Citations

Purpose Epothilones are a new class of nontaxane tubulin polymerization agents that have activity in taxane-resistant tumors. Epothilone B (BMS-247550) is a semisynthetic analog of the natural product epothilone B. This study was performed to determine the activity of BMS-247550 in patients with soft tissue sarcomas (STSs) who had not received prior chemotherapy for metastatic disease. Patients and Methods Patients with measurable, advanced, or metastatic STS with no prior chemotherapy for metastatic disease were treated with BMS-2457550 50 mg/m 2 intravenously during 1 hour every 21 days. All responses were confirmed 4 weeks later. Results Thirty-one patients (median age, 54 years; range, 19 to 78 years; 48% female) were entered onto the trial and were assessable for response. All but one patient had an Eastern Cooperative Oncology Group performance score of 0% or 1%, and 39% had received prior adjuvant chemotherapy. Mean follow-up was 22 months, with a confirmed response rate of 6% (95% CI, 0% to 17%). Median time to progression was 4.5 months (95% CI, 1.9 to 8.3 months), and 1 year progression-free survival was 17% (95% CI, 8% to 38%). Median survival was 16.4 months, with a 1-year survival of 61% (95% CI, 46% to 81%). Toxicity was mainly hematologic, with eight of 31 (26%) patients experiencing grade 3 to 4 leukopenia; 15 of 31 patients (48%) experienced grade 3 to 4 neutropenia. The grade 3 to 4 nonhematologic toxicities included neuropathies (26%), myalgia (13%), and fatigue (10%). Conclusion BMS-247550 has limited activity against STSs when given in this dose and schedule. The clinical toxicity is similar to that of taxanes.

The defining features of the widely conserved HtrA (high temperature requirement) family of serine proteases are the combination of a catalytic protease domain with one or more C-terminal PDZ domains and reversible zymogen activation. Even though HtrAs have previously been implicated in protein quality control and various diseases, including cancer, arthritis, and neuromuscular disorder, the biology of the human family members is not well understood. Our data suggest that HtrA1 is directly involved in the β-amyloid pathway as it degrades various fragments of amyloid precursor protein while an HtrA1 inhibitor causes accumulation of Aβ in astrocyte cell culture supernatants. Furthermore, HtrA1 colocalizes with β-amyloid deposits in human brain samples. Potential implications in Alzheimer's disease are discussed.

Purpose To compare once-daily radiation therapy (qdRT) with hyperfractionated accelerated radiation therapy (HART) after two cycles of induction chemotherapy. Patients and Methods Eligible patients were treatment naive, and had stage IIIA and B unresectable non-small-cell lung cancer, Eastern Cooperative Oncology Group performance status 0/1, and normal organ function. Induction chemotherapy consisted of two cycles of carboplatin area under time-concentration curve 6 mg/mL · min plus paclitaxel 225 mg/m2 on day 1. RT consisted of arm 1 (qdRT), 64 Gy (2 Gy/d), versus arm 2 (HART), 57.6 Gy (1.5 Gy tid for 2.5 weeks). A total of 388 patients were needed to detect a 50% increase in median survival from 14 months of qdRT to 21 months of HART; accrual was not achieved and the study closed prematurely. Results Of 141 patients enrolled, 83% were randomly assigned after chemotherapy to qdRT (n = 59) or HART (n = 60). Median survival was 20.3 and 14.9 months for HART and qdRT, respectively (P = .28). Overall response was 25% and 22% for HART and qdRT, respectively (P = .69). Two- and 3-year survival was 44% and 34% for HART, and 24% and 14% for qdRT, respectively. Grade ≥ 3 toxicities included esophagitis in 14 v nine patients, and pneumonitis in 0 v 6 patients for HART and qdRT, respectively. Any subsequent trials of the HART regimen must address the issues that led to early closure, including slow accrual, logistics of HART, mucosal toxicity, and the fact that concurrent chemoradiotherapy now seems more effective than sequential treatment. Conclusion After two cycles of induction chemotherapy with carboplatin-paclitaxel, HART is feasible with an acceptable toxicity profile. Although statistical significance was not achieved and the study closed early, there was a positive statistical trend suggesting a survival advantage with the HART regimen.

