bluuebunny/crossref_metadata_2025 huggingface dataset:
The New Jersey Institute of Technology Robot-Assisted Virtual Rehabilitation (NJIT-RAVR) system for children with cerebral palsy: a feasibility study
Authors: Qiu Qinyin , Ramirez Diego A , Saleh Soha , Fluet Gerard G , Parikh Heta D , Kelly Donna , Adamovich Sergei V
Published: November 2009

Background

We hypothesize that the integration of virtual reality (VR) with robot assisted rehabilitation could be successful if applied to children with hemiparetic CP. The combined benefits of increased attention provided by VR and the larger training stimulus afforded by adaptive robotics may increase the beneficial effects of these two approaches synergistically. This paper will describe the NJIT-RAVR system, which combines adaptive robotics with complex VR simulations for the rehabilitation of upper extremity impairments and function in children with CP and examine the feasibility of this system in the context of a two subject training study.

Methods

The NJIT-RAVR system consists of the Haptic Master, a 6 degrees of freedom, admittance controlled robot and a suite of rehabilitation simulations that provide adaptive algorithms for the Haptic Master, allowing the user to interact with rich virtual environments. Two children, a ten year old boy and a seven year old girl, both with spastic hemiplegia secondary to Cerebral Palsy were recruited from the outpatient center of a comprehensive pediatric rehabilitation facility. Subjects performed a battery of clinical testing and kinematic measurements of reaching collected by the NJIT-RAVR system. Subjects trained with the NJIT-RAVR System for one hour, 3 days a week for three weeks. The subjects played a combination of four or five simulations depending on their therapeutic goals, tolerances and preferences. Games were modified to increase difficulty in order to challenge the subjects as their performance improved. The testing battery was repeated following the training period.

Results

Both participants completed 9 hours of training in 3 weeks. No untoward events occurred and no adverse responses to treatment or complaints of cyber sickness were reported. One participant showed improvements in overall performance on the functional aspects of the testing battery. The second subject made improvements in upper extremity active range of motion and in kinematic measures of reaching movements.

Conclusion

We feel that this study establishes the feasibility of integrating robotics and rich virtual environments to address functional limitations and decreased motor performance in children with mild to moderate cerebral palsy.
Does neuroinflammation fan the flame in neurodegenerative diseases?
Authors: Frank-Cannon Tamy C , Alto Laura T , McAlpine Fiona E , Tansey Malú G
Published: November 2009

While peripheral immune access to the central nervous system (CNS) is restricted and tightly controlled, the CNS is capable of dynamic immune and inflammatory responses to a variety of insults. Infections, trauma, stroke, toxins and other stimuli are capable of producing an immediate and short lived activation of the innate immune system within the CNS. This acute neuroinflammatory response includes activation of the resident immune cells (microglia) resulting in a phagocytic phenotype and the release of inflammatory mediators such as cytokines and chemokines. While an acute insult may trigger oxidative and nitrosative stress, it is typically short-lived and unlikely to be detrimental to long-term neuronal survival. In contrast, chronic neuroinflammation is a long-standing and often self-perpetuating neuroinflammatory response that persists long after an initial injury or insult. Chronic neuroinflammation includes not only long-standing activation of microglia and subsequent sustained release of inflammatory mediators, but also the resulting increased oxidative and nitrosative stress. The sustained release of inflammatory mediators works to perpetuate the inflammatory cycle, activating additional microglia, promoting their proliferation, and resulting in further release of inflammatory factors. Neurodegenerative CNS disorders, including multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), tauopathies, and age-related macular degeneration (ARMD), are associated with chronic neuroinflammation and elevated levels of several cytokines. Here we review the hallmarks of acute and chronic inflammatory responses in the CNS, the reasons why microglial activation represents a convergence point for diverse stimuli that may promote or compromise neuronal survival, and the epidemiologic, pharmacologic and genetic evidence implicating neuroinflammation in the pathophysiology of several neurodegenerative diseases.
Pulmonary fibrosis associated with psychotropic drug therapy: a case report
Authors: Thornton Clare , Maher Toby M , Hansell David , Nicholson Andrew G , Wells Athol U
Published: November 2009

Introduction

Sertraline and Risperidone are commonly used psychotropic drugs. Sertraline has previously been associated with eosinopilic pneumonia. Neither drug is recognised as a cause of diffuse fibrotic lung disease. Our report represents the first such case.

Case Presentation

We describe the case of a 33 year old Asian male with chronic schizophrenia who had been treated for three years with sertraline and risperidone. He presented to hospital in respiratory failure following a six month history of progressive breathlessness. High resolution CT scan demonstrated diffuse pulmonary fibrosis admixed with patchy areas of consolidation. Because the aetiology of this man's diffuse parenchymal lung disease remained unclear a surgical lung biopsy was undertaken. Histological assessment disclosed widespread fibrosis with marked eosinophillic infiltration and associated organising pneumonia - features all highly suggestive of drug induced lung disease. Following withdrawal of both sertraline and risperidone and initiation of corticosteroid therapy the patient's respiratory failure resolved and three years later he remains well albeit limited by breathlessness on heavy exertion.

