bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical Trials and Lipid Guidelines for Type II Diabetes
Authors: Prisant L. Michael
Published: March 2004

The management of dyslipidemia in adults with diabetes is receiving more attention. However, there is a paucity of large, prospective, randomized outcome trials designed for diabetic patients. Diabetic dyslipidemia is characterized by an increase in triglyceride levels, low high‐density lipoprotein (HDL) cholesterol concentrations, and small, dense low‐density lipoprotein (LDL) particles. The treatment goals include an LDL cholesterol less than 100 mg/dL, triglyceride level less than 150 mg/dL, and an HDL greater than 40 mg/dL for men and more than 50 mg/dL for women. In the Diabetic Atherosclerosis Intervention Study, fenofibrate resulted in a 42% less increase in the percent stenosis, as assessed by quantitative coronary arteriography. The Heart Protection Study documented the unambiguous benefit of simvastatin in reducing all‐cause mortality among 5963 diabetic patients. The Lescol Intervention Prevention Study observed a reduction in major adverse cardiac events in diabetics undergoing percutaneous intervention who received fluvastatin. The Veterans Affairs HDL Cholesterol Intervention Trial reported a reduction in major coronary events among 627 diabetic patients with low HDL cholesterol who sustained a myocardial infarction. The Fenofibrate Intervention and Event Lowering in Diabetics (FIELD) Trial (n = 9795), the Action to Control Cardiovascular Risk in Diabetes (ACCORD, n = 10,000), the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non Insulin Dependent Diabetes Mellitus (ASPEN, n = 2421), and the Collaborative Atorvastatin Diabetes Study (CARDS, n = 2140) will provide the prospective outcome data that are needed for the management of patients. Combination drug therapy will be necessary to achieve treatment goals. Careful monitoring will be required to avoid myositis and hepatotoxicity.
Epidemiology of Diabetes
Authors: Winer Nathaniel , Sowers James R.
Published: March 2004

The incidence of diabetes mellitus, particularly type 2 diabetes, is increasing dramatically in the United States and in other Westernized, industrialized societies because of increasing obesity, sedentary lifestyle, and population aging. There are currently 20 million persons with diabetes in the United States, of whom more than 5 million remain undiagnosed. The diabetic population consumes a disproportionate share of health care resources because of both microvascular and macrovascular complications. Diabetes is a major cause of new‐onset blindness, end‐stage renal disease, and nontraumatic amputation in the United States. Cardiovascular disease accounts for up to 80% of premature excess mortality in diabetic patients. Strategies to lessen the disease burden in these patients include hygienic measures (diet and exercise) as well as rigorous treatment of hypertension, dyslipidemia, and hyperglycemia.
Preventing Type II Diabetes Mellitus
Authors: Prisant L. Michael
Published: March 2004

Burgeoning obesity is increasing the prevalence of type II diabetes mellitus. As a consequence, there will be an even greater burden of cardiovascular disease, end‐stage renal disease, blindness, and lower extremity amputations. If diagnosed, impaired glucose tolerance presents an opportunity for intervention that potentially could delay or prevent the development of diabetes. Recent prospective studies document the effectiveness of exercise and weight reduction in preventing diabetes. Metformin is less effective than intense lifestyle interventions. Acarbose, losartan, orlistat, pravastatin, ramipril, and hormone replacement therapy are associated with lower rates of the development of diabetes. The Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial and the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial were designed to assess not only the prevention of diabetes but also the impact on cardiovascular morbidity and mortality.
Intense Management of Diabetes Mellitus: Role of Glucose Control and Antiplatelet Agents
Authors: Mudaliar Sunder
Published: March 2004

Type 2 diabetes has now reached epidemic proportions across the world and is the cause of substantial morbidity and mortality. Patients with diabetes suffer from their mircovascular complications of retinopathy (blindness), nephropathy (renal failure, dialysis), and neuropathy (neropathic pain, trophic ulcers). However, ultimately, the majority of diabetics will die from macrovascular cardiovascular disease. Not only does cardiovascular disease develop earlier in the presence of diabetes, mortality from cardiovascular disease is increased by a factor of two to three in persons with diabetes as compared with the general population. To reduce this increased risk, a multifactorial approach to the management of type 2 diabetes has been advocated. The American Diabetes Association recommends not only good glycemic control but also identification and aggressive treatment of associated cardiovascular risk factors, with more stringent target levels for lipids and blood pressure than those recommended for the general population. Studies have shown that an intensified and goal‐oriented approach to the treatment of type 2 diabetes addressing tight glucose control, optimal lipid and blood pressure management and the use of antiplatelet agents like aspirin reduces cardiovascular events, as well as nephropathy, retinopathy, and neuropathy.
Blood Pressure Control and Nephroprotection in Diabetes
Authors: Abbott Kevin , Basta Emad , Bakris George L.
Published: March 2004

