SWOG S0800 (NCI CDR0000636131): addition of bevacizumab to neoadjuvant nab-paclitaxel with dose-dense doxorubicin and cyclophosphamide improves pathologic complete response (pCR) rates in inflammatory or locally advanced breast cancer.

SWOG S0800, a randomized open-label Phase II clinical trial, compared the combination of weekly nab-paclitaxel and bevacizumab followed by dose-dense doxorubicin and cyclophosphamide (AC) with nab-paclitaxel followed or preceded by AC as neoadjuvant treatment for HER2-negative locally advanced breast cancer (LABC) or inflammatory breast cancer (IBC). Patients were randomly allocated (2:1:1) to three neoadjuvant chemotherapy arms: (1) nab-paclitaxel with concurrent bevacizumab followed by AC; (2) nab-paclitaxel followed by AC; or (3) AC followed by nab-paclitaxel. The primary endpoint was pathologic complete response (pCR) with stratification by disease type (non-IBC LABC vs. IBC) and hormone receptor status (positive vs. negative). Overall survival (OS), event-free survival (EFS), and toxicity were secondary endpoints. Analyses were intent-to-treat comparing bevacizumab to the combined control arms. A total of 215 patients were accrued including 11 % with IBC and 32 % with triple-negative breast cancer (TNBC). The addition of bevacizumab significantly increased the pCR rate overall (36 vs. 21 %; p = 0.019) and in TNBC (59 vs. 29 %; p = 0.014), but not in hormone receptor-positive disease (24 vs. 18 %; p = 0.41). Sequence of administration of nab-paclitaxel and AC did not affect the pCR rate. While no significant differences in OS or EFS were seen, a trend favored the addition of bevacizumab for EFS (p = 0.06) in TNBC. Overall, Grade 3-4 adverse events did not differ substantially by treatment arm. The addition of bevacizumab to nab-paclitaxel prior to dose-dense AC neoadjuvant chemotherapy significantly improved the pCR rate compared to chemotherapy alone in patients with triple-negative LABC/IBC and was accompanied by a trend for improved EFS. This suggests reconsideration of the role of bevacizumab in high-risk triple-negative locally advanced breast cancer.

Conservative management of early-stage epithelial ovarian cancer: results of a large retrospective series.

BACKGROUND: To assess the long-term oncological outcome and the fertility of young women with early-stage epithelial ovarian cancer (ES/EOC) treated with fertility-sparing surgery (FSS). PATIENTS AND METHODS: All patients treated with FSS for ES/EOC in two Italian centers were considered for this analysis. Univariate and multivariate analyses were used to test demographic characteristics and clinical features for the association with overall survival (OS), recurrence-free survival (RFS) and fertility. RESULTS: From 1982 to 2010, 240 patients with malignant ES/EOC were treated with FSS in two tertiary centers in Italy. At a median follow-up of 9 years, 27 patients had relapsed (11%) and 11 (5%) had died of progressive disease. Multivariate analysis found only grade 3 negatively affected the prognosis of patients [hazard ratio (HR) for recurrence: 4.2, 95% confidence interval (CI): 1.5-11.7, P=0.0067; HR for death: 7.6, 95% CI: 2.0-29.3, P=0.0032]. Grade 3 was also significantly associated with extra-ovarian relapse (P=0.006). Of the 105 patients (45%) who tried to become pregnant, 84 (80%) were successful. CONCLUSIONS: Conservative treatment can be proposed to all young patients when tumor is limited to the ovaries, as ovarian recurrences can always be managed successfully. Patients with G3 tumors are more likely to have distant recurrences and should be closely monitored.

A study of the psychometric properties of the Brazilian...Portuguese version of Bronchiectasis Health Questionnaire.

