bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modulation of Irinotecan Metabolism by Ketoconazole
Authors: Kehrer Diederik F.S. , Mathijssen Ron H.J. , Verweij Jaap , de Bruijn Peter , Sparreboom Alex 
Published: October 2002

PURPOSE: Irinotecan (CPT-11) is a prodrug of SN-38 and has been registered for the treatment of advanced colorectal cancer. It is converted by the cytochrome P450 3A4 isozyme (CYP3A4) into several inactive metabolites, including 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin (APC). To investigate the role of CYP3A4 in irinotecan pharmacology, we evaluated the consequences of simultaneous treatment of irinotecan with a potent enzyme inhibitor, ketoconazole, in a group of cancer patients. PATIENTS AND METHODS: A total of seven assessable patients was treated in a randomized, cross-over design with irinotecan (350 mg/m2 intravenously for 90 minutes) given alone and followed 3 weeks later by irinotecan (100 mg/m2) in combination with ketoconazole (200 mg orally for 2 days) or vice versa. Serial plasma, urine, and feces samples were obtained up to 500 hours after dosing and analyzed for irinotecan, metabolites (7-ethyl-10-hydroxycamptothecin [SN-38], SN-38 glucuronide [SN-38G], and APC), and ketoconazole by high-performance liquid chromatography. RESULTS: With ketoconazole coadministration, the relative formation of APC was reduced by 87% (P = .002), whereas the relative exposure to the carboxylesterase-mediated SN-38 as expected on the basis of dose (area under the plasma concentration-time curve normalized to dose) was increased by 109% (P = .004). These metabolic alterations occurred without substantial changes in irinotecan clearance (P = .90) and formation of SN-38G (P = .93). CONCLUSION: Inhibition of CYP3A4 in cancer patients treated with irinotecan leads to significantly increased formation of SN-38. Simultaneous administration of various commonly prescribed inhibitors of CYP3A4 can potentially result in fatal outcomes, and up to four-fold reductions in irinotecan dose are indicated.
Rituximab as First-Line and Maintenance Therapy for Patients With Indolent Non-Hodgkin’s Lymphoma
Authors: Hainsworth John D. , Litchy Sharlene , Burris Howard A. , Scullin Daniel C. , Corso Steven W. , Yardley Denise A. , Morrissey Lisa , Greco F. Anthony 
Published: October 2002

PURPOSE: To evaluate response to single-agent rituximab in patients with indolent non-Hodgkin’s lymphoma (NHL) and no previous systemic therapy, and the feasibility, toxicity, and efficacy of maintenance rituximab, administered at 6-month intervals, in patients with objective response or stable disease after first-line rituximab therapy. PATIENTS AND METHODS: Patients with indolent NHL (follicular or small lymphocytic subtypes) previously untreated with systemic therapy received rituximab 375 mg/m2 intravenously weekly for 4 weeks. Patients were restaged at week 6 for response; those with objective response or stable disease received maintenance rituximab courses (identical dose and schedule) at 6-month intervals. Maintenance was continued for a maximum of four rituximab courses or until progression. Between March 1998 and May 1999, 62 patients were entered onto this trial; minimum follow-up was 24 months. RESULTS: Sixty patients (97%) completed the first 4-week course of rituximab and were assessable for response. All have now completed rituximab therapy; 36 (58%) received four courses at 6-month intervals. The objective response rate at 6 weeks was 47%; 45% of patients had stable disease. With continued maintenance, final response rate increased to 73%, with 37% complete responses. Response was similar in patients with follicular versus small lymphocytic subtypes (76% v 70%, respectively). Median actuarial progression-free survival was 34 months. Two patients experienced grade 3/4 toxicity with the first dose; one patient was removed from treatment. No cumulative or additional toxicities were seen with maintenance courses. CONCLUSION: Rituximab is highly active and extremely well tolerated as first-line single-agent therapy for indolent NHL. First-line treatment with scheduled maintenance at 6-month intervals produces high overall and complete response rates and a longer progression-free survival (34 months) than has been reported with a standard 4-week treatment.
Consultation Planning to Help Breast Cancer Patients Prepare for Medical Consultations: Effect on Communication and Satisfaction for Patients and Physicians
Authors: Sepucha Karen R. , Belkora Jeffrey K. , Mutchnick Stephanie , Esserman Laura J. 
Published: October 2002