Achievement of recommended levels of blood pressure as prescribed by guidelines (i.e., systolic blood pressure of < 130 mmHg in people with nephropathy secondary to type 2 diabetes) generally requires three or more different antihypertensive agents that have complementary modes of action. This systolic goal blood pressure, recommended by generally all international guideline committees, was derived from largely observational studies demonstrating a greater reduction of cardiovascular risk and preservation of kidney function at these levels. Commonly used antihypertensive combinations include angiotensin‐converting enzyme (ACE) inhibitors or angiotensin receptor blockers, which have compelling indications for use in people with kidney disease and/ or diabetes, combined with a diuretic, generally a thiazide‐type agent. If additional therapy is required, either a betablocker or a calcium antagonist may be added to this antihypertensive “cocktail.” Beta‐blockers are particularly effective in people with a high sympathetic drive (i.e., high pulse rates) to lower blood pressure and reduce cardiovascular risk. Moreover, in recent studies, their benefits on kidney function, both by reducing macroalbuminuria and slowing the decline of kidney function, make them good agents to add in the appropriate clinical setting. With all these potential benefits of achieving blood pressure goals, it is unfortunate that only 11% of people being treated for hypertension with diabetic kidney disease achieve the blood pressure goal of < 130 mmHg, likely contributing to the climbing incidence of people starting dialysis. Physicians need to work harder and educate patients on the importance of achieving these lower blood pressure guidelines.
Estimating Mass Balance for Inhaled Drugs in Humans: An Example with a VLA‐4 Antagonist, IVL745
Authors: Rohatagi Shashank , Shah Bharti , Zhang Jie , Zeng Zhaopie , Kirkesseli Stephane , Jensen Bradford K.
Published: March 2004

IVL745 is an inhaled VLA‐4 antagonist developed for the treatment of asthma. Following inhalation (Inh), a fraction of the drug is deposited in the oropharynx, and the rest is deposited in the lungs. For inhaled drugs, it is technically and ethically difficult to formulate and administer radiolabeled drugs. Hence, if the drug is metabolically stable in the lungs, mass balance and metabolism of inhaled drugs, such as IVL745, can be determined by administering radiolabeled intravenous (IV) and oral drugs and by comparing with the data following Inh administration. The study was a three‐period crossover design in 6 healthy subjects to evaluate the absorption, distribution, metabolism, and elimination following IV and oral administration of 14C‐IVL745 (4 mg/50 μCi) and inhaled (10‐mg) dose. Serial sampling of blood and excreta was performed maximally up to 168 hours postdose. Plasma IVL745 concentrations were determined using a liquid chromatography tandem mass spectrometry (LC/MS/MS) method with a minimum quantifiable limit of 10 pg/mL. Overall, the drug was safe and well tolerated. The recovery of the radioactive dose varied from 94.8% to 117% for both IV and oral administration. Following IV administration, 90.2% of the radioactive dose was recovered in the feces, suggesting extensive biliary excretion of the drug. After oral administration, 99.7% of the radioactivity was recovered in the feces, and no radioactivity was detected in plasma, suggesting lack of absorption of the drug. Negligible 14C‐radioactivity concentrations were observed in the red blood cell fractions. The mean t1/2 values were 1.6, 1.5, and 4.4 hours following IV, oral, and Inh administration, respectively. The oral bioavailability of IVL745 was low (< 2%), and the inhaled bioavailability was 26%. The volume of distribution at steady state (Vss) was low (19.0 L). The predicted blood clearance of IVL745 was 86 L/h, which was comparable to the commonly used liver blood flow value of 90 L/h. Only a minor fraction of the dose was excreted in the urine with low to moderate renal clearance. The parent drug accounted for 77% to 89% of the dosed radioactivity in excreta. Two major metabolites observed in excreta were mono‐o‐desmethyl IVL745 and di‐o‐desmethyl IVL745. The data showed that the drug had negligible oral bioavailability, low oral absorption, 26% inhaled bioavailability, low extent of metabolism, high biliary excretion, and low renal clearance. This knowledge may aid in the prediction of potentially relevant drug‐drug interactions and dosing adjustments in high‐risk populations for IVL745.
Preventing Contrast Nephropathy: What Is the Best Strategy? A Review of the Literature
Authors: Cox Craig D. , Tsikouris James P.
Published: March 2004

Patients receiving radiocontrast for diagnostic and interventional procedures are at risk for developing contrast nephropathy (CN). In fact, radiocontrast nephropathy is currently the third leading cause of hospital‐acquired renal failure. Understanding that CN has been associated with increased length of hospitalization and mortality, determining the best prevention strategy is of utmost importance. Patients at the greatest risk for developing acute renal failure are patients with diabetes and underlying renal insufficiency. Several therapies have been investigated for the prevention of CN; unfortunately, very few have shown a consistent benefit. Therapies that have been studied include saline hydration, N‐acetylcysteine (NAC), theophylline, calcium channel blockers, diuretics, dopamine, endothelin receptor antagonists, atrial natriuretic peptide, angiotensin‐converting enzyme inhibitors, and prostaglandin E‐1. Using adequate hydration, using low‐osmolar dyes, and minimizing the dose of contrast have all been shown to be effective in reducing CN and are considered the standard of care. While trials with many pharmacologic agents have produced conflicting results, intervention with NAC has also been promising. This article reviews the pathophysiology, risk factors, and therapies that are currently available for the prevention of CN.
Influence of Azimilide on CYP2C19‐Mediated Metabolism
Authors: El Mouelhi Mohamed , Worley Dan J. , Kuzmak Barbara , Destefano Anthony J. , Thompson Gary A.
Published: March 2004

