bluuebunny/crossref_metadata_2025_split huggingface dataset:
First-In-Man Study of CPX-351: A Liposomal Carrier Containing Cytarabine and Daunorubicin in a Fixed 5:1 Molar Ratio for the Treatment of Relapsed and Refractory Acute Myeloid Leukemia
Authors: Feldman Eric J. , Lancet Jeffrey E. , Kolitz Jonathan E. , Ritchie Ellen K. , Roboz Gail J. , List Alan F. , Allen Steven L. , Asatiani Ekatherine , Mayer Lawrence D. , Swenson Christine , Louie Arthur C. 
Published: February 2011

Purpose This phase I dose-escalation trial was performed to determine the maximum-tolerated dose, dose-limiting toxicities, and pharmacokinetics of CPX-351. Patients and Methods CPX-351 induction was administered on days 1, 3, and 5 by 90-minute infusion to 48 relapsed or refractory patients with acute myeloid leukemia (AML) or high-risk myelodysplasia. Doses started at 3 units/m2 with dose doublings in single-patient cohorts until a pharmacodynamic effect (treatment-related adverse events or reduction in bone marrow cellularity or blast count) was observed, followed by 33% escalations in three patient cohorts until dose-limiting toxicity (DLT) occurred. Results The maximum-tolerated dose was 101 units/m2. DLTs consisted of hypertensive crisis, congestive heart failure, and prolonged cytopenias. Adverse events were consistent with cytarabine and daunorubicin treatment. Response occurred at doses as low as 32 units/m2. Of 43 patients with AML, nine had complete response (CR) and one had CR with incomplete platelet recovery; of patients with acute lymphoblastic leukemia, one of three had CR. Eight CRs were achieved among the 31 patients with prior cytarabine and daunorubicin treatment. CR in AML occurred in five of 26 patients age ≥ 60 years and in five of 17 patients younger than age 60 years. Median half-life was 31.1 hours (cytarabine) and 21.9 hours (daunorubicin), with both drugs and their metabolites detectable > 7 days after the last dose. The targeted 5:1 molar ratio was maintained at all dose levels for up to 24 hours. Conclusion The recommended dose of CPX-351 for phase II study is 101 units/m2. Further exploration of efficacy and safety is ongoing in phase II trials in newly diagnosed and first-relapse patients with AML.
Phase I Study of Navitoclax (ABT-263), a Novel Bcl-2 Family Inhibitor, in Patients With Small-Cell Lung Cancer and Other Solid Tumors
Authors: Gandhi Leena , Camidge D. Ross , Ribeiro de Oliveira Moacyr , Bonomi Philip , Gandara David , Khaira Divis , Hann Christine L. , McKeegan Evelyn M. , Litvinovich Elizabeth , Hemken Philip M. , Dive Caroline , Enschede Sari H. , Nolan Cathy , Chiu Yi-Lin , Busman Todd , Xiong Hao , Krivoshik Andrew P. , Humerickhouse Rod , Shapiro Geoffrey I. , Rudin Charles M. 
Published: February 2011

Purpose Resistance to chemotherapy-induced apoptosis represents a major obstacle to cancer control. Overexpression of Bcl-2 is seen in multiple tumor types and targeting Bcl-2 may provide therapeutic benefit. A phase I study of navitoclax, a novel inhibitor of Bcl-2 family proteins, was conducted to evaluate safety, pharmacokinetics, and preliminary efficacy in patients with solid tumors. Patients and Methods Patients enrolled to intermittent dosing cohorts received navitoclax on day −3, followed by dosing on days 1 to 14 of a 21-day cycle. Patients on continuous dosing received a 1-week lead-in dose of 150 mg followed by continuous daily administration. Blood samples were collected for pharmacokinetic analyses, biomarker analyses, and platelet monitoring. Results Forty-seven patients, including 29 with small-cell lung cancer (SCLC) or pulmonary carcinoid, were enrolled between 2007 and 2008, 35 on intermittent and 12 on continuous dosing cohorts. Primary toxicities included diarrhea (40%), nausea (34%), vomiting (36%), and fatigue (34%); most were grade 1 or 2. Dose- and schedule-dependent thrombocytopenia was seen in all patients. One patient with SCLC had a confirmed partial response lasting longer than 2 years, and eight patients with SCLC or carcinoid had stable disease (one remained on study for 13 months). Pro-gastrin releasing peptide (pro-GRP) was identified as a surrogate marker of Bcl-2 amplification and changes correlated with changes in tumor volume. Conclusion Navitoclax is safe and well tolerated, with dose-dependent thrombocytopenia as the major adverse effect. Preliminary efficacy data are encouraging in SCLC. Efficacy in SCLC and the utility of pro-GRP as a marker of treatment response will be further evaluated in phase II studies.
Aspirin, Warfarin, or Enoxaparin Thromboprophylaxis in Patients With Multiple Myeloma Treated With Thalidomide: A Phase III, Open-Label, Randomized Trial
Authors: Palumbo Antonio , Cavo Michele , Bringhen Sara , Zamagni Elena , Romano Alessandra , Patriarca Francesca , Rossi Davide , Gentilini Fabiana , Crippa Claudia , Galli Monica , Nozzoli Chiara , Ria Roberto , Marasca Roberto , Montefusco Vittorio , Baldini Luca , Elice Francesca , Callea Vincenzo , Pulini Stefano , Carella Angelo M. , Zambello Renato , Benevolo Giulia , Magarotto Valeria , Tacchetti Paola , Pescosta Norbert , Cellini Claudia , Polloni Claudia , Evangelista Andrea , Caravita Tommaso , Morabito Fortunato , Offidani Massimo , Tosi Patrizia , Boccadoro Mario 
Published: February 2011

