bluuebunny/crossref_metadata_2025 huggingface dataset:
Two-year outcomes of Elektra prosthesis for trapeziometacarpal osteoarthritis: a longitudinal cohort study
Authors: Hernández-Cortés P. , Pajares-López M. , Robles-Molina M. J. , Gómez-Sánchez R. , Toledo-Romero M. A. , De Torres-Urrea J.
Published: July 2011

The aim of this study was to evaluate clinical and radiographic outcomes of Elektra® trapeziometacarpal prostheses after 2 years. We present a longitudinal cohort study of 19 prostheses for the treatment of Eaton stage II and III osteoarthritis (mean follow-up of 29 months). QuickDASH score, pinch strength and mobility were determined, and radiographs were analysed. Isotope scans were taken in patients with persistent pain or suspected loosening. Although the QuickDASH score was 69 before and 38 after surgery, nine patients had pain at the trapeziometacarpal joint with radiographic osteolysis around the trapezium component and a positive bone scan uptake at subsequent follow-up. The implant was revised in three of these nine patients and another patient underwent surgery for periprosthetic fracture. Only ten of the 19 implants showed no sign of failure. Most problems derived from the trapezium cup. Because of these poor outcomes after only 2 years, we cannot recommend this implant.
Extending the duration of first-line chemotherapy in metastatic breast cancer: a perspective review
Authors: Gennari Alessandra , D’amico Mauro , Corradengo Davide
Published: July 2011

The treatment of metastatic breast cancer is mainly palliative, but optimal management might result in survival improvement as well. For this reason, many trials have attempted to optimize the therapeutic approach in this disease setting. Among the possible options, chemotherapy represents the backbone of the treatment and survival improvements that have been shown by the use of modern chemotherapeutic agents. Whereas the type of chemotherapy is generally dictated by patient characteristics and those of their disease, substantial controversy still remains on how long chemotherapy should be administered after disease control is achieved. In this review, we have analysed all available evidence on the duration of first-line chemotherapy in advanced breast cancer.
The Language of Performance Evaluations
Authors: Biernat Monica , Tocci M. J. , Williams Joan C.
Published: July 2011

Performance evaluations of male and female junior attorneys in a Wall Street law firm were analyzed. Male supervisors judged male attorneys more favorably than female attorneys on numerical ratings that mattered for promotion but offered narrative comments that showed either no sex effects or greater favorability toward women. Judgments of male attorneys were more consistent overall than they were for female attorneys, and predictors of numerical ratings differed by sex: Narrative ratings of technical competence mattered more for men than women, and narrative ratings of interpersonal warmth mattered more for women than men. Open-ended use of positive performance words—the only outcome that favored women—did not translate into positive numerical ratings for women. The data suggest subtle patterns of gender bias, in which women were harmed by not meeting gendered expectations of interpersonal warmth but were less benefited than men by meeting masculine standards of high technical competence.
Information Processing Differences in Active Versus Passive Person Perceivers
Authors: Waggoner Ashley S. , Smith Eliot R.
Published: July 2011

Previous work has shown that compared to passive perceivers who view preselected information about target persons, active perceivers are less confident in their impressions, do not show increased confidence with increased amounts of information, and like targets less. The authors now explain these findings, postulating that perceivers without control over the amount of information they receive should be motivated to form impressions earlier, altering their information-processing strategies. Study 1 predicted and found that content-only active perceivers who control the content, but not the amount, of information show the same positive relationship between confidence and amount of information as passive perceivers, as well as the same reading-time patterns and level of liking. Study 2 used clearly valenced target stimuli and found support for the hypothesis that passive perceivers form more extreme early impressions, leading to greater liking when early information is positive but less liking when it is negative.
Microstructures and mechanical properties of Al2O3/AZ91 surface nanocomposite layer produced by friction stir processing
Authors: Faraji G , Dastani O , Mousavi S A A Akbari
Published: July 2011

In this paper, the effects of friction stir processing (FSP) parameters on the mechanical properties and microstructures of as-cast magnesium AZ91 alloy are investigated. Grain-growth and microhardness of friction-stir-processed specimens with and without nano-sized aluminium oxide (Al2O3) particles are compared. The effects of process parameters on tunnelling cavity and other friction stir processing defects are discussed. The paper describes the proper process parameters under which a uniform distribution of nano Al2O3 composite reinforcement with good interfacial integrity and significant grain refinement can be produced. Hardness studies revealed that the incorporation of nano-sized Al2O3 particulates in magnesium matrix caused the SZ hardness to increase.
Adaptive torque control of friction stir welding for the purpose of estimating tool wear
Authors: Gibson B , Cook G , Prater T , Longhurst W , Strauss A M , Cox C D
Published: July 2011

In this paper, an adaptive torque controller for friction stir welding (FSW) that can estimate parameters such as probe radius which may be changing throughout the welding process is presented. Implementing an adaptive controller with this capability would be of interest to industry sectors in which FSW is performed on high melting point alloys or metal matrix composites (MMC). Welding these materials has shown a greatly accelerated rate of tool wear. Simulations were conducted to examine how extreme tool wear would affect controller performance and how accurately the controller could estimate the probe radius. A simplified wear model consisting of a linear decrease in probe radius was used to verify controller performance. Next, a wear model consistent with wear patterns seen in the welding of highly abrasive materials was developed. Results indicate that torque is controlled effectively while a change in system dynamics is experienced, as would be expected with adaptive control, but also that the tool profile is accurately estimated after an initial identification period.
A conceptual microchannel system design methodology incorporating axiomatic design theory for size-controllable monodispersed microsphere generation by a liquid chopper utilizing a PZT actuator
Authors: Song K-Y , Zhang W-J , Gupta M M
Published: July 2011