Conclusion

Drug induced lung disease can be rapidly progressive and if drug exposure continues may result in respiratory failure and death. Prompt recognition is critical as drug withdrawal may result in marked resolution of disease. This case highlights sertraline and risperidone as drugs that may, in susceptible individuals, cause diffuse pulmonary fibrosis.
Epidural lipomatosis and congenital small spinal canal in spinal anaesthesia: a case report and review of the literature
Authors: Flisberg Per , Thomas Owain , Geijer Bo , Schött Ulf
Published: November 2009

Introduction

Complications after lumbar anaesthesia and epidural blood patch have been described in patients with congenital small spinal canal and increased epidural fat or epidural lipomatosis. These conditions, whether occurring separately or in combination, require magnetic resonance imaging for diagnosis and grading, but their clinical significance is still unclear.

Case presentation

A 35-year-old Caucasian woman who was undergoing a Caesarean section developed a longstanding L4-L5 unilateral neuropathy after the administration of spinal anaesthesia. There were several attempts to correctly position the needle, one of which resulted in paraesthesia. A magnetic resonance image revealed that the patient's bony spinal canal was congenitally small and had excess epidural fat. The cross-sectional area of the dural sac was then reduced, which left practically no free cerebrospinal fluid space.

Conclusion

The combination of epidural lipomatosis of varying degrees and congenital small spinal canal has not been previously discussed with spinal anaesthesia. Due to the low cerebrospinal fluid content of the small dural sac, the cauda equina becomes a firm system with a very limited possibility for the nerve roots to move away from the puncture needle when it is inserted into the dural sac. This constitutes risks of technical difficulties and neuropathies with spinal anaesthesia.
Reliability of measuring abductor hallucis muscle parameters using two different diagnostic ultrasound machines
Authors: Hing Wayne A , Rome Keith , Cameron Alyse FM
Published: November 2009

Background

Diagnostic ultrasound provides a method of analysing soft tissue structures of the musculoskeletal system effectively and reliably. The aim of this study was to evaluate within and between session reliability of measuring muscle dorso‐plantar thickness, medio‐lateral length and cross‐sectional area, of the abductor hallucis muscle using two different ultrasound machines, a higher end Philips HD11 Ultrasound machine and clinically orientated Chison 8300 Deluxe Digital Portable Ultrasound System.

Methods

The abductor hallucis muscle of both the left and right feet of thirty asymptomatic participants was imaged and then measured using both ultrasound machines. Interclass correlation coefficients (ICC) with 95% confidence intervals (CI) were used to calculate both within and between session intra‐tester reliability. Standard error of the measurement (SEM) calculations were undertaken to assess difference between the actual measured score across trials and the smallest real difference (SRD) was calculated from the SEM to indicate the degree of change that would exceed the expected trial to trial variability.

Results

The ICCs, SEM and SRD for dorso‐plantar thickness and medial‐lateral length were shown to have excellent to high within and between‐session reliability for both ultrasound machines. The between‐session reliability indices for cross‐sectional area were acceptable for both ultrasound machines.

Conclusion

The results of the current study suggest that regardless of the type ultrasound machine, intra‐tester reliability for the measurement the abductor hallucis muscle parameters is very high.
Aggrecanolysis and in vitromatrix degradation in the immature bovine meniscus: mechanisms and functional implications
Authors: Wilson Christopher G , Vanderploeg Eric J , Zuo Fengrong , Sandy John D , Levenston Marc E
Published: November 2009

Introduction

Little is known about endogenous or cytokine-stimulated aggrecan catabolism in the meniscal fibrocartilage of the knee. The objectives of this study were to characterize the structure, distribution, and processing of aggrecan in menisci from immature bovines, and to identify mechanisms of extracellular matrix degradation that lead to changes in the mechanical properties of meniscal fibrocartilage.

Methods

Aggrecanase activity in the native immature bovine meniscus was examined by immunolocalization of the aggrecan NITEGE neoepitope. To investigate mechanisms of cytokine-induced aggrecan catabolism in this tissue, explants were treated with interleukin-1α (IL-1) in the absence or presence of selective or broad spectrum metalloproteinase inhibitors. The sulfated glycosaminoglycan (sGAG) and collagen contents of explants and culture media were quantified by biochemical methods, and aggrecan catabolism was examined by Western analysis of aggrecan fragments. The mechanical properties of explants were determined by dynamic compression and shear tests.

Results

The aggrecanase-generated NITEGE neoepitope was preferentially localized in the middle and outer regions of freshly isolated immature bovine menisci, where sGAG density was lowest and blood vessels were present. In vitro treatment of explants with IL-1 triggered the accumulation of NITEGE in the inner and middle regions. Middle region explants stimulated with IL-1 exhibited substantial decreases in sGAG content, collagen content, and mechanical properties. A broad spectrum metalloproteinase inhibitor significantly reduced sGAG loss, abrogated collagen degradation, and preserved tissue mechanical properties. In contrast, an inhibitor selective for ADAMTS-4 and ADAMTS-5 was least effective at blocking IL-1-induced matrix catabolism and loss of mechanical properties.

Conclusions

Aggrecanase-mediated aggrecanolysis, typical of degenerative articular cartilage, may play a physiologic role in the development of the immature bovine meniscus. IL-1-induced release of sGAG and loss of mechanical properties can be ascribed primarily to the activity of MMPs or aggrecanases other than ADAMTS-4 and ADAMTS-5. These results may have implications for the clinical management of osteoarthritis.
Hypoxia-inducible factor-1α and vascular endothelial growth factor expression in circulating tumor cells of breast cancer patients
Authors: Kallergi Galatea , Markomanolaki Harris , Giannoukaraki Vicky , Papadaki Maria A , Strati Areti , Lianidou Evi S , Georgoulias Vassilis , Mavroudis Dimitris , Agelaki Sofia
Published: November 2009

Introduction

The detection of peripheral blood circulating tumor cells (CTCs) and bone marrow disseminated tumor cells (DTCs) in breast cancer patients is associated with a high incidence of disease relapse and disease-related death. Since hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) play an important role in angiogenesis and tumor progression, the purpose of the current study was to investigate their expression in CTCs.