INTRODUCTION AND OBJECTIVE: The Bronchiectasis Health Questionnaire (BHQ) is a simple, repeatable, and self-reporting health status questionnaire for bronchiectasis. This study aims to cross-culturally adapt the BHQ into Brazilian Portuguese and evaluate its measurement properties. METHODS: The participants answered the Saint George...s Respiratory Questionnaire (SGRQ) and the modified Medical Research Council (mMRC) scale for dyspnea. The Brazilian-Portuguese version of the Bronchiectasis Health Questionnaire (BHQ-Brazil) was used at baseline (test) and after 14 days (retest). The psychometric analyses included internal consistency, test-retest reliability, and construct validity: factorial validity, convergent validity, and discriminative validity, agreement, and ceiling and floor effects. RESULTS: The BHQ-Brazil demonstrated adequate internal consistency (Cronbach...s alpha...=...0.92) and substantial reliability (intraclass correlation coefficient...=...0.86; 95%CI: 0.79...0.90). The exploratory factorial analysis was considered suitable. All items presented a factorial load >0.40. The convergent validity of the BHQ-Brazil with mMRC was moderate (r...=......0.53, p...<...0.001), while concurrent validity with the SGRQ was strong (symptoms: r...=......0.72, activities: r...=......0.60, impact: r...=......0.60, total score: r...=......0.75, all p...<...0.001). The standard error of measurement was 4.81 points. The discriminative validity demonstrated that individuals with more pulmonary exacerbations, colonization by Pseudomonas aeruginosa, worst dyspnea, and a higher number of affected lung lobes presented the lowest quality of life. No floor or ceiling effects were observed. CONCLUSION: The BHQ-Brazil presents adequate measurement properties to evaluate the impact of bronchiectasis on health-related quality of life, and can be used in clinical and research settings.

Reproducibility, validity, and reliability of the incremental step test for subjects with moderate to severe asthma.

OBJECTIVE: We investigated the measurement properties of the incremental step test in subjects with moderate to severe asthma. METHODS: Subjects with moderate to severe persistent asthma were recruited from a tertiary university hospital specializing in treating severe asthma. All subjects performed one cardiopulmonary exercise test (CPET) and two incremental step tests (IST) in random sequences. Pulmonary gas exchange was measured during all exercise tests. The measurement properties investigated were reliability by intraclass correlation coefficient (ICC), measurement error by the standard error of measurement and minimum detectable difference, construct validity by Pearson's correlation, and interpretability by the ceiling and floor effects. RESULTS: Fifty subjects (38 females, mean [SD], age 43.7 [11.6] yr, % FEV1 70 [14.3], BMI 28.5 [5.3] kg/m2) completed the study. The peak oxygen uptake (peak VO2) for the CPET was 27.6 [±6.8] ml/kg/min, for the first IST was 22.3 [±5.3] ml/kg/min and for the second IST was 23.3 [±5.3] ml/kg/min. The IST presented excellent reliability (ICC=0.93, CI95% 0.88-0.96), very good measurement error (2.5%), and construct validity for peak VO2 measurement compared to the CPET (r = 0.85; p < 0.001) to assess exercise capacity in subjects with moderate to severe asthma, with appropriate ceiling (10%) and floor (0%) effects. CONCLUSION: The IST presented excellent reliability and very good measurement error and validity to assess exercise capacity in subjects with moderate to severe asthma, without ceiling or floor effects.

Incremental step test in patients with pulmonary hypertension.

Cardiopulmonary exercise testing (CPET) on a treadmill or cycle ergometer provides an integrated assessment of the cardiorespiratory system during exertion and is widely used in clinical practice. An incremental step test (IST) can be an alternative for eliciting maximal exercise responses. Therefore, 20 patients with pre-capillary PH (65% female, 41 ±â€¯15 yrs) randomly performed a symptom-limited CPET on a cycle ergometer and IST. Metabolic, cardiovascular, ventilatory and gas exchange variables were recorded during both tests. There was a greater desaturation and higher V̇O2PEAK in IST compared to CPET. The V̇O2GET, HR PEAK (% pred), ΔV̇E/ΔV̇CO2 and ΔHR/ΔV̇O2 were similar in both IST and CPET. By linear regression analyses, the work performed on IST [W = (mass × 9,8 m/s2 x vertical distance)] was a predictor of peak V̇O2 independent of the gender and age (r2 = 077, p = 0001). In conclusion, IST elicited higher peak cardiopulmonary responses and has a good agreement with known severity markers in patients with pre-capillary PH.

Validation and reproducibility of the Glittre activities of daily living test for individuals with Parkinson's disease. / Validación y reproducibilidad de la prueba Glittre de actividades de la vida diaria en personas con enfermedad de Parkinson.

