Autocrine VEGFR1 and VEGFR2 signaling promotes survival in human glioblastoma models in vitro and in vivo

Background

Although the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) system has become a prime target for antiangiogenic treatment, its biological role in glioblastoma beyond angiogenesis has remained controversial.

Methods

Using neutralizing antibodies to VEGF or placental growth factor (PlGF) or the tyrosine kinase inhibitor, cediranib, or lentiviral gene silencing, we delineated autocrine signaling in glioma cell lines. The in vivo effects of VEGFR1 and VEGFR2 depletion were evaluated in orthotopic glioma xenograft models.

Results

VEGFR1 and VEGFR2 modulated glioma cell clonogenicity, viability, and invasiveness in vitro in an autocrine, cell–line-specific manner. VEGFR1 silencing promoted mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling, whereas VEGFR2 silencing resulted in cell-type dependent activation of the protein kinase B (PKB)/AKT and MAPK/ERK pathways. These responses may represent specific escape mechanisms from VEGFR inhibition. The survival of orthotopic glioma-bearing mice was prolonged upon VEGFR1 silencing in the LNT-229, LN-308, and U87MG models and upon VEGFR2 silencing in LN-308 and U87MG. Disruption of VEGFR1 and VEGFR2 signaling was associated with decreased tumor size, increased tumor necrosis, or loss of matrix metalloproteinase 9 (MMP9) immunoreactivity. Neutralizing VEGF and PlGF by specific antibodies was superior to either antibody treatment alone in the VEGFR1-dependent LNT-229 model.

Conclusions

Differential dependence on autocrine signaling through VEGFR1 and VEGFR2 suggests a need for biomarker–stratified VEGF(R)-based therapeutic approaches to glioblastoma.

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Elevated levels of polymorphonuclear myeloid-derived suppressor cells in patients with glioblastoma highly express S100A8/9 and arginase and suppress T cell function

Background

Gliomas are primary brain tumors that are associated with a poor prognosis. The introduction of new treatment modalities (including immunotherapy) for these neoplasms in the last 3 decades has resulted in only limited improvement in survival. Gliomas are known to create an immunosuppressive microenvironment that hampers the efficacy of (immuno)therapy. One component of this immunosuppressive environment is the myeloid-derived suppressor cell (MDSC).

Methods

We set out to analyze the presence and activation state of MDSCs in blood (n = 41) and tumor (n = 20) of glioma patients by measuring S100A8/9 and arginase using flow cytometry and qPCR. Inhibition of T cell proliferation and cytokine production after stimulation with anti-CD3/anti-CD28 coated beads was used to measure in vitro MDSC suppression capacity.

Results

We report a trend toward a tumor grade-dependent increase of both monocytic (M-) and polymorphonuclear (PMN-) MDSC subpopulations in the blood of patients with glioma. M-MDSCs of glioma patients have increased levels of intracellular S100A8/9 compared with M-MDSCs in healthy controls (HCs). Glioma patients also have increased S100A8/9 serum levels, which correlates with increased arginase activity in serum. PMN-MDSCs in both blood and tumor tissue demonstrated high expression of arginase. Furthermore, we assessed blood-derived PMN-MDSC function and showed that these cells have potent T cell suppressive function in vitro.

Conclusions

These data indicate a tumor grade-dependent increase of MDSCs in the blood of patients with a glioma. These MDSCs exhibit an increased activation state compared with MDSCs in HCs, independent of tumor grade.

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AVAREG: a phase II, randomized, noncomparative study of fotemustine or bevacizumab for patients with recurrent glioblastoma

Background

Few prospective studies have assessed the role of bevacizumab and included a control arm with standard treatments for recurrent glioblastoma. We conducted a noncomparative phase II trial (AVAREG) to examine the efficacy of bevacizumab or fotemustine in this setting.

Methods

Eligible patients were randomized 2:1 to receive bevacizumab (10 mg/kg every 2 weeks) or fotemustine (75 mg/m² on days 1, 8, and 15, then 100 mg/m² every 3 weeks after a 35-day interval). The primary endpoint was 6-month overall survival (OS) rate (OS-6). No formal efficacy comparison was made between the treatment arms.

Results

Ninety-one patients were enrolled (bevacizumab n = 59; fotemustine n = 32). Median age was 57 years (range, 28–78 y), and patients had Eastern Cooperative Oncology Group performance status of 0 (n = 42), 1 (n = 35), or 2 (n = 14). OS-6 rate was 62.1% (95% confidence interval [CI], 48.4–74.5) with bevacizumab and 73.3% (95% CI, 54.1–87.7) with fotemustine. OS-6 rates were lower in bevacizumab-treated patients with MGMT promoter methylated tumors than in those with unmethylated tumors (50% and 85%, respectively), but higher in fotemustine-treated patients (87.5% and 50%, respectively). OS rates at 9 months were 37.9% (95% CI, 25.5–51.6) and 46.7% (95% CI, 28.3–65.7) with bevacizumab and fotemustine, respectively, and median OS was 7.3 months (95% CI, 5.8–9.2) and 8.7 months (95% CI, 6.3–15.4), respectively. Toxicity was as expected with the 2 agents.

Conclusion

Single-agent bevacizumab may have a role in patients with recurrent glioblastoma.

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Contents_Page

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Components of the eIF4F complex are potential therapeutic targets for malignant peripheral nerve sheath tumors and vestibular schwannomas

Background

The eukaryotic initiation factor 4F (eIF4F) complex plays a pivotal role in protein translation initiation; however, its importance in malignant and benign Schwann cell tumors has not been explored, and whether blocking eIF4F function is effective for treating these tumors is not known.

Methods

Immunostaining was performed on human malignant peripheral nerve sheath tumors (MPNSTs) and vestibular schwannomas (VSs) for eIF4F components. The role of eIF4A and eIF4E in cell growth was assessed by RNA interference. Various natural compounds were screened for their growth-inhibitory activity. Flow cytometry and Western blotting were performed to characterize the action of silvestrol, and its antitumor activity was verified in orthotopic mouse models.

Results

MPNSTs and VSs frequently overexpressed eIF4A, eIF4E, and/or eIF4G. Depletion of eIF4A1, eIF4A2, and eIF4E substantially reduced MPNST cell growth. From screening a panel of plant-derived compounds, the eIF4A inhibitor silvestrol was identified as a leading agent with nanomolar IC₅₀ values in MPNST and VS cells. Silvestrol induced G₂/M arrest in both NF1-deficient and NF1-expressing MPNST cells and primary VS cells. Silvestrol consistently decreased the levels of multiple cyclins, Aurora A, and mitogenic kinases AKT and ERKs. Silvestrol treatment dramatically suppressed tumor growth in mouse models for NF1^–/– MPNST and Nf2^–/– schwannoma. This decreased tumor growth was accompanied by elevated phospho-histone H3 and TUNEL labeling, consistent with G₂/M arrest and apoptosis in silvestrol-treated tumor cells.

Conclusions

The eIF4F complex is a potential therapeutic target in MPNSTs and VS, and silvestrol may be a promising agent for treating these tumors.

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Corticosteroids for peritumoral edema: time to overcome our addiction?

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Response to: "Prognostic relevance of epilepsy at presentation in lower-grade gliomas"

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PET imaging in glioma: is it time for mainstream practice?

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MiR-301a is activated by the Wnt/{beta}-catenin pathway and promotes glioma cell invasion by suppressing SEPT7

Background

miR-301a is frequently dysregulated and specific to human tumors, playing a critical role in tumorigenesis; however, the exact functions and regulatory mechanisms of miR-301a in glioma cells remain largely unknown. Herein, we show that miR-301a activated by the Wnt/β-catenin pathway promoted the invasion of glioma cells by directly targeting SEPT7.

Methods

Biochemical, luciferase reporter, and hromatin immunoprecipitation PCR assays characterized the function and regulatory mechanisms of miR-301a in glioma invasion.

Results

Initially, we detected the expression of miR-301a in glioma tissues and identified that miR-301a had increased, with ascending grades of the tumor. Furthermore, high levels of miR-301a were associated with a poorer prognosis in glioma patients. It is important to note that the Wnt/β-catenin/TCF4 pathway enhanced miR-301a expression by binding to the promoter region. To determine the oncogenic functions of miR-301a in glioma, SEPT7 was supported as the direct target gene. In addition, the Wnt/β-catenin pathway repressed SEPT7 expression, which was dependent on miR-301a in glioma cells. Finally, miR-301a was activated by Wnt/β-catenin and then promoted invasion of glioma cells by inhibiting the expression of SEPT7 in vitro and in vivo.

Conclusions

Our findings revealed the mechanism of action for miR-301a in tumor cell invasion. Moreover, the Wnt/miR-301a/SEPT7 signaling axis might be a novel target in treating glioma.

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Highlights from the Literature

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Phase I trial of p28 (NSC745104), a non-HDM2-mediated peptide inhibitor of p53 ubiquitination in pediatric patients with recurrent or progressive central nervous system tumors: A Pediatric Brain Tumor Consortium Study

Background

p53 is a promising target in human cancer. p28 is a cell-penetrating peptide that preferentially enters cancer cells and binds to both wild-type and mutant p53 protein, inhibiting COP1-mediated ubiquitination and proteasomal degradation. This results in increased levels of p53, which induces cell cycle arrest at G₂/M. We conducted a phase I study to determine the maximum-tolerated dose (MTD) and describe the dose-limiting toxicities (DLTs) and pharmacokinetics (PKs) of p28 in children.

