Citations

Abstract This study was undertaken to characterize preclinical cytotoxic interactions for human malignancies between the multikinase inhibitor sorafenib (BAY 43-9006) and proteasome inhibitors bortezomib or MG132. Multiple tumor cell lines of varying histiotypes, including A549 (lung adenocarcinoma), 786-O (renal cell carcinoma), HeLa (cervical carcinoma), MDA-MB-231 (breast), K562 (chronic myelogenous leukemia), Jurkat (acute T-cell leukemia), MEC-2 (B-chronic lymphocytic leukemia), and U251 and D37 (glioma), as well as cells derived from primary human glioma tumors that are likely a more clinically relevant model were treated with sorafenib or bortezomib alone or in combination. Sorafenib and bortezomib synergistically induced a marked increase in mitochondrial injury and apoptosis, reflected by cytochrome c release, caspase-3 cleavage, and poly(ADP-ribose) polymerase degradation in a broad range of solid tumor and leukemia cell lines. These findings were accompanied by several biochemical changes, including decreased phosphorylation of vascular endothelial growth factor receptor-2, platelet-derived growth factor receptor-β, and Akt and increased phosphorylation of stress-related c-Jun NH2-terminal kinase (JNK). Inhibition of Akt was required for synergism, as a constitutively active Akt protected cells against apoptosis induced by the combination. Alternatively, the JNK inhibitor SP600125 could also protect cells from apoptosis induced by the combination, indicating that both inhibition of Akt and activation of JNK were required for the synergism. These findings show that sorafenib interacts synergistically with bortezomib to induce apoptosis in a broad spectrum of neoplastic cell lines and show an important role for the Akt and JNK pathways in mediating synergism. Further clinical development of this combination seems warranted. [Mol Cancer Ther 2006;5(9):2378–87]

Purpose Large rotator cuff tears present a challenge to orthopaedic surgeons. Because tissue may be insufficient or of inadequate quality to undergo repair, a variety of materials have been used as adjuncts. Human dermal tissue may be processed to render it acellular, and thus less immunogenic, but with the extracellular matrix left intact, creating a collagen scaffold with favorable characteristics. Because of these traits, use in rotator cuff repair was proposed. Methods A canine model for a full‐thickness infraspinatus tendon tear was used. Tendon was excised from the bony interface to the myotendinous junction, and a human acellular dermal matrix graft (experimental) or the autologous excised tendon (control) was used to bridge the defect. Animals were sacrificed, and shoulders were evaluated histologically and biomechanically. Results At time 0, strength of control and experimental repairs was similar. At 6 weeks, the strength of the experimental repair was half that of the control side. Strength of control specimens remained the same at 6 and 12 weeks, but by 12 weeks, the strength of the experimental repair was equal to that of the control. Histologically, cells infiltrated the control and experimental specimens by 6 weeks; chronic inflammation was consistent with surgery and repair. At 6 months, control and experimental specimens mimicked normal tendon structure grossly and histologically. Conclusions Use of human acellular dermal matrix as a patch is a viable option in this model of large rotator cuff defects. Within 6 weeks, histologic evidence of native cell infiltration and neotendon development was observed. Within 12 weeks, the strength of the dermal matrix graft repair was equivalent to that of autologous tendon. At 6 months, control and graft specimens mimicked normal tendon structure grossly and histologically. Clinical Relevance This study provides in vivo animal data to support the use of this acellular dermal matrix graft for repair of full‐thickness rotator cuff defects. Additional studies are indicated to determine the role of this material in the treatment of humans with rotator cuff tears.

Because physician turnover, especially during the first 5 years after joining a practice group, has been reported to be as high as 54%, we sought to identify and quantify the factors that lead hand surgeons to leave their practices. An eight-question practice survey was administered to 10 hand surgeons, all of whom had left their practices under various circumstances. All respondents were men (mean age, 43.2 years). Nine surgeons were in their first practice and one was in his second. Time in the practice ranged from 4 months to 6.5 years (mean time, 3.4 years). Questions about surgical practice issues were asked of all survey participants, who were then asked to quantify the influence of the issue on their decision to leave their own surgical practice with a Likert scale ranging from 1 (no influence) to 5 (greatly influenced the decision to leave). The strongest influences on the decision to leave a practice were interpersonal conflict (mean, 4.7 points) and lack of decision-making ability within the practice (mean, 4.2 points). The influence of partnership determination (mean, 3.3 points) was mixed, whereas staff support (mean, 2.9 points), salary agreements (mean, 2.4 points), employment contracts (mean, 1.6 points), and retirement benefits (mean, 1.0 points) played a lesser role in the surgeons' decisions to leave their practices.