The purpose of this study was to assess the influence of multiple‐dose oral administration of azimilide dihydrochloride on CYP2C19‐mediated metabolism. A two‐period, randomized crossover study was conducted in 40 healthy male subjects who were phenotyped as extensive CYP2C19 metabolizers. Oral doses of placebo or 125 mg of azimilide dihydrochloride were administered every 12 hours for 3 days, followed by every 24 hours for 5 days; 20 mg omeprazole was coadministered on Day 8. Blood or plasma samples were obtained over 24 hours and analyzed for azimilide or omeprazole/5‐hydroxyomeprazole using high‐performance liquid chromatography with tandem mass spectrometry. Data were analyzed using “noncompartmental” analysis. Azimilide blood concentrations observed in this study were similar to those previously observed at steady state in patients. Based on AUCm/AUCp for omeprazole, azimilide does not significantly inhibit CYP2C19‐mediated metabolism (90% confidence interval [CI] = 104%‐111%). For 5‐hydroxyomeprazole, no significant changes in pharmacokinetics were observed. For omeprazole, a statistically significant decrease (∼12%) was observed for AUC. However, this change was small and is not expected to be clinically important since the CI was contained within those used to establish bioequivalence. These results indicate that azimilide does not inhibit CYP2C19‐mediated metabolism. Since this isozyme had the lowest in vitro IC50 values for the cytochrome P450s most commonly involved with the metabolism of drugs (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4), azimilide‐related drug interactions mediated via these isozymes are not anticipated.
The Pharmacokinetics and Pharmacodynamics of Ximelagatran, an Oral Direct Thrombin Inhibitor, Are Unaffected by a Single Dose of Alcohol
Authors: Sarich Troy C. , Johansson Susanne , Schützer Kajs‐Marie , Wall Ulrika , Kessler Eva , Teng Renli , Eriksson Ulf G.
Published: March 2004

Ximelagatran—a direct thrombin inhibitor rapidly converted to its active form, melagatran, after oral administration—is being developed for the prevention and treatment of thromboembolic disease. The pharmacokinetics, pharmacodynamics, and tolerability/safety of ximelagatran following a single 36‐mg oral dose of ximelagatran ± a single oral dose of alcohol (0.5 and 0.6 g ethanol/kg to women and men, respectively) were assessed in a randomized, open‐label, two‐way crossover study (n = 26). The 90% confidence intervals (CIs) and least squares mean estimates for the ratio of ximelagatran plus alcohol to ximelagatran alone for melagatran AUC (1.04 [90% CI = 1.00–1.08]) and Cmax (1.08 [90% CI = 1.03–1.14]) fell within the bounds demonstrating no interaction. Alcohol did not alter the melagatran‐induced prolongation of the activated partial thromboplastin time or the good tolerability/safety profile of ximelagatran. In conclusion, the pharmacokinetics, pharmacodynamics, and tolerability/safety of oral ximelagatran were not affected by alcohol.
No Clinically Relevant CYP3A Induction with the Dual Angiotensin‐Converting Enzyme/Neutral Endopeptidase Inhibitor, M100240
Authors: Martin Nancy E. , Howell Stanley R. , Martin Louis L. , Cirillo Iolanda , Barrett Jeffrey S.
Published: March 2004

M100240, an acetate thioester of MDL 100,173, is a dual angiotensin‐converting enzyme/neutral endopeptidase inhibitor currently in Phase II development. M100240 and MDL 100,173 were evaluated in an in vitro cytochrome P450 human hepatocyte model for enzyme induction. Although a dose‐dependent CYP3A induction was observed between 10 and 100 μM, at 1 μM—which approaches clinically relevant plasma concentrations in humans—there was no evidence of CYP3A induction. An in vitro reporter gene assay also demonstrated the CYP3A isozyme induction potential of M100240 and MDL 100,173 with an EC50 ∼ 1.5 μM. The present study evaluated the potential for CYP3A enzyme induction in healthy volunteers. In an open‐label, single‐sequence, replicate‐design study using midazolam as a CYP3A probe in 13 healthy volunteers, we found no evidence of clinically relevant CYP3A induction after multiple‐dose administration of 50 mg M100240 orally once daily for 15 days. Single and multiple doses of M100240 increased the midazolam AUC0–24 h about 1.6‐fold compared to baseline, suggesting weak CYP3A inhibition. Concomitant administration of midazolam and M100240 was generally safe and well tolerated. Although in vitro CYP3A induction at exposures in excess of clinically relevant human plasma concentrations has been demonstrated, there is no clinical evidence of CYP3A induction with M100240 administration at proposed therapeutic doses.
Assessment of Visual Analog versus Categorical Scale for Measurement of Osteoarthritis Pain
Authors: Averbuch Mordechai , Katzper Meyer
Published: March 2004

There is disagreement in the literature regarding which scales to use in pain measurement. The difference has usually been between nonverbal scales, such as visual analog scales and verbal ones, which usually provide only a limited number of response categories. A 12‐week, randomized, double‐blind naproxen sodium (500 mg bid) and placebo‐controlled trial using the hip osteoarthritis (OA) flare‐up pain mode, in which pain was measured on both visual analog and categorical scales simultaneously, was analyzed. The authors found a good correlation (> 0.995) between the time‐series average of the unconstrained visual analog scale and a 5‐point categorical scale pain measurement in the osteoarthritis pain model in both active and placebo treatment arms. However, for individuals, there is a wide range of VAS responses for each categorical score, with overlaps between categories. The visual analog and categorical scales appear as effective in determining average osteoarthritis pain. However, a combined metric scale for pain measurement that provides the subject with multiple cues may improve communication and concordance between scales for individual pain determination.
A systematic approach to diagnosis of mature T-cell leukemias reveals heterogeneity among WHO categories
Authors: Herling Marco , Khoury Joseph D. , Washington LaBaron T. , Duvic Madeleine , Keating Michael J. , Jones Dan
Published: March 2004

