majority of cases of a foetus with chromosome defects. They represent ''alarm bells'' that intrigue us to uncover any average case with more tests. It is for this that many more efforts are made to identify echographical markers which allow us to select among the pregnant women those that are not at risk and to advise those that may be of the existence of a specific cytogenetic test. One of these markers is actually represented by the single umbilical artery. This anomaly is made up of the presence of only two vessels (an artery and a vein) at the level of the umbilical cord, and its lack of an artery. The clinical meaning of this pathology is not yet completely known today. Often, in fact, when isolated, it is not associated with a chromosome defect and to other foetal pathologies. When, however, it is presented as associated to other soft markers or other structural anomalies, the risk of a chromosome defect is notably higher.

Systemic cytokine levels and the effects of etanercept in TNF receptor-associated periodic syndrome (TRAPS) involving a C33Y mutation in TNFRSF1A.

OBJECTIVE: To investigate the levels of the pro-inflammatory cytokines IL-6, TNF-alpha, IL-1beta, IL-8, IL-10 and IL-12p70 in the plasma of patients with TNF receptor-associated periodic syndrome (TRAPS) in relation to CRP levels and treatment with etanercept. METHODS: Cytokine concentrations were measured in sequential plasma samples obtained from eight patients with a C33Y mutation in TNFRSF1A and diagnosed with TRAPS, using cytokine bead array. The TRAPS samples were compared with samples from normal controls and rheumatoid arthritis patients. RESULTS: Levels of IL-6 were significantly elevated in C33Y TRAPS patients and these correlated with CRP levels in some of the patients. IL-8 levels were also significantly elevated in the TRAPS patients. However, neither TNF-alpha nor IL-1beta demonstrated a similar increase. This differed from the patients with rheumatoid arthritis, for whom levels of IL-6, IL-8, TNF-alpha, IL-1beta and IL-10 were significantly elevated. The levels of detectable TNF-alpha in the TRAPS patients' plasma were elevated during etanercept treatment. CONCLUSIONS: The cytokine profile of C33Y TRAPS differs from that of a typical autoimmune inflammatory condition such as rheumatoid arthritis, as only IL-6 and IL-8 were elevated in C33Y TRAPS patients, as distinct from a generalized elevation of pro-inflammatory cytokines. However, only some of the C33Y patients tested showed a relationship between elevated IL-6 and CRP. This is consistent with clinical observations that there is marked heterogeneity between individuals with TRAPS, including those in the same family cohort. Although etanercept has a therapeutic effect in some TRAPS patients, it induces increased plasma concentrations of TNF-alpha, possibly by increasing TNF-alpha stability.

Citizens and family doctors facing awareness and management of traditional cardiovascular risk factors: results from the Global Cardiovascular Risk Reduction Project (Help Your Heart Stay Young Study).

BACKGROUND AND AIM: The numerous guidelines and multiple approaches to managing cardiovascular risk factors have reduced the number of fatal events but not the incidence of cardiovascular disease (CVD). One rarely explored aspect is the extent to which individuals perceive their own risk in relation to their education and history of CVD. Furthermore, Italy has a State-based Health System, in which family doctors (FDs) may be an extremely useful and relatively low cost resource for risk management, but the degree of their involvement in individual CVD risk management has not been previously assessed. METHODS AND RESULTS: The Department of Clinical and Experimental Medicine of Federico II University, Naples, Italy, and the Neapolitan Section of the Italian Society of Family Doctors (SIMG), developed an epidemiological survey to evaluate the level and awareness of CVD risk in subjects in the urban area of Naples, and the degree of involvement of FDs in CVD risk management. During a period of a few months, the subjects who visited their FDs were invited to respond to a standard self-explanatory questionnaire, and the FDs were required to provide quantitative information concerning the CVD risk factors of each enrolled subject from their databases in order to assess global CVD risk. The data included cholesterol and blood pressure (BP) levels, and had to be collected within six months of the visit; if the date were missing, the fact was recorded. The present analysis was based on data concerning the 5,687 subjects who had entered the study by January 2002, 7.6% of whom reported CVD (myocardial infarction (MI), stroke, angina, cerebral transient ischemic attack: CD+) and 92.4% did not (CVD-). MI was the most frequent CVD, and 18% of the CVD+ cases reported more than one non-fatal cardiovascular event. On average, the CVD+ subjects were older and more often men. After adjusting for age and FD, they also had a higher body mass index (BMI) and prevalence of obesity, higher self-reported BP, a lower education level, and more often referred high cholesterol levels, hypertension and diabetes. On the contrary, the proportion of smokers was higher in the CVD- group. Among the subjects who declared that they did not have a high cholesterol level, 11% reported recent values of > 200 mg/dL. The FDs of 36% of the cases were unable to assess the individual global CV risk level using quantitative data from their electronic databases. The most frequently missing information was the level of total cholesterol. Missing data were more frequent in the CVD- than the CVD+ subjects, regardless of age and FD. CONCLUSIONS: The results of our study suggest that the awareness of CVD risk among subjects is somewhat vague. The FDs were generally able to provide a quantitative assessment of CVD risk in their patients. CVD risk prevention programmes may be more successful if they stress knowledge and awareness in the population, and stimulate FDs to undertake more stringent quantitative assessments of CVD risk factors.

