Aromatase Inhibitors in Postmenopausal Women with Hormone Receptor-Positive Breast Cancer: Profiles of Psychological Symptoms and Quality of Life in Different Patient Clusters.

BACKGROUND: Aromatase inhibitors (AIs) as adjuvant therapy after breast cancer (BC) surgery have demonstrated to reduce the risk of disease recurrence, to lower the risk of contralateral BC, and to improve survival when compared to tamoxifen in patients with limited-stage hormone receptor-positive (HR+) BC. However, AIs are associated with adverse events that can have a significant impact on patient quality of life (QoL). AIM: This study aimed to identify profiles of psychological symptoms and QoL in HR+ BC patients undergoing AI therapy. METHOD: Data were collected with questionnaires administered at three time points: AI initiation (t0); 3 months after AI initiation (t1); and 6 months after AI initiation (t2). The FACT-G, FACT-B, and FACT-ES questionnaires were used to assess QoL; psychological symptoms were assessed using the SCL-90-R. RESULTS: 43 women were enrolled in the study (t0), and 37 completed the t1 evaluation and 29 the t2 evaluation. We found (1) a progressive decrease over time in FACT-G and FACT-ES scores, in particular in the Physical, Emotional, and Endocrine subscales, and an increase in the SOM (somatization) subscale of the SCL-90-R; (2) the presence of 4 clusters related to different psychological symptoms and QoL evolution over time; (3) that patients belonging to the cluster characterized by worsening symptoms and QoL during time differed from the others in the Emotional subscale of the FACT-B and in the GSI (Global Score), OCD (obsessive-compulsive), DEP (depression), ANX (anxiety), and SLP (sleep disorders) dimensions of the SCL-90-R and had significantly higher BMI levels; and (4) that 3 items from the SCL-90-R and 2 items from FACT Emotional Well-Being subscale were predictive of the "worst" cluster. CONCLUSIONS: Although larger studies are needed to confirm these results, our data open up new ways of investigation into the effects of AIs on QoL in HR+ BC patients.

[Implementation of the ICD-ICF model in rehabilitation medicine: report of a clinical case in rehabilitative cardiology]. / Implementazione del modello ICD-ICF in medicina riabilitativa: presentazione di un caso clinico in cardiologia riabilitativa.

SUMMARY: This patient entered a Cardiac Rehabilitation Program after coronary artery bypass graft. Concomitant diseases and the degree of disability have been coded according to International Classification of Functioning (ICF). Rehabilitation multidisciplinary program has been started (physician, nurses, physiotherapist and nutritionist); atrial fibrillation, anaemia, pleural effusion, surgical wounds inflammation were treated. Educational program allowed a better knowledge of the diseases the patient is bearing; low functional capability diagnosed at admittance improved thanks to the coordinated intervention of professionals involved. Coding diseases and disabilities at admission ensured a detailed identification of patient's issues and allowed the identification and the proposal for a targeted rehabilitation program. The improvement of medical ICF codes b280, b810 and b820, of physiotherapeutic codes b235, d450, d4551 and d455 and of nursing codes b280, b810 and b820 depends on the marked reduction of disability level.

Peri-procedural brain lesions prevention in CAS (3PCAS): Randomized trial comparing CGuard™ stent vs. Wallstent™.