AIM: To investigate the validity and reproducibility of the Glittre Activities of Daily Living (Glittre-ADL) test for individuals with Parkinson's disease. SUBJECTS AND METHODS: Thirty individuals with Parkinson's disease and 19 healthy individuals (control group) were evaluated. Parkinson's disease group was evaluated by the Unified Parkinson's Disease Rating Scale (UPDRS) and underwent the Glittre-ADL test, six-minute walk test (6MWT) and ten-meter walk test (10mWT). Control group performed the Glittre-ADL test. For the intraobserver analysis, two Glittre-ADL tests were performed. For the interobserver analysis, the Glittre-ADL test was repeated on a different day by a second examiner. RESULTS: The Glittre-ADL test was significantly correlated with UPDRS Section II, Section III, and total score. The Glittre-ADL test was inversely correlated with the 6MWT and positively correlated with the 10mWT. The time required to perform the Glittre-ADL test was shorter on the retest in the intraobserver analysis and in the interobserver analysis. The mean difference between the first and second tests, the standard error of measurement and minimum detectable change in minutes were 0.40, 0.08 and 0.24, respectively, for intraobserver, and 0.40, 0.22 and 0.62, for interobserver. CONCLUSION: The Glittre-ADL test is valid and reproducible to evaluate functional capacity in individuals with Parkinson's disease.

TITLE: Validación y reproducibilidad de la prueba Glittre de actividades de la vida diaria en personas con enfermedad de Parkinson.Objetivo. Investigar la validez y la reproducibilidad de la prueba Glittre de actividades de la vida diaria (AVD-Glittre) para personas con enfermedad de Parkinson. Sujetos y métodos. Se evaluó a 30 pacientes con enfermedad de Parkinson y 19 sujetos sanos (grupo de control). El grupo con enfermedad de Parkinson fue evaluado con la Unified Parkinson's Disease Rating Scale (UPDRS) y sometido a la prueba AVD-Glittre, la prueba de marcha de seis minutos (6MWT) y la prueba de marcha de 10 metros (10mWT). El grupo de control realizó la prueba AVD-Glittre. Para el análisis intraobservador se realizaron dos pruebas AVD-Glittre, y para el análisis interobservador, la prueba se repitió otro día con un segundo examinador. Resultados. La prueba AVD-Glittre se correlacionó significativamente con la sección II, la sección III y la puntuación total de la UPDRS. Se correlacionó inversamente con la 6MWT y positivamente con la 10mWT. El tiempo requerido para realizar la prueba AVD-Glittre fue más corto en la nueva prueba en el análisis intraobservador y en el análisis interobservador. La diferencia de medias entre la primera y la segunda pruebas, el error estándar de medición y el cambio mínimo detectable en minutos fueron 0,40, 0,08 y 0,24, respectivamente, para el análisis intraobservador, y 0,40, 0,22 y 0,62, respectivamente, para el análisis interobservador. Conclusión. La prueba AVD-Glittre es válida y reproducible para evaluar la capacidad funcional en personas con enfermedad de Parkinson.

Defective ubiquitinylation of EGFR mutants of lung cancer confers prolonged signaling.

Several distinct mutations within the kinase domain of the epidermal growth factor receptor (EGFR) are associated with non-small cell lung cancer, but mechanisms underlying their oncogenic potential are incompletely understood. Although normally ligand-induced kinase activation targets EGFR to Cbl-mediated receptor ubiquitinylation and subsequent degradation in lysosomes, we report that certain EGFR mutants escape this regulation. Defective endocytosis characterizes a deletion mutant of EGFR, as well as a point mutant (L858R-EGFR), whose association with c-Cbl and ubiquitinylation are impaired. Our data raise the possibility that refractoriness of L858R-EGFR to downregulation is due to enhanced heterodimerization with the oncogene product HER2, which leads to persistent stimulation.

Pro-metastatic signaling by c-Met through RAC-1 and reactive oxygen species (ROS).