Purpose In patients with myeloma, thalidomide significantly improves outcomes but increases the risk of thromboembolic events. In this randomized, open-label, multicenter trial, we compared aspirin (ASA) or fixed low-dose warfarin (WAR) versus low molecular weight heparin (LMWH) for preventing thromboembolism in patients with myeloma treated with thalidomide-based regimens. Patients and Methods A total of 667 patients with previously untreated myeloma who received thalidomide-containing regimens and had no clinical indication or contraindication for a specific antiplatelet or anticoagulant therapy were randomly assigned to receive ASA (100 mg/d), WAR (1.25 mg/d), or LMWH (enoxaparin 40 mg/d). A composite primary end point included serious thromboembolic events, acute cardiovascular events, or sudden deaths during the first 6 months of treatment. Results Of 659 analyzed patients, 43 (6.5%) had serious thromboembolic events, acute cardiovascular events, or sudden death during the first 6 months (6.4% in the ASA group, 8.2% in the WAR group, and 5.0% in the LMWH group). Compared with LMWH, the absolute differences were +1.3% (95% CI, −3.0% to 5.7%; P = .544) in the ASA group and +3.2% (95% CI, −1.5% to 7.8%; P = .183) in the WAR group. The risk of thromboembolism was 1.38 times higher in patients treated with thalidomide without bortezomib. Three major (0.5%) and 10 minor (1.5%) bleeding episodes were recorded. Conclusion In patients with myeloma treated with thalidomide-based regimens, ASA and WAR showed similar efficacy in reducing serious thromboembolic events, acute cardiovascular events, and sudden deaths compared with LMWH, except in elderly patients where WAR showed less efficacy than LMWH.
Donor Lymphocyte Infusions Modulate Relapse Risk in Mixed Chimeras and Induce Durable Salvage in Relapsed Patients After T-Cell–Depleted Allogeneic Transplantation for Hodgkin's Lymphoma
Authors: Peggs Karl S. , Kayani Irfan , Edwards Noha , Kottaridis Panagiotis , Goldstone Anthony H. , Linch David C. , Hough Rachael , Morris Emma C. , Fielding Adele , Chakraverty Ronjon , Thomson Kirsty J. , Mackinnon Stephen 
Published: February 2011