The current World Health Organization (WHO) classification of hematopoietic malignancies defines several types of mature T-cell leukemia including T-cell prolymphocytic leukemia (T-PLL), Sezary syndrome (SS), and T-cell large granular lymphocytic (T-LGL) leukemia. These neoplasms can show overlapping features with each other and with T-cell lymphomas involving peripheral blood (PB). We analyzed the spectrum of clinicopatho-logic features in 102 mature T-cell leukemias and compared them to 10 hepatosplenic T-cell lymphomas that involved PB. T-PLL, defined as a T-cell leukemia showing rapidly rising PB lymphocyte counts, was the only tumor type expressing the oncoprotein TCL1 (71% of cases) and could present with relatively low lymphocyte levels or small tumor cell morphology. SS, defined by accompanying erythrodermic skin disease, was frequently associated with peripheral eosinophilia but could also develop high numbers of prolymphocytes, especially late in the disease course. T-LGL leukemia, defined by accompanying cytopenias or autoimmune phenomena (or both), had the best clinical outcome and generally showed the lowest circulating lymphocyte levels with only a few cases developing marked lymphocytosis. Using the dominant clinical or phenotypic feature, we describe here the degree of overlap among currently recognized WHO categories and identify areas where further clarification is needed. Our results indicate that incorporation of additional criteria, such as TCL1 expression status and hematologic parameters, can assist in a more accurate classification. (Blood. 2004;104:328-335)
Skeletal Morbidity in Childhood Acute Lymphoblastic Leukemia
Authors: Mandel Karen , Atkinson Stephanie , Barr Ronald D. , Pencharz Paul
Published: March 2004

Purpose

Treatment for acute lymphoblastic leukemia (ALL) in childhood results in a reduction in bone mineral density (BMD). Whether there is a recovery of this lost bone mass in survivors of ALL is not known. We sought to determine if changes in BMD are common long-term sequelae in children with ALL.

Methods

Bone mineral densitometry of the lumbar spine and femoral neck was performed on 106 patients. The results were compared with those of age-matched normal controls. The effect of treatment was examined in those with low BMD compared with the remainder of the study group.

Results

When data were tested with respect to age, sex, and age and sex, no difference was observed in BMD between survivors of childhood ALL and controls. In the subgroup of patients with low BMD, the difference was not related to age, age at diagnosis, or years since diagnosis. Low BMD of the spine was not explained by radiotherapy (RT), methotrexate (MTX) dose, or corticosteroid dose. Low BMD of the femur was not explained by RT. However, those with low femoral BMD were more likely to have received high-dose MTX or higher-dose corticosteroids compared with the remainder of the group.

Conclusion

It appears that survivors of childhood ALL as a whole recover normal BMD. However, those patients who received a total MTX dose of greater than 40,000 mg/m2 or a total corticosteroid dose of greater than 9,000 mg/m2 may not recover normal BMD and therefore should be screened for decreased BMD of the femoral neck.
Predictors of Oral Mucositis in Patients Receiving Hematopoietic Cell Transplants for Chronic Myelogenous Leukemia
Authors: Robien Kim , Schubert Mark M. , Bruemmer Barbara , Lloid Michele E. , Potter John D. , Ulrich Cornelia M.
Published: March 2004

Purpose

Oral mucositis is a nearly universal and often severe complication following hematopoietic cell transplantation (HCT). The objective of this study was to evaluate factors predicting oral mucositis severity among 133 patients undergoing allogeneic HCT for chronic myelogenous leukemia.

Patients and Methods

All patients were transplanted between 1992 and 1999, were ≥ 18 years of age, received either cyclophosphamide/total-body irradiation (TBI) or busulfan/cyclophosphamide conditioning regimens, and received four doses of methotrexate for graft-versus-host disease prophylaxis post-transplant. Oral mucositis was measured by a trained examiner every 2 to 3 days using the Oral Mucositis Index (OMI). Multiple linear regression analysis was used to identify predictors of mean OMI during days 6 to 12, 1 to 18, and the maximum OMI score between days 1 to 18.

Results

TBI containing conditioning regimens, body mass index ≥ 25, and methylenetetrahydrofolate reductase 677 TT genotype were found to be predictive of higher mean OMI scores (P < .05). Pretransplant multivitamin supplement use was associated with lower mean OMI scores compared to those who did not use supplements. Smoking status, race, pretransplant treatment with interferon-alfa or hydroxyurea, and patient/donor ABO compatibility were not associated with mean OMI scores.

Conclusion

Patients who are scheduled to receive conditioning regimens containing TBI, have a pretransplant body mass index ≥ 25, or carry the methylenetetrahydrofolate reductase 677 TT genotype should be considered at greater risk of developing oral mucositis following HCT. Future studies should investigate whether multivitamin supplementation before HCT could reduce mucositis severity.
18F-2-Fluoro-2-Deoxy-d-Glucose Positron Emission Tomography in Staging of Locally Advanced Breast Cancer
Authors: van der Hoeven Jacobus J.M. , Krak Nanda C. , Hoekstra Otto S. , Comans Emile F.I. , Boom Robert P.A. , van Geldere Dick , Meijer Sybren , van der Wall Elsken , Buter Jan , Pinedo Herbert M. , Teule Gerrit J.J. , Lammertsma Adriaan A.
Published: March 2004

Purpose

To prospectively evaluate the effect of adding whole-body 18F-2-fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (PET) to conventional screening for distant metastases in patients with locally advanced breast cancer (LABC).