Methods

The expression of cytokeratins (CK), VEGF, vascular endothelial growth factor receptor-2 (VEGF2), HIF-1α and phosphorylated-focal adhesion kinase (pFAK) in CTCs from 34 patients with metastatic breast cancer who had detectable CK-19 mRNA-positive CTCs was assessed using double staining experiments and confocal laser scanning microscopy. Peripheral blood mononuclear cells (PBMCs) were stained with a monoclonal A45-B/B3 pancytokeratin antibody in combination with either VEGF or VEGFR2 or HIF-1α or pFAK antibodies, respectively.

Results

pFAK expression in circulating tumor cells was detected in 92% of patients whereas expression of VEGF, VEGF2 and HIF-1α was observed in 62%, 47% and 76% of patients, respectively. VEGF, VEGF2, HIF-1α and pFAK were expressed in 73%, 71%, 56% and 81%, respectively, of all the detected CTCs. Vascular endothelial growth mRNA was also detected by quantitative real-time RT-PCR in immunomagnetically-separated CTCs. Double and triple staining experiments in cytospins of immunomagnetically-isolated CTCs showed that VEGF co-expressed with HIF-1α and VEGF2.

Conclusions

The expression of pFAK, HIF-1α, VEGF and VEGF2 in CTCs of patients with metastatic breast cancer could explain the metastatic potential of these cells and may provide a therapeutic target for their elimination.
Ventilator-induced endothelial activation and inflammation in the lung and distal organs
Authors: Hegeman Maria A , Hennus Marije P , Heijnen Cobi J , Specht Patricia AC , Lachmann Burkhard , Jansen Nicolaas JG , van Vught Adrianus J , Cobelens Pieter M
Published: November 2009

Introduction

Results from clinical studies have provided evidence for the importance of leukocyte-endothelial interactions in the pathogenesis of pulmonary diseases such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), as well as in systemic events like sepsis and multiple organ failure (MOF). The present study was designed to investigate whether alveolar stretch due to mechanical ventilation (MV) may evoke endothelial activation and inflammation in healthy mice, not only in the lung but also in organs distal to the lung.

Methods

Healthy male C3H/HeN mice were anesthetized, tracheotomized and mechanically ventilated for either 1, 2 or 4 hours. To study the effects of alveolar stretchin vivo, we applied a MV strategy that causes overstretch of pulmonary tissue i.e. 20 cmH2O peak inspiratory pressure (PIP) and 0 cmH20 positive end expiratory pressure (PEEP). Non-ventilated, sham-operated animals served as a reference group (non-ventilated controls, NVC).

Results

Alveolar stretch imposed by MV did not only inducede novosynthesis of adhesion molecules in the lung but also in organs distal to the lung, like liver and kidney. No activation was observed in the brain. In addition, we demonstrated elevated cytokine and chemokine expression in pulmonary, hepatic and renal tissue after MV which was accompanied by enhanced recruitment of granulocytes to these organs.

Conclusions

Our data implicate that MV causes endothelial activation and inflammation in mice without pre-existing pulmonary injury, both in the lung and distal organs.
The leading causes of death after burn injury in a single pediatric burn center
Authors: Williams Felicia N , Herndon David N , Hawkins Hal K , Lee Jong O , Cox Robert A , Kulp Gabriela A , Finnerty Celeste C , Chinkes David L , Jeschke Marc G
Published: November 2009

Introduction

Severe thermal injury is characterized by profound morbidity and mortality. Advances in burn and critical care, including early excision and grafting, aggressive resuscitation and advances in antimicrobial therapy have made substantial contributions to decrease morbidity and mortality. Despite these advances, death still occurs. Our aim was to determine the predominant causes of death in burned pediatric patients in order to develop new treatment avenues and future trajectories associated with increased survival.

Methods

Primary causes of death were reviewed from 144 pediatric autopsy reports. Percentages of patients that died from anoxic brain injuries, sepsis, or multi-organ failure were calculated by comparing to the total number of deaths. Data was stratified by time (from 1989 to 1999, and 1999 to 2009), and gender. Statistical analysis was done by chi-squared, Student's t-test and Kaplan-Meier for survival where applicable. Significance was accepted as P < 0.05.

Results

Five-thousand two-hundred-sixty patients were admitted after burn injury from July 1989 to June 2009, and of those, 145 patients died after burn injury. Of these patients, 144 patients had an autopsy. The leading causes of death over 20 years were sepsis (47%), respiratory failure (29%), anoxic brain injury (16%), and shock (8%). From 1989 to 1999, sepsis accounted for 35% of deaths but increased to 54% from 1999 to 2009, with a significant increase in the proportion due to antibiotic resistant organisms (P < 0.05).