Purpose Reduced-intensity conditioning has minimized nonrelapse-related mortality rates after allogeneic transplantation in patients with Hodgkin's lymphoma, and relapse has now become the major cause for treatment failure. We aimed to assess the impact of donor lymphocyte infusions (DLIs) on relapse incidence when administered for mixed chimerism and their utility as salvage therapy when given for relapse. Patients and Methods This study reports the outcomes of 76 consecutive patients with multiply relapsed or refractory Hodgkin's lymphoma who underwent allogeneic transplantation that incorporated in vivo T-cell depletion. Forty-two patients had related donors and 34 had unrelated donors. DLIs were administered in a dose-escalating fashion to 22 patients for mixed chimerism (median time of first dose, 9 months post-transplantation) and to 24 patients for relapse. Results Three-year donor lymphocyte–related mortality was 7%, relating mainly to the induction of graft-versus-host disease. Nineteen (86%) of 22 patients receiving donor lymphocytes for mixed chimerism converted to full donor status. Four-year relapse incidence was 5% in these 22 patients compared with 43% in patients who remained relapse free but full donor chimeras at 9 months post-transplantation (P = .0071). Nineteen (79%) of 24 patients receiving donor lymphocytes for relapse responded (14 complete responses, five partial responses). Four-year overall survival from relapse was 59% in recipients of donor lymphocytes, contributing to a 4-year overall survival from transplantation of 64% and a 4-year current progression-free survival of 59% in all 76 patients. Conclusion These data demonstrate the potential for allogeneic immunotherapy with donor lymphocytes both to reduce relapse risk and to induce durable antitumor responses in patients with Hodgkin's lymphoma after hematopoietic stem-cell transplantation that incorporates in vivo T-cell depletion.
Mammary-specific inactivation of E-cadherin and p53 impairs functional gland development and leads to pleomorphic invasive lobular carcinoma in mice
Authors: Derksen Patrick W. B. , Braumuller Tanya M. , van der Burg Eline , Hornsveld Marten , Mesman Elly , Wesseling Jelle , Krimpenfort Paul , Jonkers Jos 
Published: February 2011

SUMMARY
Breast cancer is the most common malignancy in women of the Western world. Even though a large percentage of breast cancer patients show pathological complete remission after standard treatment regimes, approximately 30–40% are non-responsive and ultimately develop metastatic disease. To generate a good preclinical model of invasive breast cancer, we have taken a tissue-specific approach to somatically inactivate p53 and E-cadherin, the cardinal cell-cell adhesion receptor that is strongly associated with tumor invasiveness. In breast cancer, E-cadherin is found mutated or otherwise functionally silenced in invasive lobular carcinoma (ILC), which accounts for 10–15% of all breast cancers. We show that mammary-specific stochastic inactivation of conditional E-cadherin and p53 results in impaired mammary gland function during pregnancy through the induction of anoikis resistance of mammary epithelium, resulting in loss of epithelial organization and a dysfunctional mammary gland. Moreover, combined inactivation of E-cadherin and p53 induced lactation-independent development of invasive and metastatic mammary carcinomas, which showed strong resemblance to human pleomorphic ILC. Dissemination patterns of mouse ILC mimic the human malignancy, showing metastasis to the gastrointestinal tract, peritoneum, lung, lymph nodes and bone. Our results confirm that loss of E-cadherin contributes to both mammary tumor initiation and metastasis, and establish a preclinical mouse model of human ILC that can be used for the development of novel intervention strategies to treat invasive breast cancer.
Sociodemographic and socioeconomic determinants of health services utilization in Greece: the Hellas Health I study
Authors: Tountas Yannis , Oikonomou Nikolaos , Pallikarona Georgia , Dimitrakaki Christine , Tzavara Chara , Souliotis Kyriakos , Mariolis Anargiros , Pappa Evelina , Kontodimopoulos Nick , Niakas Dimitris 
Published: February 2011

The purpose of the study was to estimate the demographic and socioeconomic determinants of utilization of the Greek primary and hospital health care services. Data were obtained from the cross-sectional nationwide household survey Hellas Health I (2006). The sample ( N = 1005) was representative of the Greek adult population in terms of age and residency, and was selected by means of a three-stage, proportional-to-size sampling design. The presence of a family doctor was reported in a higher degree by participants of higher social classes and private insurance. After adjusting for self-perceived general health and chronic illness, contacts with health care professionals during the past four weeks were found less for residents of rural areas, while contacts with health care professionals during the past 12 months were found less for men than women, for individuals without private insurance and for individuals of lower education. More out-of-pocket payments were reported by the 34–44 age group, rural area residents and individuals with private insurance. Higher use of private health care services was reported by participants of higher social classes and residents of rural areas and private insurance. Only hospital admissions were not directly influenced by demographic and socioeconomic factors. The findings imply the existence of inequities in access and use of primary health services with clear implications to related policies.
A co-productive health leadership model to support the liberation of the NHS
Authors: Nicol Edward , Sang Bob 
Published: February 2011

Summary Following the recent white paper – Equity and Excellence: Liberating the NHS – we need a 21st-century model of leadership in the NHS that re-focuses on the centrality of the relationship between clinicians and patients. This paper argues the case for co-productive ‘Health Leadership’ that can meet the challenges set by the current Big Society agenda, Darzi and Wanless, so that we achieve a sustainable, high quality NHS, fit for the 21st century.
Outcomes of acetabular fracture fixation with ten years’ follow-up
Authors: Briffa N. , Pearce R. , Hill A. M. , Bircher M. 
Published: February 2011

