Biomedical subjects

John R Johnson

Publications and source records attributed to John R Johnson.

At least 19 recordsLinked to original sources

PubMed2007

The role of SN-38 exposure, UGT1A1*28 polymorphism, and baseline bilirubin level in predicting severe irinotecan toxicity.

Irinotecan, an anticancer drug, is associated with severe and potentially fatal diarrhea and neutropenia. The objective of this analysis was to evaluate the role of SN-38 exposure, the active metabolite of irinotecan, UGT1A1 genotypes, and baseline bilirubin on the maximum decrease (nadir) in absolute neutrophil counts following irinotecan. This analysis extended the work of a previous study that examined the effect of UGT1A1 genotypes on the incidence of severe neutropenia in 86 advanced cancer patients following irinotecan treatment. Regression analysis showed that the absolute neutrophil count nadir depended on SN-38 exposure (AUC) and UGT1A1*28 homozygous 7/7 genotype. An increased SN-38 AUC and the 7/7 genotype were significantly associated with a lower absolute neutrophil count nadir (R2 = .49). An alternate model suggested that higher baseline bilirubin and the 7/7 genotype were also significantly associated with a lower absolute neutrophil count nadir, although with a lower coefficient of determination (R2 = .31). Based on these findings and other reports, the irinotecan label was modified to indicate the role of UGT1A1*28 polymorphism in the metabolism of irinotecan and the associated increased risk of severe neutropenia. The label modifications also included recommendations for lower starting doses of irinotecan in patients homozygous for the UGT1A1*28 (7/7) polymorphism.

Antineoplastic Agents, Phytogenic↗

PubMed2006

Posterolateral lumbar spine fusion with INFUSE bone graft.

BACKGROUND CONTEXT: INFUSE has been proven effective in conjunction with threaded cages and bone dowels for single-level anterior lumbar interbody fusion (ALIF). The published experience with posterolateral fusion, although encouraging, utilizes a significantly higher dose and concentration of recombinant human bone morphogenic protein-2 (rhBMP-2) and a different carrier than the commercially available INFUSE. PURPOSE: To present an assessment of fusion rate for posterolateral spine fusion with INFUSE Bone Graft. STUDY DESIGN/SETTING: Retrospective review of patients treated using INFUSE in posterolateral spine fusion in a single institution. PATIENT SAMPLE: 91 patients with minimum 2-year follow-up who underwent posterolateral spine fusion using INFUSE as an iliac crest bone graft (ICBG) substitute. OUTCOME MEASURES: Fusion rate based on fine-cut computed tomographic (CT) scans with sagittal and coronal reconstructions. METHODS: Fusion was performed using one large INFUSE kit (12 mg rhBMP-2, 1.5 mg/mL), which was prepared according to the manufacturer's instructions. The INFUSE sponge was wrapped around the local bone or graft extender and placed over the decorticated surfaces in the lateral gutters. Postoperative CT scans with reconstructions were reviewed by two independent orthopedic spine surgeons. CT scans of a comparison group of 35 patients who underwent primary single-level posterolateral fusion with ICBG were also reviewed. RESULTS: The overall group had a mean 4.38 CT fusion grade and a 6.6% nonunion rate. Primary one-level fusion cases (n=48) had a mean 4.42 fusion grade a 4.2% nonunion rate. Primary multilevel fusions (n=27) had a mean 4.65 CT grade and no nonunions detected. Assessment of the 35 primary one-level ICBG control cases demonstrated a mean CT grade of 4.35 and a nonunion rate of 11.4%. In the 16 cases of revision for prior nonunion, mean CT grade was 3.81 and 4 subjects had nonunions. Additional subgroup analysis showed that smokers (n=14) had a mean 4.32 CT grade with no nonunions. Men had a mean 4.04 CT grade and an 11.1% nonunion rate compared with a mean 4.61 CT grade and 3.6% nonunion rate in women. This difference was statistically significant (p=.036). No significant differences in fusion rate were observed based upon the specific graft extender used (p=.200). CONCLUSIONS: Posterolateral spine fusion involves a more difficult healing environment with a limited surface for healing, a gap between transverse processes and the milieu of distractive forces. Historically, only ICBG has been able to overcome these challenges and reliably generate a successful posterolateral lumbar spine fusion. In contrast to prior studies, clinically available INFUSE delivers only 12 mg rhBMP-2 at a concentration of 1.5 mg/mL. Despite the lower dose and concentration of rhBMP-2, this study suggests that fusion success with INFUSE is equivalent to ICBG for posterolateral spine fusion. As with ICBG, development of solid fusion or nonunion is a multifactorial process. The use of INFUSE is not a substitute for proper surgical technique or optimization of patient-related risk factors. Additional studies are needed to determine the incremental benefit of a greater rhBMP-2 dose or use of alternative carriers for posterolateral fusion. Finally, correlation between radiographic findings and clinical outcomes, and a cost-benefit analysis are needed. Despite these issues, this study presents compelling evidence that commercially available INFUSE is an effective ICBG substitute for one- and two-level posterolateral instrumented spine fusion.