Methods

Children aged 3–21 years with recurrent or progressive central nervous system tumors were eligible. Intravenous p28 was administered 3 times weekly for 4 consecutive weeks of a 6-week cycle at 4.16 mg/kg/dose (the adult recommended phase II dose) using a rolling-6 study design. Expression status of p53 was characterized by immunohistochemistry, and serum PK parameters were established on the second dose.

Results

Of the 18 eligible patients enrolled in the study, 12 completed the DLT monitoring period and were evaluable for toxicity. p28 was well-tolerated; 7 participants received ≥2 courses, and the most common adverse event attributed to the drug was transient grade 1 infusion-related reaction. PK analysis revealed a profile similar to adults; however, an increased area under the curve was observed in pediatric patients. High p53 expression in tumor cell nuclei was observed in 6 of 12 available tissue samples. There were no objective responses; 2 participants remained stable on the study for >4 cycles.

Conclusions

This phase I study demonstrated that p28 is well-tolerated in children with recurrent CNS malignancies at the adult recommended phase II dose.

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Response Assessment in Neuro-Oncology working group and European Association for Neuro-Oncology recommendations for the clinical use of PET imaging in gliomas

This guideline provides recommendations for the use of PET imaging in gliomas. The review examines established clinical benefit in glioma patients of PET using glucose (¹⁸F-FDG) and amino acid tracers (¹¹C-MET, ¹⁸F-FET, and ¹⁸F-FDOPA). An increasing number of studies have been published on PET imaging in the setting of diagnosis, biopsy, and resection as well radiotherapy planning, treatment monitoring, and response assessment. Recommendations are based on evidence generated from studies which validated PET findings by histology or clinical course. This guideline emphasizes the clinical value of PET imaging with superiority of amino acid PET over glucose PET and provides a framework for the use of PET to assist in the management of patients with gliomas.

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Announcements

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Creation of an NCI comparative brain tumor consortium: informing the translation of new knowledge from canine to human brain tumor patients

On September 14–15, 2015, a meeting of clinicians and investigators in the fields of veterinary and human neuro-oncology, clinical trials, neuropathology, and drug development was convened at the National Institutes of Health campus in Bethesda, Maryland. This meeting served as the inaugural event launching a new consortium focused on improving the knowledge, development of, and access to naturally occurring canine brain cancer, specifically glioma, as a model for human disease. Within the meeting, a SWOT (strengths, weaknesses, opportunities, and threats) assessment was undertaken to critically evaluate the role that naturally occurring canine brain tumors could have in advancing this aspect of comparative oncology aimed at improving outcomes for dogs and human beings. A summary of this meeting and subsequent discussion are provided to inform the scientific and clinical community of the potential for this initiative. Canine and human comparisons represent an unprecedented opportunity to complement conventional brain tumor research paradigms, addressing a devastating disease for which innovative diagnostic and treatment strategies are clearly needed.

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A new patient-derived orthotopic malignant meningioma model treated with oncolytic herpes simplex virus

Background

Higher-grade meningiomas (HGMs; World Health Organization grades II and III) pose a clinical problem due to high recurrence rates and the absence of effective therapy. Preclinical development of novel therapeutics requires a disease model that recapitulates the genotype and phenotype of patient HGM. Oncolytic herpes simplex virus (oHSV) has shown efficacy and safety in cancers in preclinical and clinical studies, but its utility for HGM has not been well characterized.

Methods

Tumorsphere cultures and serial orthotopic xenografting in immunodeficient mice were used to establish a patient-derived HGM model. The model was pathologically and molecularly characterized by immunohistochemistry, western blot, and genomic DNA sequencing and compared with the patient tumor. Anti-HGM effects of oHSV G47 were assessed using cell viability and virus replication assays in vitro and animal survival analysis following intralesional injections of G47.

Results

We established a serially transplantable orthotopic malignant meningioma model, MN3, which was lethal within 3 months after tumorsphere implantation. MN3 xenografts exhibited the pathological hallmarks of malignant meningioma such as high Ki67 and vimentin expression. Both the patient tumor and xenografts were negative for neurofibromin 2 (merlin) and had the identical NF2 mutation. Oncolytic HSV G47 efficiently spread and killed MN3 cells, as well as other patient-derived HGM lines in vitro. Treatment with G47 significantly extended the survival of mice bearing subdural MN3 tumors.

Conclusions

We established a new patient-derived meningioma model that will enable the study of targeted therapeutic approaches for HGM. Based on these studies, it is reasonable to consider a clinical trial of G47 for HGM.

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Glycolysis and the pentose phosphate pathway are differentially associated with the dichotomous regulation of glioblastoma cell migration versus proliferation

Background

The dichotomy between glioblastoma cell migration and proliferation is regulated by various parameters including oxygen tension. In glioblastoma stem-like cells, hypoxia induces downregulation of pentose phosphate pathway (PPP) enzymes and a flux shift towards glycolysis. We investigated whether the 2 parallel glucose metabolic pathways are intrinsically linked with cell function and whether these pathways are mechanistically involved in regulating functional programs.

Methods

Enzyme expression, migration, and proliferation under hypoxia were studied in multiple cell types. Rapidly and slowly dividing or migrating glioblastoma cells were separated, and enzyme profiles were compared. Glucose-6-phosphate dehydrogenase (G6PD) and Aldolase C (ALDOC), the most strongly inversely regulated PPP and glycolysis enzymes, were knocked down by short hairpin RNA.

Results

Hypoxia caused downregulation of PPP enzymes and upregulation of glycolysis enzymes in a broad spectrum of cancer and nonneoplastic cells and consistently stimulated migration while reducing proliferation. PPP enzyme expression was increased in rapidly dividing glioblastoma cells, whereas glycolysis enzymes were decreased. Conversely, glycolysis enzymes were elevated in migrating cells, whereas PPP enzymes were diminished. Knockdown of G6PD reduced glioblastoma cell proliferation, whereas ALDOC knockdown decreased migration. Enzyme inhibitors had similar effects. G6PD knockdown in a highly proliferative but noninvasive glioblastoma cell line resulted in prolonged survival of mice with intracerebral xenografts, whereas ALDOC knockdown shortened survival. In a highly invasive glioblastoma xenograft model, tumor burden was unchanged by either knockdown.

Conclusions

Cell function and metabolic state are coupled independently of hypoxia, and glucose metabolic pathways are causatively involved in regulating "go or grow" cellular programs.

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Primary CNS lymphoma at first relapse/progression: characteristics, management, and outcome of 256 patients from the French LOC network

Background

Treatment of relapsed/refractory (R/R) primary CNS lymphoma (PCNSL) is poorly defined, because randomized trials and large studies are lacking. The aim of this study was to analyze the characteristics, management, and outcome of R/R PCNSL patients after first-line therapy in a nationwide cohort.

Methods

We analyzed R/R PCNSL patients following first-line treatment who had been prospectively registered in the database of the French network for oculocerebral lymphoma (LOC) between 2011 and 2014.

Results

Among 563 PCNSL patients treated with first-line therapy, we identified 256 with relapsed (n = 93, 16.5%) or refractory (n = 163, 29.0%) disease. Patients who were asymptomatic at relapse/progression (25.5%), mostly diagnosed on routine follow-up neuroimaging, tended to have a better outcome. Patients who received salvage therapy followed by consolidation (mostly intensive chemotherapy plus autologous hematopoietic stem cell transplantation [ICT + AHSCT]) experienced prolonged survival compared with those who did not receive salvage or consolidation therapy. Independent prognostic factors at first relapse/progression were: KPS ≥ 70 vs KPS < 70), sensitivity to first-line therapy (relapsed vs refractory disease), duration of first remission (progression-free survival [PFS] ≥1 y vs <1 y), and management at relapse/progression (palliative care vs salvage therapy). Patients who relapsed early after first-line therapy (ie, PFS < 1 y) had a poor outcome, comparable to that of refractory patients. Conversely, patients experiencing late relapses (PFS ≥ 1 y) and/or undergoing consolidation with ICT + AHSCT experienced prolonged survival.

Conclusions

About a third of PCNSL patients are primary refractory to first line treatment. We identified several independent prognostic factors that can guide the management of R/R PCNSL patients.

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Novel MET/TIE2/VEGFR2 inhibitor altiratinib inhibits tumor growth and invasiveness in bevacizumab-resistant glioblastoma mouse models

Background

Glioblastoma highly expresses the proto-oncogene MET in the setting of resistance to bevacizumab. MET engagement by hepatocyte growth factor (HGF) results in receptor dimerization and autophosphorylation mediating tumor growth, invasion, and metastasis. Evasive revascularization and the recruitment of TIE2-expressing macrophages (TEMs) are also triggered by anti-VEGF therapy.

Methods

We investigated the activity of altiratinib (a novel balanced inhibitor of MET/TIE2/VEGFR2) against human glioblastoma stem cell lines in vitro and in vivo using xenograft mouse models. The biological activity of altiratinib was assessed in vitro by testing the expression of HGF-stimulated MET phosphorylation as well as cell viability after altiratinib treatment. Tumor volume, stem cell and mesenchymal marker levels, microvessel density, and TIE2-expressing monocyte infiltration were evaluated in vivo following treatment with a control, bevacizumab alone, bevacizumab combined with altiratinib, or altiratinib alone.