BACKGROUND: Aim of this study was to evaluate peri-procedural incidence of new diffusion-weighted-magnetic-resonance-imaging (DWMRI) brain lesions in CAS patients treated by carotid mesh stent (CGuard™) or closed-cell stent (Wallstent™). METHODS: Consecutive patients with asymptomatic carotid stenosis ≥ 70% were submitted to preoperative DW-MRI scan, to exclude the presence of preoperative silent cerebral lesions. Patients were randomized to CGuard or Wallstent. DWMRI was performed immediately after the intervention and at 72-hour postoperatively. Moreover, pre and postoperative Mini-Mental-State-Examination Test (MMSE) and a Montreal-Cognitive-Assessment (MoCA) test were conducted, and S100ß and NSE neurobiomarkers were measured at 5-time points (preoperatively, 2, 12, 24, and 48 h postoperatively). RESULTS: From January 2015 to October 2016, sixty-one consecutive eligible patients were submitted to preoperative DWMRI scan. Three patients were excluded because of preoperative silent cerebral lesions. In 29 CGuard patients, 1 developed a minor stroke and 8 silent new lesions were observed in the 72 h-DWMRI (31%): 4 lesions were ipsilateral, and 4 lesions were contra or bilateral. In 29 Wallstent patients, 7 clinically-silent new lesions were found in the 72 h-DWMRI (24.1%; p = 0.38). In 4 cases lesions were ipsilateral and in 3 cases contra or bilateral. S100B values doubled at 48 h in 24 patients, and among them 12 presented new DWMRI lesions. 48-h S100B increase was significantly related to 72-h DWMRI lesions (p = 0.012). CONCLUSIONS: In our experience both stents showed an acceptable rate of subclinical neurological events with no significant differences at 72-hour DWMRI between groups. Bilateral/contralateral lesions suggest that periprocedural neurological damage may have extra-carotid sources.

The Hydrophobin HYTLO1 Secreted by the Biocontrol Fungus Trichoderma longibrachiatum Triggers a NAADP-Mediated Calcium Signalling Pathway in Lotus japonicus.

Trichoderma filamentous fungi are increasingly used as biocontrol agents and plant biostimulants. Growing evidence indicates that part of the beneficial effects is mediated by the activity of fungal metabolites on the plant host. We have investigated the mechanism of plant perception of HYTLO1, a hydrophobin abundantly secreted by Trichoderma longibrachiatum, which may play an important role in the early stages of the plant-fungus interaction. Aequorin-expressing Lotus japonicus suspension cell cultures responded to HYTLO1 with a rapid cytosolic Ca2+ increase that dissipated within 30 min, followed by the activation of the defence-related genes MPK3, WRK33, and CP450. The Ca2+-dependence of these gene expression was demonstrated by using the extracellular Ca2+ chelator EGTA and Ned-19, a potent inhibitor of the nicotinic acid adenine dinucleotide phosphate (NAADP) receptor in animal cells, which effectively blocked the HYTLO1-induced Ca2+ elevation. Immunocytochemical analyses showed the localization of the fungal hydrophobin at the plant cell surface, where it forms a protein film covering the plant cell wall. Our data demonstrate the Ca2+-mediated perception by plant cells of a key metabolite secreted by a biocontrol fungus, and provide the first evidence of the involvement of NAADP-gated Ca2+ release in a signalling pathway triggered by a biotic stimulus.

Phytochemical analysis and effects on ingestive behaviour of a Caralluma fimbriata extract.

Caralluma fimbriata Wall. is currently used as a "natural slimming" food supplement, likely due to its content in pregnane glycosides. In the present study, a commercially available Caralluma fimbriata extract (Slimaluma®; CFE, 100 mg/kg) has been evaluated for its ability to affect the ingestive behaviour in female rats, also with reference to the modulation of the brain neuropeptides NPY and ORX.The interference of CFE with α-amylase and lipase enzymes has been investigated in vitro, as possible peripheral mechanism of action. Also, the chemical composition of CFE has been assessed by NMR and spectrophotometric analysis. Results from in vivo study showed that CFE induced effects neither on blood parameters, nor on liver and gut histomorphology. Interestingly, a reduction in body weight gain with an increase in water intake and hypothalamic levels of NPY and ORX peptides were found. Phytochemical analysis, showed CFE contained about 12% of pregnane glycosides and 1.3% of polyphenols. Present results suggest possible effects of C. fimbriata on ingestive behaviour, likely mediated by central and peripheral mechanisms.

Mixotrophic cultivation of Chlorella for local protein production using agro-food by-products.