Adult↗

PubMed2006

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).

Animals↗

PubMed2006

Lumbar degenerative classification study.

The purpose of this study was to develop and validate a classification of indications for fusion in lumbar degenerative disease. Nineteen spine surgeons reviewed a series of 32 case histories and selected the indication for fusion based on an outlined classification system. To determine the degree of interrater variability, K coefficients were calculated (K for all 32 cases, 0.63). Results from this study show the significant difficulty in classifying the indication for fusion in lumbar degenerative disease. The level of the 19 surgeons' agreement regarding surgical indication was only moderate, despite a study design that eliminated controversial issues of patient and procedure selection. To a significant extent, the difficulty in classifying indication for fusion underlines the importance of the process. If we cannot agree on why a specific patient is selected for fusion, it is then impossible to accurately compare outcomes for a given disease process or surgical technique. For this reason, an ongoing effort to refine nomenclature and classification is necessary.

Adult↗

PubMed2005

Food and Drug Administration Drug approval summary: temozolomide plus radiation therapy for the treatment of newly diagnosed glioblastoma multiforme.

On March 15, 2005, the U.S. Food and Drug Administration approved temozolomide (Temodar capsules, Schering-Plough Research Institute) for the treatment of adult patients with newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and then as maintenance treatment. Five hundred seventy-three glioblastoma multiforme patients were randomized to receive either temozolomide + radiotherapy (n = 287) or radiotherapy alone (n = 286). Patients in the temozolomide + radiotherapy arm received concomitant temozolomide (75 mg/m2) once daily for the duration of radiation therapy (42-49 days). This was followed, 4 weeks later, by six cycles of temozolomide, 150 or 200 mg/m2 daily for 5 days, every 4 weeks. Patients in the control arm received radiotherapy only. In both arms, radiotherapy was delivered as 60 Gy/30 fractions to the tumor site with a 2 to 3 cm margin. Pneumocystis carinii pneumonia prophylaxis was required during temozolomide + radiotherapy treatment and was continued until recovery of lymphocytopenia (Common Toxicity Criteria grade <1). At disease progression, temozolomide salvage treatment was given to 161 of 282 patients (57%) in the radiotherapy alone arm, and to 62 of 277 patients (22%) in the temozolomide + radiotherapy arm. Patients receiving concomitant and maintenance temozolomide + radiotherapy had significantly improved overall survival. The hazard ratio was 0.63 (95% confidence interval, 0.52-0.75; log-rank, P < 0.0001). Median survival was 14.6 months (temozolomide + radiotherapy) versus 12.1 months (radiotherapy alone). Adverse events during temozolomide treatment included thrombocytopenia, nausea, vomiting, anorexia, constipation, alopecia, headache, fatigue, and convulsions.