This paper proposes a design methodology for conceptual design of microchannel systems by applying axiomatic design theory (ADT). The microchannel system concerned, as an example, in this paper is for the purpose of preparing uniform microspheres based on the phase separation principle. There are two general design goals for this system: controllability of the size of microspheres and uniformity or narrow size distribution of microspheres. The conventional microchannel system designs in literature are found to be the so-called ‘coupled design’, which is regarded as a poor design, according to ADT. This paper proposes a ‘decoupled design’ process, which is considered better than a ‘coupled design’ process according to ADT. This paper demonstrates the effectiveness of such a ‘decoupled design’ process with a new microchannel system with an embedded liquid chopper utilizing a PZT actuator by simulation.
A repertoire-independent and cell-intrinsic defect in murine GVHD induction by effector memory T cells
Authors: Juchem Kathryn W. , Anderson Britt E. , Zhang Cuiling , McNiff Jennifer M. , Demetris Anthony J. , Farber Donna L. , Caton Andrew J. , Shlomchik Warren D. , Shlomchik Mark J.
Published: July 2011

Effector memory T cells (TEM) do not cause graft-versus-host disease (GVHD), though why this is has not been elucidated. To compare the fates of alloreactive naive (TN) or memory (TM) T cells, we developed a model of GVHD in which donor T cells express a transgene-encoded TCR specific for an antigenic peptide that is ubiquitously expressed in the recipient. Small numbers of naive TCR transgenic (Tg) T cells induced a robust syndrome of GVHD in transplanted recipients. We then used an established method to convert TCR Tg cells to TM and tested these for GVHD induction. This allowed us to control for the potentially different frequencies of alloreactive T cells among TN and TM, and to track fates of alloreactive T cells after transplantation. TEM caused minimal, transient GVHD whereas central memory T cells (TCM) caused potent GVHD. Surprisingly, TEM were not inert: they, engrafted, homed to target tissues, and proliferated extensively, but they produced less IFN-γ and their expansion in target tissues was limited at later time points, and local proliferation was reduced. Thus, cell-intrinsic properties independent of repertoire explain the impairment of TEM, which can initiate but cannot sustain expansion and tissue damage.
β-thalassemia: a model for elucidating the dynamic regulation of ineffective erythropoiesis and iron metabolism
Authors: Ginzburg Yelena , Rivella Stefano
Published: July 2011

β-thalassemia is a disease characterized by anemia and is associated with ineffective erythropoiesis and iron dysregulation resulting in iron overload. The peptide hormone hepcidin regulates iron metabolism, and insufficient hepcidin synthesis is responsible for iron overload in minimally transfused patients with this disease. Understanding the crosstalk between erythropoiesis and iron metabolism is an area of active investigation in which patients with and models of β-thalassemia have provided significant insight. The dependence of erythropoiesis on iron presupposes that iron demand for hemoglobin synthesis is involved in the regulation of iron metabolism. Major advances have been made in understanding iron availability for erythropoiesis and its dysregulation in β-thalassemia. In this review, we describe the clinical characteristics and current therapeutic standard in β-thalassemia, explore the definition of ineffective erythropoiesis, and discuss its role in hepcidin regulation. In preclinical experiments using interventions such as transferrin, hepcidin agonists, and JAK2 inhibitors, we provide evidence of potential new treatment alternatives that elucidate mechanisms by which expanded or ineffective erythropoiesis may regulate iron supply, distribution, and utilization in diseases such as β-thalassemia.
A reliable ex vivo invasion assay of human reticulocytes by Plasmodium vivax
Authors: Russell Bruce , Suwanarusk Rossarin , Borlon Céline , Costa Fabio T. M. , Chu Cindy S. , Rijken Marcus J. , Sriprawat Kanlaya , Warter Lucile , Koh Esther G. L. , Malleret Benoit , Colin Yves , Bertrand Olivier , Adams John H. , D'Alessandro Umberto , Snounou Georges , Nosten Francois , Rénia Laurent
Published: July 2011

Currently, there are no reliable RBC invasion assays to guide the discovery of vaccines against Plasmodium vivax, the most prevalent malaria parasite in Asia and South America. Here we describe a protocol for an ex vivo P vivax invasion assay that can be easily deployed in laboratories located in endemic countries. The assay is based on mixing enriched cord blood reticulocytes with matured, trypsin-treated P vivax schizonts concentrated from clinical isolates. The reliability of this assay was demonstrated using a large panel of P vivax isolates freshly collected from patients in Thailand.
Detection of autoreactive CD4 T cells using major histocompatibility complex class II dextramers
Authors: Massilamany Chandirasegaran , Upadhyaya Bijaya , Gangaplara Arunakumar , Kuszynski Charles , Reddy Jay
Published: July 2011

Background

Tetramers are useful tools to enumerate the frequencies of antigen-specific T cells. However, unlike CD8 T cells, CD4 T cells - especially self-reactive cells - are challenging to detect with major histocompatibility complex (MHC) class II tetramers because of low frequencies and low affinities of their T cell receptors to MHC-peptide complexes. Here, we report the use of fluorescent multimers, designated MHC dextramers that contain a large number of peptide-MHC complexes per reagent.