Patients and Methods

All women with LABC referred for participation in the LABC Spinoza trial were considered eligible for this study. Patients were included if chest x-ray, bone scan, liver ultrasound, or computed tomography scan performed by the referring physician failed to reveal distant metastases. They underwent whole-body FDG PET scanning before therapy. Patients with subsequently proven distant metastases were switched to alternative forms of chemotherapy, hormonal therapy, or both.

Results

Among the 48 patients evaluated with PET, 14 had abnormal FDG uptake, and metastases were suspected in 12. After simple clinical evaluation (plain x-ray, history), 10 sites that were suggestive of abnormality remained. Further work-up revealed that four sites were metastases. Proven false positivity occurred in one patient with sarcoidosis. In the other five patients, the reason for abnormal FDG uptake (liver, lung, bone) remained unclear, and patients were treated as planned. Eleven months later, distant metastases were found in one patient at sites unrelated to the previous FDG uptake.

Conclusion

The addition of FDG PET to the standard work-up of patients with LABC may lead to the detection of unexpected distant metastases. This may contribute to a more realistic stratification between patients with true stage III breast cancer and those who are in fact suffering from stage IV disease. Abnormal PET findings should be confirmed to prevent patients from being denied appropriate treatment.
Biology of Epithelial Ovarian Cancer: Implications for Screening Women at High Genetic Risk
Authors: Hogg Russell , Friedlander Michael
Published: March 2004

Purpose

Our aim was to analyze the clinicopathologic features of screen-detected ovarian cancers identified in women, either at general population risk or high genetic risk of ovarian cancer, who have participated in screening studies.

Methods

Studies published between 1988 and April 2003 were categorized by the population screened and the primary screening modalities used. Each report was examined with reference to the histologic type, stage, and grade of screen-detected cancers. Reports of studies of prophylactically removed ovaries from women at high risk of ovarian cancer were also reviewed.

Results

Of the stage I tumors detected by screening women at population risk, almost half were borderline ovarian tumors, granulosa-cell tumors, or germ-cell tumors, which is disproportionate to their frequency. Furthermore, of the stage I invasive epithelial cancers diagnosed in women at population risk, the majority were endometrioid, clear-cell, and mucinous histologic subtypes. Most ovarian cancers that occur in women at high genetic risk are high-grade serous cancers, and these are infrequently screen detected at an early stage.

Conclusion

The clinicopathologic features of screen-detected ovarian cancers suggest that screening may not reduce mortality in women at increased genetic risk. Prospective screening studies are required in genetically high-risk populations to answer this important question. Women electing surveillance should be aware of the lack of proven benefit and the low likelihood of detecting early stage serous cancers. Bilateral salpingo-oophorectomy appears to be the most effective approach to decrease the risk of ovarian cancer and thereby reduce mortality in high-risk women.
Intravenous Iron Optimizes the Response to Recombinant Human Erythropoietin in Cancer Patients With Chemotherapy-Related Anemia: A Multicenter, Open-Label, Randomized Trial
Authors: Auerbach Michael , Ballard Harold , Trout J. Richard , McIlwain Marilyn , Ackerman Alan , Bahrain Huzefa , Balan Stefan , Barker Lance , Rana Jeevindra
Published: March 2004

Purpose

Recombinant human erythropoietin (rHuEPO) is the standard of care for patients with chemotherapy-related anemia. Intravenous (IV) iron improves hemoglobin (Hb) response and decreases dosage requirements in patients with anemia of kidney disease, but its effect has not been studied in randomized trials in cancer patients.

Methods

This prospective, multicenter, open-label, randomized trial enrolled 157 patients with chemotherapy-related anemia (Hb ≤ 105 g/L, serum ferritin ≤ 450 pmol/L or ≤ 675 pmol/L with transferrin saturation ≤ 19%) receiving subcutaneously rHuEPO 40,000 U once weekly to: (1) no-iron; (2) oral iron 325 mg twice daily; (3) iron dextran repeated 100mg IV bolus; or (4) iron dextran total dose infusion (TDI). Hb and quality of life (QOL) were measured at baseline and throughout.

Results

All groups showed Hb (P < .0001) increases from baseline. Mean Hb increases for both IV iron groups were greater (P < .02) than for no-iron and oral iron groups. The percentage of patients with hematopoietic responses was higher (P < .01) in both IV iron groups (each case 68%) compared with no-iron (25%) and oral iron (36%) groups. IV iron groups showed increases in energy, activity, and overall QOL from baseline, compared with a decrease in energy and activity for no-iron group and no change in activity or overall QOL for oral iron group.

Conclusion

rHuEPO increases Hb levels and improves QOL in patients with chemotherapy-related anemia. Magnitude of Hb increase and QOL improvement is significantly greater if IV iron is added.
Determinants of Outcome in Melanoma Patients With Cerebral Metastases
Authors: Fife K.M. , Colman M.H. , Stevens G.N. , Firth I.C. , Moon D. , Shannon K.F. , Harman R. , Petersen-Schaefer K. , Zacest A.C. , Besser M. , Milton G.W. , McCarthy W.H. , Thompson J.F.
Published: March 2004

Purpose

To analyze prognostic factors, effects of treatment, and survival for patients with cerebral metastases from melanoma.

Patients and Methods

All melanoma patients with cerebral metastases treated at the Sydney Melanoma Unit between 1952 and 2000 were identified. From 1985 to 2000, patients were diagnosed and treated using consistent modern techniques and this cohort was analyzed in detail. Multivariate analysis of prognostic factors for survival was performed.