Overexpression of the c-Met/hepatocyte growth factor receptor(HGF-R) proto-oncogene and abnormal generation of intracellular oxygen species (reactive oxygen species (ROS)) have been linked, by independent lines of evidence, to cell transformation and to malignant growth. By comparing two subpopulations of the B16 mouse melanoma (B16-F0 and B16-F10) endowed with different lung metastasis capacities (low and high, respectively) we found that both the expression/phosphorylation of c-Met and the steady-state levels of ROS positively correlated with metastatic growth. shRNA-mediated downregulation of c-Met in F10 cells led to a parallel decrease in the generation of oxygen species and in metastatic capacity, suggesting that oxidants may mediate the pro-metastatic activity of the HGF receptor. c-Met activation by a ligand elicits the formation of oxidant species through the oxidase-coupled small GTPase Rac-1, a relevant downstream target of the HGF-R. Moreover, cell treatment with the catalytic ROS scavengers EUK-134 and EUK-189 attenuates Met signaling to ERKs and inhibits the anchorage-independent growth of F10 cells, consistent with a critical role for oxygen species in HGF signaling and in aggressive cell behavior. Finally, genetic manipulation of the Rac-ROS cascade at different levels demonstrated its crucial role in the pro-metastatic activity of c-Met in vivo. Thus, we have outlined a novel cascade triggered by c-Met and mediated by ROS, linked to metastasis and potentially targetable by new antimetastatic, redox-based therapies.

Dual MET/EGFR therapy leads to complete response and resistance prevention in a MET-amplified gastroesophageal xenopatient cohort.

Amplification of the MET oncogene occurs in 2-4% of gastroesophageal cancers and defines a small and aggressive subset of tumors. Although in vitro studies have given very promising results, clinical trials with MET inhibitors have been disappointing, showing few and short lasting responses. The aim of the work was to exploit a MET-amplified patient-derived xenograft model to optimize anti-MET therapeutic strategies in gastroesophageal cancer. We found that despite the high MET amplification level (26 gene copies), in the absence of qualitative or quantitative alterations of EGFR, MET inhibitors induced only tumor growth inhibition, whereas dual MET/EGFR inhibition led to complete tumor regression. Importantly, the combo treatment completely prevented the onset of resistance, which quite rapidly appeared in tumors treated with MET monotherapy. We found that this secondary resistance was due to EGFR activation and could be overcome by dual MET/EGFR inhibition. Similar results were also obtained in a MET-addicted, established gastric cancer cell line. In vitro experiments performed on tumor-derived primary cells confirmed that MET inhibitors were not able to abrogate the activation of downstream transducers and that only the combined MET/EGFR treatment completely shut off the signaling. Previously reported cases, as well as those described here, showed only partial and transient sensitivity to anti-MET therapy. The finding that combined anti-MET/EGFR therapy-even in the absence of EGFR genetic alterations-induced complete and durable response, represents a proof of concept and guarantees further investigations, opening a new perspective of treatment for these patients.

Initial phase I evaluation of the novel thymidylate synthase inhibitor, LY231514, using the modified continual reassessment method for dose escalation.

PURPOSE: To determine the toxicities, maximal-tolerated dose (MTD), pharmacokinetic profile, and potential antitumor activity of LY231514, a novel thymidylate synthase (TS) inhibitor. PATIENTS AND METHODS: Patients with advanced solid tumors were administered LY231514 intravenously over 10 minutes, weekly for 4 weeks, every 42 days. Dose escalation was based on the modified continual reassessment method (MCRM), with one patient treated at each minimally toxic dose level. Pharmacokinetic studies were performed in all patients. RESULTS: Twenty-five patients were administered 58 courses of LY231514 at doses that ranged from 10 to 40 mg/m2/wk. Reversible neutropenia was the dose-limiting toxicity. Inability to maintain the weekly treatment schedule due to neutropenia limited dose escalation on this schedule. Nonhematologic toxicities observed included mild fatigue, anorexia, and nausea. At the 40-mg/m2/wk dose level, the mean harmonic half-life, maximum plasma concentration, clearance, and apparent volume of distribution at steady-state were 2.02 hours, 11.20 micrograms/mL, 52.3 mL/min/m2, and 6.64 L/m2, respectively. No major antitumor responses were observed; however, minor responses were achieved in two patients with advanced colorectal cancer. CONCLUSION: The dose-limiting toxicity, MTD, and recommended phase II dose of LY231514 when administered weekly for 4 weeks every 42 days are neutropenia, 40 mg/m2, and 30 mg/m2, respectively.

Plexin signaling hampers integrin-based adhesion, leading to Rho-kinase independent cell rounding, and inhibiting lamellipodia extension and cell motility.