Results

The utility of MHC dextramers was evaluated in three autoimmune disease models: 1) proteolipid protein (PLP) 139-151-induced experimental autoimmune encephalomyelitis in SJL/J (H-2s) mice; 2) myelin oligodendrocyte glycoprotein (MOG) 35-55-induced experimental autoimmune encephalomyelitis in C57Bl/6 (H-2b) mice; and 3) cardiac myosin heavy chain (Myhc)-α 334-352-induced experimental autoimmune myocarditis in A/J (H-2a) mice. Flow cytometrically, we demonstrate that IAs/PLP 139-151, IAb/MOG 35-55 and IAk/Myhc-α 334-352 dextramers detect the antigen-sensitized cells with specificity, and with a detection sensitivity significantly higher than that achieved with conventional tetramers. Furthermore, we show that binding of dextramers, but not tetramers, is less dependent on the activation status of cells, permitting enumeration of antigen-specific cellsex vivo.

Conclusions

The data suggest that MHC dextramers are useful tools to track the generation and functionalities of self-reactive CD4 cells in various experimental systems.
The prevalence, incidence and natural history of primary sclerosing cholangitis in an ethnically diverse population
Authors: Toy Elaine , Balasubramanian Sripriya , Selmi Carlo , Li Chin-Shang , Bowlus Christopher L
Published: July 2011

Background

Primary sclerosing cholangitis (PSC) is a rare chronic cholestatic liver disease often associated with inflammatory bowel diseases (IBD). Current epidemiological data are limited to studies of predominantly Caucasian populations. Our aim was to define the epidemiology of PSC in a large, ethnically diverse US population.

Methods

The Northern California Kaiser Permanente (KP) database includes records from over 3 million people and was searched for cases of PSC between January 2000 and October 2006. All identified charts were reviewed for diagnosis confirmation, IBD co-morbidity, and major natural history endpoints.

Results

We identified 169 (101 males) cases fulfilling PSC diagnostic criteria with a mean age at diagnosis of 44 years (range 11-81). The age-adjusted point prevalence was 4.15 per 100,000 on December 31, 2005. The age-adjusted incidence per 100,000 person-years was not significantly greater in men 0.45 (95% CI 0.33 - 0.61) than women 0.37 (95% CI 0.26 - 0.51). IBD was present in 109/169 (64.5%) cases and was significantly more frequent in men than women with PSC (73.3% and 51.5%, respectively, p = 0.005). The cumulative average yearly mortality rate was 1.9%. Age and serum sodium, creatinine and bilirubin at diagnosis and albumin at last entry were identified as significant factors associated with death, liver transplant or cholangiocarcinoma.

Conclusions

The incidence and prevalence of PSC observed in a representative Northern California population are lower compared to previous studies in Caucasian populations and this might reflect differences in the incidence of PSC among various ethnic groups.
Brain-derived neurotrophic factor expression predicts adverse pathological & clinical outcomes in human breast cancer
Authors: Patani Neill , Jiang Wen G , Mokbel Kefah
Published: July 2011

Introduction

Brain-derived neurotrophic factor (BDNF) has established physiological roles in the development and function of the vertebrate nervous system. BDNF has also been implicated in several human malignancies, including breast cancer (BC). However, the precise biological role of BDNF and its utility as a novel biomarker have yet to be determined. The objective of this study was to determine the mRNA and protein expression of BDNF in a cohort of women with BC. Expression levels were compared with normal background tissues and evaluated against established pathological parameters and clinical outcome over a 10 year follow-up period.

Methods

BC tissues (n = 127) and normal tissues (n = 33) underwent RNA extraction and reverse transcription, BDNF transcript levels were determined using real-time quantitative PCR. BDNF protein expression in mammary tissues was assessed with standard immuno-histochemical methodology. Expression levels were analyzed against tumour size, grade, nodal involvement, TNM stage, Nottingham Prognostic Index (NPI) and clinical outcome over a 10 year follow-up period.

Results

Immuno-histochemical staining revealed substantially greater BDNF expression within neoplastic cells, compared to normal mammary epithelial cells. Significantly higher mRNA transcript levels were found in the BC specimens compared to background tissues (p = 0.007). The expression of BDNF mRNA was demonstrated to increase with increasing NPI; NPI-1 vs. NPI-2 (p = 0.009). Increased BDNF transcript levels were found to be significantly associated with nodal positivity (p = 0.047). Compared to patients who remained disease free, higher BDNF expression was significantly associated with local recurrence (LR) (p = 0.0014), death from BC (p = 0.018) and poor prognosis overall (p = 0.013). After a median follow up of 10 years, higher BDNF expression levels were significantly associated with reduced overall survival (OS) (106 vs. 136 months, p = 0.006). BDNF emerged as an independent prognostic variable in multivariate analysis for disease free survival (DFS) (p = 0.026) and approached significance for OS (p = 0.055).

Conclusion

BDNF expression was found to be significantly higher in BC specimens compared to normal tissue. Higher transcript levels were significantly associated with unfavourable pathological parameters including nodal positivity and increasing NPI; and adverse clinical outcomes including LR, death from BC, poor prognosis, reduced DFS and OS. BDNF offers utility as a prognostic marker and potential for targeted therapeutic strategies.
The assessment of quality of life in acute cough with the Leicester Cough Questionnaire (LCQ-acute)
Authors: Yousaf Nadia , Lee Kai K , Jayaraman Bhagyashree , Pavord Ian D , Birring Surinder S
Published: July 2011

Introduction

Acute cough has a significant impact on physical and psychosocial health and is associated with an impaired quality of life (QOL). The Leicester Cough Questionnaire (LCQ) is a validated cough-related health status questionnaire designed for patients with chronic cough. The purpose of this study was to validate the LCQ for the assessment of health related QOL in patients with acute cough and determine the clinical minimal important difference (MID).