Conclusions

Sepsis is the leading cause of death after burn injury. Multiple antibiotic resistant bacteria now account for the bulk of deaths due to sepsis. Further improvement in survival may require improved strategies to deal with this problem.
BioGPS: an extensible and customizable portal for querying and organizing gene annotation resources
Authors: Wu Chunlei , Orozco Camilo , Boyer Jason , Leglise Marc , Goodale James , Batalov Serge , Hodge Christopher L , Haase James , Janes Jeff , Huss Jon W , Su Andrew I
Published: November 2009

Online gene annotation resources are indispensable for analysis of genomics data. However, the landscape of these online resources is highly fragmented, and scientists often visit dozens of these sites for each gene in a candidate gene list. Here, we introduce BioGPS http://biogps.gnf.org, a centralized gene portal for aggregating distributed gene annotation resources. Moreover, BioGPS embraces the principle of community intelligence, enabling any user to easily and directly contribute to the BioGPS platform.
Phase II Multicenter Trial of Maintenance Biotherapy After Induction Concurrent Biochemotherapy for Patients With Metastatic Melanoma
Authors: O'Day Steven J. , Atkins Michael B. , Boasberg Peter , Wang He-Jing , Thompson John A. , Anderson Clay M. , Gonzalez Rene , Lutzky Jose , Amatruda Thomas , Hersh Evan M. , Weber Jeffrey S.
Published: November 2009

Purpose

Biochemotherapy improves responses in metastatic melanoma, but not overall survival, in randomized trials. We developed a maintenance biotherapy regimen after induction biochemotherapy in an attempt to improve durability of responses and overall survival.

Patients and Methods

One hundred thirty-three chemotherapy-naïve patients with metastatic melanoma without CNS metastases were treated at 10 melanoma centers. The biochemotherapy induction regimen included cisplatin, vinblastine, dacarbazine, decrescendo interleukin-2 (IL-2), and interferon alfa-2b with granulocyte-macrophage colony-stimulating factor (GM-CSF) cytokine support. Patients not experiencing disease progression were eligible for maintenance biotherapy with low-dose IL-2 and GM-CSF followed by intermittent pulses of decrescendo IL-2 over 12 months. Patients were observed for response, progression-free survival, toxicity, and overall survival.

Results

The response rate to induction biochemotherapy was 44% (95% CI, 35% to 52%; complete response, 8%; partial response, 36%; stable disease, 29%). The median number of biochemotherapy cycles was four, and the median number of maintenance biotherapy cycles was five. The median progression-free survival was 9 months, and the median survival was 13.5 months. The 12-month and 24-month survival rates were 57% and 23%, respectively. Twenty percent of patients remain alive (12 without disease), with median follow-up of 30 months (95% CI, 25+ to 45+ months). Thirty-nine percent of patients developed CNS metastases. The median times to CNS progression and death were 8 months and 5 months, respectively.

Conclusion

Maintenance biotherapy after induction biochemotherapy seems to prolong progression-free survival and improve overall survival compared with recent multicenter trials of biochemotherapy or chemotherapy. The regimen should be studied in a randomized clinical trial in patients with advanced metastatic melanoma. CNS progression remains a formidable challenge.
Pancreatic Endocrine Tumors: Expression Profiling Evidences a Role for AKT-mTOR Pathway
Authors: Missiaglia Edoardo , Dalai Irene , Barbi Stefano , Beghelli Stefania , Falconi Massimo , della Peruta Marco , Piemonti Lorenzo , Capurso Gabriele , Di Florio Alessia , delle Fave Gianfranco , Pederzoli Paolo , Croce Carlo M. , Scarpa Aldo
Published: November 2009

Purpose

We investigated the global gene expression in a large panel of pancreatic endocrine tumors (PETs) aimed at identifying new potential targets for therapy and biomarkers to predict patient outcome.

Patients and Methods

Using a custom microarray, we analyzed 72 primary PETs, seven matched metastases, and 10 normal pancreatic samples. Relevant differentially expressed genes were validated by either quantitative real-time polymerase chain reaction or immunohistochemistry on tissue microarrays.

Results

Our data showed that: tuberous sclerosis 2 (TSC2) and phosphatase and tensin homolog (PTEN) were downregulated in most of the primary tumors, and their low expression was significantly associated with shorter disease-free and overall survival; somatostatin receptor 2 (SSTR2) was absent or very low in insulinomas compared with nonfunctioning tumors; and expression of fibroblast growth factor 13 (FGF13) gene was significantly associated with the occurrence of liver metastasis and shorter disease-free survival. TSC2 and PTEN are two key inhibitors of the Akt/mammalian target of rapamycin (mTOR) pathway and the specific inhibition of mTOR with rapamycin or RAD001 inhibited cell proliferation of PET cell lines.

Conclusion

Our results strongly support a role for PI3K/Akt/mTOR pathway in PET, which ties in with the fact that mTOR inhibitors have reached phase III trials in neuroendocrine tumors. The finding of differential SSTR expression raises the potential for SSTR expression to be evaluated as a marker of response to somatostatin analogs. Finally, we identified FGF13 as a new prognostic marker that predicted poorer outcome in patients who were clinically considered free from disease.
Infantile Fibrosarcoma: Management Based on the European Experience
Authors: Orbach Daniel , Rey Annie , Cecchetto Giovanni , Oberlin Odile , Casanova Michela , Thebaud Estelle , Scopinaro Marcelo , Bisogno Gianni , Carli Modesto , Ferrari Andrea
Published: November 2009

Purpose

To retrospectively analyze the clinical features and results of treatment in 56 infants with fibrosarcoma enrolled onto cooperative European protocols between 1979 and 2005 and treated with a combination of surgery and chemotherapy.

