Effect of olanzapine on body composition and energy expenditure in adults with first-episode psychosis.

OBJECTIVE: Weight gain is a commonly observed adverse effect of atypical antipsychotic medications, but associated changes in energy balance and body composition are not well defined. The authors report here the effect of olanzapine on body weight, body composition, resting energy expenditure, and substrate oxidation as well as leptin, insulin, glucose, and lipid levels in a group of outpatient volunteers with first-episode psychosis. METHOD: Nine adults (six men and three women) experiencing their first psychotic episode who had no previous history of antipsychotic drug therapy began a regimen of olanzapine and were studied within 7 weeks and approximately 12 weeks after olanzapine initiation. RESULTS: After approximately 12 weeks of olanzapine therapy, the median increase in body weight was 4.7 kg, a significant increase of 7.3% from first observation. Body fat, measured by dual-energy x-ray absorptiometry, increased significantly, with a propensity for central fat deposition. Lean body mass and bone mineral content did not change. Resting energy expenditure, measured by indirect calorimetry, did not change. Respiratory quotient significantly increased 0.12 with olanzapine and was greatest in those who gained >5% of their initial weight. Fasting insulin, C-peptide, and triglyceride levels significantly increased, but there were no changes in glucose levels; total, high density lipoprotein, or low density lipoprotein cholesterol levels; or leptin levels. CONCLUSIONS: Olanzapine appears to have induced an increase in central body fat deposition, insulin, and triglyceride levels, suggesting the possible development of insulin resistance. The decrease in fat oxidation may be secondary or predispose patients to olanzapine-induced weight gain.

A population-based study of the prevalence and influence of gifts to radiation oncologists from pharmaceutical companies and medical equipment manufacturers.

PURPOSE: Hospital-based physicians are responsible for the purchase of expensive equipment. Little is known about the influence of gift giving on their behavior. We wanted to ascertain the prevalence of gift giving from the pharmaceutical industry and medical equipment manufacturers to radiation oncologists and determine whether or not the size of accepted gifts influences their opinions regarding gifts. METHODS AND MATERIALS: A population-based survey of hospital-based physicians conducted between 2002 and 2003. The study population consisted of all radiation oncologists who were members of the American Society of Therapeutic Radiology and Oncology between 2000 and 2001. A random number generator was used to identify 20% of the population. This group was invited by e-mail and conventional mail to complete a Likert scale questionnaire. Those asked to complete the questionnaire electronically were directed to a specially designed web site. RESULTS: Of 640 individuals who were asked to participate, 241 (38%) completed the questionnaire. 96% admitted accepting gifts. The most commonly accepted low value gifts were: pen or pencil (78%), drug samples for patient's use (70%), meal (66%), and a note pad (59%). The most commonly accepted high value gifts were trips to "equipment-users meetings" (15%), honoraria for speaking at a conference (10%), and participation in a conference call (9%). Only 5% of radiation oncologists agreed with the statement "my prescribing practices are affected" by gifts; however, 33% agreed with the statement "I believe that other physicians prescribing practices are affected." Similarly, although only 4% felt that their recommendations concerning purchases of medical equipment are affected by gifts, 19% felt that other physicians would be influenced. A test of the hypothesis that physicians believe that their conduct is less affected than those of their colleagues (i.e., "I am not influenced by gifts but someone else is" was strongly affirmed by a correlation statistic) (p < 0.0001). Of the radiation oncologists surveyed, 74% felt that they should be free to accept gifts of small value, 31% felt they should be free to accept meals or gifts of any type, 16% felt that residency programs should ban free meals provided by companies, 13% felt professional associations should discourage companies from hosting parties at the annual meeting, 17% felt that gift giving should stop, and 66% agreed that clinical information provided by companies provides a useful continuing medical education service. Those who accepted larger gifts were far more likely to disagree with statements such as "professional societies should actively discourage companies from hosting parties and providing free meals and giving gifts to physicians attending the annual meeting" (p = 0.0003) and "the practice of gift giving by companies should stop" (p = 0.0017); they were slightly more likely to agree with statements such as "clinical information provided to radiation oncologists by companies provides a useful continuing medical education service." CONCLUSIONS: To our knowledge, this study represents the first large-scale population based study of a hospital-based specialty and gift giving. This study demonstrates that: (1) Gift giving in radiation oncology is endemic. (2) Although each physician is likely to consider himself or herself immune from being influenced by gift giving, he or she is suspicious that the "next person" is influenced. (3) There is a correlation between the willingness of individual physician to accept gifts of high value and their sympathy toward this practice.

Long-term changes in pulmonary function tests after definitive radiotherapy for lung cancer.