Plexins encode receptors for semaphorins, molecular signals guiding cell migration, and axon pathfinding. The mechanisms mediating plexin function are poorly understood. Plexin activation in adhering cells rapidly leads to retraction of cellular processes and cell rounding "cell collapse"). Here we show that, unexpectedly, this response does not require the activity of Rho-dependent kinase (ROCK) nor the contraction of F-actin cables. Interestingly, integrin-based focal adhesive structures are disassembled within minutes upon plexin activation; this is followed by actin depolymerization and, eventually, by cellular collapse. We also show that plexin activation hinders cell attachment to adhesive substrates, blocks the extension of lamellipodia, and thereby inhibits cell migration. We conclude that plexin signaling uncouples cell substrate-adhesion from cytoskeletal dynamics required for cell migration and axon extension.

Parental stress and growth outcome in growth-deficient children.

OBJECTIVE: In order to examine the relationship between parental stress, child psychosocial factors, anemia, lead poisoning, and growth deficiency (GD), 48 children attending a GD referral program were recruited consecutively and matched with 50 comparison subjects from a primary care program. METHOD: Parents completed the Parenting Stress Index (PSI) with subscales and provided demographic data. Children received developmental screening, hemoglobin levels, Pb levels, and growth evaluation. They also received medical evaluation for GD. T tests were used to evaluate group differences. Spearman Rho correlation analyses were computed between group coefficients and PSI scales, Pb, and hemoglobin levels. RESULTS: No differences were found on the PSI with regard to overall parental stress. GD parents perceived themselves as less competent (P < .001), and their children as less adaptable (P < .006). They also reported more social isolation (P < .05). The GD group had more anemia and Pb poisoning (P < .002 and P < .001, respectively); however, these variables were not related to differences in child adaptability or growth outcome. A high sense of parental competence and high child adaptability were associated with improved growth outcomes (P < .001 and P < .02, respectively). CONCLUSIONS: We conclude that parents of GD children seen in an outpatient referral setting show no difference in overall perceived stress levels versus comparison subjects. Increased parental competence and child adaptability are strongly associated with improved growth outcome. Decreased child adaptability may contribute to GD pathology. These findings challenge the traditional view of GD etiology.

Diffuse alveolar hemorrhage following autologous bone marrow infusion.

Autologous BMT performed in a 57-year-old woman with relapsed large cell lymphoma was complicated by two consecutive episodes of diffuse alveolar hemorrhage (DAH). The second episode occurred immediately after infusion of autologous BM. DAH is an increasingly recognized complication of autologous BMT and carries a high mortality. It is characterized by dyspnea, cough, bilateral pulmonary infiltrates and progressively bloodier aliquots of bronchoalveolar lavage fluid. The pathogenesis is probably multifactorial involving an initial insult to lung endothelium with inflammatory cells serving as the mediators of subsequent injury. The rapid development of DAH following marrow infusion strongly implicates DMSO as a potential cause in our patient.

Isolated rupture of the popliteus with posterior tibial nerve palsy.

We report the case of a 59-year-old man with severe knee pain and inability to flex his toes or invert his plantar flexed foot after an external rotation injury to his knee. MRI showed rupture of the popliteus with a haematoma compressing the neurovascular bundle in the proximal calf, and electromyography demonstrated signs of an axonotmesis of the posterior tibial nerve. There was progressive nerve recovery over 24 weeks. Isolated rupture of the popliteus should be considered in any patient with an acute haemarthrosis, lateral tenderness and a stable knee, especially after an external rotation injury.

Arthroscopy of the acromioclavicular joint.

For many years the Mumford procedure or open resection of the distal clavicle has been the procedure of choice for the treatment of recalcitrant acromioclavicular joint pain. With advancement in shoulder arthroscopy and bursoscopy, arthroscopic resection of the distal clavicle can reproduce similar excellent results, avoiding some of the risks of the open procedure, including joint instability and muscle weakness. The arthroscopist can select from two approaches, a direct or superior approach or the indirect or subacromial approach. Both approaches are effective if the resection is performed in a systematic fashion and the amount of resection measured post-operatively. The authors have attempted to describe the pertinent anatomy of the acromioclavicular joint, clinical indications, and surgical technique for arthroscopic resection of the distal clavicle.