Patients and Methods

We performed a retrospective case review of infants under the age of 2 years with fibrosarcoma treated between 1979 and 2005 in six European studies. Patients were staged according to the Intergroup Rhabdomyosarcoma Staging System international classification as a function of the type of initial surgery and the extent of disease and were treated with surgery and chemotherapy. Survival was calculated using the Kaplan-Meier method.

Results

Primary tumor site was the limbs in 66% of patients; median tumor diameter was more than 5 cm in 63% of patients; and postoperative staging was as follows: group I, 22%; group II, 27%; group III, 47%; and group IV, 4%. Response rate to chemotherapy was 75%, and the specific response rate to vincristine-dactinomycin was 71%. Local control was obtained in 84% of patients. At the end of follow-up, 45% of survivors had been treated by surgery alone, 6% by chemotherapy alone, 46% by surgery and chemotherapy, and 2% by surgery, chemotherapy, and radiotherapy. The 5-year overall survival (OS) rate was 89%. The 5-year OS and event-free survival rates for localized patients were 89% and 81%, respectively.

Conclusion

Although complete resection is rarely feasible at diagnosis, conservative surgery remains the mainstay treatment for infantile fibrosarcoma. An alkylating agent–free and anthracycline-free regimen is usually effective and should be chosen as first-line chemotherapy for inoperable tumors. Overall prognosis is good, but progression or relapse, mainly local, remains possible.
Impact of Two Supportive Care Interventions on Anxiety, Depression, Quality of Life, and Unmet Needs in Patients With Nonlocalized Breast and Colorectal Cancers
Authors: Girgis Afaf , Breen Sibilah , Stacey Fiona , Lecathelinais Christophe
Published: November 2009

Purpose

Patients with cancer experience considerable symptom burden, psychological morbidity, and unmet psychosocial needs. Research suggests that feedback of patient-reported outcomes to clinicians or caseworkers, alongside management strategies, may result in improved patient functioning. Two intervention models were developed to test this effect in a randomized, controlled trial against usual care (UC): a telephone caseworker (TCW) model and an oncologist/general practitioner (O/GP) model. Primary end points included anxiety, depression, physical/emotional functioning, and unmet supportive care needs.

Patients and Methods

Participants with nonlocalized breast or colorectal cancers were surveyed by computer-assisted telephone interview (CATI) at three time points: baseline, 3 months, and 6 months. Data collected from participant CATIs in the supportive care models were used to generate feedback to either each participant's designated TCW, or their nominated O/GPs. Data obtained from participants in the UC model were used only to assess the impact of supportive care models. In total, 356 participants consented to study participation, completed the baseline CATI, and were randomly assigned to the UC, TCW, or O/GP groups.

Results

No overall intervention effect was observed. Physical functioning was significantly improved at the third CATI for participants in the TCW model (P = .01), and there was a trend toward fewer participants with unmet needs (P = .07). TCW group participants also were more likely to have the following: identified issues of need discussed (P < .0001); referrals made (P < .0001); and strong agreement that the intervention improved communication with their health care team (P = .0005).

Conclusion

The TCW model holds some promise; however, additional work in at-risk populations is required before we recommend implementation.
Randomized, Double-Blind Trial of Carboplatin and Paclitaxel With Either Daily Oral Cediranib or Placebo in Advanced Non–Small-Cell Lung Cancer: NCIC Clinical Trials Group BR24 Study
Authors: Goss Glenwood D. , Arnold Andrew , Shepherd Frances A. , Dediu Mircea , Ciuleanu Tudor-Eliade , Fenton David , Zukin Mauro , Walde David , Laberge Francis , Vincent Mark D. , Ellis Peter M. , Laurie Scott A. , Ding Keyue , Frymire Eliot , Gauthier Isabelle , Leighl Natasha B. , Ho Cheryl , Noble Jonathan , Lee Christopher W. , Seymour Lesley
Published: November 2009

Purpose

This phase II/III double-blind study assessed efficacy and safety of cediranib with standard chemotherapy as initial therapy for advanced non–small-cell lung cancer (NSCLC).

Patients and Methods

Paclitaxel (200 mg/m2) and carboplatin (area under the serum concentration-time curve 6) were given every 3 weeks, with daily oral cediranib or placebo at 30 mg (first 45 patients received 45 mg). Progression-free survival (PFS) was the primary outcome of the phase II interim analysis; phase III would proceed if the hazard ratio (HR) for PFS ≤ 0.77 and toxicity were acceptable.

Results

A total of 296 patients were enrolled, 251 to the 30-mg cohort. The phase II interim analysis demonstrated a significantly higher response rate (RR) for cediranib than for placebo, HR of 0.77 for PFS, no excess hemoptysis, and a similar number of deaths in each arm. The study was halted to review imbalances in assigned causes of death. In the primary phase II analysis (30-mg cohort), the adjusted HR for PFS was 0.77 (95% CI, 0.56 to 1.08) with a higher RR for cediranib than for placebo (38% v 16%; P < .0001). Cediranib patients had more hypertension, hypothyroidism, hand-foot syndrome, and GI toxicity. Hypoalbuminemia, age ≥ 65 years, and female sex predicted increased toxicity. Survival update (N = 296) 10 months after study unblinding favored cediranib over placebo (median of 10.5 months v 10.1 months; HR, 0.78; 95% CI, 0.57 to 1.06; P = .11). Causes of death in the cediranib 30-mg cohort were NSCLC (81%), protocol toxicity ± NSCLC (13%), and other (6%); for the placebo group, they were 98%, 0%, and 2%, respectively.