PURPOSE: To measure the prevalence of communication barriers between breast cancer patients and their physicians and to present the results of a study evaluating the impact of two visit preparation techniques on communication and satisfaction for breast cancer patients and their physicians. PATIENTS AND METHODS: We recruited 132 breast cancer patients from two outpatient cancer centers in a sequential, controlled trial. Ninety-four consented and completed the trial. Patients were assigned to one of two visit preparation interventions before their appointment with either a surgeon or a medical oncologist. In the control intervention, called Productive Listening, a researcher listened to and prompted patients to reflect on their experiences communicating with physicians. In the experimental intervention, called Consultation Planning, a researcher elicited questions and concerns, generated a printed agenda for the upcoming consultation, and engaged patients in techniques to improve communication with their physicians. Valid and reliable surveys measured communication barriers, satisfaction with the intervention, and patients’ and physicians’ satisfaction with the consultation. RESULTS: Sixty-four percent of the patients reported three or more communication barriers. Patients reported a significant reduction in communication barriers after both the intervention and the control session. Patients reported significantly higher satisfaction after the Consultation Planning sessions. Physicians reported significantly higher satisfaction with those patients who had participated in a Consultation Planning session. CONCLUSION: Visit preparation sessions help patients prepare for medical consultations and reduce barriers to communication. Consultation Planning sessions, in which a researcher solicited the patient’s agenda, were more satisfying to patients and physicians than the Productive Listening sessions.
Tamoxifen, Radiation Therapy, or Both for Prevention of Ipsilateral Breast Tumor Recurrence After Lumpectomy in Women With Invasive Breast Cancers of One Centimeter or Less
Authors: Fisher Bernard , Bryant John , Dignam James J. , Wickerham D. Lawrence , Mamounas Eleftherios P. , Fisher Edwin R. , Margolese Richard G. , Nesbitt Lois , Paik Soonmyung , Pisansky Thomas M. , Wolmark Norman 
Published: October 2002

PURPOSE: This trial was prompted by uncertainty about the need for breast irradiation after lumpectomy in node-negative women with invasive breast cancers of ≤ 1 cm, by speculation that tamoxifen (TAM) might be as or more effective than radiation therapy (XRT) in reducing the rate of ipsilateral breast tumor recurrence (IBTR) in such women, and by the thesis that both modalities might be more effective than either alone. PATIENTS AND METHODS: After lumpectomy, 1,009 women were randomly assigned to TAM (n = 336), XRT and placebo (n = 336), or XRT and TAM (n = 337). Rates of IBTR, distant recurrence, and contralateral breast cancer (CBC) were among the end points for analysis. Cumulative incidence of IBTR and of CBC was computed accounting for competing risks. Results with two-sided P values of .05 or less were statistically significant. RESULTS: XRT and placebo resulted in a 49% lower hazard rate of IBTR than did TAM alone; XRT and TAM resulted in a 63% lower rate than did XRT and placebo. When compared with TAM alone, XRT plus TAM resulted in an 81% reduction in hazard rate of IBTR. Cumulative incidence of IBTR through 8 years was 16.5% with TAM, 9.3% with XRT and placebo, and 2.8% with XRT and TAM. XRT reduced IBTR below the level achieved with TAM alone, regardless of estrogen receptor (ER) status. Distant treatment failures were infrequent and not significantly different among the groups (P = .28). When TAM-treated women were compared with those who received XRT and placebo, there was a significant reduction in CBC (hazard ratio, 0.45; 95% confidence interval, 0.21 to 0.95; P = .039). Survival in the three groups was 93%, 94%, and 93%, respectively (P = .93). CONCLUSION: In women with tumors ≤ 1 cm, IBTR occurs with enough frequency after lumpectomy to justify considering XRT, regardless of tumor ER status, and TAM plus XRT when tumors are ER positive.
Phase II Study of Carboplatin in Children With Progressive Low-Grade Gliomas
Authors: Gururangan Sridharan , Cavazos Christina M. , Ashley David , Herndon James E. , Bruggers Carol S. , Moghrabi Albert , Scarcella Deborah L. , Watral Melody , Tourt-Uhlig Sandra , Reardon David , Friedman Henry S. 
Published: October 2002