PURPOSE: To evaluate the long-term changes in pulmonary function tests (PFTs) in patients surviving at least 2 years after definitive radiotherapy (RT) for unresectable lung cancer. METHODS AND MATERIALS: Between 1992 and 2000, 277 patients were enrolled in a prospective clinical study to relate RT-induced changes in lung function with dosimetric and functional metrics. Of these, 128 received definitive RT for lung cancer, and 13 of these had follow-up PFTs for approximately >/=2 years without evidence of recurrent or progressive cancer. PFTs were obtained before RT and approximately every 6 months after RT. The results were evaluated on the basis of each study's "percentage of predicted" of normal values (i.e., adjusted for age, gender, height), and a patient's sequential examinations were compared with their initial study and a percentage of the baseline value was calculated. Follow-up PFTs were available for a median of 38 months (range 23-95). The median patient age was 65 years (range 40-74), 6 patients were men, and 10 were white. Most had Stage T2-T4 and N2-N3. The median RT dose was 71.4 Gy (range 60-73), 6 had twice-daily RT. Four patients received chemotherapy, one concurrent and three neoadjuvant. None of the patients continued to smoke after their treatment. The median pre-RT PFT results were (percentage of predicted) forced expiratory volume in 1 s, 67% (range 24-121); forced vital capacity, 72% (range 45-116); and diffusing capacity of lung for carbon monoxide, 70% (range 41-129). RESULTS: At 6 months, all PFT values had declined, with some stabilization by 1 year. However, after 1 year, a gradual reduction occurred in all three parameters. Ten patients (77%) developed RT-induced respiratory symptoms (2 cough only, 8 dyspnea) at 2-21 months (median 5) after treatment. Two patients required inhalers, another required long-term steroids and oxygen. Of the 8 patients with dyspnea, 7 had an increase in symptoms beyond 2 years. No patient died of RT-induced pulmonary insufficiency. CONCLUSION: RT caused a decline in PFTs that was apparent at 6 months and continued well beyond 1 year. The continued decline in PFTs is suggestive of progressive/evolving RT-induced lung injury. "Late" pulmonary symptoms have also occurred in these patients. Because of the high mortality rate of unresectable lung cancer, few patients can be evaluated for long-term analysis. Additional studies and pooling of data from multiple institutions may help to clarify better the long-term impact of RT on pulmonary function in this subset of patients.

Increased sectioning of pathologic specimens with ductal carcinoma in situ of the breast: are there clinical consequences?

To assess if there has been increased sectioning of pathologic specimens with ductal carcinoma in situ (DCIS), identify sources of this change, and consider the clinical consequences, pathologic data from patients who underwent initial excisional biopsies at our institution and were referred to the radiation oncology department with DCIS from 1992-2002 were retrospectively reviewed. One hundred forty-four of 480 patients with DCIS were eligible for review. Specimen size was recorded as length, to the nearest 0.1 cm, in 3 dimensions. Specimen volume was approximated by the product of the 3 dimensions of the specimen. The primary endpoint was the number of microscopic sections taken from gross specimens, corrected for specimen size. Other analysis included margin status, use of a previous stereotactic needle biopsy, and whether a subsequent repeat excision was performed. Over time, there was an increase in size of the excisional biopsy specimens (mean of 49 cm3 from 1992 to 1994 and 90 cm3 from 2001 to 2002; P = 0.045). Mean numbers of slides per centimeter of specimen were 2.5, 2.7, 3.9, and 5.8 for the intervals 1992-1994, 1995-1997, 1998-2000, and 2001-2002, respectively (P < 0.001 for 1992-1997 vs. 1998-2002). Adjusting for volume, the increase over time in the number of slides per specimen was statistically significant (parameter significance, P < 0.001). For a given volume, the number of slides increased approximately 9.1% per year, on average, during the study period. The positive margin rates were 52%, 46%, 23%, and 25% from 1992 to 1994, from 1995 to 1997, from 1998 to 2000, and from 2001 to 2002, respectively. The degree of sectioning, corrected for specimen length and volume, increased over time.

Dose-intense cyclophosphamide and etoposide for patients with refractory or high-risk non-Hodgkin's lymphoma.