Conclusion

The addition of cediranib to carboplatin/paclitaxel results in improved response and PFS, but does not appear tolerable at a 30-mg dose. Consequently, the National Cancer Institute of Canada Clinical Trials Group and the Australasian Lung Cancer Trials Group initiated a randomized, double-blind, placebo-controlled trial of cediranib 20 mg with carboplatin and paclitaxel in advanced NSCLC.
Induction Chemotherapy and Cetuximab for Locally Advanced Squamous Cell Carcinoma of the Head and Neck: Results From a Phase II Prospective Trial
Authors: Kies Merrill S. , Holsinger Floyd Christopher , Lee J. Jack , William William N. , Glisson Bonnie S. , Lin Heather Y. , Lewin Jan S. , Ginsberg Lawrence E. , Gillaspy Katharine A. , Massarelli Erminia , Byers Lauren , Lippman Scott M. , Hong Waun K. , El-Naggar Adel K. , Garden Adam S. , Papadimitrakopoulou Vassiliki
Published: November 2009

Purpose

To determine the potential efficacy of combining cetuximab with chemotherapy in patients with advanced nodal disease, we conducted a phase II trial with induction chemotherapy (ICT) consisting of six weekly cycles of paclitaxel 135 mg/m2 and carboplatin (area under the curve = 2) with cetuximab 400 mg/m2 in week 1 and then 250 mg/m2 (PCC).

Patients and Methods

Forty-seven previously untreated patients (41 with oropharynx primaries; 33 men, 14 women; median age, 53 years; performance status of 0 or 1) with squamous cell carcinoma of the head and neck (SCCHN; T1-4, N2b/c/3) were treated and evaluated for clinical and radiographic response. After ICT, patients underwent risk-based local therapy, which consisted of either radiation, concomitant chemoradiotherapy, or surgery, based on tumor stage and site at diagnosis.

Results

After induction PCC, nine patients (19%) achieved a complete response, and 36 patients (77%) achieved a partial response. The most common grade 3 or 4 toxicity was skin rash (45%), followed by neutropenia (21%) without fever. At a median follow-up time of 33 months, locoregional or systemic disease progression was observed in six patients. The 3-year progression-free survival (PFS) and overall survival (OS) rates were 87% (95% CI, 78% to 97%) and 91% (95% CI, 84% to 99%), respectively. Human papillomavirus (HPV) 16, found in 12 (46%) of 26 biopsies, was associated with improved PFS (P = .012) and OS (P = .046).

Conclusion

ICT with weekly PCC followed by risk-based local therapy seems to be feasible, effective, and well tolerated. PFS is promising, and this sequential treatment strategy should be further investigated. Patients with HPV-positive tumors have an excellent prognosis.
Tumor-Associated Lymphocytes As an Independent Predictor of Response to Neoadjuvant Chemotherapy in Breast Cancer
Authors: Denkert Carsten , Loibl Sibylle , Noske Aurelia , Roller Marc , Müller Berit Maria , Komor Martina , Budczies Jan , Darb-Esfahani Silvia , Kronenwett Ralf , Hanusch Claus , von Törne Christian , Weichert Wilko , Engels Knut , Solbach Christine , Schrader Iris , Dietel Manfred , von Minckwitz Gunter
Published: November 2009

Purpose

Preclinical data suggest a contribution of the immune system to chemotherapy response. In this study, we investigated the prespecified hypothesis that the presence of a lymphocytic infiltrate in cancer tissue predicts the response to neoadjuvant chemotherapy.

Methods

We investigated intratumoral and stromal lymphocytes in a total of 1,058 pretherapeutic breast cancer core biopsies from two neoadjuvant anthracycline/taxane-based studies (GeparDuo, n = 218, training cohort; and GeparTrio, n = 840, validation cohort). Molecular parameters of lymphocyte recruitment and activation were evaluated by kinetic polymerase chain reaction in 134 formalin-fixed, paraffin-embedded tumor samples.

Results

In a multivariate regression analysis including all known predictive clinicopathologic factors, the percentage of intratumoral lymphocytes was a significant independent parameter for pathologic complete response (pCR) in both cohorts (training cohort: P = .012; validation cohort: P = .001). Lymphocyte-predominant breast cancer responded, with pCR rates of 42% (training cohort) and 40% (validation cohort). In contrast, those tumors without any infiltrating lymphocytes had pCR rates of 3% (training cohort) and 7% (validation cohort). The expression of inflammatory marker genes and proteins was linked to the histopathologic infiltrate, and logistic regression showed a significant association of the T-cell–related markers CD3D and CXCL9 with pCR.

Conclusion

The presence of tumor-associated lymphocytes in breast cancer is a new independent predictor of response to anthracycline/taxane neoadjuvant chemotherapy and provides useful information for oncologists to identify a subgroup of patients with a high benefit from this type of chemotherapy.
Peritoneal Colorectal Carcinomatosis Treated With Surgery and Perioperative Intraperitoneal Chemotherapy: Retrospective Analysis of 523 Patients From a Multicentric French Study
Authors: Elias Dominique , Gilly François , Boutitie Florent , Quenet François , Bereder Jean-Marc , Mansvelt Baudouin , Lorimier Gérard , Dubè Pierre , Glehen Olivier
Published: November 2009

Purpose

Peritoneal carcinomatosis (PC) from colorectal cancer traditionally is considered a terminal condition. Approaches that combine cytoreductive surgery (CRS) and perioperative intraperitoneal chemotherapy (PIC) have been developed recently. The purpose of this study was to assess early and long-term survival in patients treated with that strategy.