From meaning to meaning: the influence of translation techniques on non-English focus group research.

Language translation techniques are at the core of many cross-cultural qualitative research projects. The purpose of this article is to examine the impact of translation techniques on the collection and interpretation of non-English to English qualitative data and, in particular, on focus-group data collection and analysis. The goal is to offer suggestions that will minimize potential threats to validity. This article includes a working definition of translation, a discussion of issues related to translation in quantitative research, a discussion of how translation issues differ in focus group research, evaluation criteria for translators and interpreters, and an example of translation techniques used in a research study of perimenopausal Hispanic women.

Out-of-hospital cardiac arrest in a child without overt cardiac disease: emergency department management.

This case report describes the successful resuscitation of a 7-year-old girl who had no previous history of cardiac disease other than one episode of syncope. She developed ventricular fibrillation for 10 min. External chest compressions, early defibrillation and orotracheal intubation were used with a successful outcome.

Inappropriate left ventricular mass in normotensive and hypertensive patients.

We evaluated cardiovascular features of normotensive and hypertensive adults with left ventricular (LV) mass values exceeding levels predicted for given stroke work, gender, and height, termed "inappropriate" LV mass. Inappropriate LV mass is associated with overweight, concentric LV geometry, and low myocardial systolic function not only in hypertensive subjects, but also in normotensive subjects.

Endogenous tissue factor pathway inhibitor modulates thrombus formation in an in vivo model of rabbit carotid artery stenosis and endothelial injury.

BACKGROUND: Tissue factor pathway inhibitor (TFPI) is the sole known inhibitor of the extrinsic coagulation pathway of physiological importance; however, its role in modulating thrombosis in vivo is still unclear. METHODS AND RESULTS: Intravascular thrombosis was initiated by placing an external constrictor around endothelially injured rabbit carotid arteries (n=10). Carotid blood flow velocity was measured by a Doppler flow probe. After placement of the constrictor, cyclic flow reductions (CFRs), due to recurrent thrombosis, developed at the site of stenosis. Transstenotic TFPI plasma activity was measured in blood samples before induction of CFRs and after 30, 60, and 180 minutes of CFRs. TFPI plasma activity distal to the site of thrombosis was significantly lower than the corresponding proximal values at 30, 60, and 180 minutes of CFRs. In addition, a progressive decrease in TFPI plasma activity was observed in both the proximal and the distal samples, indicating consumption of TFPI during thrombus formation. In 10 additional rabbits, CFRs were abolished by administration of aspirin (10 mg/kg). In the animals in which aspirin abolished CFRs, endogenous TFPI was depleted by a bolus of a polyclonal antibody against rabbit TFPI, and the effects on restoration of CFRs were monitored. In 5 of 6 animals in which aspirin abolished CFRs, depletion of endogenous TFPI activity caused full restoration of CFRs. CONCLUSIONS: The data of the present study support the involvement of endogenous TFPI in the process of thrombus formation in vivo and its active role in modulating arterial thrombosis.

Marginalized women's comparisons of their hospital and freestanding birth center experiences: a contrast of inner-city birthing systems.

The process of birth provides a structure around which social and cultural forces guide its expression. These social and cultural forces reflect the organization of power in a society while creating the potential for diversity in birth beliefs, practices, and experiences. In this article, marginalized women contrast their experiences in the cultures of two divergent birth systems: the technocratic hospital system and a freestanding midwifery managed birth center system. The women in this study come from many different cultures, yet they share a common desire to (a) control the birth environment, (b) establish supportive interpersonal connections with providers, (c) have a safe birth, and (d) be treated with dignity and respect. However, the descriptions in this article illustrate the gender, race, and class power inequities experienced when technocratic cultural forces conflicted with oppressed women's basic needs for respect and control.

Ultrasound-fluoroscopy guided access to the intrarenal excretory system.