A local strain of Chlorella vulgaris was cultivated by using cheese whey (CW), white wine lees (WL) and glycerol (Gly), coming from local agro-industrial activities, as C sources (2.2gCL-1) to support algae production under mixotrophic conditions in Lombardy. In continuous mode, Chlorella increased biomass production compared with autotrophic conditions by 1.5-2 times, with the best results obtained for the CW substrate, i.e. 0.52gL-1d-1 of algal biomass vs. 0.24gL-1d-1 of algal biomass for autotrophic conditions, and protein content for both conditions adopted close to 500gkg-1 DM. Mixotrophic conditions gave a much higher energy recovery efficiency (EF) than autotrophic conditions, i.e. organic carbon energy efficiency (EFoc) of 32% and total energy efficiency (Eft) of 8%, respectively, suggesting the potential for the culture of algae as a sustainable practice to recover efficiently waste-C and a means of local protein production.

Pitfalls in oncology: a unique case of thoracic splenosis mimicking malignancy in a patient with resected breast cancer.

Thoracic splenosis (TS) is a condition of autotransplantation of splenic tissue into the pleural cavity after thoraco-abdominal trauma, with diaphragmatic and spleen injury. It is usually asymptomatic and discovered as an incidental finding at imaging performed for other reasons. Its differential diagnosis regards different benign and malignant conditions and should be discerned avoiding invasive procedures. We report a case of thoracic mass associated with pleural nodules mimicking malignancy in a patient with resected breast cancer for whom a diagnosis of TS was made early by using non-invasive methods. Briefly, we review the literature data on TS, comment concisely the possible implications of using invasive procedures and describe the current non-invasive techniques available. Furthermore, we highlight the importance of an accurate medical history collection, the role of the multidisciplinary board and their impact on treatment decision making. Finally, we conclude that clinical information and imaging would be the discriminating factors to avoid unnecessary invasive procedures.

Intestinal permeability and systemic endotoxemia in patients with acute pancreatitis.

BACKGROUND: The bacterial contamination of pancreatic necrosis in acute pancreatitis is supposed to occur through translocation of intestinal bacteria. The aim of this clinical study was to evaluate intestinal mucosa permeability and endotoxemia in patients with acute pancreatitis. METHODS: Sixtythree patients with acute pancreatitis were studied. Classification 42 patients had mild and 21 patients severe pancreatitis. Intestinal permeability was assessed at day 0, 1, 3, 7, 9 and 11 using the lactulose/mannitol differential absorption test. Serial venous blood samples were taken at 0, 30, 60, 90, 120, and 180 minutes, at 12, 24 hours, and at days 3, 7, 9 and 11 for endotoxin measurement RESULTS: Patients with severe pancreatitis had higher intestinal barrier dysfunction compared with patients with mild pancreatitis, the L:M ratio being 0.36 ± 0.15 and 0.051 ± 0.013 respectively (p< 0.05). The systemic endotoxin concentration were higher in patients with severe pancreatitis as regards mild pancreatitis (p < 0.05). A significant correlation was observed between the maximum systemic endotoxin concentration and intestinal permeability measured at day 7 in patients with mild (rs = 0.721; p = 0.001) and severe (rs = 0.956; p= 0.001) pancreatitis. CONCLUSION: Gut permeability is increased in patients with acute pancreatitis. Patients with severe pancreatitis may be more exposed to impaired gut barrier function. Moreover the pancreatits (especially severe) can lead to systemic endotoxemia. This agrees with the hypothesis that the splanchnic hypoperfusion, during the pancreatitis, may impair intestinal mucosal barrier function and contribute to the systemic inflammatory response and multiorgan failure. KEY WORDS: Acute pacreatitis, Endotoxemia, Intestinal permeability.