Patients and Methods

A retrospective-cohort, multicentric study from French-speaking countries was performed. All consecutive patients with PC from colorectal cancer who were treated with CRS and PIC (with or without hyperthermia) were included. Patients with PC of appendiceal origin were excluded.

Results

The study included 523 patients from 23 centers in four French-speaking countries who underwent operation between 1990 and 2007. The median follow-up was 45 months. Mortality and grades 3 to 4 morbidity at 30 days were 3% and 31%, respectively. Overall median survival was 30.1 months. Five-year overall survival was 27%, and five-year disease-free survival was 10%. Complete CRS was performed in 84% of the patients, and median survival was 33 months. Positive independent prognostic factors identified in the multivariate analysis were complete CRS, PC that was limited in extent, no invaded lymph nodes, and the use of adjuvant chemotherapy. Neither the grade of disease nor the presence of liver metastases had a significant prognostic impact.

Conclusion

This combined treatment approach against PC achieved low postoperative morbidity and mortality, and it provided good long-term survival in patients with peritoneal scores lower than 20. These results should improve in the future, because the different teams involved will gain experience. This approach, when feasible, is now considered the gold standard in the French guidelines.
Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Malignant Peritoneal Mesothelioma: Multi-Institutional Experience
Authors: Yan Tristan D. , Deraco Marcello , Baratti Dario , Kusamura Shigeki , Elias Dominique , Glehen Olivier , Gilly François N. , Levine Edward A. , Shen Perry , Mohamed Faheez , Moran Brendan J. , Morris David L. , Chua Terence C. , Piso Pompiliu , Sugarbaker Paul H.
Published: November 2009

Purpose

This multi-institutional registry study evaluated cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) for diffuse malignant peritoneal mesothelioma (DMPM).

Patients and Methods

A multi-institutional data registry that included 405 patients with DMPM treated by a uniform approach that used CRS and HIPEC was established. The primary end point was overall survival. The secondary end point was evaluation of prognostic variables for overall survival.

Results

Follow-up was complete in 401 patients (99%). The median follow-up period for the patients who were alive was 33 months (range, 1 to 235 months). The mean age was 50 years (standard deviation [SD], 14 years). Three hundred eighteen patients (79%) had epithelial tumors. Twenty-five patients (6%) had positive lymph nodes. The mean peritoneal cancer index was 20. One hundred eighty-seven patients (46%) had complete or near-complete cytoreduction. Three hundred seventy-two patients (92%) received HIPEC. One hundred twenty-seven patients (31%) had grades 3 to 4 complications. Nine patients (2%) died perioperatively. The mean length of hospital stay was 22 days (SD, 15 days). The overall median survival was 53 months (1 to 235 months), and 3- and 5-year survival rates were 60% and 47%, respectively. Four prognostic factors were independently associated with improved survival in the multivariate analysis: epithelial subtype (P < .001), absence of lymph node metastasis (P < .001), completeness of cytoreduction scores of CC-0 or CC-1 (P < .001), and HIPEC (P = .002).

Conclusion

The data suggest that CRS combined with HIPEC achieved prolonged survival in selected patients with DMPM.
Clinical Results of Long-Term Follow-Up of a Large, Active Surveillance Cohort With Localized Prostate Cancer
Authors: Klotz Laurence , Zhang Liying , Lam Adam , Nam Robert , Mamedov Alexandre , Loblaw Andrew
Published: November 2009

Purpose

We assessed the outcome of a watchful-waiting protocol with selective delayed intervention by using clinical prostate-specific antigen (PSA), or histologic progression as treatment indications for clinically localized prostate cancer.

Patients and Methods

This was a prospective, single-arm, cohort study. Patients were managed with an initial expectant approach. Definitive intervention was offered to those patients with a PSA doubling time of less than 3 years, Gleason score progression (to 4 + 3 or greater), or unequivocal clinical progression. Survival analysis and Cox proportional hazard model were applied to the data.

Results

A total of 450 patients have been observed with active surveillance. Median follow-up was 6.8 years (range, 1 to 13 years). Overall survival was 78.6%. The 10-year prostate cancer actuarial survival was 97.2%. Overall, 30% of patients have been reclassified as higher risk and have been offered definitive therapy. Of 117 patients treated radically, the PSA failure rate was 50%, which was 13% of the total cohort. PSA doubling time of 3 years or less was associated with an 8.5-times higher risk of biochemical failure after definitive treatment compared with a doubling time of more than 3 years (P < .0001). The hazard ratio for nonprostate cancer to prostate cancer mortality was 18.6 at 10 years.