Methods

10 subjects with cough due to acute upper respiratory tract infection underwent focused interviews to investigate the face validity of the LCQ. The LCQ was also evaluated by a multidisciplinary team. 30 subjects completed the revised LCQ-acute and a cough visual analogue score (VAS: 0-100 mm) within one week of onset of cough and again <2 weeks later and at resolution of cough. The concurrent validity, internal reliability, repeatability and responsiveness of the LCQ-acute were also assessed. Patients also completed a Global Rating of Change Questionnaire that assessed the change in cough severity between visits. The MID was calculated as the change in LCQ-acute score for patients responding to GRCQ category representing the smallest change in health status that patients found worthwhile.

Results

Health status was severely impaired at baseline affecting all domains; median (interquartile range) total LCQ-acute score 13.0 (3.4). All subjects found the LCQ-acute questionnaire acceptable for assessing their cough. Internal reliability of the LCQ-acute was good for all domains and total score, Cronbach's α coefficients >0.9. There was a significant correlation between LCQ-acute and VAS (ρ = -0.48, p = 0.007). The LCQ-acute and its domains were highly responsive to change; effect sizes 1.7-2.3. The MID for total LCQ and VAS were 2.5 and 13 mm respectively.

Conclusion

The LCQ-acute is a brief, simple and valid instrument to assess cough specific health related QOL in patients with acute cough. It is a highly responsive tool suggesting that it will be particularly useful to assess the effect of antitussive therapy.
Population genetics of Glossina palpalis palpalis from central African sleeping sickness foci
Authors: Melachio Trésor Tito Tanekou/TT , Simo Gustave , Ravel Sophie , De Meeûs Thierry , Causse Sandrine , Solano Philippe , Lutumba Pascal , Asonganyi Tazoacha , Njiokou Flobert
Published: July 2011

Background

Glossina palpalis palpalis (Diptera: Glossinidae) is widespread in west Africa, and is the main vector of sleeping sickness in Cameroon as well as in the Bas Congo Province of the Democratic Republic of Congo. However, little is known on the structure of its populations. We investigated G. p. palpalis population genetic structure in five sleeping sickness foci (four in Cameroon, one in Democratic Republic of Congo) using eight microsatellite DNA markers.

Results

A strong isolation by distance explains most of the population structure observed in our sampling sites of Cameroon and DRC. The populations here are composed of panmictic subpopulations occupying fairly wide zones with a very strong isolation by distance. Effective population sizes are probably between 20 and 300 individuals and if we assume densities between 120 and 2000 individuals per km2, dispersal distance between reproducing adults and their parents extends between 60 and 300 meters.

Conclusions

This first investigation of population genetic structure of G. p. palpalis in Central Africa has evidenced random mating subpopulations over fairly large areas and is thus at variance with that found in West African populations of G. p. palpalis. This study brings new information on the isolation by distance at a macrogeographic scale which in turn brings useful information on how to organise regional tsetse control. Future investigations should be directed at temporal sampling to have more accurate measures of demographic parameters in order to help vector control decision.
Complete Surgical Resection Is Curative for Children With Hepatoblastoma With Pure Fetal Histology: A Report From the Children's Oncology Group
Authors: Malogolowkin Marcio H. , Katzenstein Howard M. , Meyers Rebecka L. , Krailo Mark D. , Rowland Jon M. , Haas Joel , Finegold Milton J.
Published: July 2011

Purpose

Children with pure fetal histology (PFH) hepatoblastoma treated with complete surgical resection and minimal adjuvant therapy have been shown to have excellent outcomes when compared with other patients with hepatoblastoma. We prospectively studied the safety and efficacy of reducing therapy in all children with stage I PFH enrolled onto two consecutive studies.

Patients and Methods

From August 1989 to December 1992, 9 children with stage I PFH were treated on the Intergroup Hepatoblastoma study INT-0098 and were nonrandomly assigned to receive chemotherapy after surgical resection with single-agent bolus doxorubicin for 3 consecutive days. From March 1999 to November 2006, 16 children with stage I PFH enrolled onto Children's Oncology Group Study P9645 were treated with observation after resection. Central confirmation of the histologic diagnosis by a study group pathologist was mandated. The extent of liver disease was assigned retrospectively according to the pretreatment extent of disease (PRETEXT) system and is designated “retro-PRETEXT” to clarify the retrospective group assignment.

Results

Five-year event-free and overall survival for the 9 patients treated on INT-0098 were 100%. All 16 patients enrolled onto the P9645 study were alive and free of disease at the time of last contact, with a median follow-up of 4.9 years. Retro-PRETEXT for the 21 patients with available data revealed seven patients with stage I disease, 10 patients with stage II disease, and four patients with stage III disease.

Conclusion

Children with completely resected PFH hepatoblastoma can achieve long-term survival without additional chemotherapy. When feasible, surgical resection of hepatoblastoma at diagnosis, without chemotherapy, can identify children for whom no additional therapy is necessary.
Health-Related Quality of Life During the 10 Years After Diagnosis of Colorectal Cancer: A Population-Based Study
Authors: Jansen Lina , Herrmann Antje , Stegmaier Christa , Singer Susanne , Brenner Hermann , Arndt Volker
Published: July 2011

Purpose

To compare long-term quality of life (QoL) of colorectal cancer survivors with QoL in the general population and investigate changes in QoL of survivors during the 10 years after diagnosis.