Endoluminal calprotectin measurement in assessment of pouchitis and a new index of disease activity: a pilot study

Pouchitis is the most common complication following proctocolectomy with ileal pouch-anal anastomosis for ulcerative colitis (UC). To provide a standardized definition of pouchitis clinical, endoscopic and histological markers were grouped and weighted in the pouch disease activity index (PDAI). However, the delay in the assessment of the final score due to the time requested for histological analysis remains the main obstacle to the index implementation in clinical practice so that the use of modified- PDAI (mPDAI) with exclusion of histologic subscore has been proposed. We tested the ability of calprotectin measurement in the pouch endoluminal content to mimic the histologic score as defined in the PDAI, the index that we adopted as gold standard for pouchitis diagnosis. Calprotectin was measured by ELISA in the pouch endoluminal content collected during endoscopy in 40 consecutive patients with J-pouch. In each patient PDAI and mPDAI were calculated and 15% of patients were erroneously classified by mPDAI. ROC analysis of calprotectin values vs. acute histological subscore ≥ 3 identified different calprotectin cut-off values with corresponding sensitivity and specificity allowing the definition and scoring of different range of calprotectin subscores. We incorporated the calprotectin score in the mPDAI obtaining a new score that shows the same specificity as PDAI for diagnosis of pouchitis and higher sensitivity when compared with mPDAI. The use of the proposed new score, once validated in a larger series of patients, might be useful in the early management of patients with symptoms of pouchitis (AU)

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Endoluminal calprotectin measurement in assessment of pouchitis and a new index of disease activity: a pilot study.

Pouchitis is the most common complication following proctocolectomy with ileal pouch-anal anastomosis for ulcerative colitis (UC). To provide a standardized definition of pouchitis clinical, endoscopic and histological markers were grouped and weighted in the pouch disease activity index (PDAI). However, the delay in the assessment of the final score due to the time requested for histological analysis remains the main obstacle to the index implementation in clinical practice so that the use of modified-PDAI (mPDAI) with exclusion of histologic subscore has been proposed. We tested the ability of calprotectin measurement in the pouch endoluminal content to mimic the histologic score as defined in the PDAI, the index that we adopted as gold standard for pouchitis diagnosis. Calprotectin was measured by ELISA in the pouch endoluminal content collected during endoscopy in 40 consecutive patients with J-pouch. In each patient PDAI and mPDAI were calculated and 15% of patients were erroneously classified by mPDAI. ROC analysis of calprotectin values vs. acute histological subscore ≥ 3 identified different calprotectin cut-off values with corresponding sensitivity and specificity allowing the definition and scoring of different range of calprotectin subscores. We incorporated the calprotectin score in the mPDAI obtaining a new score that shows the same specificity as PDAI for diagnosis of pouchitis and higher sensitivity when compared with mPDAI. The use of the proposed new score, once validated in a larger series of patients, might be useful in the early management of patients with symptoms of pouchitis.

Bevacizumab Prevents Brain Metastases Formation in Lung Adenocarcinoma.

Patients with nonsquamous non-small cell lung cancer (nsNSCLC; largely lung adenocarcinoma) are at high risk of developing brain metastases. Preclinical data suggested that anti-VEGF-A therapy may prevent the formation of nsNSCLC brain metastases. Whether non-brain metastases are also prevented, and whether bevacizumab shows a brain metastases-preventive activity in cancer patients is unknown. Data of one nsNSCLC (stage IIIB/IV, AVAiL) and two breast cancer bevacizumab trials (HER2 negative, AVADO; HER2 positive, AVEREL) were retrospectively analyzed regarding the frequency of the brain versus other organs being the site of first relapse. For animal studies, the outgrowth of PC14-PE6 lung adenocarcinoma cells to brain macrometastases in mice was measured by intravital imaging: under control IgG (25 mg/kg) treatment, or varying doses of bevacizumab (25 mg/kg, 2.5 mg/kg, 0.25 mg/kg). Brain metastases as site of first relapse were significantly less frequent in the bevacizumab arm of the AVAiL trial (HR = 0.36, P < 0.001). In AVADO and AVEREL, no significant difference was seen. In mice, bevacizumab treatment led to secondary regressions of non-brain macrometastases, but did not reduce their total incidence, and did not improve survival. In a brain-seeking nsNSCLC metastasis model, treatment with bevacizumab inhibited brain metastases formation, which resulted in improved overall survival. In summary, bevacizumab has the potential to prevent brain metastases in nsNSCLC, but no preventive activity could be detected outside the brain. These data indicate that anti-VEGF-A agents might be particularly relevant for those stage III nsNSCLC patients who are at high risk to develop future brain metastases. Mol Cancer Ther; 15(4); 702-10. ©2016 AACR.