Conclusion

We observed a low rate of prostate cancer mortality. Among the patients who were reclassified as higher risk and who were treated, PSA failure was relatively common. Other-cause mortality accounted for almost all of the deaths. Additional studies are warranted to improve the identification of patients who harbor more aggressive disease despite favorable clinical parameters at diagnosis.
Interpreting Hucbald on Mode
Authors: Fuller Sarah
Published: November 2009

Hucbald of St. Amand's treatise Musica took shape in the late Carolingian era in a time of intense and independent music-theoretical activity. Hucbald has been recognized as a pioneer who brought elements from Greek music theory to bear upon plainsong, but his view of mode has been considered rather routine. Through scrutiny of modal references and explanatory rhetoric within the treatise, this study corrects some modern readings of Hucbald's teaching on mode and offers a new assessment of the relationship between modal lore and venerable Boethian theory in Hucbald's theoretical universe. In Musica, a substratum of preexistent modal knowledge replaces Boethian number relationships as the foundation underlying basic elements of music theory.
Music in Dialogue
Authors: Judd Cristle Collins
Published: November 2009

This article takes Thomas Morley's A Plaine and Easie Introduction to Practicall Musicke (1597) as a point of departure for exploring a group of sixteenth-century texts that place music, especially as represented by musical notation, within the form of a dialogue. Music and musical writings have barely figured in the study of the Renaissance dialogue, yet these works offer specific insights about the nature of the genre. In addition to Morley's treatise, works discussed in detail include Anton Francesco Doni's Dialogo della musica (1544), Gioseffo Zarlino's Dimostrationi harmoniche (1571), and Ercole Bottrigari's Il desiderio overo de' concerti (1594). The article focuses on the uniquely hybrid nature of each of these texts and the ways in which various generic constraints and demands of format interact. Musical treatises in dialogue format offer a special means of understanding the broader history of the dialogue and the role of spatiality and temporality in creating verisimilitude. While Doni's Dialogo may be seen as an attempt at interpolating “real music” into the conversational and literary genre of the dialogue, Morley's didactic treatise represents the culmination of that interpolation: the means for taking part in the original conversation, namely the ability to sing.
Reconsidering “High Style” and “Low Style” in Medieval Song
Authors: Aubrey Elizabeth
Published: November 2009

Using the concept of “style” in analysis runs the risk of circularity, where features of individual works are identified as belonging to a style whose definition itself is derived from those features. This pitfall undermines studies of the songs of the twelfth- and thirteenth-century troubadours and trouvères that delineate a “high style,” including chansons, and a “low style,” including dances and pastourelles. The dichotomy originated in the nineteenth century with Gaston Paris's concept of amour courtois, from which Roger Dragonetti later derived the term grand chant courtois, now a common label for “high-style” songs. Other literary scholars, notably Paul Zumthor and Pierre Bec, have discussed problems in classifying styles and genres. References to genres in medieval texts are ambiguous, and manuscripts rarely group songs by genre. Theorists such as Raimon Vidal, Jofre de Foixà, and Johannes de Grocheio do not present a clear-cut or consistent stratification of genres. John Stevens, Christopher Page, and others have proposed features of “high style” and “low style” that do not entirely agree. An examination of their examples and additional ones demonstrates that a perception of “style” can be subjective and circular, and that the notion of “high style” and “low style” is an oversimplification.
Hildegard, Hermannus, and Late Chant Style
Authors: Bain Jennifer
Published: November 2009

The music of Hildegard of Bingen (1098-1179) has often been described as standing outside medieval chant traditions. This article argues that although many features of her music deviate from early chant, her repertoire conforms instead in remarkable ways with a late chant style, which appeared first in the eleventh century. Detailed analysis and comparison of the music (and theory) of Hermannus Contractus (1013-1054) with Hildegard's demonstrates a shared emphasis on Hermannus's modal nodes of final, fifth, and octave. Further analyses of antiphons from the later Middle Ages for Saints Hubert and Roch, as found in the Salzinnes Antiphonal, confirm that this musical style prevailed for several centuries. A contextualization of Hildegard's musical output makes it clear that she was not as isolated musically (or as musically untutored) as generally thought, but rather immersed in the musical traditions of her day. A historiographical overview reveals that nineteenth-century scholars were already aware of these similarities, in contrast to scholarship of the last thirty years, which has focused on Hildegard's originality.
Competent minors and health-care research: autonomy does not rule, okay?
Authors: Biggs Hazel
Published: November 2009

A dearth of clinical research involving children has resulted in off-licence and sometimes inappropriate medications being prescribed to the paediatric population. In this environment, recent years have seen the introduction of a raft of regulation aimed at increasing the involvement of children in clinical trials research and generating evidence-based medicinal preparations for their use. However, this regulation pays scant attention to the autonomy of competent minors. In particular, it makes no provision for the ability of competent minors to consent to participate in medical research and is therefore at odds with best ethical practice. This article explores the tensions between law and ethics in relation to clinical research involving minors and concludes that greater respect should be given to the autonomy of those minors who are competent to decide for themselves.
Subject positions in research ethics committee letters: a discursive analysis
Authors: O'Reilly Michelle , Armstrong Natalie , Dixon-Woods Mary
Published: November 2009

Ethical review of applications to conduct research projects continues to be a focus of scrutiny and controversy. We argue that attention to the actual practices of ethical review has the potential to inform debate. We explore how research ethics committees (RECs) establish their position and authority through the texts they use in their correspondence with applicants. Using a discursive analysis applied to 260 letters, we identify four positions of particular interest: RECs positioned as disinterested and responsible; as representing the interests of potential participants; as facilitating ethically sound, high-quality research; and as engaged in dialogue. These positions are used strategically to deflect criticism or complaint. This analysis has implications for reducing contestation between researchers and RECs, suggesting that more dialogic rather than hierarchical approaches to positioning might be helpful.