PURPOSE: To assess the rate of tumor response and activity of carboplatin in stabilizing the growth of progressive low-grade gliomas. PATIENTS AND METHODS: Eligible patients received carboplatin 560 mg/m2 intravenously every 4 weeks for 1 year after maximum tumor response or until disease progression or unacceptable toxicity. RESULTS: Between October 1993 and October 2000, 81 children (median age, 79 months; range, 6 to 204) were enrolled onto this study. Patients received a median of 11 cycles of carboplatin (range, one to 29). Median follow-up from the time of enrollment was 55 months (range, 10 to 93). The overall objective response (complete response [CR] + partial response [PR] + minor response [MR]) and disease stabilization (CR + PR + stable disease + MR) rates to carboplatin treatment were 28% (95% confidence interval [CI], 18% to 38%) and 85% (95% CI, 74% to 93%), respectively. Eleven and 14 patients suffered progressive disease on study and after stopping therapy, respectively. Toxicity was predominantly myelosuppression and included grade 3/4 neutropenia in 56 patients and grade 3/4 thrombocytopenia in 40 patients. The 3-year failure-free survival (FFS) and overall survival (OS) for all patients were 64% (95% CI, 54% to 76%) and 84% (95% CI, 76% to 93%), respectively. Patients with diencephalic tumors had inferior FFS and OS compared with those with tumor at other sites (38% v 74% for FFS, P = .011; 54% v 91% for OS, P = .004). Neurofibromatosis type 1 patients with progressive low-grade glioma had a significantly better OS (95% v 80%; P = .052). CONCLUSION: Carboplatin, in the schedule used in this study, produced disease stabilization or improvement in a majority of children with progressive low-grade glioma, with manageable toxicity. Improved treatment strategies are particularly required for patients with diencephalic tumors.
Evaluation of the inhibition effect of thiolated poly(acrylates) on vaginal membrane bound aminopeptidase N and release of the model drug LH-RH
Authors: Valenta Claudia , Marschütz Michaela , Egyed Christiane , Bernkop-Schnürch Andreas 
Published: October 2002

AbstractThe purpose of this study was to evaluate the inhibitory effect of thiolated carbopol 974P (carbcys) on the enzymatic activity of vaginal aminopeptidase N in-vitro. Mediated by a carbodiimide, L-cysteine was covalently linked to carbopol 974P. Depending on the weight ratio of polymer to cysteine during the coupling reaction, resulting conjugates displayed 31.3–54.4 μmol thiol groups per g polymer. The inhibitory effect of carb-cys conjugates was evaluated towards isolated aminopeptidase N and aminopeptidase-N-like activity of excised vaginal mucosa covered with native mucus, respectively. Enzymatic activity was assayed spectrophotometrically using L-leucine-p-nitroanilide (L-leu-pNA) as a synthetic substrate. Carb-cys thereby showed a significantly higher inhibitory effect than unmodified polymer towards both isolated enzyme and vaginal mucosa. Moreover, enzyme inhibition was strongly dependent on the amount of thiol groups being immobilised. The more thiol groups available the higher was the inhibitory effect. Due to its additional high cohesive properties and the possibility of a sustained drug release, which could be shown for the model drug LH-RH, carb-cys appears interesting for the development of vaginal peptide drug-delivery systems.
Late infantile neuronal ceroid lipofuscinosis: Quantitative description of the clinical course in patients with CLN2 mutations
Authors: Steinfeld Robert , Heim Peter , von Gregory Henning , Meyer Kerstin , Ullrich Kurt , Goebel Hans H. , Kohlschütter Alfried 
Published: October 2002

AbstractWe examined 26 individuals with clinical and electron microscopic signs of late infantile neuronal ceroid lipofuscinosis (LINCL). In 22 cases, we found both pathogenic alleles. Sixteen patients exclusively carried either one or a combination of the two common mutations R208X and IVS5–1G > C. In the remaining cases, four missense mutations could be detected, of which R127Q, N286S, and T353P represent novel, previously not described alleles. A clinical performance score was developed by rating motor, visual, and verbal functions and the incidence of cerebral seizures in 3‐month intervals during the course of the disease. A Total Disability Score was derived by summing up the single scores for motor, visual, and verbal functions. The 16 individuals with the two common mutations were grouped together (referred to as standard patients), and the 5th, 50th, and 95th centiles were calculated and graphically depicted over time. The scores for motor function and language ability dropped earliest and progressed very similarly in the standard patients. The performance curves of two children with the N286S mutation slightly diverged from the 95th centile. However, the performance curves of one patient with atypical LINCL carrying the R127Q mutation fell far beyond the 95th centile. The presented performance rating clearly and quantitatively delineates the disease course of the LINCL patients and hence offers a useful tool for clinical evaluation of future therapeutic interventions. In addition, the described performance score system can be applied to other types of neuronal ceroid lipofuscinoses and could be adapted to various other neurodegenerative diseases of childhood. © 2002 Wiley‐Liss, Inc.
How does interferon work? Does it even matter?
Authors: Sondak Vernon K. 
Published: October 2002