The access to the collecting system can be performed under fluoroscopy computerized tomography, ultrasonographic, mixed ultrasonographic and fluoroscopic guidance. In this paper the creation of a percutaneous transparenchymal ultrasound-fluoroscopy guided access to the intrarenal collecting system completely performed by urologist for different purposes is presented. In five years 297 patients underwent 330 percutaneous kidney accesses to perform derivative nephrostomies (217 pts), percutaneous nephrolithotomies (37 pts), antegrade ureteral manoeuvres (34 pts), antegrade endopyelotomies (7 pts), transitional cell carcinoma of the upper tract resection (2 pts). 11 patients out of these had a percutaneous kidney access in a transplanted kidney. The percutaneous access was successful in 98% of the attemps. A posterior calyx of the lower group (74%), of the medium group (25%) or of the upper group (1%) was accessed. In 73 accesses the mean target calyx diameter was 12.8 mm (range 5-45 mm), the mean operative time 5.4 minutes and the mean fluoroscopy time 5.1 seconds. In 84.5% of the patients the access was performed under local anesthesia when a dilation of the tract was not required. Gross haematuria was observed in 3.9% of the accesses and an arterial lesion treated by embolization in 0.9% of the accesses. Blood transfusion was required in 0.3% of the patients. The ultrasound-fluoroscopy guided access is at least as precise as the fluoroscopy guided one moreover it makes the procedure less invasive and it makes more precise the surgical planning.

Evaluation of urinary level of NMP22 as a diagnostic marker for stage pTa-pT1 bladder cancer: comparison with urinary cytology and BTA test.

BACKGROUND: In the present study we compared the clinical value of two new specific tests for transitional cell carcinoma, urinary nuclear matrix protein (NMP22) levels and bladder tumor antigen (BTA) test, with that of urinary cytology in the follow-up of patients with superficial bladder cancer. MATERIALS AND METHODS: Hundred and five bladder cancer patients were recruited: 30 stage pTa and 45 stage pT1 (group A), and 30 with a history of bladder cancer but no recurrence at the time of the study (group B). Urine samples were collected before any instrumental manipulation of the genitourinary tract. All patients were negative for urinary tract infections at conventional urine analysis. RESULTS: NMP22 at a cutoff value of 6 U/ml showed a sensitivity of 83.3% in pTa cases and 97.7% in pT1 cases, with a false-positive rate of 23.3%. The BTA test was positive in 26.6% of patients with cancer stage pTa and in 66.6% of pT1 stage, with 30% false-positives in the non-neoplastic group. Urinary cytology, performed on three consecutive samples, was positive in 20% of patients with cancer stage pTa and in 64.4% of pT1 stage and did not show any false-positive cases. Stratifying the neoplastic patients according to lesion grade, NMP22 (at a cutoff value of 6 U/ml) was positive in 86.2% of G1, 97.2% of G2 and 90% of G3. BTA was positive in 37.9, 52.7 and 70% of G1, G2 and G3, respectively, while urinary cytology was positive in 37.9, 44.4 and 80%.

Toxicity of dopamine and dopaminochrome on cultured cells.

Cultured rat fibroblasts, monkey kidney tumor cells (line Vero) and murine neuroblastoma cells were exposed to dopamine or dopaminochrome in the presence and absence of ascorbic acid. Ascorbic acid is able to potentiate the toxicity of both dopamine and dopaminochrome for all the tested cells. The toxicity of dopaminochrome was higher than that of dopamine. There is a correlation between toxicity and levels of bioreductive defenses of the cells, e.g. DT-diaphorase (NAD(P)H:quinone oxidoreductase EC 1.6.99.2) and glutathione. In general, tumor cells have lower defenses and seem to be more sensitive to the toxic action.

Four contiguous amino acid substitutions, identified in patients with Laron syndrome, differently affect the binding affinity and intracellular trafficking of the growth hormone receptor.

We have analyzed the GH receptor (GHR) gene in four individuals with Laron syndrome, and a missense mutation was identified for each patient in the extracellular domain of the GHR (D152H, I153T, Q154P, and V155G). The D152H mutation was previously reported. We have reproduced the three novel mutations in the GHR complementary DNA and analyzed their consequences in human 293 transfected cells. In cells expressing the I153T and V155G mutants, binding of [125I]human GH at the cell surface was very low, whereas binding to total membrane fractions was much less affected, suggesting impaired cell surface expression. Binding assays with cells expressing the Q154P mutant revealed severe defects both at the cell surface and in total particulate membrane fractions. Immunofluorescence experiments confirmed that cell surface expression of the three mutants was altered, and colocalization studies suggested that most of the mutant receptors are retained in the endoplasmic reticulum. Endoglycosidase H resistance tests also indicated that the majority of I153T and V155G GHRs are trapped in the endoplasmic reticulum. Thus, mutations on contiguous amino acids of the GHR result in various defects. The I153T, Q154P, and V155G mutations mainly affect intracellular trafficking and binding affinity of the receptor, whereas the D152H mutation affects receptor expression, dimerization, and signaling.