Results

In vitro, HGF-stimulated MET phosphorylation was completely suppressed by altiratinib in GSC17 and GSC267, and altiratinib markedly inhibited cell viability in several glioblastoma stem cell lines. More importantly, in multiple xenograft mouse models, altiratinib combined with bevacizumab dramatically reduced tumor volume, invasiveness, mesenchymal marker expression, microvessel density, and TIE2-expressing monocyte infiltration compared with bevacizumab alone. Furthermore, in the GSC17 xenograft model, altiratinib combined with bevacizumab significantly prolonged survival compared with bevacizumab alone.

Conclusions

Together, these data suggest that altiratinib may suppress tumor growth, invasiveness, angiogenesis, and myeloid cell infiltration in glioblastoma. Thus, altiratinib administered alone or in combination with bevacizumab may overcome resistance to bevacizumab and prolong survival in patients with glioblastoma.

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Upfront bevacizumab may extend survival for glioblastoma patients who do not receive second-line therapy: an exploratory analysis of AVAglio

Background

In this post-hoc, exploratory analysis, we examined outcomes for patients enrolled in the AVAglio trial of front-line bevacizumab or placebo plus radiotherapy/temozolomide who received only a single line of therapy.

Methods

Patients with newly diagnosed glioblastoma received protocol-defined treatment until progressive disease (PD). Co-primary endpoints were investigator-assessed progression-free survival (PFS) and overall survival (OS). After confirmed PD, patients were treated at the investigators' discretion. PFS/OS were assessed in patients with a PFS event who did not receive post-PD therapy (Group 1) and patients with a PFS event who received post-PD therapy plus patients who did not have a PFS event at the final data cutoff (Group 2). Kaplan–Meier methodology was used. A multivariate Cox proportional hazards model for known prognostic variables was generated.

Results

Baseline characteristics were balanced. In patients with a PFS event who did not receive post-PD therapy (Group 1; n = 225 [24.4% of the intent-to-treat population]), the addition of bevacizumab to radiotherapy/temozolomide resulted in a 3.6-month extension in both median PFS (hazard ratio [HR]: 0.62, P = .0016) and median OS (HR: 0.67, P = .0102). Multivariate analyses supported this OS benefit (HR: 0.66). In the remaining patients (Group 2; n = 696), a 5.2-month PFS extension was observed in bevacizumab-treated patients (HR: 0.61, P < .0001); OS was comparable between the treatment arms (HR: 0.88, P = .1502). No significant differences in safety were observed between the 2 groups.

Conclusion

This exploratory analysis suggests that the addition of bevacizumab to standard glioblastoma treatment prolongs PFS and OS for patients with PD who receive only one line of therapy.

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Corrigendum

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Headache yesterday in Karnataka state, India: prevalence, impact and cost

The Global Campaign against Headache has pioneered evaluation of the prevalence and impact of headache on the preceding day ("headache yesterday") as a new approach to the estimation of headache-attributed bur...

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Exablate Neuro Focused Ultrasound System Effectively Treats Essential Tremor Without Surgery

The New England Journal of Medicine just published a study evaluating InSightec's Exablate Neuro focused ultrasound system for treatment of essential tremor. The system received FDA approval to market the device only last month and the study results make clear why. Essentially, transcranial focused ultrasound thalamotomy was effective in reducing hand tremor at three and stayed reduced compared to a control group a year following treatment.

There were side effects, such as unusual sensations felt by 38% of patients that stayed with 14% a year after therapy was administered. About the same numbers apply to people who experienced gait disturbances. This is not unexpected since even though there's no traditional incision, lesions are created where the ultrasound energy is delivered and concentrated.

All this is very positive not just for patients with essential tremor, but also the future benefits that these findings herald for focused ultrasound in other applications.

Here are the basic findings from the study abstract:

Seventy-six patients were included in the analysis. Hand-tremor scores improved more after focused ultrasound thalamotomy (from 18.1 points at baseline to 9.6 at 3 months) than after the sham procedure (from 16.0 to 15.8 points); the between-group difference in the mean change was 8.3 points (95% confidence interval [CI], 5.9 to 10.7; P<0.001). The improvement in the thalamotomy group was maintained at 12 months (change from baseline, 7.2 points; 95% CI, 6.1 to 8.3). Secondary outcome measures assessing disability and quality of life also improved with active treatment (the blinded thalamotomy cohort)as compared with the sham procedure (P<0.001 for both comparisons). Adverse events in the thalamotomy group included gait disturbance in 36% of patients and paresthesias or numbness in 38%; these adverse events persisted at 12 months in 9% and 14% of patients, respectively.

Here's an InSightec video explaining the Exablate Neuro:

Flashback: Exablate Neuro MRI-Guided Focused Ultrasound for Essential Tremor Now Available in U.S…

Study in NEJM: A Randomized Trial of Focused Ultrasound Thalamotomy for Essential Tremor…

This post Exablate Neuro Focused Ultrasound System Effectively Treats Essential Tremor Without Surgery appeared first on Medgadget.

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Adding checkpoint inhibitors to tyrosine kinase inhibitors targeting EGFR/ALK in non-small cell lung cancer: a new therapeutic strategy

Summary

After the massive approval of checkpoint inhibitors in the treatment of numerous malignancies and settings, checkpoint inhibitors-based combination therapies are emerging as a new therapeutic modality. Nivolumab and pembrolizumab (anti-PD1 agents) were recently approved as second-line treatment in NSCLC after progression on platinum-doublets. In parallel, targeting EGFR/ALK in NSCLC using tyrosine kinase inhibitors (TKI) demonstrated remarkable outcomes and was approved as standard treatment, in patients with EGFR mutation or ALK rearrangement. Combining TKI targeting EGFR/ALK with checkpoint inhibitors seems a promising therapeutic option and is being evaluated in different trials. We aimed in this paper to elucidate the rationale behind this combination, to report the premilinary results of ongoing trials evaluating this association and finally, to discuss briefly the possible future indication of this treatment modality.

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FPGA-based accurate star segmentation with moon interference

Abstract

Star sensors, which are based on matching obtained star information to the star catalogue, are instruments widely used to determine a spacecraft's attitude in space. Thus, a highly accurate extraction of real-time star information is a major issue in star sensor designs. In this study, a novel field programmable gate array (FPGA)-based accurate star segmentation algorithm is proposed to satisfy real-time requirements. Windows with a star or its parts are found using a maximum filtering based local gradient and local gradient threshold that is adaptively calculated using the local mean. An adaptive threshold, which is based on local mean and local median, can be used to determine whether the center pixel of the window is a pixel of a star. The algorithm can properly segment bright and dark stars, and completely eliminate moon interference. A precision of <0.09 pixels can be maintained in images at different Gaussian noise levels. A parallel and pipeline architecture also utilized in FPGA implementation, and the processing time is 22.22 ms for a 2048 × 2048 gray-level image.

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Sequential Multiple LSB methods and real-time data hiding: variations for Visual Cryptography ciphers

Abstract

In this paper, a general model approach of real-time data hiding and watermarking for image, video and audio communications is proposed. The aim is the development of security robustness variations and data-rate (capacity) extensions of Steganography fast schemes for RT (real time) or NRT (near real time) image, video and audio media communication and data hiding, with no significant distortion of the medium. Additionally, this paper includes the proposal of specific case models such as Steganography of the total of Visual Cryptography schemes of black and white images. Influenced by our survey on Spatial Domain Steganography techniques such as Multiple LSB (Least Significant Bit) algorithm, Matrix Embedding and Parity Coding, a new potential method is introduced called in brief from now on SMLSB (Sequential Multiple LSB) method comparing other respective methods and algorithms researched, SMLSB is a different approach on real-time and non-real-time data hiding, which gives an advantage of robustness, while it provides various modes of the method depending on the requirements. Also the method can be used for the specific occasion of Visual Cryptography Ciphers' Steganography.

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Digital mammography versus digital breast tomosynthesis for detection of breast cancer in the intraoperative specimen during breast-conserving surgery

Abstract

Purpose

To compare the diagnostic ability of specimen radiography using digital mammography (DM) and digital breast tomosynthesis (DBT) for detecting breast cancer and evaluating its extension in the intraoperative specimen.

Methods

Sixty-five specimens from 65 women (median 62 years; range 34–86) obtained during breast-conserving surgery were prospectively investigated. Specimens underwent DM (25–40 kVp, 12–322 mA s) and DBT (25–34 kVp, 13–137 mA) in two orthogonal planes, anteroposterior (AP) and latero-lateral (LL). Images were interpreted by a radiologist to detect invasive lesions and their extensive intraductal components (EIC) or ductal carcinomas in situ (DCIS); afterwards, they were compared with histopathological findings.