Adult↗

PubMed2005

Approval summary for erlotinib for treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen.

PURPOSE: To describe the Food and Drug Administration (FDA) review and approval of erlotinib (Tarceva, OSI Pharmaceuticals, Melville, NY) for treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one prior chemotherapy regimen. EXPERIMENTAL DESIGN: The FDA reviewed raw data in electronic format from a randomized controlled clinical trial comparing erlotinib with placebo in patients with locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen. RESULTS: Patients were randomized in a 2:1 ratio (erlotinib, n = 488 and placebo, n = 243). Erlotinib was superior to placebo for survival, progression-free survival, and tumor response rate. Exploratory analyses indicate that epidermal growth factor receptor status may be an important predictor of the erlotinib survival effect. Rash (75% versus 17%) and diarrhea (54% versus 18%) in the erlotnib and placebo group respectively were the most common adverse events. Severe rash occurred in 9% and severe diarrhea in 6% of erlotinib-treated patients and each resulted in study discontinuation in 1% of patients. Dose reductions were required for 10% of patients with rash and 4% of patients with diarrhea. CONCLUSIONS: On November 18, 2004, the FDA granted erlotinib regular approval for treatment of patients with locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen. The applicant has committed to conduct post-marketing clinical trials to assess further the effect of epidermal growth factor receptor expression, measured with immunohistochemical staining, on erlotinib treatment effect.

Adolescent↗

PubMed2005

Letrozole in the extended adjuvant treatment of postmenopausal women with history of early-stage breast cancer who have completed 5 years of adjuvant tamoxifen.

PURPOSE: To present the basis of the decision of the Food and Drug Administration to grant accelerated approval for letrozole for extended adjuvant treatment of early-stage breast cancer in postmenopausal women after completion of adjuvant tamoxifen. EXPERIMENTAL DESIGN: The Food and Drug Administration reviewed the data from the MA17 trial, a single, multinational, randomized, double-blind, and placebo-controlled trial, submitted by the applicant to support the proposed new indication. RESULTS: MA17 consisted of a core study and Lipid and Bone Mineral Density safety substudies. It enrolled 5,187 patients. In the core study, median treatment duration was 24 months and median follow-up duration was 27.4 months. Using a conventional definition of disease-free survival, 122 events on letrozole and 193 events on placebo were observed (hazard ratio, 0.62; 95% confidence interval, 0.49-0.78; P = 0.00003). Distant disease-free survival also improved with letrozole, 55 versus 92 events (hazard ratio, 0.61; 95% confidence interval, 0.44-0.84; P = 0.003). No statistically significant improvement in overall survival was observed. Hot flushes, arthralgia/arthritis, myalgia, and new diagnosis of osteoporosis were more common on letrozole. Frequency of fractures and cardiovascular ischemic events was not significantly different. A statistically significant mean decrease in bone mineral density in the hip occurred at 24 months on letrozole. CONCLUSIONS: Letrozole administration led to a statistically significant prolongation in disease-free survival. Fractures and cardiovascular events were similar to placebo; however, new diagnoses of osteoporosis were more frequent. Short duration of treatment and follow-up precluded assessment of long-term safety and efficacy. Thus, accelerated approval was granted instead of regular approval.

Aged↗

PubMed2005

Initial fusion rates with recombinant human bone morphogenetic protein-2/compression resistant matrix and a hydroxyapatite and tricalcium phosphate/collagen carrier in posterolateral spinal fusion.