Patients and Methods

Health-related QoL was assessed 1, 3, 5, and 10 years after diagnosis in a population-based cohort starting with 439 patients with colorectal cancer from Saarland, Germany, using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30. QoL after 5 and 10 years and time course of QoL during the 10 years after diagnosis were compared with controls from the general population of Germany, after controlling for sex and age.

Results

Overall, 234 and 196 patients were still alive after 5 and 10 years, respectively. Of these survivors, 178 (76%) responded in the 5-year follow-up, 133 (68%) in the 10-year follow-up, and 117 (60%) participated in all follow-ups. Over the entire follow-up, younger survivors (age at diagnosis, < 60 years) reported restrictions in role, social, emotional, and cognitive functioning and specific problems like constipation, diarrhea, fatigue, and insomnia. Older survivors (age at diagnosis, ≥ 70 years) reported comparable or even better QoL than controls within the first 3 to 5 years after diagnosis and comparable to worse QoL 5 to 10 years after diagnosis.

Conclusion

Although younger survivors continuously reported detriments in various QoL dimensions during the 10-year period after diagnosis, detriments in older survivors became apparent in the long run only.
Genotype-Guided Tamoxifen Dosing Increases Active Metabolite Exposure in Women With Reduced CYP2D6 Metabolism: A Multicenter Study
Authors: Irvin William J. , Walko Christine M. , Weck Karen E. , Ibrahim Joseph G. , Chiu Wing K. , Dees E. Claire , Moore Susan G. , Olajide Oludamilola A. , Graham Mark L. , Canale Sean T. , Raab Rachel E. , Corso Steven W. , Peppercorn Jeffrey M. , Anderson Steven M. , Friedman Kenneth J. , Ogburn Evan T. , Desta Zeruesenay , Flockhart David A. , McLeod Howard L. , Evans James P. , Carey Lisa A.
Published: July 2011

Purpose

We examined the feasibility of using CYP2D6 genotyping to determine optimal tamoxifen dose and investigated whether the key active tamoxifen metabolite, endoxifen, could be increased by genotype-guided tamoxifen dosing in patients with intermediate CYP2D6 metabolism.

Patients and Methods

One hundred nineteen patients on tamoxifen 20 mg daily ≥ 4 months and not on any strong CYP2D6 inhibiting medications were assayed for CYP2D6 genotype and plasma tamoxifen metabolite concentrations. Patients found to be CYP2D6 extensive metabolizers (EM) remained on 20 mg and those found to be intermediate (IM) or poor (PM) metabolizers were increased to 40 mg daily. Eighty-nine evaluable patients had tamoxifen metabolite measurements repeated 4 months later.

Results

As expected, the median baseline endoxifen concentration was higher in EM (34.3 ng/mL) compared with either IM (18.5 ng/mL; P = .0045) or PM (4.2 ng/mL; P < .001). When the dose was increased from 20 mg to 40 mg in IM and PM patients, the endoxifen concentration rose significantly; in IM there was a median intrapatient change from baseline of +7.6 ng/mL (−0.6 to 23.9; P < .001), and in PM there was a change of +6.1 ng/mL (2.6 to 12.5; P = .020). After the dose increase, there was no longer a significant difference in endoxifen concentrations between EM and IM patients (P = .84); however, the PM endoxifen concentration was still significantly lower.

Conclusion

This study demonstrates the feasibility of genotype-driven tamoxifen dosing and demonstrates that doubling the tamoxifen dose can increase endoxifen concentrations in IM and PM patients.
High-Dose Chemotherapy With Autologous Stem-Cell Support As Adjuvant Therapy in Breast Cancer: Overview of 15 Randomized Trials
Authors: Berry Donald A. , Ueno Naoto T. , Johnson Marcella M. , Lei Xiudong , Caputo Jean , Rodenhuis Sjoerd , Peters William P. , Leonard Robert C. , Barlow William E. , Tallman Martin S. , Bergh Jonas , Nitz Ulrike A. , Gianni Alessandro M. , Basser Russell L. , Zander Axel R. , Coombes R. Charles , Roché Henri , Tokuda Yutaka , de Vries Elisabeth G.E. , Hortobagyi Gabriel N. , Crown John P. , Pedrazzoli Paolo , Bregni Marco , Demirer Taner
Published: July 2011

Purpose

Adjuvant high-dose chemotherapy (HDC) with autologous hematopoietic stem-cell transplantation (AHST) for high-risk primary breast cancer has not been shown to prolong survival. Individual trials have had limited power to show overall benefit or benefits within subsets.

Methods

We assembled individual patient data from 15 randomized trials that compared HDC versus control therapy without stem-cell support. Prospectively defined primary end points were relapse-free survival (RFS) and overall survival (OS). We compared the effect of HDC versus control by using log-rank tests and proportional hazards regression, and we adjusted for clinically relevant covariates. Subset analyses were by age, number of positive lymph nodes, tumor size, histology, hormone receptor (HmR) status, and human epidermal growth factor receptor 2 (HER2) status.

Results

Of 6,210 total patients (n = 3,118, HDC; n = 3,092 control), the median age was 46 years; 69% were premenopausal, 29% were postmenopausal, and 2% were unknown menopausal status; 49.5% were HmR positive; 33.5% were HmR negative, and 17% were unknown HmR status. The median follow-up was 6 years. After analysis was adjusted for covariates, HDC was found to prolong relapse-free survival (RFS; hazard ratio [HR], 0.87; 95% CI, 0.81 to 0.93; P < .001) but not overall survival (OS; HR, 0.94; 95% CI, 0.87 to 1.02; P = .13). For OS, no covariates had statistically significant interactions with treatment effect, and no subsets evinced a significant effect of HDC. Younger patients had a significantly better RFS on HDC than did older patients.