Results

In AP views, 96 % of the invasive lesions were detected by both the methods. Of the EICs, 55 and 65 % were detected by DM and DBT, respectively (P = 0.61). Of the DICSs, 31 and 38 % were detected by DM and DBT, respectively (P > 0.99). In LL views, 71 and 13 % of the invasive lesions were detected by DBT and DM, respectively (P < 0.0001). Of the EICs, 42 and 10 % were detected by DBT and DM, respectively (P = 0.0078). Of the 13 DCISs, 42 and 8 % were detected by DBT and DM, respectively (P = 0.32). The whole lesion and contour could be delineated in 45 % by DBT and in 6.2 % by DM (P < 0.0001).

Conclusions

DBT could detect breast cancer more accurately than DM in LL views, indicating its potential to more precisely diagnose vertical invasion.

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Phase 3, open-label, randomized study comparing 3-monthly with monthly goserelin in pre-menopausal women with estrogen receptor-positive advanced breast cancer

Abstract

Background

Monthly goserelin 3.6 mg dosing suppresses estradiol (E2) production and has proven efficacy in pre-menopausal women with estrogen receptor (ER)-positive breast cancer. This non-inferiority study evaluated the efficacy and safety of 3-monthly goserelin 10.8 mg compared with monthly goserelin 3.6 mg.

Methods

This was a Phase 3, open-label, multicenter trial. Pre-menopausal women with ER-positive advanced breast cancer were randomized to 3-monthly goserelin 10.8 mg or monthly goserelin 3.6 mg; all patients received concomitant tamoxifen (20 mg daily). The primary endpoint was progression-free survival (PFS) rate at 24 weeks; non-inferiority was to be confirmed if the entire 95 % confidence interval (CI) for the treatment difference was above −17.5 %. Secondary endpoints included objective response rate (ORR), serum E2 levels, safety, and tolerability.

Results

In total, 222 patients were randomized (goserelin 10.8 mg, n = 109; goserelin 3.6 mg, n = 113). PFS rate at week 24 was 61.5 % (goserelin 10.8 mg) and 60.2 % (goserelin 3.6 mg); treatment difference (95 % CI) was 1.3 % (−11.4, 13.9), confirming non-inferiority of goserelin 10.8 mg compared with goserelin 3.6 mg. ORR was 23.9 % (goserelin 10.8 mg) and 26.9 % (goserelin 3.6 mg); treatment difference (95 % CI) was −3.0 % (−15.5, 9.7). At week 24, mean serum E2 concentrations were similar in the goserelin 10.8 mg and goserelin 3.6 mg groups (20.3 pg/mL and 24.8 pg/mL, respectively).

Conclusion

A regimen of 3-monthly goserelin 10.8 mg demonstrated non-inferiority compared with monthly goserelin 3.6 mg for PFS rate at 24 weeks, with similar pharmacodynamic and safety profiles, in pre-menopausal women with ER-positive breast cancer.

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Effect of tamoxifen and fulvestrant long-term treatments on ROS production and (pro/anti)-oxidant enzymes mRNA levels in a MCF-7-derived breast cancer cell line

Abstract

Background

Reactive oxygen species (ROS) are key players in the apoptotic effects induced by short-term tamoxifen treatment of breast cancer cells, but also in acquired resistance following long-term treatment. Whereas the use of the selective estrogen receptor down-regulator fulvestrant is promising, especially in patients who develop tamoxifen resistance, only few studies addressed its implication in the modulation of cellular redox status.

Methods

The regulation of (pro/anti)-oxidant players were first investigated at the mRNA level in a MCF-7-derived cell line after short-term (24 h) estradiol treatment. Long-term anti-estrogen treated MCF-7 derived cell lines were also developed: 3 months of 4-hydroxytamoxifen alone (MCF7L-OHTLT) or followed by 3 months of fulvestrant (MCF7L-ICILT). Growth properties, hormone sensitivity, receptor content, ROS production and relative mRNA expression of pro or antioxidant enzymes were evaluated in these long-term treated cell lines.

Results

Short-term estradiol treatment showed a hormone sensitivity of Nox2, GPx1, GPx2 and SOD1 mRNA levels. The long-term fulvestrant treatment (3 months) of MCF7L-OHTLT led to a reduced level of ROS production accompanied with a drastic drop of the accessory protein p22^phox mRNA. This ROS reduction, although not clearly related to antioxidant enzymes level, seems to be involved in fulvestrant sensitivity of long-term anti-estrogen treated cells, as suggested by the effects of antiradical tempol treatment.

Conclusion

When compared to long-term 4-hydroxytamoxifen-treated breast cancer cells, addition of fulvestrant treatment was able to diminish ROS production and p22^phox mRNA level, and made cells more sensitive to growth inhibition induced by tempol. These effects may be a valuable asset of the fulvestrant treatment.

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Comparison between Ki67 labeling index determined using image analysis software with virtual slide system and that determined visually in breast cancer

Abstract

Background

In recent papers, Ki67 labeling index (LI) has been used to classify breast cancer patients into the low and high Ki67LI groups for comparison studies, which showed significant differences in many prognostic factors. It has not been clarified whether image analysis software can be used for calculating LI in breast cancer. In our study, we examined whether Ki67LI in breast cancer calculated using image analysis software correlates with that measured on the basis of visual.

Methods

Fifty patients were randomly selected among breast cancer patients who underwent surgical operation from March, 2010 to May, 2010 in our hospital without preoperative chemotherapy. In this study, for the virtual slide system (VSS: VS120-L100, Olympus, Tokyo, Japan), the high-resolution VSs of all the 50 patients were prepared as samples. The image analysis software use for calculating LI was Tissuemorph Digital Pathology (Tissuemorph DP: Visiopharm, Hoersholm, Denmark). The calculated LI was extracted from 3 to 5 views containing hot spots. The LI calculated using Tissuemorph DP was designed as LI/image/T. The digital image of 3 to 5 LI/image/T views was printed out, and on the digital photograph, we counted visually the number of Ki67-immunopositive cells in exactly the same area, and the percentage of Ki67-immunopositive cells was designed as LI/direct. Moreover, a pathologist's assistant (PA) determined the tumor area in the same specimen using VSS and calculated LI using Tissuemorph DP, which was designed as LI/image/PA. The chief pathologist (CP) similarly calculated LI which was designed as LI/image/CP. We evaluated the degree of agreement between different data sets "LI/image/T and LI/direct" and "LI/image/T, LI/image/CP, and LI/image/PA" by using interclass correlation coefficient (ICC).

Results

The average counts of cells were as follows: LI/direct, 3209.7 ± 1970.4 (SD); LI/image/T, 2601.6 ± 1697.1; LI/image/PA, 2886.5 ± 2027.5; LI/image/CP, 18805.5 ± 22293.4. The values of LI/direct and LI/image/T showed almost perfect agreement as showed by an ICC of 0.885 (95 % CI, 0.806–0.933; p < 0.001). The agreement among three investigators was almost perfect. The obtained ICC was 0.825 (95 % CI, 0.739–0.890; p < 0.001) among the data of LI/image/T, LI/image/CP and LI/image/PA. There were five cases that immunopositivity for Ki67 showed a more than 10 % disagreement between LI/direct and LI/image/T.

Conclusion

The merits of calculating Ki67 LI using Tissuemorph DP are as follows. First, the staining intensity of the cells to be counted can be adjusted. Second, the portion of a tumor including "hot spots" for counting can be chosen. Third, many cancer cells can be counted more rapidly using Tissuemorph DP than by visual observation. However, it is important that pathologist should check and carry out the final decision of the data, when Ki67 LI using Tissuemorph DP is calculated.

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Nipple malposition after nipple-sparing mastectomy and expander–implant reconstruction

Abstract

Background

Nipple malposition after nipple-sparing mastectomy and expander–implant reconstruction performed in our institute between 2002 and 2010 was studied retrospectively, targeting breast ptosis and volume.

Methods

The preoperative nipple position relative to the inframammary fold was used as the breast ptosis index. The intraoperative resected breast tissue was measured and used as the volume index. For pre- and postoperative photograph evaluation, the vertical distance of the nipple was defined as the distance from the nipple to the midpoint of the bottoms of the sternocleidomastoid muscle. The vertical distance ratio was defined as the postoperative affected-side/unaffected-side vertical distance to the preoperative one. A correlation analysis was carried out comparing the vertical distance ratios with the preoperative nipple position relative to the inframammary fold and resection tissue weight.

Results

A total of 42 cases using the expander–implant method were analyzed. The mean vertical distance ratio was 0.88. There was a comparatively high correlation between the vertical distance ratio and the resection tissue weight (correlation coefficient −0.53, P = 0.0003) and between the vertical distance ratio and the preoperative nipple position relative to the inframammary fold (correlation coefficient 0.37, P = 0.0152).

Conclusion

In expander–implant reconstruction of a large or ptotic breast, nipple-sparing mastectomy should be performed with the expectation that ancillary procedures will be needed.

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Cytological features of complex type fibroadenoma in comparison with non-complex type fibroadenoma

Abstract

Background

To determine the cytomorphological features of complex type fibroadenoma (CFA), we reviewed fine needle aspiration (FNA) cytology with correlation to its histopathology findings, and compared them with non-complex type fibroadenoma (NCFA).

Methods

From excisional biopsy or resected specimens of fibroadenoma (FA) cases treated at our institution from 2004 to 2013, we chose 46 patients who underwent FNA before a diagnosis of FA was established. We histologically re-classified them into two groups: CFA and NCFA. FNA diagnosis was retrospectively re-evaluated from FNA reports. We further re-assessed detailed characteristics of each FNA smears to identify cytomorphological features of CFA.