Investigation of pepsin in tears of children with laryngopharyngeal reflux disease.

OBJECTIVES: Numerous investigations postulated that laryngopharyngeal reflux (LPR) is implicated in the pathogenesis of various upper airway inflammatory diseases as sinusitis or dacryostenosis. The presence of pepsin in tears might be confirmed the presuntive hypothesis of the arrival in the nasolacrimal ducts and precorneal tears film through the laryngopharyngeal reflux of either gastric acid or stomach secretions (pepsin) with inflammatory potentialities. The aim of this preliminary study was to identify the presence or absence of pepsin in the tears collected from children with a high suspicion of LPR who underwent 24-h pH (MII-pH) monitoring to confirm the disease. METHODS: This study enrolled 20 patients suffering from symptoms of laryngopharyngeal reflux that underwent 24-h multichannel intraluminal impedance (MII)-pH monitoring to confirm the disease. The findings of the study group were compared with those of a control group of patients with negative pH monitoring. The quantitative analysis of human pepsin concentration in the tear samples was performed by ELISA method in both groups. RESULTS: Four children (20%) of the study group showed pepsin in the tears. All of the subjects belonging to the control group were negative for its presence. No difference differences in the total number of reflux episodes and the number of weakly basic reflux in the pepsin positive patients vs. pepsin negative children were present. CONCLUSIONS: 20% of the children with diagnosed LPR showed pepsin in the tears. Our specific investigation might provide information regarding sinusitis or dacryostenosis.

1H NMR-based urinary metabolic profiling reveals changes in nicotinamide pathway intermediates due to postnatal stress model in rat.

The maternal separation protocol in rodents is a widely recognized model of early life stress allowing acute and chronic physiological consequences to be studied. An (1)H NMR-based metabolomic approach was applied to urines to evaluate the systemic metabolic consequences of maternal separation stress in female rats after the beginning of weaning and 4 weeks later when the rats were reaching adulthood. Furthermore, because maternal separation is considered as a model mimicking the inflammatory bowel syndrome, the lactulose/mannitol test was used to evaluate the influence of postnatal maternal separation on gut permeability and mucosal barrier function by (1)H NMR spectroscopy analysis of urine. The results showed no statistical differences in gut permeability due to maternal separation. The application of ANOVA simultaneous component analysis allowed the contributions of physiological adaptations to the animal's development to be separated from the metabolic consequences due to postnatal stress. Systemic metabolic differences in the maternally separated pups were mainly due to the tryptophan/NAD pathway intermediate levels and to the methyladenosine level. Urinary NMR-based metabolic profiling allowed us to disentangle the metabolic adaptive response of the rats to postnatal stress during the animal's growth, highlighting the metabolic changes induced by weaning, gut closure, and maturity.

Expression of stemness genes in primary breast cancer tissues: the role of SOX2 as a prognostic marker for detection of early recurrence.

The events leading to breast cancer (BC) progression or recurrence are not completely understood and new prognostic markers aiming at identifying high risk-patients and to develop suitable therapy are highly demanded. Experimental evidences found in cancer cells a deregulated expression of some genes involved in governance of stem cell properties and demonstrated a relationship between stemness genes overexpression and poorly differentiated BC subtypes. In the present study 140 primary invasive BC specimens were collected. The expression profiles of 13 genes belonging to the OCT3/SOX2/NANOG/KLF4 core circuitry by RT-PCR were analyzed and any correlation between their expression and the BC clinic-pathological features (CPfs) and prognosis was investigated. In our cohort (117 samples), NANOG, GDF3 and SOX2 significantly correlated with grade 2, Nodes negative status and higher KI67 proliferation index, respectively (p=0.019, p=0.029, p= 0.035). According to multivariate analysis, SOX2 expression resulted independently associated with increased risk of recurrence (HR= 2,99; p= p=0,004) as well as Nodes status (HR=2,44; p=0,009) and T-size >1 (HR=1,77; p=0,035). Our study provides further proof of the suitable use of stemness genes in BC management. Interestingly, a prognostic role of SOX2, which seems to be a suitable marker of early recurrence irrespective of other clinicopathological features.