Results

A total of 1,137 patients with cerebral metastases were identified; 686 were treated between 1985 and 2000. For these 686 patients, the median time from primary diagnosis to cerebral metastasis was 3.1 years (range, 0 to 41 years). A total of 646 patients (94%) have died as a result of melanoma. The median survival from the time of diagnosis of cerebral metastasis was 4.1 months (range, 0 to 17.2 years). Treatment was as follows: surgery and postoperative radiotherapy, 158 patients; surgery alone, 47 patients; radiotherapy alone, 236 patients; and supportive care alone, 210 patients. Median survival according to treatment received for these four groups was 8.9, 8.7, 3.4, and 2.1 months, respectively; the differences between surgery and nonsurgery groups were statistically significant. On multivariate analysis, significant factors associated with improved survival were surgical treatment (P < .0001), no concurrent extracerebral metastases (P < .0001), younger age (P = .0007), and longer disease-free interval (P = .036). Prognostic factors analysis confirmed the important influence of patient selection on treatment received.

Conclusion

This large series documents the characteristics of patients who developed cerebral metastases from melanoma. Median survival was dependent on treatment, which in turn was dependent on patient selection.
Outcome of High-Risk Stage IC, Grade 3, Compared With Stage I Endometrial Carcinoma Patients: The Postoperative Radiation Therapy in Endometrial Carcinoma Trial
Authors: Creutzberg Carien L. , van Putten Wim L.J. , Wárlám-Rodenhuis Carla C. , van den Bergh Alfons C.M. , De Winter Karin A.J. , Koper Peter C.M. , Lybeert Marnix L.M. , Slot Annerie , Lutgens Ludy C.H.W. , Stenfert Kroese Marika C. , Beerman Henk , van Lent Mat
Published: March 2004

Purpose

Stage IC, grade 3 endometrial cancer is regarded as a high-risk category. Stage IC, grade 3 patients were not eligible for the randomized Postoperative Radiation Therapy in Endometrial Carcinoma (PORTEC) trial, but were registered and received postoperative radiotherapy.

Patients and Methods

The PORTEC trial included 715 patients with stage IC, grade 1 or 2, and stage IB, grade 2 or 3 endometrial cancer. Patients were randomly assigned after surgery to receive pelvic radiotherapy (RT) or no further treatment. A total of 104 patients with stage IC, grade 3 endometrial cancer were registered, of whom 99 could be evaluated. Patterns of relapse and survival were compared with PORTEC patients receiving RT. Median follow-up was 83 months.

Results

The actuarial 5-year rates of locoregional relapse were 1% to 3% for PORTEC patients who received RT, compared with 14% for stage IC, grade 3 patients. Five-year distant metastases rates were 3% to 8% for grade 1 and 2 tumors; 20% for stage IB, grade 3 tumors; and 31% for stage IC, grade 3 tumors. Overall survival rates were 83% to 85% for grades 1 and 2; 74% for stage IB, grade 3; and 58% for stage IC, grade 3 patients (P < .001). In multivariate analysis grade 3 was the most important adverse prognostic factor for relapse and death as a result of endometrial cancer (hazard ratios, 5.4 and 5.5; P < .0001).

Conclusion

Patients with stage IC, grade 3 endometrial carcinoma are at high risk of early distant spread and endometrial carcinoma-related death. Novel strategies for adjuvant therapy should be explored to improve survival for this patient group.
Prognostic Impact of Alterations in P-Cadherin Expression and Related Cell Adhesion Markers in Endometrial Cancer
Authors: Stefansson Ingunn M. , Salvesen Helga B. , Akslen Lars A.
Published: March 2004

Purpose

Reduced tumor cell adhesion is associated with invasive growth and unfavorable prognosis. In endometrial carcinoma, the prognostic impact of adhesion markers (E-cadherin, beta-catenin [β-catenin], P-cadherin, and p120ctn) is partly unknown. We wanted to examine the expression pattern and prognostic value of these molecules in a population-based series of endometrial carcinoma patients.

Patients and Methods

All patients diagnosed with endometrial carcinoma between 1981 and 1990 in Hordaland County, Norway, were included. Paraffin-embedded tumor tissue was available for 96% of the patients (n = 286), and was studied immunohistochemically for expression of E-cadherin, β-catenin, P-cadherin, and p120ctn. The tissue microarray technique was used for P-cadherin and p120ctn. Median follow-up time for survivors was 9 years (range, 4 to 16 years) and follow-up was complete.

Results

Pathologic expression of P-cadherin, E-cadherin, and β-catenin was associated with a majority of the clinicopathologic variables. In univariate survival analyses, all adhesion markers influenced survival significantly (P < .05). Tumors with pathologic expression of both E-cadherin (low expression) and P-cadherin (high expression; 19%), and β-catenin (low expression) and P-cadherin (high expression; 16%), had significantly reduced survival compared with the remaining samples (P < .001 for both). In multivariate models, all markers except E-cadherin showed independent prognostic significance in addition to the traditional tumor features.