Results

We found that 15 cases fulfilled the diagnostic criteria of CFA, in which 7 (46.7 %) had an FNA diagnosis of "suspicious for malignancy" or "indeterminate" while only 2 NCFA cases had that of "indeterminate" (p = 0.004). FNA smears from CFA cases showed discohesiveness, enlarged nuclei, prominent nucleoli, and fewer myoepithelial cells more often than NCFA. Although no significant difference was noted in patients' age and tumor size between CFA and NCFA, 5 CFA cases (33.3 %) were accompanied by the presence of carcinoma in the same breast or the contralateral breast while no NCFA cases had carcinoma in the breast.

Conclusions

FNA of CFA can lead to erroneous or indeterminate interpretation, due to proliferative and/or hyperplastic changes of ductal epithelium with or without atypia. It is important to recognize the disease entity and characteristic cytomorphological findings of CFA to reach accurate FNA diagnosis of breast lesions.

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The value of primary tumor 18 F-FDG uptake on preoperative PET/CT for predicting intratumoral lymphatic invasion and axillary nodal metastasis

Abstract

Background

The preoperative evaluation of axillary lymph node (LN) status is important for prognostic prediction of breast cancer. We investigated the ability of ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT) to predict intratumoral lymphatic invasion and axillary LN metastasis.

Methods

The preoperative ¹⁸F-FDG PET/CT images and pathologic reports for 428 breast cancer patients between January 2003 and December 2008 were evaluated retrospectively. The maximum standardized uptake value (SUV_max) of the primary tumor on ¹⁸F-FDG PET/CT, the degree of lymphatic invasion, and axillary LN metastasis identified by pathologic reports were assessed. Univariate and multivariate logistic regression analyses were performed to identify the significant features of the primary tumor that were associated with pathologically confirmed axillary LN metastasis.

Results

The mean SUV_max of primary tumors with lymphatic invasion was higher than that of tumors without lymphatic invasion (5.13 ± 3.49 vs. 3.00 ± 2.47; p < 0.0001). The mean SUV_max of primary tumors with pathologically confirmed axillary LN metastasis was higher than that of tumors without LN metastasis (4.93 ± 3.32 vs. 3.22 ± 2.78; p < 0.0001). The degree of lymphatic invasion correlated strongly with axillary LN metastasis (p = 0.0001). Multiple logistic regression analysis showed that the high SUV_max of the primary tumor (>2.8), the high SUV_max of the axillary LN (>0.72) and the degree of lymphatic invasion were significant predictive factors of the development of axillary LN metastasis.

Conclusion

Breast cancer patients with higher primary tumor ¹⁸F-FDG uptake are at higher risk of concurrent intratumoral lymphatic invasion and axillary LN metastasis.

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The influence of familial factors on the choice of the place of death for terminally ill breast cancer patients: a retrospective single-center study

Abstract

Background

The social or familial factors influencing the location chosen for end-of-life (EOL) care for terminally ill breast cancer patients are unknown.

Methods

We retrospectively analyzed 195 patients with recurrent or progressive breast cancer who received anticancer treatment at the National Cancer Center Hospital between January 2008 and May 2012. Detailed data concerning the patients' demographic, familial, and clinical characteristics were collected, and multivariate and Cox logistic regression analyses were performed to evaluate the impact of these characteristics on the place of EOL care and on survival, respectively.

Results

Sixty-eight patients (34.9 %) died in a hospital, 26 patients (13.3 %) at home, and 101 patients (51.8 %) in hospice. Most of the patients having caregivers received EOL care at palliative care facilities (hospice or home) [odds ratio (OR) 2.57; 95 % confidence interval (CI) 1–6.6; p = 0.05]. In contrast, patients with factors suggesting a clinically severe status (performance status ≥2, use of opioids, delirium, and ascites) more often received EOL care in a hospital. Among patients who received EOL care at hospice or home, patients with minor children received EOL care at home (OR 0.08; 95 % CI 0.02–0.38; p = 0.001). Patients with brain metastases chose hospice (OR 12.37; 95 % CI 2.25–68.13; p = 0.004). Furthermore, having a caregiver was associated with prolonged survival (hazard ratio 0.62; 95 % CI 0.39–0.97; p = 0.035).

Conclusion

Familial factors such as having children and caregivers significantly influenced the place of EOL care for terminally ill breast cancer patients.

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Preoperatively diagnosed ductal carcinoma in situ: risk prediction of invasion and effects on axillary management

Abstract

Background

Preoperatively diagnosed ductal carcinoma in situ (DCIS) has the potential to have occult invasion. The predictors of invasive carcinoma underestimation in patients with DCIS diagnosed by preoperative percutaneous biopsy were identified and the effects of underestimation on axillary management were evaluated.

Methods

Medical records of 280 patients preoperatively diagnosed as DCIS who underwent surgery were retrospectively analyzed. The patients were divided into non-invasive and invasive carcinoma groups according to the final pathological diagnosis. Risk predictors of invasive carcinoma underestimation and axillary lymph node (ALN) metastasis were analyzed. The axillary status estimated by pathological diagnosis and one-step nucleic acid amplification (OSNA) assay was evaluated.

Results

The presence of an invasive carcinoma was overlooked in 104 (37.1 %) patients. A clinically palpable mass was an independent risk predictor of invasive carcinoma underestimation by multivariate analysis. There was no risk predictor of ALN metastasis. No ALN metastasis was seen in non-invasive carcinoma group. Six (6.2 %) patients in invasive carcinoma group had macro- or micrometastasis in sentinel lymph nodes (SLNs). Non-SLN metastasis was observed in 3 patients of them. Fourteen patients with only isolated tumor cells (ITCs) or only OSNA-positive SLNs had no metastasis in non-SLNs.

Conclusions

SLN biopsy and, if necessary, subsequent ALN dissection (ALND) should be performed in patients with DCIS who have a risk predictor of underestimation. ALND can be avoided in patients who have histologically negative or ITC-positive SLNs, regardless of the presence of invasion on final pathological diagnosis.

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Dissimilarity between sporadic, non-BRCA1/2 families and hereditary breast cancer, linked to BRCA genes, in the Tunisian population

Abstract

Background

Most breast cancers (90 %) are sporadic. Only 5–10 % of all cancer cases can be attributed to genetic defects. BRCA genes are strongly incriminated in the hereditary predisposition to the disease. The purpose of our study was to provide more efficient approach to identify pathogenic BRCA mutation carriers and to determine subgroups within the non-BRCA tumor class.

Methods

Different clinicopathological features, reproductive factors, as well as psychosocial ones were compared in women carrying mutations in the BRCA1/BRCA2 genes (12 cases) with non-BRCA1/2 family tumors (36 cases) and age-matched sporadic cases, unselected for family history (44 cases).

Results

A BRCA‐related class was yielded based on age at diagnosis (age ≤ 35 years; p = 0.1), molecular subtypes(the triple-negative subtype was predominant: 43 % of cases; p = 0.025) and age at menarche (p = 0.04). Furthermore, a "probably sporadic" class was distinguished using hormonal contraceptive use (through 30–40 years of age; p = 0.039), the number of full-term pregnancies (age ≥40 years; p = 0.01), age at menopause(age > 50 years; p = 0.04) and psychosocial factors (age ≥ 40 years; p = 0.01). However, analysis of non-BRCA1/2 family tumors indicated that they constitute a heterogeneous class, showing few perceptible differences with sporadic group, but distinct from BRCA1/2 tumors.

Conclusions

In Tunisian population, breast cancer can be classified with a high level of accuracy as sporadic or related to BRCA germline mutations by combining different clinicopathological features and reproductive factors. This can be clinically useful in genetic counseling and decision making for BRCA genetic test.

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Magnetic resonance examination to predict pathological complete response following neoadjuvant chemotherapy: when is it appropriate for HER2-positive and triple-negative breast cancers?

Abstract

Background

To clarify appropriate timing for magnetic resonance examination to predict pathological complete response to neoadjuvant chemotherapy for patients with human epidermal growth factor receptor 2 (HER2)-positive and triple-negative breast cancers in terms of tumor volume change.

Methods

Between September 2009 and December 2014, 113 women with HER2-positive (n = 51) and triple-negative (n = 62) invasive breast cancers undergoing neoadjuvant chemotherapy were enrolled. Patients with HER2-positive tumors underwent neoadjuvant chemotherapy with an anthracycline-based regimen followed by docetaxel with trastuzumab. Patients with triple-negative tumors underwent neoadjuvant chemotherapy with anthracycline-based (first in most cases) and taxane-based regimens. Magnetic resonance imaging was performed before neoadjuvant chemotherapy, between the regimens (midpoint examination), and after neoadjuvant chemotherapy (final examination). Response ratio of tumor volume was calculated and receiver-operating characteristic analyses for them for both subtypes were performed at the midpoint and final examinations.

Results

Twenty-eight women with HER2-positive tumors (54.9 %) and 29 women with triple-negative tumors (46.8 %) had pathological complete response. The response ratios were better in cases with pathological complete response than in those without (p = 0.0341, p < 0.0001). The area under the curve at the final examination was higher than that at the midpoint examination for HER2-positive tumors (p = 0.039); whereas for the triple-negative tumors, no significant difference between the two examinations was shown (p = 0.5218).

