United States Food and Drug Administration approval summary: bortezomib for the treatment of progressive multiple myeloma after one prior therapy.

PURPOSE: On March 25, 2005, bortezomib (Velcade for Injection; Millennium Pharmaceuticals, Inc., Cambridge, MA, and Johnson & Johnson Pharmaceutical Research & Development, L.L.C.) received regular approval from the U.S. Food and Drug Administration (U.S. FDA) for the treatment of multiple myeloma (MM) progressing after at least one prior therapy. This approval was based on bortezomib's efficacy and safety which was shown in a single, large, comparative international open-label phase 3 trial that randomized 669 patients with MM previously treated with at least one systemic regimen to receive single-agent bortezomib or high-dose dexamethasone. The FDA analysis of the trial data and bortezomib's regulatory development are summarized here. EXPERIMENTAL DESIGN AND RESULTS: Following a preplanned interim analysis of time to disease progression (the primary end point), an independent data-monitoring committee advised the sponsor to halt the study and offer bortezomib to all dexamethasone-treated study patients. Time to progression was significantly prolonged in the bortezomib treatment arm (median, 6.2 months) compared with the dexamethasone arm (median, 3.5 months; log-rank test, P < 0.0001; hazard ratio, 0.55; 95% confidence interval, 0.44-0.69). Analysis of overall survival done on the interim database (with 20% of events) showed the superiority of bortezomib for patients (log-rank test, P < 0.05; hazard ratio, 0.57; 95% confidence interval, 0.40-0.81). Using criteria from the European Group for Blood and Marrow Transplantation, the response rate (complete plus partial response) with bortezomib was also superior to dexamethasone (38% versus 18%; P < 0.0001). Adverse events on the bortezomib arm were similar to those previously observed in phase 2 studies; some notable adverse events included asthenia, peripheral neuropathy, thrombocytopenia, and neutropenia. CONCLUSIONS: The U.S. FDA had earlier (May 2003) granted bortezomib accelerated approval for the treatment of patients with MM progressing after two prior therapies. The results of the phase 3 trial and the FDA analysis of the data, along with the sponsor's completion of other postmarketing commitments, confirm bortezomib's benefit and support regular approval.     

Approval summary: nelarabine for the treatment of T-cell lymphoblastic leukemia/lymphoma.

PURPOSE: To describe the clinical studies, chemistry manufacturing and controls, and clinical pharmacology and toxicology that led to Food and Drug Administration approval of nelarabine (Arranon) for the treatment of T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma. EXPERIMENTAL DESIGN: Two phase 2 trials, one conducted in pediatric patients and the other in adult patients, were reviewed. The i.v. dose and schedule of nelarabine in the pediatric and adult studies was 650 mg/m2/d daily for 5 days and 1,500 mg/m2 on days 1, 3, and 5, respectively. Treatments were repeated every 21 days. Study end points were the rates of complete response (CR) and CR with incomplete hematologic or bone marrow recovery (CR*). RESULTS: The pediatric efficacy population consisted of 39 patients who had relapsed or had been refractory to two or more induction regimens. CR to nelarabine treatment was observed in 5 (13%) patients and CR+CR* was observed in 9 (23%) patients. The adult efficacy population consisted of 28 patients. CR to nelarabine treatment was observed in 5 (18%) patients and CR+CR* was observed in 6 (21%) patients. Neurologic toxicity was dose limiting for both pediatric and adult patients. Other severe toxicities included laboratory abnormalities in pediatric patients and gastrointestinal and pulmonary toxicities in adults. CONCLUSIONS: On October 28, 2005, the Food and Drug Administration granted accelerated approval for nelarabine for treatment of patients with relapsed or refractory T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma after at least two prior regimens. This use is based on the induction of CRs. The applicant will conduct postmarketing clinical trials to show clinical benefit (e.g., survival prolongation).     

Radiology curriculum for medical students: Clinicians’ perspectives

This study was conducted to establish clinicians’ perspectives of a set of radiology curriculum topics for medical student teaching, which were held to be important by radiologists. A questionnaire was sent to clinicians in all specialties. Forty‐six clinicians (51.1%) out of 90 returned the questionnaires. All curriculum topics were scored above an average of 4 (agree). The five highest ranking curriculum topics in order of importance were: developing a system for viewing chest radiographs (5.59), developing a system for viewing abdominal radiographs (5.56), developing a system for viewing bone and joint radiographs (5.33), distinguishing normal structures from abnormal in chest and abdominal radiographs (5.33) and identifying gross bone or joint abnormalities in skeletal radiographs (5.22). Correlative analysis between speciality groups showed surgical and medical specialities were significantly different in their responses of two learning outcomes: basic knowledge about the contrast media benefits and risks (P= 0.01) and ability to select the most appropriate and the most cost‐effective methods of radiological investigations for clinical situations (P= 0.03). Acute specialities were not significantly different from the other two groups for these two learning outcomes. There was no statistically significant difference for other learning outcomes between the three speciality groups.     