Conclusion

Differential expression of P-cadherin and β-catenin seems to be important in endometrial carcinoma and is associated with aggressive subgroups. Our findings also indicate that a shift from E-cadherin to P-cadherin expression (cadherin switch) is an important prognostic feature in these tumors.
Prospective Randomized Trial of Intrapleural Bleomycin Versus Interferon Alfa-2b via Ultrasound-Guided Small-Bore Chest Tube in the Palliative Treatment of Malignant Pleural Effusions
Authors: Sartori Sergio , Tassinari Davide , Ceccotti Piercarlo , Tombesi Paola , Nielsen Ingrid , Trevisani Lucio , Abbasciano Vincenzo
Published: March 2004

Purpose

To compare bleomycin pleurodesis and immunotherapy with intrapleural interferon alfa-2b (IFN) in the palliation of malignant pleural effusions.

Patients and Methods

One hundred sixty patients with rapidly recurrent malignant pleural effusion were randomly assigned to intrapleural bleomycin (83 patients) or IFN (77 patients). A 9-French intrapleural catheter was placed under sonographic guidance, and pleural effusion was completely drained before starting the treatment. Bleomycin 0.75 mg/kg was administered as a single dose. An additional dose was given if daily fluid output did not drop to less than 100 mL/d within 3 days. IFN 1 million units/10 kg was administered for six courses at 4-day intervals. Thirty-day and long-term responses were evaluated under the intention-to-treat principle.

Results

Thirty-day response was 84.3% in the bleomycin arm and 62.3% in IFN arm (P = .002). Median time to progression was 93 days (range, 12 to 395 days) in bleomycin group, and 59 days (range, 7 to 292 days) in the IFN group (P < .001). Median survival was 96 days (range, 15 to 395) and 85 days (range, 16 to 292) in the bleomycin and IFN groups, respectively. Twenty-three patients received two doses of bleomycin, as their daily fluid output remained higher than 100 mL after the first dose. Thirteen of them had complete response, which lasted until death.

Conclusion

Intrapleural bleomycin is more effective than IFN and is a valid option for the palliative treatment of massive, rapidly recurrent malignant pleural effusions. The administration of a second dose of bleomycin to patients not responding to the first one can remarkably improve the overall outcome of the treatment.
Survival of Patients With Advanced Colorectal Cancer Improves With the Availability of Fluorouracil-Leucovorin, Irinotecan, and Oxaliplatin in the Course of Treatment
Authors: Grothey Axel , Sargent Daniel , Goldberg Richard M. , Schmoll Hans-Joachim
Published: March 2004

Purpose

Fluorouracil (FU)-leucovorin (LV), irinotecan, and oxaliplatin administered alone or in combination have proven effective in the treatment of advanced colorectal cancer (CRC). Combination protocols using FU-LV with either irinotecan or oxaliplatin are currently regarded as standard first-line therapies in this disease. However, the importance of the availability of all three active cytotoxic agents, FU-LV, irinotecan, and oxaliplatin, on overall survival (OS) has not yet been evaluated.

Materials and Methods

We analyzed data from seven recently published phase III trials in advanced CRC to correlate the percentage of patients receiving second-line therapy and the percentage of patients receiving all three agents with the reported median OS, using a weighted analysis.

Results

The reported median OS is significantly correlated with the percentage of patients who received all three drugs in the course of their disease (P = .0008) but not with the percentage of patients who received any second-line therapy (P = .19). In addition, the use of combination protocols as first-line therapy was associated with a significant improvement in median survival of 3.5 months (95% CI, 1.27 to 5.73 months; P = .0083).

Conclusion

Our results support the strategy of making these three active drugs available to all patients with advanced CRC who are candidates for such therapy to maximize OS. In addition, our findings suggest that, with the availability of effective salvage options, OS should no longer be regarded as the most appropriate end point by which to assess the efficacy of a palliative first-line treatment in CRC.
Chinatown, Whose Chinatown? Defining America's Borders with Musical Orientalism
Authors: Garrett Charles Hiroshi
Published: March 2004

The music of Tin Pan Alley has proven an extremely rich source for investigations of race, ethnicity, and identity in America, most clearly with respect to Jewish American identity-making and the cultural history of black/white racial relations. The existence of a large body of Asian-themed Tin Pan Alley songs suggests, however, that other important trajectories involving the construction of ethnic and racial identity have been overlooked. To illuminate the role of music in molding ideas of Asia and Asian America, this essay focuses on the song "Chinatown, My Chinatown" by lyricist William Jerome and composer Jean Schwartz, offering detailed accounts of its origin, its 1910 Broadway debut, its presentation as sheet music, and its extensive performance history. By caricaturing local Chinatowns as foreign, opium-infested districts within U.S. borders, the song exemplifies turn-of-the-century musical orientalism as it was directed toward a local immigrant community. Yet the popular standard continues to resonate today in performance, recordings, film, television, cartoons, advertising, and the latest entertainment products. To account for the song's enduring cultural impact, this essay traces its history across diverse performance contexts over the last century.
Eighteenth-Century Traditional and Mozart's "Jupiter" Symphony K.551
Authors: Brown A. Peter Brown
Published: March 2004

Although the "Jupiter" Symphony has been the subject of much analytical commentary, little attention has been paid to placing the work within the context of Mozart's times and the heritage of earlier 18th-century practices on which it draws. Filling this lacuna involves the consideration of myriad factors, including Mozart's exposure to the music of J. S. and C. P. E. Bach, Joseph Haydn, Michael Haydn, Carlo d'Ordonez, Antonio Salieri, and others; his knowledge of Killian Rheinhardt's Rubriche Generali; his exposure to the Viennese C major trumpet-symphony tradition; and the possible effect of the Turkish War under way in 1788 on the Charakter of K.543, 550, and 551 both in terms of their individual movements and the cycle as a whole. In this larger context, K.543 is the most normal work of the series; K.550, in minor, is dominated by music of mourning; and K.551 is both an elevated and celebratory symphony most appropriate for a victory after battle. Given the C major trumpet-symphony tradition of the first movement of K.551, the elevated nature of the slow second movement's French sarabande, the mixture of idioms of the minuet, and the fugal finale, Mozart fulfills in K.551 every Viennese celebratory requirement.
The Eroticism of Emasculation: Confronting the Baroque Body of the Castrato
Authors: Freitas Roger Freitas
Published: March 2004