Conclusions

Magnetic resonance examination to predict pathological complete response would be feasible after completion of a regimen including trastuzumab for HER2-positive tumors and at the midpoint of neoadjuvant chemotherapy for triple-negative tumors.

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The value of cytoplasmic Y-box-binding protein 1 as a prognostic marker for breast cancer in Korean

Abstract

Background

The human Y-box-binding protein 1 (YB-1) is a member of the DNA/RNA-binding family of proteins that regulates transcription and translation of genes. Previous studies suggest that YB-1 may have an oncogenic role in various cancers. In this study, we evaluate the prognostic value of cytoplasmic YB-1 with respect to breast cancer.

Methods

Immunohistochemical staining study was performed with YB-1 using tissue block from 233 patients with invasive ductal carcinoma. Patients were divided into two groups according to expression of cytoplasmic YB-1 in tumor cell (high versus low). The relationship between the expression of YB-1, clinicopathological characteristics and breast cancer prognosis was analyzed.

Results

Hormone receptor negativity, worse histologic and nuclear grade, high tumor stage, lymphovascular invasion and high Ki67 (≥14 %) were related with the increased expression of cytoplasmic YB-1 in tumor cell (p < 0.05). Although there was no significant difference in relapse-free survival (RFS) between the two groups (p = 0.412), difference in overall survival (OS) was statistically significant (p = 0.035). In multivariate analysis for OS, YB-1 was an independent prognostic factor (p = 0.043).

Conclusion

This suggests that the increased expression of cytoplasmic YB-1 in tumor cells can be regarded as an independent prognostic factor for breast cancer, related to poor prognostics. Expression of cytoplasmic YB-1 in cancer cell could be used as an independent prognostic marker for predicting OS in breast cancer.

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Clinicopathological features of breast angiosarcoma

Abstract

Background

Breast angiosarcomas are rare neoplasm. Due to its rarity, our therapeutic strategy is extremely limited. Therefore, we investigated the clinicopathologic features and examined the treatment for angiosarcoma compared with some literatures.

Methods

We conducted a retrospective chart and slide review of all patients in our division seen from 1997 to 2012 with a diagnosis of primary or secondary breast angiosarcoma at the National Cancer Center Hospital (Tokyo, Japan).

Results

Nine patients were diagnosed with breast angiosarcoma (six primary and three secondary cases). The median age of patients with primary angiosarcoma was 39 years (range 27–65 years). The median tumor size was 6.78 cm (range 3.0–8.8 cm). In the primary tumor, 4 patients had total mastectomy and 2 had a breast conserving surgery. 3- and 5-year disease-free survival (DFS) of the patients with primary angiosarcoma was 20 and 0 %. 5-year surviving rate of primary angiosarcoma was 50 %. In all patients with secondary angiosarcoma, recurrence was observed in all cases. But one case obtained long-term survival in local control therapy.

Conclusions

Our study demonstrates breast angiosarcoma exhibits high recurrence rates. Tumor size and surgical margin may be important factor to obtain long-term survival. In this point of view, total mastectomy with adequate tumor margin with early detection is desired. In case of recurrence, if it is local, surgery may be potentially curative.

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Survival benefit of anti-HER2 therapy after whole-brain radiotherapy in HER2-positive breast cancer patients with brain metastasis

Abstract

Aim

We aimed to assess the survival benefit of epidermal growth factor receptor 2 (HER2)-positive breast cancer patients with brain metastasis (BM) after whole-brain radiotherapy (WBRT) in combination with systemic treatments, especially anti-HER2 therapy.

Methods

This retrospective study analyzed the overall survival (OS) of 60 HER2-positive breast cancer patients with BM after WBRT in combination with systemic treatments. Among them, 42 patients received chemotherapy while 18 patients did not receive after WBRT. With regard to anti-HER2 therapy, after WBRT, 17 patients received anti-HER2 treatment without prior adjuvant trastuzumab-based therapy, 7 patients received anti-HER2 treatment with prior adjuvant trastuzumab-based therapy, and 36 patients did not receive further anti-HER2 treatment. All patients were followed up regularly until January 23, 2013.

Results

The median OS of patients with BM was 12 months. Patients who received anti-HER2 therapy and chemotherapy after WBRT had significantly better survival compared with patients who did not receive further treatment. Patients who received anti-HER2 treatment after WBRT but did not receive adjuvant trastuzumab-based therapy for early breast cancer had better OS, followed by patients who received anti-HER2 agent both in adjuvant treatment and after WBRT and patients who did not receive anti-HER2 treatment. Multivariate analysis showed that Karnofsky Performance Status, control of extracranial metastases, chemotherapy after WBRT, and anti-HER2 therapy combined with WBRT were all independent predictors for OS.

Conclusion

Both chemotherapy and anti-HER2 therapy after WBRT could improve OS. Moreover, patients without prior exposure to adjuvant anti-HER2 treatment may have survival benefit superior to those of patients with prior exposure.

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Phase I study of concurrent vinorelbine and radiation therapy in high-risk postmastectomy breast cancer patients

Abstract

Background

Postmastectomy chest wall irradiation is recommended for high-risk breast cancer patients, such as those with ≥4 positive nodes. Irradiation is performed sequentially rather than concurrently with chemotherapy. However, the 5-year locoregional recurrence-free survival was statistically better in the concurrent method in node-positive patients in a prior study. The benefit of concurrent chemoradiotherapy for postmastectomy breast cancer patients is uncertain. Vinorelbine is often used as concurrent chemoradiotherapy for non-small cell lung cancer in Japan and has antitumor activity in breast cancer as well. Thus, we planned this dose-finding study of concurrent vinorelbine and radiation therapy in high-risk postmastectomy breast cancer patients.

Methods

High-risk postmastectomy breast cancer patients were recruited. Patients received weekly vinorelbine administered concurrently with radiation therapy. The radiation dose was 50 Gy in 25 fractions over 5 weeks. Vinorelbine was administered weekly without a break, so the maximum number of vinorelbine cycles was five. A 3 + 3 dose-escalation design was used for determining maximal tolerable dose, recommended dose and safety.

Results

A total of 10 patients were enrolled in cohorts of 10 and 15 mg/m². Dose-limiting toxicity was observed in one case in 10 mg/m² and two cases in 15 mg/m². Therefore, the maximal tolerable dose was defined at 15 mg/m² and the recommended dose was determined at 10 mg/m². The main adverse events included radiation dermatitis and neutropenia. Recurrence was observed in one patient with a median follow-up of 40 months.

Conclusions

Concurrent vinorelbine and radiation therapy has a manageable safety profile at 10 mg/m² in high-risk postmastectomy breast cancer patients.

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Pre-treatment mean platelet volume associates with worse clinicopathologic features and prognosis of patients with invasive breast cancer

Abstract

Background

Mean platelet volume (MPV) is one of the four platelet parameters (platelet count, MPV, platelet distribution width and plateletcrit), which indicates the activation of platelet. We aim to investigate the associations between pre-treatment MPV levels and clinical hematology parameters, pathology parameters and prognosis of patients with invasive breast cancer (IBC).

Methods

Medical records of 340 breast tumor patients (170 IBC vs. 170 breast benign tumor) were retrospectively reviewed. Patients in two groups were matched for age, body mass index, smoking status and complications. To analyze: differences in pre-treatment MPV levels between IBC group and breast benign tumor group; differences between pre- and postoperative MPV levels in IBC patients; correlations between pre-treatment MPV and clinical hematology parameters, clinicopathologic parameters and prognosis in IBC patients.

Results

As we analyzed, pre-treatment MPV levels of IBC patients were significantly higher than the controls (8.65 ± 0.98 vs 8.34 ± 0.78, P = 0.002), and preoperative MPV levels were significantly higher than the postoperative in IBC patients (8.65 ± 0.98 vs 8.44 ± 0.91, P = 0.042). In IBC group, pre-treatment MPV level associated, significantly, with clinical hematology parameters (platelet, fibrinogen, albumin, fasting blood glucose, P = 0.003, 0.042, 0.032, 0.046, respectively) and with clinicopathological parameters (distant metastasis, primary tumor size, tumor node metastasis stages, P = 0.039, 0.002, 0.001, respectively). Furthermore, univariate and multivariate survival analysis demonstrated that MPV was significant prognostic factor (P = 0.035, HR 1.86, 95 % confidence interval 1.06–3.25).

Conclusion

High pre-treatment MPV level in IBC patients was a potential predictive factor and significant independent prognostic factor.

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APOBEC3B high expression status is associated with aggressive phenotype in Japanese breast cancers

Abstract

Background

The members of AID/APOBEC protein family possess cytidine deaminase activity that converts cytidine residue to uridine on DNA and RNA. Recent studies have shown the possible influence of APOBEC3B (A3B) as DNA mutators of breast cancer genome. However, the clinical significance of A3B expression in Japanese breast cancer has not been studied in detail.

Methods

Ninety-three primary breast cancer tissues (74 estrogen-receptor (ER) positive, 3 ER and HER2 positive, 6 HER2 positive, and 10 triple negative) including 37 tumor-normal pairs were assessed for A3B mRNA expression using quantitative real-time RT-PCR. We analyzed the relation between A3B expression, mutation analysis of TP53 and PIK3CA by direct sequencing, polymorphic A3B deletion allele and human papillomavirus (HPV) infection in tumors.