Conclusion

Adjuvant HDC with AHST prolonged RFS in high-risk primary breast cancer compared with control, but this did not translate into a significant OS benefit. Whether HDC benefits patients in the context of targeted therapies is unknown.
Randomized, Phase III Trial of Sequential Epirubicin and Docetaxel Versus Epirubicin Alone in Postmenopausal Patients With Node-Positive Breast Cancer
Authors: Coombes R. Charles , Bliss Judith M. , Espie Marc , Erdkamp Frans , Wals Jacob , Tres Alejandro , Marty Michel , Coleman Robert E. , Tubiana-Mathieu Nicole , den Boer Marinus O. , Wardley Andrew , Kilburn Lucy S. , Cooper Derek , Thomas Marina W.K. , Reise Justine A. , Wilkinson Katie , Hupperets Pierre
Published: July 2011

Purpose

The Docetaxel Epirubicin Adjuvant (DEVA) trial evaluated the efficacy and toxicity of incorporating docetaxel after epirubicin to create a sequential anthracycline-taxane regimen in early breast cancer.

Patients and Methods

After complete tumor excision, postmenopausal women with node-positive early breast cancer were randomly assigned to either epirubicin 50 mg/m2 on days 1 and 8 every 4 weeks for six cycles (EPI × 6) or three cycles of epirubicin 50 mg/m2 on days 1 and 8 every 4 weeks followed by three cycles of docetaxel 100 mg/m2 on day 1 every 3 weeks (EPI-DOC). A subset of patients also participated in a quality of life (QOL) study. The primary end point was disease-free survival (DFS).

Results

From 1997 to 2005, 803 patients entered DEVA (EPI × 6, n = 397; EPI-DOC, n = 406). At a median follow-up of 64.7 months (interquartile range, 45.2 to 84.4 months), 198 DFS events had been reported (EPI × 6, n = 114; EPI-DOC, n = 84). The 5-year DFS rates were 72.7% (95% CI, 68.0% to 77.3%) for epirubicin alone and 79.5% (95% CI, 75.2% to 83.8%) for epirubicin followed by docetaxel; evidence of improvement in DFS was observed with EPI-DOC (hazard ratio [HR], 0.68; 95% CI, 0.52 to 0.91; P = .008). One hundred twenty-seven patients have died (EPI × 6, n = 75; EPI-DOC, n = 52); a reduction in deaths was observed with EPI-DOC (HR, 0.66; 95% CI, 0.46 to 0.94; P = .02). The 5-year overall survival rates were 81.8% (95% CI, 77.7% to 85.9%) for epirubicin and 88.9% (95% CI, 85.5% to 92.2%) for epirubicin followed by docetaxel. Assessment of toxicity and QOL showed that EPI-DOC was associated with greater toxicity but with no difference in QOL between arms during follow-up.

Conclusion

These results suggest, within a relatively small trial, that substitution of docetaxel for epirubicin for the last three cycles of chemotherapy results in improved outcome in postmenopausal women with node-positive, early breast cancer compared with six cycles of epirubicin monotherapy.
Phase I Pharmacokinetic and Pharmacodynamic Study of the Multikinase Inhibitor Sorafenib in Combination With Clofarabine and Cytarabine in Pediatric Relapsed/Refractory Leukemia
Authors: Inaba Hiroto , Rubnitz Jeffrey E. , Coustan-Smith Elaine , Li Lie , Furmanski Brian D. , Mascara Gerard P. , Heym Kenneth M. , Christensen Robbin , Onciu Mihaela , Shurtleff Sheila A. , Pounds Stanley B. , Pui Ching-Hon , Ribeiro Raul C. , Campana Dario , Baker Sharyn D.
Published: July 2011

Purpose

To assess the toxicity, pharmacokinetics, and pharmacodynamics of multikinase inhibitor sorafenib in combination with clofarabine and cytarabine in children with relapsed/refractory leukemia.

Patients and Methods

Twelve patients with acute leukemia (11 with acute myeloid leukemia [AML]) received sorafenib on days 1 to 7 and then concurrently with cytarabine (1 g/m2) and clofarabine (stratum one: 40 mg/m2, n = 10; stratum two [recent transplantation or fungal infection]: 20 mg/m2, n = 2) on days 8 to 12. Sorafenib was continued until day 28 if tolerated. Two sorafenib dose levels (200 mg/m2 and 150 mg/m2 twice daily) were planned. Sorafenib pharmacokinetic and pharmacodynamic studies were performed on days 7 and 8.

Results

At sorafenib 200 mg/m2, two of four patients in stratum one and one of two patients in stratum two had grade 3 hand-foot skin reaction and/or rash as dose-limiting toxicities (DLTs). No DLTs were observed in six patients in stratum one at sorafenib 150 mg/m2. Sorafenib inhibited the phosphorylation of AKT, S6 ribosomal protein, and 4E-BP1 in leukemia cells. The rate of sorafenib conversion to its metabolite sorafenib N-oxide was high (mean, 33%; range, 17% to 69%). In vitro, the N-oxide potently inhibited FLT3–internal tandem duplication (ITD; binding constant, 70 nmol/L) and the viability of five AML cell lines. On day 8, sorafenib decreased blast percentages in 10 of 12 patients (median, 66%; range, 9% to 95%). After combination chemotherapy, six patients (three FLT3-ITD and three FLT3 wild-type AML) achieved complete remission, two (both FLT3-ITD AML) had complete remission with incomplete blood count recovery, and one (FLT3 wild-type AML) had partial remission.