The D152H mutation found in growth hormone insensitivity syndrome impairs expression and function of human growth hormone receptor but is silent in rat receptor.

In two patients with growth hormone (GH) insensitivity syndrome (Laron syndrome), in whom the GH receptor is able to bind the hormone, the D152H mutation was identified, and lack of dimerization was proposed to explain GH resistance in these patients. To examine further the consequences of the substitution of conserved aspartate 152 on the function of the GH receptor (GHR), we reproduced the mutation in vitro on the full length GH receptor cDNA from man and rat. Effects of the mutation on expression and activity of the GHR were analyzed in 293 cells transfected with wild-type and mutant GHR cDNAs. Mutant human receptor protein was expressed at a lower level than wild-type receptor and its activity was reduced: GH-dependent signal transducer and activator of transcription 5 (Stat5)-mediated transactivation of a reporter gene was lower in 293 cells transfected with mutant GHR cDNA than in transfected cells expressing a comparable level of wild-type GHR. The membrane-bound form of the mutant and of the wild-type human GHR were able to homodimerize, as suggested by the size of the complexes detected in cross-linking experiments with 125I-human (h) GH, and also by the activity in the functional test. With the soluble GHR resulting from proteolysis of the wild-type membrane form, no dimeric complexes could be detected. However, when a soluble receptor lacking the transmembrane and cytoplasmic domains of the receptor was expressed, wild-type and not mutant GH binding protein (GHBP) was able to form dimers in the presence of hGH. The amino acid substitution has no effect on either expression or function of the rat receptor. Structural modeling of D152H soluble human and rat GHR (GHBP) supports the species-specific functional consequences of the mutation. Evaluation of the functional importance of the mutation strongly suggests that impairment in expression and activity of the mutant receptor, rather than complete lack of dimerization, explains the GH resistance of the patients.

[Conservative treatment of renal cell carcinoma: framework, incidence and classification]. / La terapia conservativa nel carcinoma renale: inquadramento, incidenza e classificazione.

Recent interest in nephron sparing surgery for renal cell carcinoma has been stimulated by advances in diagnostic imaging, following an increasing number of incidentally discovered low stage renal cell carcinoma and good long term survival in patients undergoing this form of treatment. Tosaka et al reported a 5-years survival of 94.7% in patients with incidental renal cell carcinoma compared with 60.9% in diagnosed because symptomatic. Along with a diagnosis of carcinoma more and more premature, a whole string of little lesions is present, not easily identifiable by the recent diagnostic imaging. Tosaka and others examined renal lesions going by the ultrasonography as a check-up or as a first frame in patients suffering from microscopic hematuria; they proved that neoplastic lesions represent 5.4% of all the masses identifiable by diagnostic imaging. The frequent discovery of limited carcinoma, the difficulty in the diagnostic attribution and demonstration of the good survival of patients who were treated by a nephron sparing surgery, added to the one of patients undergone to radical nephrectomy, caused an interest in nephron-sparing surgery for incidental renal carcinoma also for patients with normal controlateral kidney and not very extended tumors, usually in peripheral sites. At the moment record of cases concerning nephron sparing surgery is quite limited, any way it shows a survival equal to 90% with only two local recurrences, reported only in one experience and caused by an incomplete resection or by multicentric neoplastic lesions.

Inhibition of leucocyte and platelet adhesion reduces neointimal hyperplasia after arterial injury.

Restenosis following coronary angioplasty is though to result from migration and proliferation of medial smooth muscle cells. However, the factors that initiate this proliferation are still unknown. In a rabbit model of carotid artery injury, we tested the hypothesis that activated platelets and leucocytes might contribute to the development of neointimal hyperplasia. Following arterial injury, rabbits received either no treatment, R15.7, a monoclonal antibody against the leucocyte CD11/CD18 adhesion complex, aurintricarboxylic acid (ATA), a substance that inhibits platelet glycoprotein Ib-von Willebrand factor interaction, or the combination of R15.7 and ATA. After 21 days, the extent of neointimal hyperplasia was evaluated by planimetry on histological arterial sections. The area of neointima averaged 0.51 +/- 0.07 mm2 in control animals and it was significantly reduced by administration of either R15.7 or ATA alone to 0.12 +/- 0.05 and 0.20 +/- 0.01 mm2, respectively (p < 0.05 vs controls for both groups). The animals that received the combination of R15.7 and ATA showed a further reduction in neointimal hyperplasia, as compared to animals that received ATA alone (p < 0.05 vs ATA alone). These data indicate that platelets and leucocytes play an important role in the pathophysiology of neointimal hyperplasia in this experimental model. Interventions that reduce platelet and leucocyte adhesion to vessel wall might have beneficial effects in reducing restenosis following coronary angioplasty.