Experience with video-assisted thoracoscopic surgery in the management of complicated pneumonia in children

PURPOSE: The aim of this study was to assess the impact of video assisted thoracoscopic surgery (VATS) in the management of empyema in children. METHODS: This report involves cases of complicated pneumonia in children requiring surgical intervention after failure of medical treatment with antibiotics, with or without drainage from November 1997 to October 1999. The impact of VATS has been studied prospectively from October 1998 when VATS was introduced. The results have been compared with the previous year when similar cases were dealt with open thoracotomy. These 2 groups of patients with VATS (V) or without VATS (O) were studied for their progress in hospital and the final outcome. RESULTS: A total of 39 immunocompetent children with community-acquired pneumonia were studied. There were 17 cases in O and 22 in V. There were 2 conversions to open thoracotomy in V. Both of these cases required resection of the lung parenchyma for severe necrosis and bronchopleural fistula. The mean age in years was 5.3 (O) and 4.9 (V). Parameters that were significantly less in V compared with O include timing of referral (O, 13.6 days; V, 5.3 days), number of lung resections (O, 8; V, 2), blood transfusion (O, 14; V, 2), analgesia requirements (O, 7.8 days; V, 2.9 days), postoperative length of stay in hospital (O, 10.4 days; V, 4.6 days), time to become normothermic (O, 5.6 days; V, 1.7 days); and time to removal of chest drains (O, 6.0 days; V, 2.7 days). Cosmesis is superior in cases of VATS compared with open thoracotomy. All the children recovered well on follow-up with resolution of symptoms and no recurrences. CONCLUSIONS: (1) VATS has ushered in a new era of hope for patients with complicated pneumonia. (2) Thoracotomy, lung resections, and the attending morbidity rate have decreased. (3) Patients are being referred earlier by the physicians because the management protocol is changing.     

The cost-effectiveness of opportunistic salpingectomy versus standard tubal ligation at the time of cesarean delivery for ovarian cancer risk reduction

Objectives

Opportunistic salpingectomy is a cost-effective strategy recommended for ovarian cancer (OvCa) risk reduction at the time of gynecologic surgery in women who have completed childbearing. We aimed to evaluate the cost-effectiveness of opportunistic salpingectomy compared to standard tubal ligation (TL) during cesarean delivery.

HEPARIN-REBOUND IN THE EARLY POSTOPERATIVE PHASE FOLLOWING CARDIOPULMONARY BYPASS

The incidence of the ‘heparin-rebound’ phenomenon after protamine neutralization of systemic heparinization required for cardiopulmonary bypass (CPB) was investigated. Heparin-effect was detected in 43% of patients studied at 2h, 31% at 4h, and 37% at 8h after reversal of circuit heparin on CPB. Heparin-rebound was shown to be associated with a small but significant increase in postoperative bleeding which was not of clinical importance.     

Utilizing prognostic and predictive factors in breast cancer

Opinion statement In order to make optimal treatment recommendations for patients with early-stage breast cancer, it is essential to accurately determine the patient’s underlying risk of disease recurrence and choose a therapy to which the individual is most likely to respond. Lymph node status, tumor size, histopathologic features including tumor type and grade, and hormone receptor status are well-accepted prognostic factors related to breast cancer. In addition, hormone receptor status is a very strong predictor of response to hormonal therapy. However, our currently accepted prognostic and predictive factors fall short and there is a critical need to more accurately identify those most likely to require or benefit from particular therapies. Attention has therefore focused on the determination of novel prognostic and predictive factors. The most promising new factor is the level of urokinase plasminogen activator and its inhibitor plasminogen activator inhibitor. Other putative factors include proliferative rate, the presence of lymphatic or vascular invasion, human epidermal growth factor receptor 2 (HER-2/neu or erbB-2) positivity, the presence of micrometastases in lymph nodes or bone marrow, and gene expression profile by microarray analysis, and by RNA-based methodology. Data regarding potential new prognostic factors are constantly emerging. These studies are frequently challenging to interpret as they are often retrospective, based on relatively small numbers of patients, include a mix of treated and untreated women, and often do not control for other known prognostic factors. Therefore, new data must be interpreted with caution.