This study suggests that, against the background of early modern views of sexuality, the castrato appears not as the asexual creature sometimes implied today, but as a super-natural manifestation of a widely-held erotic ideal. Recent work in the history of sexuality has shown the prevalence in the early modern period of the "one-sex" model, in which the distinction between male and female is quantitative (with respect to "vital heat") rather than qualitative. This model provides for a large middle ground, encompassing prepubescent children, castrati, and other unusual figures. And that middle ground, in fact, seems to have been a prime locus of sexual desire: the art, literature, and historical accounts of the period argue that boys especially were often viewed -perhaps by both sexes-as erotic objects. Further evidence suggests that this sexual charge also applied to castrati. The plausibility of such an erotic image is strengthened by investigation into the actual sexual function of these singers, which seems to have fallen somewhere between historical legend and modern skepticism. Finally, a survey of castrato roles in opera, from Monteverdi to Handel, shows how these singers were deployed and suggests that their popularity could not have depended entirely on vocal skills. Instead, I argue that castrati were prized at least in part for their unique physicality, their spectacularly exaggerated embodiment of the ideal lover.
Viator ducens ad celestia Eucharistic Piety, Papal Politics, and an Early Fifteenth-Century Motet
Authors: Brand Benjamin Brand
Published: March 2004

Fifteenth-century Italy witnessed the marked expansion of the patron's role in the composition and performance of music. Despite the concern and resources that Renaissance princes and ecclesiastics devoted to their musical institutions, however, instances of actual collaboration between patrons and composers are quite rare. This essay considers just such an instance, Matteo da Perugia's Ave sancta mundi / Agnus Dei. A careful examination of this early 15th-century Eucharistic motet reveals that the composer's patron, the cardinal and friar Peter of Candia, likely played a crucial role in selecting the motet text, and was very possibly its author. Read within the context of the enduring and influential works of St. Bonaventure and other Franciscan luminaries, Ave sancta mundi appears to be not simply a general statement of Eucharistic theology, but rather an articulation of Franciscan piety. The most likely impetus for such an articulation was Peter's election to the papacy in 1409 at the Council of Pisa. As heard at the council, not only would the motet have alluded to Peter's status as a prominent member of the Friars Minor, it would have functioned as a forceful plea for ecclesiastical unity in the face of the Great Schism. Matteo's setting employs several musical strategies, including genre blending and chromaticism, which inflect Peter's text in such a way as to amplify these associations. Through a variety of literary allusions and musical processes, then, patron and composer joined in the creative process, fashioning a work that spoke to Peter's deeply held Franciscan beliefs and the aspirations of his fledgling papacy.
Stravinsky's Les Noces (Svadebka), and The Prohibition Against Expressive Timing
Authors: Van Den Toorn Pieter C. Van Den Toorn
Published: March 2004

In Stravinsky's Les Noces, folklike fragments are repeated relentlessly and literally (ritualistically). They are not varied or developed, strictly speaking, but are cut up and displaced metrically. Typically, displacement results in a disruption of the meter. Conflicting expectations of metrical parallelism are raised in the mind of the listener, expectations which catch the listener off guard. And if this disruptive effect is indeed to materialize, then the beat must be held firmly and without expressive nuance. This analytical perspective suggests a specifically musical rationale for exact, metronomic readings of the composer's music, and it also offers a way out of the doomsday aesthetics of "anti-humanism" (T. W. Adorno) with which the inflexible elements of the composer's idiom have been identified. The psychology of metrical entrainment and disruption can speak to the vitality of Les Noces, the ability of this music to excite in ways unrelated to the familiar socio-political equations.
Mendelssohn's Second Piano Concerto, Op. 40, and the Origins of his Serenade and Allegro Giojoso, Op. 43
Authors: Kimber Marian Wilson
Published: March 2004

Felix Mendelssohn's Serenade and Allegro giojoso, op. 43, was composed rapidly for his performance in a concert in Leipzig on 2 April 1838. Originally entitled Adagio and Rondo, the concert piece underwent substantial revision before its publication in late February the following year. The autograph sources reveal that Mendelssohn's Piano Concerto No. 2 in D minor, op. 40, composed less than a year before in 1837, influenced the Serenade and Allegro giojoso's musical content. Not only do the two works for piano and orchestra share a key and thematic material, but an extended sketch found in the Mendelssohn Nachlaß 19 (Staatsbibliothek zu Berlin, Preußischer Kulturbesitz) was part of the compositional history of the concerto, yet served as the basis for a transition, later rejected, between the Serenade and Allegro giojoso's two movements. Revisions to the Mendelssohn Nachlaß 30 draft of op. 43 show Mendelssohn working to make his new work more like the D minor concerto. Not only were parts of the early stages of op. 43 derived from op. 40 sketches, but the finished work suggests that Mendelssohn, facing the proof sheets for op. 40 while working on the Serenade and Allegro giojoso, had not yet worked the concerto's musical material out of his artistic consciousness.