We report the outcome of 161 of 257 surgically fixed acetabular fractures. The operations were undertaken between 1989 and 1998 and the patients were followed for a minimum of ten years. Anthropometric data, fracture pattern, time to surgery, associated injuries, surgical approach, complications and outcome were recorded. Modified Merle D’Aubigné score and Matta radiological scoring systems were used as outcome measures. We observed simple fractures in 108 patients (42%) and associated fractures in 149 (58%). The result was excellent in 75 patients (47%), good in 41 (25%), fair in 12 (7%) and poor in 33 (20%). Poor prognostic factors included increasing age, delay to surgery, quality of reduction and some fracture patterns. Complications were common in the medium- to long-term and functional outcome was variable. The gold-standard treatment for displaced acetabular fractures remains open reduction and internal fixation performed in dedicated units by specialist surgeons as soon as possible.
Biomechanical testing of a concept of posterior pelvic reconstruction in rotationally and vertically unstable fractures
Authors: Berber O. , Amis A. A. , Day A. C. 
Published: February 2011

The purpose of this study was to assess the stability of a developmental pelvic reconstruction system which extends the concept of triangular osteosynthesis with fixation anterior to the lumbosacral pivot point. An unstable Tile type-C fracture, associated with a sacral transforaminal fracture, was created in synthetic pelves. The new concept was compared with three other constructs, including bilateral iliosacral screws, a tension band plate and a combined plate with screws. The pubic symphysis was plated in all cases. The pelvic ring was loaded to simulate single-stance posture in a cyclical manner until failure, defined as a displacement of 2 mm or 2°. The screws were the weakest construct, failing with a load of 50 N after 400 cycles, with maximal translation in the craniocaudal axis of 12 mm. A tension band plate resisted greater load but failure occurred at 100 N, with maximal rotational displacement around the mediolateral axis of 2.3°. The combination of a plate and screws led to an improvement in stability at the 100 N load level, but rotational failure still occurred around the mediolateral axis. The pelvic reconstruction system was the most stable construct, with a maximal displacement of 2.1° of rotation around the mediolateral axis at a load of 500 N.
Biomechanical comparison of interfragmentary compression in transverse fractures of the olecranon
Authors: Wilson J. , Bajwa A. , Kamath V. , Rangan A. 
Published: February 2011

Compression and absolute stability are important in the management of intra-articular fractures. We compared tension band wiring with plate fixation for the treatment of fractures of the olecranon by measuring compression within the fracture. Identical transverse fractures were created in models of the ulna. Tension band wires were applied to ten fractures and ten were fixed with Acumed plates. Compression was measured using a Tekscan force transducer within the fracture gap. Dynamic testing was carried out by reproducing cyclical contraction of the triceps of 20 N and of the brachialis of 10 N. Both methods were tested on each sample. Paired t-tests compared overall compression and compression at the articular side of the fracture. The mean compression for plating was 819 N (sd 602, 95% confidence interval (CI)) and for tension band wiring was 77 N (sd 19, 95% CI) (p = 0.039). The mean compression on the articular side of the fracture for plating was 343 N (sd 276, 95% CI) and for tension band wiring was 1 N (sd 2, 95% CI) (p = 0.038). During simulated movements, the mean compression was reduced in both groups, with tension band wiring at −14 N (sd 7) and for plating −173 N (sd 32). No increase in compression on the articular side was detected in the tension band wiring group. Pre-contoured plates provide significantly greater compression than tension bands in the treatment of transverse fractures of the olecranon, both over the whole fracture and specifically at the articular side of the fracture. In tension band wiring the overall compression was reduced and articular compression remained negligible during simulated contraction of the triceps, challenging the tension band principle.
Comminuted fractures of the radial head and neck
Authors: Neumann M. , Nyffeler R. , Beck M. 
Published: February 2011