Trans-thoracic biopsy of lung lesions: FNAB or CNB? Our experience and review of the literature.

PURPOSE: This study was performed to determine the type and incidence of complications of fine-needle aspiration biopsy (FNAB) and core biopsy (CNB) performed under computed tomography (CT) guidance to characterise lung lesions, and assess the diagnostic accuracy of the two techniques. MATERIALS AND METHODS: In 2009-2011, we performed 124 lung biopsies (66 CNB and 56 FNAB) on 121 patients with a mean age of 72.4 years. Exclusion criteria were pulmonary resection, pleural lesions and/or effusions, and inadequate blood-coagulation profile. All examinations were acquired after contrast-agent administration in a craniocaudal direction from the lung apex to base during a single inspiratory breath-hold, with standardised parameters. Each lesion was scanned with 13-15 slices that could be repeated whenever necessary to document the needle track and for lesion centring, by positioning a metallic marker perpendicular to the centring light to indicate the point of needle access. Unless otherwise clinically indicated, 4 h after the procedure chest radiography was performed. RESULTS: Age was found to be a factor influencing the complications: pneumothorax in young subjects (31 %) and parenchymal haemorrhage in the elderly (30 %), with CNB but not with FNAB. We had more complications with the right lung: 50 % of pneumothorax cases in the upper lobe with CNB and 40 % of cases of haemorrhage in the lower lobe with FNAB. The anterior approach gave rise to more complications with CNB, while the posterior approach with FNAB. CNB had more complications than FNAB for lesions ≤ 3.5 cm (31 vs. 18 % pneumothorax), and >3.5 cm (34 vs. 9 % haemorrhage). There was no significant correlation with lesion histology, needle calibre or number of passes (probably due to the small number of procedures done with needles other than 18 G in CNB or 22 G in FNAB or involving more than one needle pass). The diagnostic accuracy of FNAB, done with a pathologist's extemporaneous assessment of sample adequacy, was 94.83 % against 81.82. % of CNB. CONCLUSIONS: FNAB under CT guidance is subject to a lower rate of complications and, if performed in the presence of the pathologist, has a greater diagnostic accuracy compared to CNB.

Chelidonium majus L. does not potentiate the hepatic effect of acetaminophen.

AIM: The present study assessed the ability of Chelidonium majus to potentiate the hepatic effect of a sub-toxic dose of acetaminophen, in rats. RESULTS: C. majus, when administered alone, did not alter the liver function parameters in male, whereas an increase in fibrinogen level was found in female rats. Moreover, it did not affect the hepatic histomorphology in both male and female rats. The sub-toxic dose of acetaminophen induced: a significant increase in activated partial thromboplastin time in both genders, a focal hepatocellular necrosis with minor lymphocytes infiltrate and a slight but significant increase in total bilirubin, AST, and ALT in male rats, and in prothrombin time in female rats. The co-administration of C. majus did not increase the effects induced by acetaminophen, in both genders. CONCLUSIONS: C. majus does not modify the hepatic effects of acetaminophen in our in vivo experimental model.

Is a dexamethasone-sparing strategy capable of preventing acute and delayed emesis caused by combined doxorubicin and paclitaxel for breast cancer? Analysis of a phase II trial.