STUDY DESIGN: Prospective, randomized, unblinded study of iliac crest bone graft (ICBG) versus recombinant human bone morphogenetic protein-2/compression resistant matrix (rhBMP-2/CRM)in a posterolateral instrumented fusion procedure. OBJECTIVES: Document initial radiographic characteristics, based on computed tomography, with rhBMP-2/CRM for posterolateral fusion at 6 and 12-month intervals. SUMMARY OF BACKGROUND DATA: As the acceptance of INFUSE bone graft as an ICBG replacement becomes more widespread, surgeons have begun to study applications for rhBMP-2 in posterior spinal fusion. Preclinical studies have examined variables including carrier composition, rhBMP-2 concentration, and rhBMP-2 dose. Pilot studies have been performed with encouraging initial results. METHODS: Patients with single level lumbar degenerative disease were enrolled in a randomized study of ICBG versus rhBMP-2/CRM in a posterolateral instrumented fusion procedure. Computed tomography scans at 6 and 12 months were graded as demonstrating no fusion (grade 1), partial or limited unilateral fusion (grade 2), partial or limited bilateral fusion (grade 3), solid unilateral fusion (grade 4), or solid bilateral fusion (grade 5). RESULTS: At our institution, 74 patients (38 rhBMP-2/CRM, 36 ICBG) reached minimum 1-year follow-up and were included in this analysis. Mean fusion grade (scale1-5) at 6 months after surgery was 4.35 in the rhBMP-2/CRM group versus 3.09 in the ICBG group (P < 0.0001). At 1 year after surgery mean fusion grade was 4.62 in the rhBMP-2/CRM group versus 3.77 in the ICBG group (P < 0.0023). CONCLUSIONS: These early results are encouraging and suggest a more rapid incorporation and development of the fusion mass with rhBMP-2/CRM than iliac crest autograft in a single level posterior instrumented fusion.

Adult↗

PubMed2005

Pemetrexed in malignant pleural mesothelioma.

PURPOSE: This report describes the data and analysis leading to the approval of pemetrexed (LY 231514, MTA, Alimta, Eli Lilly and Co., Indianapolis, IN) by the U.S. Food and Drug Administration (FDA) of a New Drug Application for the treatment of malignant pleural mesothelioma (MPM). EXPERIMENTAL DESIGN: The FDA review of the efficacy and safety of pemetrexed assessed in a randomized clinical trial of 448 patients with unresectable MPM comparing pemetrexed plus cisplatin with cisplatin alone, as well as preclinical pharmacology and chemistry data, are described. The basis for marketing approval is discussed. RESULTS: In one randomized, single-blind, multicenter international trial, 226 patients were randomized to the pemetrexed and cisplatin arm and 222 patients were randomized to cisplatin alone. Median survival times were 12.1 months for pemetrexed and cisplatin and 9.3 months for cisplatin (P = 0.021; hazard ratio, 0.766; 95% confidence interval, 0.61-0.96). Myelosuppression, predominantly neutropenia, was the most common toxicity of pemetrexed plus cisplatin. Other common adverse events were fatigue, leucopenia, nausea, dyspnea, vomiting, chest pain, anemia, thrombocytopenia, and anorexia. CONCLUSIONS: Pemetrexed in combination with cisplatin was approved by the FDA on February 4, 2004 for the treatment of patients with MPM whose disease is either unresectable or who are otherwise not candidates for curative surgery. The recommended dose of pemetrexed is 500 mg/m(2) intra venous infusion over 10 minutes on day 1 of each 21-day cycle in combination with 75 mg/m(2) cisplatin infused over 2 hours beginning 30 minutes after the pemetrexed infusion. Patients must receive oral folic acid and vitamin B(12) injections before the start and during therapy to reduce severe toxicities. Patients should also receive corticosteroids with the chemotherapy to decrease the incidence of skin rash. Approval was based on a demonstration of survival improvement in a single randomized trial. Response rates and time to tumor progression were not included in product labeling because of inconsistencies in assessments among the investigators, independent radiologic reviewers, and the FDA, reflecting the difficulty of radiographic assessments in malignant mesothelioma. Complete prescribing information is available on the FDA Web site at http://www.fda.gov/cder/approval/index.htm.

Adult↗

PubMed2005

U.S. Food and Drug Administration Drug Approval Summary: conversion of imatinib mesylate (STI571; Gleevec) tablets from accelerated approval to full approval.