Adjuvant therapy for patients with melanoma using interferon α remains controversial despite numerous randomized clinical trials. In the current study, Kirkwood et al. present the results of a biologic companion trial to Intergroup Trial E1690, which compared high‐dose and low‐dose interferon α2b with observation after surgery. The implications for current practice and future clinical trials are discussed.See also pages 1102‐12.
Role of metallothioneins in irradiated human rectal carcinoma
Authors: Bouzourene Hanifa , Chaubert Pascal , Gebhard Sandra , Bosman Fred T. , Coucke Philippe 
Published: October 2002

AbstractBACKGROUNDMetallothioneins (MT) are low‐molecular weight, metal‐binding proteins that play a role in cellular proliferation and differentiation, as well as in cellular defense mechanisms. They act as scavengers of free radicals produced by irradiation. A number of in vitro and in vivo studies have linked overexpression of cellular MT with tumor cell resistance to radiation. This is the first study that investigates whether MT expression is involved in the radioresistance of rectal carcinoma.METHODSUsing a mouse monoclonal antibody, MT expression was analyzed by immunohistochemistry on surgical samples (n = 85) from 85 patients with locally advanced rectal carcinoma who were treated preoperatively with a hyperfractionated and accelerated radiotherapy schedule and on tumor biopsies (n = 13) obtained before treatment. The potential correlations between MT expression and pathologic variables and survival were examined.RESULTSMT were expressed strongly in both the cytoplasm and nucleus of tumor cells in 7 biopsy and 42 surgical samples. A comparison of MT expression in biopsy and surgical specimens showed that MT expression did not change after irradiation in most cases. Against all expectations, MT were expressed more frequently in tumors from responders than in those from the nonresponders (P = 0.02). There was no correlation between MT expression and tumor stage, histology after radiotherapy, or survival.CONCLUSIONThese findings do not support the hypothesis that MT overexpression at the end of radiotherapy is a marker for radiation resistance. Cancer 2002;95:1003–8. © 2002 American Cancer Society.DOI 10.1002/cncr.10780
Salvage chemotherapy for recurrent spinal cord ependymona
Authors: Chamberlain Marc C. 
Published: October 2002

AbstractBACKGROUNDEpendymomas are reported to constitute 4% of all primary central nervous system (CNS) malignancies in adults, 30% of which occur in the spinal cord. A prospective Phase II study to determine toxicity and response to chronic oral etoposide in patients with recurrent low‐grade intramedullary spinal cord ependymoma (SCE) was conducted.METHODSTen patients (6 males and 4 females with a median age of 30 years) with recurrent SCE were treated with oral etoposide (50mg/m2/day given daily for 21 days followed by a 14‐day break and then repeated constituted a cycle of therapy). All patients had failed surgery and radiotherapy and four patients had failed one prior chemotherapy. Blood counts were obtained weekly, and neurologic examination and a chemistry panel were performed monthly. Contrast‐enhanced magnetic resonance imaging of the spine was performed every 8 weeks after a cycle of etoposide and before the next cycle of chemotherapy was initiated.RESULTSTreatment‐related complications included alopecia in 9 patients, nonbloody diarrhea in 6 patients, a baseline weight loss of > 10% in 5 patients, Grade (according to the National Cancer Institute Common Toxicity Scale) 3‐4 neutropenia in 3 patients, Grade 3‐4 thrombocytopenia in 3 patients, and Grade 3‐4 anemia in 2 patients. There were no treatment‐related deaths reported. After 1 cycle of etoposide, 3 patients (30%) demonstrated progressive disease, 2 patients (20%) achieved a partial response, and 5 patients (50%) maintained stable disease. The overall median response or stable disease duration (disease‐free progression) was 15 months (range, 2.5–45+ months). The overall median survival was 17.5 months (range, 3–45+ months).CONCLUSIONSChronic oral etoposide appears to be well tolerated, has modest toxicity, and had apparent activity in the small cohort of adults in the current study with surgically and medically refractory, recurrent, intradural intramedullary SCE. Cancer 2002;95:997–1002. © 2002 American Cancer Society.DOI 10.1002/cncr.10826
A generalized lot sizing model for the process cycling problem
Authors: Matthews John P. 
Published: October 2002