Conclusion

Sorafenib in combination with clofarabine and cytarabine is tolerable and shows activity in relapsed/refractory pediatric AML.
Patterns of Adjuvant Chemotherapy Use in a Population-Based Cohort of Patients With Resected Stage II or III Colon Cancer
Authors: Abrams Thomas A. , Brightly Rick , Mao Jianbin , Kirkner Gregory , Meyerhardt Jeffrey A. , Schrag Deborah , Fuchs Charles S.
Published: July 2011

Purpose

Previous studies have examined predictors for initiation of adjuvant chemotherapy in stages II and III colon cancer. However, little is known regarding the use of specific chemotherapy regimens or treatment duration.

Patients and Methods

We studied treatment records for 2,560 patients with stage II or III colon cancer who received adjuvant chemotherapy between January 2004 and April 2010 at US cancer care facilities participating in a nationwide, commercially available chemotherapy order entry system that captures patient demographics, stage, and details of chemotherapy treatment. Multivariate analyses of prospectively recorded patient and provider characteristics identified predictors of specific therapeutic approaches.

Results

The addition of oxaliplatin to fluoropyrimidine-based adjuvant therapy increased during the study period (P trend < .001), and this combination represented 78% and 90% of adjuvant chemotherapy in stage II or III disease, respectively, by 2007. Older patients, those with diminished performance status, and those treated in a private practice setting were significantly less likely to receive oxaliplatin. Thirty percent of patients discontinued adjuvant therapy after less than 3 months. Older age, oxaliplatin-containing therapy, and receipt of treatment from a physician with a low volume of patients were each independently associated with premature discontinuation. Six percent of patients received bevacizumab as part of their adjuvant regimen.

Conclusion

After 2004, oxaliplatin and fluoropyrimidine-based therapy rapidly became the predominant adjuvant treatment for both stage II and stage III colon cancer in this large US cohort. Both increasing patient age and lower volume of an oncologist's practice were associated with early termination of adjuvant therapy.
The National and the International in Public Health: Carlos Chagas and the Rockefeller Foundation in Brazil, 1917 – 1930s
Authors: Stepan Nancy Leys
Published: July 2011

This article examines the relationship between the Rockefeller Foundation (RF) and Brazil in the era of Dr. Carlos Chagas, from the RF’s first visit to Brazil in 1916 to the late 1920s. Chagas’s discovery in 1909 of a hitherto unknown human disease (American trypanosomiasis) made him arguably the best-known medical scientist in the country. As the federal director of public health and the director as well of the Oswaldo Cruz Institute, he appeared to be well positioned to collaborate fruitfully with RF initiatives in public health and medical education. Yet in many respects the relationship was not what was hoped for. Using RF and Brazilian sources, the article examines the political, medical, and other divisions in Brazil that complicated and to a certain extent frustrated Brazil’s relationship with the RF; only in the 1930s, under different political circumstances, did the relationship flourish. The article emphasizes the national dimensions in the success or otherwise of the RF’s agenda in international health.
Footprints on the Future: Looking Forward to the History of Health and Medicine in Latin America in the Twenty-First Century
Authors: Birn Anne-Emanuelle , López Raúl Necochea
Published: July 2011

This essay analyzes the current state of the field of history of health and medicine in Latin America and proposes questions and areas for further investigation. Using a variety of databases to identify relevant historiographical sources from across the Americas, the authors focus on a range of subjects that have substantially engaged contemporary historians while opening up still more research avenues. These include the health of diverse populations; new perspectives on religion and on women’s health; the historicizing of health systems, health politics, and social medicine; and the local-global nexus in Latin American health and medicine. These themes both draw from and extend beyond those addressed in pathbreaking works such as Nancy Leys Stepan’s Beginnings of Brazilian Science. Among the most stimulating developments of recent years are the incorporation of interdisciplinary perspectives on historical analysis, and the elucidation of regional patterns of and preoccupations with the interrelations among state, society, and medicine. The proliferation of historical knowledge regarding the health and medical landscape of Latin America has made this one of the most dynamic fields in historical scholarship today. The authors conclude by discussing emerging methodological and theoretical challenges, including Cold War studies and postcolonialism, and by reflecting on the shared scholarly and political responsibilities of Latin Americanists.
Beginnings of Cuban Bacteriology: Juan Santos Fernández, Medical Research, and the Search for Scientific Sovereignty, 1880 – 1920
Authors: Palmer Steven
Published: July 2011

The paper reassesses the model of scientific success on the periphery advanced in Nancy Leys Stepan’s analysis of the Oswaldo Cruz Institute in Beginnings of Brazilian Science by looking at a comparable, though ultimately less successful, bacteriological research facility in Havana Cuba in the late nineteenth and early twentieth centuries. The Instituto Histobacteriológico y de Vacunación Antirrábica de la Crónica Médico-Quirúrgica de la Habana was a private initiative sustained by wealthy Cuban ophthalmologist Juan Santos Fernández y Hernández. At the center of attempts to establish a creole scientific sovereignty during the late Spanish Empire, the institute brought together a dynamic research team and collaborated with leading international figures in microbiology. The second Cuban War of Independence interrupted the institute’s research momentum and the US occupation government created a new state laboratory facility, displacing the Instituto from its position at the apex of scientific life in the new republic and leading to its demise. No comparable facility capable of undertaking original medical research took its place. The roles of timing and political process are emphasized as key variables in achieving scientific success on the periphery.
Spondylodiscitis in children
Authors: Chandrasenan J. , Klezl Z. , Bommireddy R. , Calthorpe D.
Published: July 2011