UNLABELLED: Imatinib mesylate (Gleevec, Novartis Pharmaceuticals East Manruer, NJ) received accelerated approval on May 10, 2001 for the treatment of patients with chronic myeloid leukemia (CML) in (a) chronic phase after failure of IFN-alpha therapy, (b) accelerated phase, and (c) blast crisis. The accelerated approval was accompanied by a postmarketing commitment by Novartis Pharmaceuticals to continue patient follow-up to determine duration of treatment response and survival. The present review, based on a safety and efficacy report submitted on December 20, 2002, summarizes data applicable to the conversion of these three CML indications to full approval status. RESULTS: Chronic phase CML: Five hundred thirty-two chronic phase CML patients who had not benefited from prior IFN therapy were treated at a starting imatinib mesylate dose of 400 mg p.o. qd; dose escalation to 800 mg p.o. qd was allowed. Patients had received a median of 14 months of IFN therapy at doses > or =25 million IU/wk and were all in late chronic phase, with a median time from diagnosis of 32 months. Median duration of imatinib mesylate treatment was 29 months, with 81% of patients treated for > or =24 months (maximum 31.5 months). Initial favorable treatment responses were sustained. An estimated 87.8% of patients who had a major cytogenetic response maintained their response 2 years after their initial response. After 2 years of treatment, an estimated 85.4% of patients were free of progression to accelerated phase or blast crisis, and the estimated overall survival was 90.8% (95% confidence interval, 88.3-93.2). Accelerated phase CML: Patients enrolled totaled 293: 235 with CML accelerated phase, 48 with relapsed/refractory acute lymphocytic leukemia, 2 with relapsed/refractory acute myelocytic leukemia, and 8 with relapsed/refractory CML in lymphoid blast crisis. Patients received imatinib mesylate 400 or 600 mg p.o. qd. Dose escalation was permitted, to a maximum of 800 mg/d, taken as 400 mg bid. Efficacy results were improved in patients receiving imatinib mesylate 600 mg qd versus patients receiving 400 mg qd. The median duration of hematologic response was 29 versus 17 months and the estimated 24-month maintained hematologic response rate was 61% versus 42%. The median survival of patients treated with imatinib mesylate 600 mg qd was not reached versus 20.9 months for patients receiving 400 mg qd. Estimated 24-month survival rate was 66% versus 46%. The median survival in the advanced leukemia population (acute lymphocytic leukemia, acute myelocytic leukemia, and lymphoid blast crisis) was only 5 months, and only two patients are still on treatment. Blast crisis CML: A total of 260 patients were recruited. The imatinib mesylate dose was initially 400 mg qd (37 patients) but was subsequently increased to 600 mg qd (223 patients). Patients receiving imatinib mesylate 600 mg qd had a higher hematologic response rate than did patients receiving 400 mg (33% versus 16%). Major cytogenetic responses occurred in 15% of the 260 study patients. The overall median survival was 6.9 months: 7.1 months for patients treated with imatinib mesylate 600 mg and 4.7 months for patients receiving imatinib mesylate 400 mg. Estimated 12-month survival rate for all study patients was 32.1% and estimated 24-month survival rate was 18.3%. SAFETY: Imatinib mesylate was generally well tolerated, but relatively frequent reports of common toxicity criteria grade 3/4 neutropenia and thrombocytopenia were encountered. The most frequently reported adverse events included gastrointestinal disturbances, edema, rash, and musculoskeletal complaints. These rarely led to discontinuation of therapy. CONCLUSIONS: The results confirm those of the interim analysis and suggest that imatinib mesylate represents an effective therapeutic agent for the treatment of patients with CML in chronic phase after failure of IFN-alpha therapy, in blast crisis, and in accelerated phase.

Adolescent↗

PubMed2005

FDA drug approval summary: erlotinib (Tarceva) tablets.