ABSTRACT Tefibazumab (Aurexis), a humanized monoclonal antibody that binds to the surface-expressed adhesion protein clumping factor A, is under development as adjunctive therapy for serious Staphylococcus aureus infections. Sixty patients with documented S. aureus bacteremia (SAB) were randomized and received either tefibazumab at 20 mg/kg of body weight as a single infusion or a placebo in addition to an antibiotic(s). The primary objective of the study was determining safety and pharmacokinetics. An additional objective was to assess activity by a composite clinical end point (CCE). Baseline characteristics were evenly matched between groups. Seventy percent of infections were healthcare associated, and 57% had an SAB-related complication at baseline. There were no differences between the treatment groups in overall adverse clinical events or alterations in laboratory values. Two patients developed serious adverse events that were at least possibly related to tefibazumab; one hypersensitivity reaction was considered definitely related. The tefibazumab plasma half-life was 18 days. Mean plasma levels were <100 μg/ml by day 14. A CCE occurred in six patients (four placebo and two tefibazumab patients) and included five deaths (four placebo and one tefibazumab patient). Progression in the severity of sepsis occurred in four placebo and no tefibazumab patients. Tefibazumab was well tolerated, with a safety profile similar to those of other monoclonal antibodies. Additional trials are warranted to address the dosing range and efficacy of tefibazumab.

Background— In the elderly, mitral regurgitation (MR) is frequent, but surgery risks are considered high. Benefits and indications of MR surgery are uncertain in the elderly. Methods and Results— Baseline characteristics, outcome, and trends for surgical results improvement were analyzed in elderly patients (≥75 years of age; n=284) operated on for MR in 1980 to 1995 compared with younger patients (65 to 74 years of age, n=504; and <65 years of age, n=556). Preoperatively, class III to IV symptoms, atrial fibrillation, coronary disease, creatinine, and comorbidity index were more severe in elderly patients (all P <0.002). In the long term after surgery, observed survival stratified by age (≥75, 65 to 74, <65 years) was lower in elderly than in younger patients (at 5 years, 57±3%, 73±2%, and 85±2%, respectively; P <0.001), but ratios of observed to expected survival were similar (83%, 85%, and 88%, respectively). In multivariate analysis adjusted to expected survival, elderly patients showed no difference in life expectancy restoration compared with younger patients (adjusted hazard ratio, 0.89; 95% confidence interval, 0.73 to 1.30; P =0.54). Temporal trends showed that risk of operative mortality, although higher in elderly patients ( P <0.001), declined markedly for all ages (27% to 5% in those ≥75 years of age, P <0.01; 21% to 4% in those 65 to 74 years of age, P <0.01; and 7% to 2% in those <65 years of age, P =0.06), with a parallel decline in low cardiac output and length of hospital stay. Over time, valve repair feasibility increased in all age groups (30% to 84% overall and 31% to 93% in degenerative MR; P <0.0001). Conclusions— Elderly patients undergoing MR surgery display more severe preoperative characteristics and incur higher operative risks than younger patients. However, restoration of life expectancy after surgery is similar in elderly and younger patients, and outstanding recent surgical improvements particularly benefited elderly patients. Thus, elderly patients with MR can now carefully be considered for surgery before refractory heart failure is present.

Purpose Anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytoma (AOA) are treated with surgery and radiotherapy (RT) at diagnosis, but they also respond to procarbazine, lomustine, and vincristine (PCV), raising the possibility that early chemotherapy will improve survival. Furthermore, better outcomes in AO have been associated with 1p and 19q allelic loss. Patients and Methods Patients with AO and AOA were randomly assigned to PCV chemotherapy followed by RT versus postoperative RT alone. The primary end point was overall survival. The status of 1p and 19q alleles was assessed by fluorescence in situ hybridization. Results Two hundred eighty-nine eligible patients were randomly assigned to either PCV plus RT (n = 147) or RT alone (n = 142). At progression, 80% of patients randomly assigned to RT had chemotherapy. With 3-year follow-up on most patients, the median survival times were similar (4.9 years after PCV plus RT v 4.7 years after RT alone; hazard ratio [HR] = 0.90; 95% CI, 0.66 to 1.24; P = .26). Progression-free survival time favored PCV plus RT (2.6 years v 1.7 years for RT alone; HR = 0.69; 95% CI, 0.52 to 0.91; P = .004), but 65% of patients experienced grade 3 or 4 toxicity, and one patient died. Patients with tumors lacking 1p and 19q (46%) compared with tumors not lacking 1p and 19q had longer median survival times (> 7 v 2.8 years, respectively; P ≤ .001); longer progression-free survival was most apparent in this subset. Conclusion For patients with AO and AOA, PCV plus RT does not prolong survival. Longer progression-free survival after PCV plus RT is associated with significant toxicity. Tumors lacking 1p and 19q alleles are less aggressive or more responsive or both.