OBJECTIVE: The effectiveness of palonosetron without delayed dexamethasone dosing against emesis was investigated in patients scheduled to receive the corticosteroid-containing combination of doxorubicin and paclitaxel (AT) for 3 cycles. METHODS: Chemo-naïve women with breast cancer receiving doxorubicin (60 mg/m(2)) and paclitaxel (200 mg/m(2)) were eligible. Patients received palonosetron 0.25 mg intravenously before chemotherapy, however, all patients also received a premedication consisting of prednisone (25 mg orally the evening before therapy) and hydrocortisone (250 mg intravenously just before paclitaxel). The primary end point was complete control (CC; no vomiting, no rescue anti-emetics, and no more than mild nausea) during the overall phase (days 1-5) following cycle 1. RESULTS: Seventy-six patients were enrolled and evaluable (median age 50 years). Fifty-six patients (74%; 95% CI 62-83%) achieved overall CC. Acute (day 1) and delayed (days 2-5) CC rates were 78 and 74%, respectively. No vomiting rates for the acute, delayed and overall phases were 85, 85 and 83%, respectively. An exploratory analysis showed only a small decrease in the probability of achieving CC between cycle 1 (74%) and cycle 3 (66%). CONCLUSION: The dexamethasone-sparing strategy prevented emesis in more than 70% of breast cancer patients receiving their initial cycle of AT chemotherapy.

AVEREL: a randomized phase III Trial evaluating bevacizumab in combination with docetaxel and trastuzumab as first-line therapy for HER2-positive locally recurrent/metastatic breast cancer.

PURPOSE The AVEREL trial [A Study of Avastin (Bevacizumab) in Combination With Herceptin (Trastuzumab)/Docetaxel in Patients With HER2-Positive Metastatic Breast Cancer] evaluated first-line bevacizumab-containing therapy for human epidermal growth factor receptor 2 (HER2) -positive locally recurrent/metastatic breast cancer (LR/MBC). PATIENTS AND METHODS Patients with measurable/evaluable HER2-positive LR/MBC who had not received trastuzumab or chemotherapy for LR/MBC were stratified by prior adjuvant trastuzumab, prior (neo)adjuvant taxane, hormone receptor status, and measurable disease and were randomly assigned to receive docetaxel 100 mg/m(2) plus trastuzumab 8 mg/kg loading dose followed by 6 mg/kg either with bevacizumab 15 mg/kg or without bevacizumab, all administered every 3 weeks. The primary end point was progression-free survival (PFS). Additional end points included overall survival, response rate (RR), safety, quality of life, and translational research. Results Baseline characteristics of the 424 patients were balanced between treatment arms. Most patients had visceral metastases, 43% had a disease-free interval less than 12 months, and 85% had measurable disease. Median follow-up was 26 months. The hazard ratio for investigator-assessed PFS was 0.82 (95% CI, 0.65 to 1.02; P = .0775; median PFS, 13.7 v 16.5 months in the non-bevacizumab and bevacizumab arms, respectively; PFS events in 72%). The Independent Review Committee-assessed PFS hazard ratio was 0.72 (95% CI, 0.54 to 0.94; P = .0162; median PFS, 13.9 v 16.8 months, respectively; PFS events in 53%). The RR was 70% versus 74%, respectively (P = .3492). Grade ≥ 3 febrile neutropenia and hypertension were more common with bevacizumab-containing therapy. High baseline plasma vascular endothelial growth factor A (VEGF-A) concentrations were associated with greater bevacizumab benefit (not statistically significant). CONCLUSION Combining bevacizumab with docetaxel and trastuzumab did not significantly improve investigator-assessed PFS. The potential predictive value of plasma VEGF-A is consistent with findings in HER2-negative LR/MBC, warranting prospective evaluation.

Assessment of MDA efficiency for genotyping using cloned embryo biopsies.

The possibility to genotype embryos prior to implantation would have advantages for increasing the speed of selection of cattle. Reliable genotyping requires more DNA than can be obtained from biopsies of embryos, if they are to remain viable. Multiple displacement amplification (MDA) is a whole genome amplification technique used to increase the amount of DNA from biopsies for analysis. Reduced genome coverage resulting in Allele Drop Out (ADO) at heterozygous loci or missing genotypes are drawbacks of MDA. The present article describes the correlation between the input DNA quantity or embryo biopsy size and MDA success. Missing genotypes and ADO drastically increased when fewer than 30-40 cells or the genomic equivalents were used. However, embryo viability was found to be reduced if biopsied with more than 10 cells. Therefore, in vitro cell culture was investigated as a means to increase the number of cells available and the genotyping reliability.