On November 18, 2004, erlotinib (Tarceva); OSI Pharmaceuticals, Inc., Melville, NY, http://www.osip.com, and Genentech, Inc., South San Francisco, CA, http://www.gene.com) received regular approval as monotherapy for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one prior chemotherapy regimen. Survival of erlotinib-treated patients was superior to that of placebo-treated patients. The median survival duration of erlotinib-treated patients was 6.67 months, compared with 4.70 months for placebo-treated patients. Exploratory univariate analyses showed a larger survival prolongation in two subsets of patients: those who never smoked and those with epidermal growth factor receptor (EGFR)-positive tumors. Patients who never smoked and were EGFR-positive had a large erlotinib survival benefit. Erlotinib was also superior to placebo for progression-free survival and a response rate of 8.9% versus 0.9%. Skin rash and diarrhea were the most common erlotinib adverse events. Severe rash occurred in 8%, and severe diarrhea occurred in 6% of erlotinib-treated patients. In the first-line treatment of NSCLC, two large, controlled, randomized trials showed no benefit from adding erlotinib to doublet, platinum-based chemotherapy. Therefore, erlotinib is not indicated for use in this setting.

Adenocarcinoma↗

PubMed2004

Treatment of pyogenic vertebral osteomyelitis with anterior debridement and fusion followed by delayed posterior spinal fusion.

STUDY DESIGN: Case series. OBJECTIVES: The results of surgical treatment of osteomyelitis with anterior debridement and fusion followed by delayed posterior stabilization and fusion are presented. METHODS: Forty-two patients with vertebral osteomyelitis are presented. There were 5 cervical, 12 thoracic, 1 thoracolumbar, 19 lumbar, and 5 lumbosacral lesions. The most frequently identified organism was Staphylococcus aureus. Most patients had significant comorbidities, including diabetes, or were immunocompromised. Ninety percent had elevated erythrocyte sedimentation rates and C-reactive proteins, while white blood cell counts were less reliably elevated. Imaging studies included radiographs, CT scans, and MRIs. All patients were treated with anterior debridement and strut grafting followed by 14.4 days of intravenous antibiotics and delayed instrumented posterior fusions and received 6 weeks of intravenous antibiotics after surgery. RESULTS: All patients had resolution of their infections with no recurrence. There were two deaths. Neurologic deficits resolved in all patients. The diagnosis of pyogenic vertebral osteomyelitis is frequently delayed and presents a significant surgical challenge. The indications for surgical debridement were neurologic compromise, failed medical treatment, soft tissue extension, extensive vertebral body and disc space destruction, and progressive deformity. Many of these patients were severely ill at presentation and required urgent treatment. Anterior debridement and fusion followed by intravenous antibiotics allows for restoration of anterior column support and control of the infection before posterior instrumentation and fusion. CONCLUSION: This study demonstrates that anterior surgical debridement with fusion, followed by a period of intravenous antibiotics and delayed instrumented posterior fusion, is highly effective in the treatment of pyogenic osteomyelitis that has failed medical management.

Adult↗

PubMed2004

Mitochondrial DNA and prehistoric settlements: native migrations on the western edge of North America.

We analyzed previously reported mtDNA haplogroup frequencies of 577 individuals and hypervariable segment 1 (HVS1) sequences of 265 individuals from Native American tribes in western North America to test hypotheses regarding the settlement of this region. These data were analyzed to determine whether Hokan and Penutian, two hypothesized ancient linguistic stocks, represent biological units as a result of shared ancestry within these respective groups. Although the pattern of mtDNA variation suggests regional continuity and although gene flow between populations has contributed much to the genetic landscape of western North America, some evidence supports the existence of both the Hokan and Penutian phyla. In addition, a comparison between coastal and inland populations along the west coast of North America suggests an ancient coastal migration to the New World. Similarly high levels of haplogroup A among coastal populations in the Northwest and along the California coast as well as shared HVS1 sequences indicate that early migrants to the New World settled along the coast with little gene flow into the interior valleys.

British Columbia↗

PubMed2004

FDA drug approval summaries: pemetrexed (Alimta).