We retrospectively reviewed the records of 16 children treated for spondylodiscitis at our hospital between 2000 and 2007. The mean follow-up was 24 months (12 to 38). There was a mean delay in diagnosis in hospital of 25 days in the ten children aged less than 24 months. At presentation only five of the 16 children presented with localising signs and symptoms. Common presenting symptoms were a refusal to walk or sit in nine children, unexplained fever in six, irritability in five, and limping in four. Plain radiography showed changes in only seven children. The ESR was the most useful investigation when following the clinical course of the disease. Positive blood cultures were obtained in seven children with Staphylococcus aureus being isolated in five. Antibiotics were used in 14 children and spinal bracing in six. Children with spondylodiscitis often present with a confusing clinical picture leading to late diagnosis.

The early use of MRI in the investigation of children with an atypical picture may avoid unnecessary delay in starting treatment and possibly prevent long-term problems. All except one of our children had made a complete clinical recovery at final follow-up. However, all six children in the > 24-month age group showed radiological evidence of degenerative changes which might cause problems in the future.
Intercalary diaphyseal endoprosthetic reconstruction for malignant tibial bone tumours
Authors: Sewell M. D. , Hanna S. A. , McGrath A. , Aston W. J. S. , Blunn G. W. , Pollock R. C. , Skinner J. A. , Cannon S. R. , Briggs T. W. R.
Published: July 2011

The best method of reconstruction after resection of malignant tumours of the tibial diaphysis is unknown. In the absence of any long-term studies analysing the results of intercalary endoprosthetic replacement, we present a retrospective review of 18 patients who underwent limb salvage using a tibial diaphyseal endoprosthetic replacement following excision of a malignant bone tumour. There were ten men and eight women with a mean age of 42.5 years (16 to 76). Mean follow-up was 58.5 months (20 to 141) for all patients and 69.3 months (20 to 141) for the 12 patients still alive. Cumulative patient survival was 59% (95% confidence interval (CI) 32 to 84) at five years. Implant survival was 63% (95% CI 35 to 90) at ten years. Four patients required revision to a proximal tibial replacement at a mean follow-up of 29 months (10 to 54). Complications included metastases in five patients, aseptic loosening in four, peri-prosthetic fracture in two, infection in one and local recurrence in one. The mean Musculoskeletal Tumor Society score and the mean Toronto Extremity Salvage Score were 23 (17 to 28) and 74% (53 to 91), respectively.

Although rates of complication and revision were high, custom-made tibial diaphyseal replacement following resection of malignant bone tumours enables early return to function and provides an attractive alternative to other surgical options, without apparent compromise of patient survival.
Cost-effectiveness of universal ultrasound screening compared with clinical examination alone in the diagnosis and treatment of neonatal hip dysplasia in Austria
Authors: Thaler M. , Biedermann R. , Lair J. , Krismer M. , Landauer F.
Published: July 2011

Between 1978 and 1997 all newborns in the Austrian province of Tyrol were reviewed regarding hip dysplasia and related surgery. This involved a mean of 8257 births per year (7766 to 8858). Two observation periods were determined: 1978 to 1982 (clinical examination alone) and 1993 to 1997 (clinical examination and universal ultrasound screening). A retrospective analysis compared the number and cost of interventions due to hip dysplasia in three patient age groups: A, 0 to < 1.5 years; B, ≥ 1.5 to < 15 years; and C, ≥ 15 to < 35 years.

In group A, there was a decrease in hip reductions from a mean of 25.2 (sd 2.8) to 7.0 (sd 1.4) cases per year. In group B, operative procedures decreased from a mean of 17.8 (sd 3.5) to 2.6 (sd 1.3) per year. There was a 75.9% decrease in the total number of interventions for groups A and B.

An increase of €57 000 in the overall cost per year for the second period (1993 to 1997) was seen, mainly due to the screening programme. However, there was a marked reduction in costs of all surgical and non-surgical treatments for dysplastic hips from €410 000 (1978 to 1982) to €117 000 (1993 to 1997). We believe the small proportional increase in costs of the universal ultrasound screening programme is justifiable as it was associated with a reduction in the number of non-surgical and surgical interventions. We therefore recommend universal hip ultrasound screening for neonates.
Preliminary results after reconstruction of bony defects of the proximal humerus with an allograft-resurfacing composite
Authors: Ruggieri P. , Mavrogenis A. F. , Guerra G. , Mercuri M.
Published: July 2011

We retrospectively studied 14 patients with proximal and diaphyseal tumours and disappearing bone (Gorham’s) disease of the humerus treated with wide resection and reconstruction using an allograft-resurfacing composite (ARC). There were ten women and four men, with a mean age of 35 years (8 to 69). At a mean follow-up of 25 months (10 to 89), two patients had a fracture of the allograft. In one of these it was revised with a similar ARC and in the other with an intercalary prosthesis. A further patient had an infection and a fracture of the allograft that was revised with a megaprosthesis. In all patients with an ARC, healing of the ARC-host bone interface was observed. One patient had failure of the locking mechanism of the total elbow replacement. The mean post-operative Musculoskeletal Tumor Society score for the upper extremity was 77% (46.7% to 86.7%), which represents good and excellent results; one patient had a poor result (46.7%).

In the short term ARC effectively relieves pain and restores shoulder function in patients with wide resection of the proximal humerus. Fracture and infection remain significant complications.