Purpose To determine whether a response classification based on integration of fluorine-18–fluorodeoxyglucose positron emission tomography (FDG-PET) into the International Workshop Criteria (IWC) provides a more accurate response assessment than IWC alone in patients with non-Hodgkin's lymphoma (NHL). Patients and Methods Fifty-four patients with aggressive NHL who underwent FDG-PET and computed tomography 1 to 16 weeks after four to eight cycles of chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone were assessed for complete response (CR), unconfirmed CR (CRu), partial response (PR), stable disease (SD), and progressive disease (PD) by the IWC and by integrated IWC and FDG-PET (IWC+PET). Progression-free survival (PFS) was also compared between IWC- and IWC+PET-assigned response designations. Results By IWC, 17 patients had a CR, seven had a CRu, 19 had a PR, nine had SD, and two had PD. In comparison, by IWC+PET, 35 patients had a CR, 12 had a PR, six had SD, one had PD, and zero had a CRu. In separate multivariate models, PFS was significantly shorter in patients with PR than in those with a CR using IWC (hazard ratio [HR], 8.9; P = .021) or IWC+PET (HR, 29.7; P = .0003). However, when the two classifications were included in the same multivariate model, only IWC+PET was a statistically significant independent predictor for PFS (P = .008 v P = .72 for IWC). In addition, when patients with a PR by IWC and a CR by IWC+PET were compared with those with a CR by IWC and a CR by IWC+PET, there was no significant difference in PFS (HR, 1.6; P = .72), indicating that IWC+PET identified a subset of IWC-PR patients with a more favorable prognosis. Conclusion Compared with IWC, the IWC+PET-based assessment provides a more accurate response classification in patients with aggressive NHL.

Objective. Primary hyperparathyroidism (HPT) is unusual in children. We reviewed our experience with HPT to better characterize these children. Methods. The retrospective review of patients <19 years old who underwent parathyroid resection for primary HPT from 1970 to 2000 was performed at a single institution.. Results. Fifty-two patients were identified. Median age was 16.8 years (range: 4–18.9) with a female-to-male ratio of 3:2. Eighty-five percent had an elevated parathyroid hormone (PTH) level, and 15% had an inappropriately normal PTH level during hypercalcemia. Serum calcium was elevated in all patients except for 2 with multiple endocrine neoplasma (MEN)-IIA and 1 with familial non-MEN HPT, but both had elevated PTH levels. Alkaline phosphatase levels were significantly higher in children with documented bone involvement. At presentation 41 patients (79%) were symptomatic and end-organ damage (nephrocalcinosis, nephrolithiasis, acute pancreatitis, or bone involvement) occurred in 23 patients (44%). Thirty-four patients (65%) had a single adenoma; hyperplasia was identified in 16 patients (27%), and of these cases, 57% occurred in patients diagnosed with MEN-I. Short-term complications included transient hypocalcemia in 29 patients (56%) and transient vocal cord paralysis in 2 patients (4%). Long-term complications were significant for permanent hypocalcemia in 2 patients (4%) and no recurrent laryngeal nerve injuries. No parathyroid abnormalities were identified during exploration in 4 (8%) children. Long-term follow-up was achieved in 98% of patients for a mean and median of 13 years. Resolution of hypercalcemia was achieved in 94% of cases. Conclusion. The diagnosis of primary HPT in pediatric patients is frequently delayed, is commonly symptomatic, and has significant morbidity. For children in whom HPT is suspected, evaluation of serum calcium and PTH levels is diagnostic in 100% of children. Parathyroid resection is effective at restoring normal serum calcium, has few complications, and is the treatment of choice for children with primary hyperparathyroidism.