The purpose of this report is to summarize information on pemetrexed (LY231514; MTA; Alimta; Eli Lilly and Company; Indianapolis, IN), a drug recently approved by the U.S. Food and Drug Administration (FDA). The review of the efficacy and safety of pemetrexed is summarized below. Pemetrexed is a pyrrolopyrimidine antifolate. It inhibits thymidylate synthase, glycinamide ribonucleotide formyltransferase, and dihydrofolate reductase. In a single, randomized, single-blind, multicenter phase III trial, the efficacy and safety of pemetrexed combined with cisplatin (Platinol; Bristol-Myers Squibb; Princeton, NJ) were compared with those of single-agent cisplatin in 448 patients with malignant pleural mesothelioma. Two hundred twenty-six patients were randomized to receive pemetrexed and cisplatin, while 222 patients were randomized to receive cisplatin alone. The primary study end point was survival. Median survival times were 12.1 months for the pemetrexed plus cisplatin treated arm and 9.3 months for the cisplatin alone arm. Pemetrexed causes myelosuppression. The most common adverse events were neutropenia, fatigue, leukopenia, nausea, dyspnea, and vomiting. On February 4, 2004, pemetrexed was approved by the FDA in combination with cisplatin for the treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery. The recommended dose of pemetrexed is 500 mg/m(2) administered as an i.v. infusion over 10 minutes on day 1 of each 21-day cycle together with cisplatin at a dose of 75 mg/m(2) infused over 2 hours beginning 30 minutes after the pemetrexed infusion. Patients must receive oral folic acid and vitamin B(12) injections prior to the start of therapy and continue these during therapy to reduce severe toxicities. Patients should also receive corticosteroids with chemotherapy to reduce the risk of skin rashes. Approval was based on superior survival as a clinical benefit.

Adrenal Cortex Hormones↗

PubMed2003

End points and United States Food and Drug Administration approval of oncology drugs.

PURPOSE: To summarize the end points used by the United States Food and Drug Administration (FDA) to approve new cancer drug applications over the last 13 years. MATERIALS AND METHODS: The FDA granted marketing approval to 71 oncology drug applications between January 1, 1990, and November 1, 2002. The end points used as the approval basis for each application are presented, and the rationale for each end point is discussed. RESULTS: The FDA grants either regular marketing approval or accelerated marketing approval for oncology drug applications. Regular approval is based on end points that demonstrate that the drug provides a longer life, a better life, or a favorable effect on an established surrogate for a longer life or a better life. Accelerated approval (AA) is based on a surrogate end point that is less well established but that is reasonably likely to predict a longer or a better life. Tumor response was the approval basis in 26 of 57 regular approvals, supported by relief of tumor-specific symptoms in nine of these 26 regular approvals. Relief of tumor-specific symptoms provided critical support for approval in 13 of 57 regular approvals. Approval was based on tumor response in 12 of 14 AAs. CONCLUSION: End points other than survival were the approval basis for 68% (39 of 57) of oncology drug marketing applications granted regular approval and for all 14 applications granted accelerated approval from January 1, 1990, to November 1, 2002.

Antineoplastic Agents↗

PubMed2003

Native American mtDNA prehistory in the American Southwest.

This study examines the mtDNA diversity of the proposed descendants of the multiethnic Hohokam and Anasazi cultural traditions, as well as Uto-Aztecan and Southern-Athapaskan groups, to investigate hypothesized migrations associated with the Southwest region. The mtDNA haplogroups of 117 Native Americans from southwestern North America were determined. The hypervariable segment I (HVSI) portion of the control region of 53 of these individuals was sequenced, and the within-haplogroup diversity of 18 Native American populations from North, Central, and South America was analyzed. Within North America, populations in the West contain higher amounts of diversity than in other regions, probably due to a population expansion and high levels of gene flow among subpopulations in this region throughout prehistory. The distribution of haplogroups in the Southwest is structured more by archaeological tradition than by language. Yumans and Pimans exhibit substantially greater genetic diversity than the Jemez and Zuni, probably due to admixture and genetic isolation, respectively. We find no evidence of a movement of mtDNA lineages northward into the Southwest from Central Mexico, which, in combination with evidence from nuclear markers, suggests that the spread of Uto-Aztecan was facilitated by predominantly male migration. Southern Athapaskans probably experienced a bottleneck followed by extensive admixture during the migration to their current homeland in the Southwest.