AbstractMost scheduling/lot sizing models for the single‐machine problem assume that aggregate demand equals aggregate production; and that backorders are to be avoided. Where working inventories are low, the scheduler may wish to avoid short production runs and willingly incur some backorder penalties so as to increase the length of production runs and reduce setup costs per unit of time. The model proposed here identifies optimal lot sizes with respect to the backorder/setup cost relationships. Use of the model will result in an optimally balanced inventory even when aggregate inventory levels are changing.
Load‐limited order release in job shop scheduling systems
Authors: Kanet John J. 
Published: October 2002

AbstractThis report examines the practice of using work load limits to control the release of orders to a job shop. Load limits function in the following general way. Whenever the inventory of work at a work center exceeds some critical value (its “load limit”), further release of orders which are routed to that work center are blocked from entering the shop. After the inventory is “worked off,” release of work to the shop gateways is again permitted. Load‐limited order release is intuitively appealing because it appears to be a method for reducing system inventory and flow times. The practice of load limiting order release is becoming popularized by some of the recent production planning software products now on the market. A notable example is OPT. In this report, analytical results for an M/M/1 queueing model, along with existing simulation studies of multi‐machine job shops are interpreted to form a theory about the effects of using load limits.The major finding here is the proposition that system flow time, inventory, and order tardiness all deteriorate to the extent that load limits introduce idle time into the schedule. Based on the arguments presented here, a very cautious approach toward the use of input control schemes for anywhere but gateway work centers would be advised. The conclusions drawn here are to a great extent arrived at by interpreting the research results of others, so there is a clear need for further research which tests these assertions in a more direct and controlled way.
A risk/benefit analysis of sourcing strategies: Single vs. multiple sourcing
Authors: Treleven Mark , Bergman Schweikhart Sharon 
Published: October 2002

AbstractAs more companies recognize the importance of quality to their long‐term survival they are, among other actions, attempting to formulate sourcing strategies that are consistent with their quality strategies and policies. The two major sourcing strategy options available are multiple and single sourcing. Unfortunately, the literature has lagged behind the practitioner's needs for direction in this area and, therefore, provides little help to managers wrestling with this important and difficult issue.This study uses a risk/benefit approach to carefully examine sourcing strategies from the perspective of the purchaser, or vendee. To ensure a complete and accurate identification and description of the various factors which influence sourcing decisions, intensive interviews were conducted with purchasing and quality personnel at the Manager and Director levels within a number of large, international organizations. Most of the interview data was collected at Control Data, General Mills, Honeywell, Pillsbury, and Unisys. This data was supplemented with information from managers at other companies and the literature which exists in this area.The paper begins by describing the various definitions of single sourcing and the definition which is used for the purposes of this paper. Next, the factors which should influence managers' sourcing decisions are identified and classified into five risk/benefit categories. These categories are then incorporated into a conceptual risk/benefit assessment model for managers to use in the evaluation of their sourcing strategy. The conceptual model is an adaptation of the additive rating model used for facility location decisions [1].It is suggested that the model would most appropriately be applied at the family of parts level. Application at this level would likely result in different sourcing strategies for different part families (and different organizations), depending on the characteristics of each family. This is consistent with the conclusions of Hahn, Kim and Kim [10].This work contributes to the literature in several ways. The first of these contributions is the complete definition of the various levels of single sourcing. Compilation of the many factors associated with both single and multiple sourcing decisions is another contribution. Prior to this research, the identification of these factors had been incomplete, limited to single sourcing, fragmented across a number of articles, and disseminated largely by word of mouth. The construction of a framework within which these factors can be categorized is also new to the literature. The final contribution of this research is the development of a conceptual model to analyze the combined effects of these factors.