A retrospective review was performed on the toxicity and response to one cycle of dose-intense cyclophosphamide/etoposide, followed by consolidation in patients with refractory or previously untreated, high-risk non-Hodgkin's lymphoma (NHL). Fifty-five patients with refractory NHL and 13 with untreated, high-risk NHL were administered one cycle of daily cyclophosphamide 1.5 g/m2 intravenously on days 1-4 and etoposide 300 mg/m2 intravenously every 12 hours on days 1-3. Responders then received other consolidated regimens. Twenty-seven percent of patients with refractory disease had moderate or severe stomatitis, and 44% had moderate or severe infections with 6 (11%) dying of this complication. Similar complication rates were noted in the previously untreated, high-risk group, but there was no treatment-related mortality. The overall response rate to this one cycle of therapy was 31% in the refractory group, with 18% complete response and 13% partial response. The overall response rate in the previously untreated, high-risk group was 69%, with 54% complete and 15% partial responses. In responders, the 2-year event-free survival was 27% in the refractory group and 56% in high-risk group. Dose-intense cyclophosphamide/etoposide has promising efficacy; however, nonhematologic toxicity can be considerable. The better tolerance, high response rate, and encouraging 2-year survival of this regimen in combination with further dose-dense consolidation in patients with high-risk NHL are encouraging.

Obesity and type 2 diabetes mellitus: a population-based study of adolescents.

A cross-sectional, population-based study was conducted on 1,647 Turkish adolescents to determine the prevalence of obesity, impaired fasting glucose (IFG) and type 2 diabetes mellitus (DM2), and to determine whether the recent increase in DM2 prevalence in some countries is applicable to this population. Information was gathered through a questionnaire. All children were screened with physical examination and fasting plasma glucose. 10.7% of adolescents were overweight (BMI 85-95th percentile) and 3.6% were obese (BMI > or =95th percentile). Mean BMI was 20.25 +/- 3.31 kg/m2 with maximum BMI 35.88 kg/m2. No child was diagnosed with DM2; 1.96% had IFG (110-126 mg/dl). No significant relationship was found between IFG and obesity, socio-economic status (SES) or family history of DM. The risk of obesity was increased among children with family history of DM or obesity, and among those who had low physical activity and were of high SES level. This analysis represents the population-based data upon which future studies will be based.

A phase II study of gemcitabine and capecitabine in metastatic renal cancer: a report of Cancer and Leukemia Group B protocol 90008.

BACKGROUND: The objective of this study was to verify previous reports of activity with gemcitabine plus a fluoropyrimidine in patients with metastatic renal cell cancer in a multiinstitutional setting. METHODS: Eligibility included a Zubrod performance status from 0 to 2, no prior gemcitabine or fluoropyrimidine therapy, and normal organ function. Patients received gemcitabine at a dose of 1000 mg/m2 on Days 1, 8, and 15 and capecitabine at a dose of 830 mg/m2 twice daily on Days 1 through 21 on a 28-day cycle with specified dose reductions for baseline renal insufficiency. The primary endpoint was the response rate, which was assessed every 8 weeks. The statistical plan tested the hypothesis that the response rate was 5% versus an alternative of 15%. RESULTS: Sixty patients were enrolled, and 4 of those patients never started treatment. Of the 56 evaluable patients, 79% of patients underwent prior nephrectomy, 75% of patients received prior systemic therapy, and 75% of patients had clear cell histology. Risk stratification revealed that 34%, 43%, and 16% of patients were in Risk Groups 1, 2, and 3, respectively. Toxicity (graded according to the National Cancer Institute's Common Toxicity Criteria [version 2.0]) included Grade 3 or 4 neutropenia in 45% of patients, Grade 2 or greater fatigue in 32% of patients, Grade 2 or greater nausea in 29% of patients, Grade 2 or greater hand-foot reaction in 39% of patients, and Grade 2 or greater diarrhea in 22% of patients. Six patients responded (11%; 95% confidence interval, 4-22%), and the overall median survival was 14.5 months. CONCLUSIONS: Gemcitabine plus capecitabine had modest activity in patients with metastatic renal cancer, although the degree of activity and its associated toxicity would not support further evaluation in a Phase III trial of unselected patients. More focused investigations to identify patients most likely to benefit or to enhance activity with additional agents would be reasonable.

Adoptive immunotherapy by allogeneic stem cell transplantation for metastatic renal cell carcinoma: a CALGB intergroup phase II study.