Mason type III fractures of the radial head are treated by open reduction and internal fixation, resection or prosthetic joint replacement. When internal fixation is performed, fixation of the radial head to the shaft is difficult and implant-related complications are common. Furthermore, problems of devascularisation of the radial head can result from fixation of the plate to the radial neck. In a small retrospective study, the treatment of Mason type III fractures with fixation of the radial neck in 13 cases (group 2) was compared with 12 cases where no fixation was performed (group 1). The mean clinical and radiological follow-up was four years (1 to 9). The Broberg-Morrey index showed excellent results in both groups. Degenerative radiological changes were seen more frequently in group 2, and removal of the implant was necessary in seven of 13 cases. Post-operative evaluation of these two different techniques revealed similar ranges of movement and functional scores. We propose that anatomical reconstruction of the radial head without metalwork fixation to the neck is preferable, and the outcome is the same as that achieved with the conventional technique. In addition degenerative changes of the elbow joint may develop less frequently, and implant removal is not necessary.
Biodegradable antibiotic delivery systems
Authors: El-Husseiny M. , Patel S. , MacFarlane R. J. , Haddad F. S. 
Published: February 2011

Bacterial infection in orthopaedic surgery can be devastating, and is associated with significant morbidity and poor functional outcomes, which may be improved if high concentrations of antibiotics can be delivered locally over a prolonged period of time. The two most widely used methods of doing this involve antibiotic-loaded polymethylmethacrylate or collagen fleece. The former is not biodegradable and is a surface upon which secondary bacterial infection may occur. Consequently, it has to be removed once treatment has finished. The latter has been used successfully as an adjunct to systemic antibiotics, but cannot effect a sustained release that would allow it to be used on its own, thereby avoiding systemic toxicity.This review explores the newer biodegradable carrier systems which are currently in the experimental phase of development and which may prove to be more effective in the treatment of osteomyelitis.
Hyperosmolarity protects chondrocytes from mechanical injury in human articular cartilage
Authors: Amin A. K. , Huntley J. S. , Patton J. T. , Brenkel I. J. , Simpson A. H. R. W. , Hall A. C. 
Published: February 2011

The aim of this study was to determine whether exposure of human articular cartilage to hyperosmotic saline (0.9%, 600 mOsm) reduces in situ chondrocyte death following a standardised mechanical injury produced by a scalpel cut compared with the same assault and exposure to normal saline (0.9%, 285 mOsm). Human cartilage explants were exposed to normal (control) and hyperosmotic 0.9% saline solutions for five minutes before the mechanical injury to allow in situ chondrocytes to respond to the altered osmotic environment, and incubated for a further 2.5 hours in the same solutions following the mechanical injury. Using confocal laser scanning microscopy, we identified a sixfold (p = 0.04) decrease in chondrocyte death following mechanical injury in the superficial zone of human articular cartilage exposed to hyperosmotic saline compared with normal saline. These data suggest that increasing the osmolarity of joint irrigation solutions used during open and arthroscopic articular surgery may reduce chondrocyte death from surgical injury and could promote integrative cartilage repair.
A multicentre study of the long-term results of using a flat-back polyethylene glenoid component in shoulder replacement for primary osteoarthritis
Authors: Young A. , Walch G. , Boileau P. , Favard L. , Gohlke F. , Loew M. , Molé D. 
Published: February 2011

We report the long-term clinical and radiological outcomes of the Aequalis total shoulder replacement with a cemented all-polyethylene flat-back keeled glenoid component implanted for primary osteoarthritis between 1991 and 2003 in nine European centres. A total of 226 shoulders in 210 patients were retrospectively reviewed at a mean of 122.7 months (61 to 219) or at revision. Clinical outcome was assessed using the Constant score, patient satisfaction score and range of movement. Kaplan-Meier survivorship analysis was performed with glenoid revision for loosening and radiological glenoid loosening (sd) as endpoints. The Constant score was found to improve from a mean of 26.8 (sd 10.3) pre-operatively to 57.6 (sd 20.0) post-operatively (p < 0.001). Active forward flexion improved from a mean of 85.3° (sd 27.4) pre-operatively to 125° (sd 37.3) postoperatively (p < 0.001). External rotation improved from a mean of 7° (sd 6.5) pre-operatively to 30.3° (sd 21.8°) post-operatively (p < 0.001). Survivorship with revision of the glenoid component as the endpoint was 99.1% at five years, 94.5% at ten years and 79.4% at 15 years. Survivorship with radiological loosening as the endpoint was 99.1% at five years, 80.3% at ten years and 33.6% at 15 years. Younger patient age and the curettage technique for glenoid preparation correlated with loosening. The rate of glenoid revision and radiological loosening increased with duration of follow-up, but not until a follow-up of five years. Therefore, we recommend that future studies reporting radiological outcomes of new glenoid designs should report follow-up of at least five to ten years.