[Efficacy of diltiazem in blood pressure increase caused by exertion]. / Efficacia del diltiazem sull'incremento pressorio da sforzo.

After examining the properties of the 3 most widely used calcium antagonists, the paper assesses the efficacy of Diltiazem in reducing blood pressure rises after exercise in a group of 7 patients with chronic atrial fibrillation. The blood pressure response to a standard load (50 W x 3 m2) on the exercise cycle was monitored in a group of patients under chronic digitalis treatment (phase I) after which the same patients' response to varying doses of Diltiazem (180-240 mg/day) was assessed (phase II) and finally (phase III) their response to treatment with Diltiazem alone but no digitalis. A significantly greater reduction in the systolic pressure and heart rate after exercise was noted in patients given Diltiazem with or without Digoxin than in those given digitalis alone. It is therefore concluded that Diltiazem may be useful in controlled blood pressure and heart rate increases after exercise, especially in patients with ischaemic heart disease.

Ultrasound and hormonology in the diagnosis of hydatiform mole with coexistent foetus. A case report.

The Authors report a case of hydatiform mole coexistent with a 12 week old foetus. They suggest that a diagnosis of hydatiform mole cannot always be based on the results of ultrasound examination and that combined ultrasound/hormone assay investigation is a valid obstetric tool for formulating the diagnosis and prognosis of hydatiform mole.

Patients' understanding of how genotype variation affects benefits of tamoxifen therapy for breast cancer.

BACKGROUND: CYP2D6 is a critical enzyme in the metabolism of tamoxifen and potentially a key determinant in breast cancer outcomes. Our study examined patients' beliefs about how the CYP2D6 genotype would affect their prognoses. METHODS: Women enrolled in a pharmacogenomic clinical trial and on tamoxifen for prevention or treatment of breast cancer underwent CYP2D6 genotyping (EM = extensive, IM = intermediate, PM = poor metabolizing alleles). The informed consent said that the purpose of the trial was to examine effects of dose adjustment based on genotype, but that clinical benefits were uncertain. Our embedded sub-study surveyed 320 patients prior to receiving their genotypes. We experimentally manipulated 6 vignettes to describe hypothetical tamoxifen treatment (no or yes) and hypothetical genotype (EM, IM or PM). For each vignette, women gave their perceived recurrence risk (RR; 0-100%). RESULTS: Women believed that genotype would not affect their RR if they did not take tamoxifen (p = 0.06). However, women believed that if prescribed tamoxifen, genotype would affect their RR (22% if EM, 30% if IM and 40% if PM, p < 0.001). CONCLUSION: Women believed that extensive tamoxifen metabolizers had better prognoses, despite study materials stating uncertainty about any benefit. The rapidly changing nature of genomic science calls for caution when communicating clinical utility.

Expression of DNA repair genes in ovarian cancer samples: biological and clinical considerations.

The purpose of this study was to investigate retrospectively the mRNA expression of genes involved in different DNA repair pathways implicated in processing platinum-induced damage in 171 chemotherapy-naïve ovarian tumours and correlate the expression of the different genes with clinical parameters. The expression of genes involved in DNA repair pathways (PARP1, ERCC1, XPA, XPF, XPG, BRCA1, FANCA, FANCC, FANCD2, FANCF and PolEta), and in DNA damage transduction (Chk1 and Claspin) was measured by RT-PCR in 13 stage I borderline and 77 stage I and 88 III ovarian carcinomas. ERCC1, XPA, XPF and XPG genes were significantly less expressed in stage III than in stage I carcinoma; BRCA1, FANCA, FANCC, FANCD2 gene expressions were low in borderline tumours, higher in stage I carcinomas and lower in stage III samples. High levels of ERCC1, XPA, FANCC, XPG and PolEta correlated with an increase in Overall Survival (OS) and Progression Free Survival (PFS), whilst high BRCA1 levels were associated with PFS on univariate analysis. With multivariate analyses no genes retained an association when adjusted by stage, grade and residual tumour. A tendency towards a better PFS was observed in patients with the highest level of ERCC1 and BRCA1 after platinum-based therapy than those given both platinum and taxol. The expression of DNA repair genes differed in borderline stage I, stage I and stage III ovarian carcinomas. The role of DNA repair genes in predicting the response in ovarian cancer patients seems far from being established.