A graft-versus-tumor effect through nonmyeloablative allogeneic stem cell transplantation (N-SCT) in metastatic renal cell carcinoma (RCC) has been reported. An Intergroup phase II trial was undertaken to define further the feasibility, toxicity and efficacy of this approach in a multi-institutional setting, Patients with cytokine-refractory, metastatic RCC were treated with N-SCT. The conditioning regimen was fludarabine 30 mg . m(-2) . d(-1) on day (d) -7 through d -3 and cyclophosphamide 60 mg . kg(-1) . d(-1) on d -4 and d -3. Patients received 2-8 x 10(6) CD34+ cells/kg of granulocyte colony-stimulating factor mobilized stem cells from a 6/6 HLA-matched sibling donor. Immunosuppression after transplantation included tacrolimus and methotrexate. Twenty-two patients were enrolled at 14 institutions. Greater than 90% donor T-cell chimerism was observed in 17 of 19 evaluable patients (89%) by d +120. No objective response was observed. Acute graft-versus-host disease (GVHD) was observed in 11 patients (50%). Chronic GVHD was reported in 5 patients (23%). There was 1 patient death from liver failure secondary to chronic GVHD. Regimen-related mortality was 2 of 22 (9%; liver failure, sepsis). Median survival time was 5.5 months (95% confidence interval, 3.9-12.0 months) and the median time to progression was 3.0 months (95% confidence interval, 2.3-4.2 months). N-SCT for metastatic RCC is feasible in a multi-institutional setting. Adequate donor T-cell engraftment was achieved in most patients before disease progression. A graft-versus-tumor effect was not observed in this study despite acute and chronic GVHD, thus highlighting the need for further understanding of this approach. Allogeneic SCT remains investigational in RCC.

Adjusting for observable selection bias in block randomized trials.

In this paper, we propose a model-based approach to detect and adjust for observable selection bias in a randomized clinical trial with two treatments and binary outcomes. The proposed method was evaluated using simulations of a randomized block design in which the investigator favoured the experimental treatment by attempting to enroll stronger patients (with greater probability of treatment success) if the probability of the next treatment being experimental was high, and enroll weak patients (with less probability of treatment success) if the probability of the next treatment being experimental was low. The method allows not only testing for the presence of observable selection bias, but also testing for a difference in treatment effects, adjusting for possible selection bias.

Enumerating antigen-specific T-cell responses in peripheral blood: a comparison of peptide MHC Tetramer, ELISpot, and intracellular cytokine analysis.

Detection of the circulating antigen-specific T-cell response to immunization is an important biologic end point in clinical trials of cancer vaccines. Typically employed assays are peptide MHC tetramer, ELISpot, and intracellular cytokine analysis. Although there is no agreement on the definition of a positive response in these assays, many groups have chosen a number of T cells greater than 2 standard deviations above the mean of the negative controls. The authors wished to determine how well this cutoff performed for each of these assays in detecting positive and negative T-cell responses to a model antigen, the immunodominant HLA-A*0201-restricted epitope of cytomegalovirus (CMV) pp65. For each assay, the mean + 2 standard deviations of the response for CMV seronegatives was the point that best separated the two groups. Using this value, each assay had a sensitivity of 87.5% and specificity of 95% to 100% and exhibited a high degree of concordance (kappa 0.76-0.9) with the other two. The authors conclude that currently available immunologic assays perform well in detecting biologically relevant levels of antigen-specific T cells. These assays will better define the quantity and quality of protective immune responses to viral disease and offer insight into the requirements for protective anti-cancer immunity.

Impact of race on survival in men with metastatic hormone-refractory prostate cancer.

OBJECTIVES: To determine whether blacks with hormone-refractory prostate cancer have shorter survival compared with whites with the same disease. METHODS: Data from eight multicenter trials (four Phase II and four randomized Phase III studies) conducted by the Cancer and Leukemia Group B were combined. Eligible patients had progressive prostate cancer after androgen deprivation therapy (with documented castration levels of testosterone), an Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate hematologic, renal, and hepatic function. The proportional hazards model was used to assess the prognostic importance of race, adjusting for important factors. All statistical tests were two-sided. RESULTS: Of the 1183 patients, 15% were blacks, 45% of patients had a Gleason sum of 8 or greater, and the median age was 71 years. Of the 1183 patients, 35% had measurable disease and 89% had an Eastern Cooperative Oncology Group performance status of 0 to 1. Blacks were younger, had a shorter interval between diagnosis and study entry, and had greater prostate-specific antigen levels, lower hemoglobin levels, and a lower likelihood of prior prostatectomy than whites. The median survival was 15 months (95% confidence interval 12 to 18) for blacks compared with 14 months (95% confidence interval 13 to 15) for whites. In a multivariate analysis, adjusting for age, performance status, presence of visceral disease, hemoglobin, Gleason sum, prostate-specific antigen level, alkaline phosphatase, lactate dehydrogenase, and years since diagnosis, the hazard ratio was 0.85 (95% confidence interval 0.71 to 1.02, P = 0.08) for blacks compared with whites. CONCLUSIONS: No statistically significant difference was found in overall survival between blacks and whites with metastatic hormone-refractory prostate cancer.