Results

A3B mRNA was overexpressed in tumors compared with normal tissue. Patients with high A3B expression were associated with subtype and progression of lymph node metastasis and pathological nuclear grade. However, the expression was not related to any other clinicopathological factors, including mutation of TP53 and PIK3CA, polymorphic A3B deletion allele, HPV infection and survival time.

Conclusion

The expression of A3B in breast cancer was higher than in non-cancerous tissues and was related to the lymph node metastasis and nuclear grade, which are reliable aggressive phenotype markers in breast cancer. Evaluation of A3B expression in tumor may be a marker for breast cancer with malignant potential.

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Can treatment with statins have a negative influence on the tolerance of mandibular advancement devices?

Abstract

Background

Statins are considered the most effective drugs used in the treatment of dyslipidemias. Some of their adverse effects are related to muscle problems. Myalgias produced by statins appear more often during exercise. Mandibular advancement devices (MAD) force the propulsory and elevatory musculature of the mandible to exercise by making the jaw move forward. The aim of this study is to evaluate the incidence of muscular side effects (referred, spontaneous, or under palpation pain, myofascial pain, mandibular rigidity and fatigue, tension and sensitivity of the masticatory muscles) in a group of patients with a diagnosis of obstructive sleep apnea being treated with MAD.

Methods

This was a prospective study, involving consecutively 104 patients with a diagnosis of OSAS, and who had begun treatment with a custom made oral device. Muscular side effects were collected by anamnesis (verbal request and questionnaires), psychological status and clinical assessment (manual muscle palpation in the masticatory and cervical muscle groups), before and during MAD treatment.

Results

Of the total sample, 22.1 % presented muscular side effects with the oral device. However, in patients taking statins, this percentage was 57.1 %, as opposed to 16.7 % of the non-statins patients (p < 0.001). The risk of suffering muscular alterations during oral device treatment is higher in statin patients (odds ratio 6.67, p = 0.002).

Conclusion

Treatment with statins can give rise to the appearance of undesirable side effects among patients being treated with oral devices.

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The effect of temperature exposure during shipment on a commercially available demineralized bone matrix putty

Abstract

During August and September of 2013, temperature data loggers were shipped to and from an AATB accredited and FDA registered allograft tissue processing facility in Belgrade, MT (Bacterin International, Inc.) to five warm climate cities (Dallas, TX, El Paso, TX, New Orleans, LA, Phoenix, AZ, and Tampa, FL). Shipping data acquired from 72 independent shipments were analyzed to generate an assessment of temperature exposure, shipment times, and shipping event durations experienced during routine distribution. Overall the packages experienced an average temperature of 26.2 ± 2.3 °C which mirrored the average external ambient temperature of 25.8 ± 3.0 °C. However, temperature spikes above 40 °C were frequently observed. The data from the model shipments were extrapolated to provide a worst-case high temperature spike of 52.9 °C for 12 h and 14 min. Multiple lots of a commercially available demineralized bone matrix (DBM) putty (OsteoSelect^® DBM Putty) were subjected to continuous heating at 50 °C, to multiple worst-case temperature spikes, and to multiple freeze–thaw cycles to assess the effects of these temperature extremes on the handling and osteoinductivity of the allograft tissue. Five weeks of continuous exposure to 50 °C and 12 simulated worst-case one-way shipments did not adversely affect the handling characteristics or the in vivo osteoinductivity of the product.

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Influence of the presence of ruthenium on the activity and stability of Co–Mg–Al-based catalysts in CO 2 reforming of methane for syngas production

Abstract

Hydrogen production by methane dry reforming is an important yet challenging process. A performing catalyst will favor the thermodynamic equilibrium while ensuring good hydrogen selectivity. We hereby report the synthesis of Co_x Mg_6−x Al₂ (with x = 2 and 6) mixed oxide catalysts synthesized via hydrotalcite precursors and the synthesis of a ruthenium-based catalyst on a cobalt, magnesium, and aluminum mixed oxide supports Ru/Co_x Mg_6−x Al₂ (with x = 2 and 6). The impregnation of ruthenium on the hydrotalcites was performed in two ways: by impregnation on the dried hydrotalcite and by memory effect on hydrotalcite calcined at 500 °C. The deposition of ruthenium by memory effect of the magnesium and cobalt support allows the generation of both metallic and basic sites which provides an active and stable catalyst for the dry reforming reaction of methane.

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Stroke Rehabilitation Assessment of Movement Measure

Link to instrument: STREAM

Acronym:

STREAM

Purpose:

• The STREAM was designed for use by physical therapists to provide a quantitative evaluation of motor functioning for stroke patients. The STREAM was specifically designed to be easy to administer in a clinical setting.
  

Description:

The STREAM is composed of 30 items distributed across 3 domains:

• Upper-limb movements (scored on a 3-point ordinal scale
• Lower-limb movements (scored on a 3-point ordinal scale)
• Basic mobility items (scored on a 4-point ordinal scale)

Scoring the STREAM:

• Total of 20 points for each of the limb sub-scales (40 points total)
• Total of 30 points for the mobility subscale
• Scores can be transformed, allowing for items that can't be scored
• Subscales are converted to a percentage, even though the scores are not interval based. This is done to allow for occasional items that cannot be scored.  Total scores are calculated using the average of the 3 subscale scores
• Instructions for score transformation can be found in the instruments manual

Area of Assessment: Coordination, Functional Mobility, Range of Motion

Body Part: Upper Extremity, Lower Extremity

ICF Domain: Body Function, Activity

Domain: Motor

Assessment Type: Performance Measure

Length of Test: 06 to 30 Minutes

Time to Administer:

15 minutes

Number of Items: 30

Equipment Required:

None

Training Required:

None

Type of training required: No Training

Cost: Free

Actual Cost:

Free

Age Range: Adult: 18-64 years, Elderly adult: 65+

Administration Mode: Paper/Pencil

Diagnosis: Stroke

Populations Tested:

• Stroke

Standard Error of Measurement (SEM):

Chronic Stroke: (Chen et al, 2007; n = 50; mean age = 60.9 (12.8) years; median time between stroke and assessment = 24 months, mean Barthel Index (BI) scores = 15.9 (5.3) points)

• Standard Error of Measurement (SEM) = 1.5 points

Minimal Detectable Change (MDC):

Chronic Stroke: (Chen et al, 2007)

• Smallest Real Difference (SRD) = 4.2 points

Acute Stroke: (Hsueh et al, 2008; n = 50 mean age = 61.9 (11.7) years; onset to admission 18.6 (11.7) days; stay in rehab = 22.3 (5.7) days)

• STREAM Smallest Real Difference:
  Measure	ICC	95% CI	SRD (SRD%)
  STREAM
  UE-STREAM	.97	0.96-0.98	2.8 (14.0)
  LE-STREAM	.98	0.96-0.99	2.5 (12.6)
  Motor-STREAM	.98	0.97-0.99	3.9 (9.9)
  S-STREAM
  UE-S-STREAM	.95	0.92-0.97	11.6 (11.6)
  LE-S-STREAM	.97	0.95-0.98	9.1 (9.1)
  Motor-S-STREAM	.97	0.95-0.98	17.4 (8.7)
  FM
  UE-FM	.98	0.96-0.99	7.2 (10.9)
  LE-FM	.95	0.91-0.97	3.8 (11.3)
  Motor-FM	.98	0.97-0.99	8.4 (8.4)
  S-FM
  UE-S-FM	.93	0.89-0.96	12.2 (12.2)
  LE-S-FM	.96	0.93-0.97	8.6 (8.6)
  Motor-S-FM	.96	0.94-0.98	16.0 (8.0)
  STREAM = Motor Scale of Stroke Rehabilitation Assessment of Movement S-STREAM = Simplified Motor Scale of STREAM SRD = smallest real difference FM = Fugl-Meyer Motor Scale S-FM = Simplified Fugl-Meyer Motor Scale UE = Upper Extremity LE = Lower Extremity

Minimally Clinically Important Difference (MCID):

Stroke: (Hsieh et al, 2008; n = 81 stroke patients who were recruited from Departments of Physical Medicine and Rehabilitation of three hospital in Taiwan; mean age = 55.9 (13.3) years; mean MMSE score = 25.8 (2.8) years; mean STREAM baseline score = 10.27 (7.6) for upper extremity, 9.6 (6.7) for lower extremity, and 16.1 (7.6) for mobility)

• MCID for upper-extremity subscale (n = 42) = 2.2
• MCID for lower-extremity subscale (n = 38) = 1.9
• MCID for mobility subscale (n = 43) = 4.8

Cut-Off Scores:

Not Established

Normative Data:

Acute Stroke: (Ahmed et al, 2003; n = 63; mean age = 67 (14) years; assessed within a week of stroke, then again at 4 weeks and 3 months)