DNA Transposable Elements↗

PubMed2003

Perioperative complications of posterior lumbar decompression and arthrodesis in older adults.

BACKGROUND: Lumbar arthrodesis is commonly done in elderly patients to treat degenerative spine problems. These patients may be at increased risk for complications because of their age and associated medical conditions. In this study, we examined the rates of perioperative complications associated with posterior lumbar decompression and arthrodesis in patients sixty-five years of age or older. METHODS: We reviewed the hospital records of ninety-eight patients who were sixty-five years of age or older when they had a posterior decompression and lumbar arthrodesis with instrumentation, between 1993 and 1995, to treat degenerative disease of the spine. The average age was seventy-two years (range, sixty-five to eighty-four years). RESULTS: Perioperative complications occurred in seventy-eight patients. Twenty-one patients had at least one major complication, and sixty-nine had at least one minor complication. Forty-nine patients had more than one complication. The most common major complication was wound infection (prevalence, 10%), and the most common minor complication was urinary tract infection (prevalence, 34%). The complication rate increased with older age, increased blood loss, longer operative time, and the number of levels of the arthrodesis. CONCLUSIONS: Surgeons should be vigilant about perioperative complications in elderly patients treated with multi-level lumbar decompression and arthrodesis with instrumentation. Elderly patients should be made aware that they are at increased risk for surgical complications because of their age. Attention should be paid to controlling blood loss and limiting operative time.

Aged↗

PubMed2003

Approval summary: imatinib mesylate capsules for treatment of adult patients with newly diagnosed philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase.

PURPOSE: The purpose is to describe the Food and Drug Administration (FDA) review and approval of imatinib (Gleevec; Novartis Pharmaceuticals, East Hanover, NJ) for treatment of adult patients with newly diagnosed Philadelphia chromosome-positive chronic myelogenous leukemia (CML) in chronic phase. EXPERIMENTAL DESIGN: The FDA reviewed data in electronic format from a randomized controlled clinical trial of 1106 adult patients with newly diagnosed Philadelphia chromosome-positive CML in chronic phase, comparing imatinib with the combination of IFN-alpha and cytarabine. RESULTS: Imatinib showed clinically and statistically significantly better results for time-to-progression to accelerated phase or blast crisis, progression-free survival, complete hematological response rate, and cytogenetic response rate. With a median follow-up of 14 months, a maximum follow-up of 19.5 months, and an expected median survival of 5-6 years on the IFN-alpha/cytarabine control arm, few of the expected progressions to accelerated or blast phase or deaths have occurred. Imatinib was also better tolerated. Edema, nausea, rigors, neutropenia, and headache were more frequent in women. Only 57% of the IFN-alpha target dose was administered, and only 68% of patients received any cytarabine. However, this does not appear to adequately explain the superiority of imatinib observed in this trial. Results of a population pharmacokinetic study in a subgroup of 371 patients and a separate rifampin-imatinib drug-drug interaction study in healthy volunteers are presented. CONCLUSIONS: On December 20, 2002, imatinib was granted accelerated approval under subpart H, rather than regular approval. Follow-up is short compared with the natural history of chronic phase CML or more mature results with established therapies such as IFN-alpha or transplantation. If imatinib should stop working after 1.5-2 years, the results could be importantly different from the present analysis. As a Phase IV postmarketing commitment, the applicant has agreed to provide follow-up reports on this imatinib study annually for the next 6 years.

Adult↗