STREAM Norms Over Time with Comparisons:
Instrument		Intial		5 week		3 months
Name	Domain	Mean (SD)	Median	Mean (SD)	Median	Mean (SD)	Median
STREAM	Total Score	75 (26.7)	86	86 (19.1)	94	89 (18.0)	97
	UE subscale	73 (33.3)	90	85 (26.2)	100	88 (24.0)	100
	LE subscale	75 (28.9)	85	86 (22.3)	95	90 (19.0)	100
	Mobility subscale	74 (25.9)	83	88 (16.4)	97	91 (15.0)	97
Barthel Index	Total	72 (27.9)	85	86 (20.4)	100	92 (14.0)	100
Gait speed (m/s)	Total	0.55 (0.38)	0.58	0.82 (0.43)	0.90	0.85 (0.36)	0.93
STREAM = Stroke Rehabilitation Assessment of Movement UE = Upper Extremity LE = Lower Extremity

Test-retest Reliability:

Chronic Stroke: (Chen et al, 2007, n = 50, 7 days between assessments)

 

Test re-test data for the Mobility subscale of the STREAM
First Session Mean (SD)	17.9 (7.2)
Second Session Mean (SD)	17.8 (7.6)
Mean d (SD)	0.1 (2.1)
ICC (95% CI)	0.96 (0.93 to 0.98)*
SEM	1.5
SRD	4.2
*Excellent
d = difference of score between the 2 test sessions ICC = intraclass correlation coefficient CI = confidence interval SEM = standard error of measurement SRD = smallest real difference

 

 

Interrater/Intrarater Reliability:

Chronic Stroke: (Daley et al, 1999; n = 20; mean age = 66.7 (10.7) years; mean time between stroke onset and assessment = 104.5 (42.7) days)

 

Interrater and Intrarater Reliability:
Sub scale	Direct Observation (Interrater Agreement)	Videotaped Assessments (Intrarater Agreement)
Upper-extremity subscale	.994	.963
Lower-extremity subscale	.993	.999
Basic mobility subscale	.982	.999
Total scores on STREAM	.995	.999
GCC = generalizability correlation coefficient Reliability coefficients of .95 or better are recommended

Internal Consistency:

Chronic Stroke: (Daley et al, 1999)

• Internal Consistency (Cronbach's alpha):
  • Excellent: Mobility subscale = .965
  • Excellent: Limb subscales = .979
  • Excellent: overall STREAM scores = .984

Criterion Validity (Predictive/Concurrent):

Acute Stroke: (Ahmed et al, 2003)

 

STREAM Predictive and Concurrent Validity Correlations:
Stream	Time	Box and Block (Affected UE)	Box and Block (Unaffected UE)	Barthel	Balance	TUG	Gait
Total	Initial	.73	.36	.78	.75	.80	.74
	5 weeks	.77	.37	.71	.68	.64	.62
	3 months	.78	.44	.75	.65	.57	.73
UE	Initial	.78	.31	.67	.57	.69	.56
	5 weeks	.79	.36	.66	.61	.49	.53
	3 months	.76	.31	.67	.53	.60	.64
LE	Initial	.53	.40	.71	.73	.75	.74
	5 weeks	.64	.29	.59	.55	.59	.55
	3 months	.70	.30	.63	.55	.51	.65
Mobility	Initial	.66	.55	.84	.88	.85	.83
	5 weeks	.69	.40	.75	.71	.57	.65
	3 months	.66	.40	.82	.78	.62	.76

Construct Validity (Convergent/Discriminant):

Acute Stroke: (Hsueh et al, 2003, n = 59; mean age 64.2 (11.5) years; assessed within 14 days of stroke onset, Taiwanese sample)

 

Convergent Validity and Predictive Validity of the STREAM at 4 Time Points
Days	n	Convergent Validity* (p)	Predictive Validity† (p)
14	57	0.80	0.54
30	54	0.87	0.67
90	44	0.82	0.81
180	43	0.76	--
*Relationships between the STREAM and the BI at 4 time points. †Relationships between the STREAM and the BI at 3 time points (14, 30, and 90 days) after stroke.

 

 

Content Validity:

Items from the initial STREAM were reviewed by two panels of experts made up to 20 physical therapists. Feedback from these experts were used to refine the measure.

Face Validity:

Not statistically assessed

Floor/Ceiling Effects:

Acute Stroke: (Hsueh et al, 2008)

 

STREAM Floor and Ceiling Effects at Admission and Discharge
	At Admission, n (%)		t Discharge, n (%)
	Floor	Ceiling	Floor	Ceiling
UE-STREAM	13 (26.0)	10 (20.0)	4 (8.0)	20 (40.0)
LE-STREAM	10 (20.0)	2 (4.0)	1 (2.0)	12 (24.0)
Motor-STREAM	9 (18.0)	1 (2.0)	1 (2.0)	10 (20.0)
S-STREAM	2 (4.0)	0 (0.0)	0 (0.0)	6 (12.0)
UE = Upper Extremity LE = Lower Extremity STREAM = Motor Scale of Stroke Rehabilitation Assessment of Movement S-STREAM = Simplified Motor Scale of STREAM

 

Acute Stroke: (Hsueh et al, 2003)

 

STREAM Floor and Ceiling Effects at 4 Time Points
Days after Stroke	Floor n (%)	Ceiling n (%)
14 (n = 57)	0 (0)	0 (0)
30 (n = 54)	0 (0)	2 (3.7)
90 (n = 44)	0 (0)	6 (13.6)
180 (n = 43	0 (0)	7 (16.3)

Responsiveness:

Acute Stroke: (Higgins et al, 2005; n = 55; mean age = 66 (15), assessed at 5 weeks after onset)

 

Standard Response Means (SRM) for STREAM:
Sub-scale	SRM	95% Confidence Interval
STREAM Total	0.98	0.74 − 1.17
STREAM (upper limb)	0.75	0.56 − 0.93
STREAM (lower limb)	0.63	0.36 − 0.86

 

Acute Stroke: (Hsueh et al, 2008; assessed at admission and within 48 hours of discharge; mean time in rehabilitation = 22.3 (5.7) days)

 

STREAM Responsiveness:
Scale	Change score (SD)	Strength	Effect Size d	SRM
STREAM
UE-STREAM	3.3 (4.2)	small	0.38	0.78
LE-STREAM	3.3 (3.9)	small	0.44	0.84
Motor-STREAM	6.5 (6.9)	small	0.45	0.95
S-STREAM
UE-S-STREAM	14.5 (12.2)	small	0.49	1.19
LE-S-STREAM	14.7 (12.9)	medium	0.54	1.14
Motor-S-STREAM	29.1 (23.2)	medium	0.53	1.26
FM
UE-FM	8.4 (8.5)	small	0.34	1.00
LE-FM	4.3 (5.2)	small	0.41	0.83
Motor-FM	12.7 (11.0)	small	0.38	1.16
S-FM
UE-S-FM	14.6 (14.4)	small	0.47	1.00
LE-S-FM	14.9 (17.9)	medium	0.51	0.83
Motor-S-FM	29.4 (29.7)	medium	0.51	0.99
STREAM = Motor Scale of Stroke Rehabilitation Assessment of Movement S-STREAM = Simplified Motor Scale of STREAM FM = Fugl-Meyer Motor Scale UE = Upper Extremity LE = Lower Extremity S-FM = Simplified Fugl-Meyer Motor Scale SRM = Standardized Response Mean

 

Acute Stroke: (Hsueh et al, 2003)

 

Responsiveness of the STREAM at Different Stages of Recovery
Days	n	SRM	Wilcoxon z
14–30	51	1.17	6.02*
30–90	43	0.95	4.95*
90–180	43	0.40	2.23†
14–90	43	1.61	5.72*
14–180	43	1.65	5.57*
*P < 0.001; †P < 0.05

Considerations:

 

Do you see an error or have a suggestion for this instrument summary? Please e-mail us!

Bibliography:

Ahmed, S., Mayo, N. E., et al. (2003). "The Stroke Rehabilitation Assessment of Movement (STREAM): a comparison with other measures used to evaluate effects of stroke and rehabilitation." Phys Ther 83(7): 617-630. Find it on PubMed

Chen, H. M., Hsieh, C. L., et al. (2007). "The test-retest reliability of 2 mobility performance tests in patients with chronic stroke." Neurorehabil Neural Repair 21(4): 347-352. Find it on PubMed

Daley, K., Mayo, N., et al. (1999). "Reliability of scores on the Stroke Rehabilitation Assessment of Movement (STREAM) measure." Phys Ther 79(1): 8-19; quiz 20-13. Find it on PubMed

Higgins, J., Mayo, N. E., et al. (2005). "Upper-limb function and recovery in the acute phase poststroke." J Rehabil Res Dev 42(1): 65-76. Find it on PubMed

Hsieh, Y. W., Wang, C. H., et al. (2008). "Estimating the minimal clinically important difference of the Stroke Rehabilitation Assessment of Movement measure." Neurorehabil Neural Repair 22(6): 723-727. Find it on PubMed

Hsueh, I. P., Hsu, M. J., et al. (2008). "Psychometric comparisons of 2 versions of the Fugl-Meyer Motor Scale and 2 versions of the Stroke Rehabilitation Assessment of Movement." Neurorehabil Neural Repair 22(6): 737-744. Find it on PubMed

Hsueh, I. P., Wang, C. H., et al. (2003). "Comparison of psychometric properties of three mobility measures for patients with stroke." Stroke 34(7): 1741-1745. Find it on PubMed 

Year published: 1986

Instrument in PDF Format: Yes

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