bluuebunny/crossref_metadata_2025_split huggingface dataset:
Factors That Predict Chemotherapy-Induced Myelosuppression in Lymphoma Patients: Role of the Tumor Necrosis Factor Ligand-Receptor System
Authors: Voog Eric , Bienvenu Jacques , Warzocha Krzysztof , Moullet Isabelle , Dumontet Charles , Thieblemont Catherine , Monneret Guillaume , Gutowski Marie-Claude , Coiffier Bertrand , Salles Gilles 
Published: February 2017

PURPOSE: To analyze factors that predict the occurrence of chemotherapy-induced myelosuppression and, in particular, the role of the tumor necrosis factor (TNF) ligand-receptor system in lymphoma patients at the beginning of their treatment.PATIENTS AND METHODS: We investigated the predictive factors for myelosuppression after the first course of chemotherapy in a cohort of 101 consecutive, previously untreated lymphoma patients receiving regimens that include doxorubicin and cyclophosphamide. Plasma samples were tested at baseline by enzyme-linked immunosorbent assay for TNF and its soluble receptors. Univariate and multivariate analyses were performed with a forward regression procedure that included all of the parameters that were found to be significant in the univariate analysis. The dose of chemotherapy and the prophylactic treatment with granulocyte colony-stimulating factor were deliberately included in this model.RESULTS: Sixty-seven patients experienced World Health Organization (WHO) grade 4 neutropenia, and 37 patients experienced febrile neutropenia, which was responsible for WHO grade 2 through 4 infections in 23 patients. In multiparametric regression analysis, the occurrence of grade 4 neutropenia was associated with high doses of cyclophosphamide (odds ratio [OR], 19.8; P = .008) and high levels of soluble p75-R-TNF (OR, 8.52; P = .001). The duration of grade 4 neutropenia for more than 5 days was associated with the lack of hematopoietic growth factor administration (OR, 6.76; P = .004) and high levels of soluble p75-R-TNF (OR, 5.84; P = .0023). The occurrence of febrile neutropenia was associated with high doses of cyclophosphamide (OR, 4.7; P = .007), altered performance status (OR, 18.8; P < .0001) and high levels of soluble p75-R-TNF (OR, 3.49; P = .029).CONCLUSION: This study indicates that in addition to the dose of chemotherapy and the administration of hematopoietic growth factors, poor performance status and high p75-R-TNF levels can predict the occurrence of chemotherapy-induced myelosuppression in lymphoma patients. This model may help in selecting patients for prophylactic growth factor administration.
Clinical and Immune Responses in Advanced Melanoma Patients Immunized With an Anti-Idiotype Antibody Mimicking Disialoganglioside GD2
Authors: Foon Kenneth A. , Lutzky Jose , Baral Rathindra N. , Yannelli John R. , Hutchins Laura , Teitelbaum April , Kashala Oscar L. , Das Ruma , Garrison Juanita , Reisfeld Ralph A. , Bhattacharya-Chatterjee Malaya 
Published: February 2017

PURPOSE: To determine immune responses and toxicity to the anti-idiotype vaccine, as well as clinical responses and survival, we initiated a clinical trial for patients with advanced melanoma treated with an anti-idiotype antibody (TriGem) that mimics the disialoganglioside GD2. PATIENTS AND METHODS: Forty-seven patients with advanced melanoma received either 1-, 2-, 4-, or 8-mg doses of TriGem (Titan Pharmaceuticals Inc, South San Francisco, CA) mixed with QS-21 adjuvant (Aquila Biopharmaceuticals, Inc, Worcester, MA) 100 μg subcutaneously weekly for 4 weeks and then monthly until disease progression. Median age was 57 years, there were 32 men and 15 women, 43% of patients had undergone prior therapy for metastatic disease, 55% had disease confined to soft tissue, and 45% had visceral metastasis. RESULTS: Hyperimmune sera from 40 of 47 patients showed an anti–anti-idiotype (Ab3) response. Patient Ab3 was truly Ab1′ because it specifically bound purified disialoganglioside GD2. The isotypic specificity of the Ab3 antibody consisted of predominantly immunoglobulin (Ig)G, and all IgG subclasses were represented. One patient had a complete response that persisted at 24 months, and 12 patients were stable from 14+ to 37+ months (median, 18+ months). Disease progression occurred in 32 patients on study from 1 to 17 months (median, 5.5 months), and 21 have died at 1 to 16 months (median, 6 months). The Kaplan-Meier–derived overall median survival has not been reached. Median survival has not been reached for the 26 patients with soft tissue disease only and was 13 months for 21 patients with visceral metastasis. Toxicity consisted of local reaction at the site of injection and mild fever and chills. CONCLUSION: TriGem has minimal toxicity and generates robust and specific IgG immune responses against GD2. Objective responses were minimal, but there may be a favorable impact on disease progression and survival that will require prospective randomized trials.
Impact of Quality of Life on Patient Expectations Regarding Phase I Clinical Trials
Authors: Cheng Jonathan D. , Hitt James , Koczwara Bogda , Schulman Kevin A. , Burnett Caroline B. , Gaskin Darrell J. , Rowland Julia H. , Meropol Neal J. 
Published: February 2017

PURPOSE: Quality of life (QOL) is increasingly recognized as a critical cancer-treatment outcome measure, but little is known about the impact of QOL on the patient decision-making process. A pilot study was conducted in an effort to (1) measure the expectations of patients, physicians, and research nurses regarding the potential benefits and toxicities from experimental and standard therapies, and (2) determine the relationship of QOL to patient perceptions regarding treatment options. METHODS: Thirty cancer patients enrolling in phase I clinical trials, their physicians, and their research nurses were administered questionnaires that assessed demographics, QOL, and treatment expectations. RESULTS: Compared with their physicians, patients overestimated potential benefits and toxicities from experimental therapy (mean expected benefit, 59.8% v 23.8%, P < .01; mean expected toxicity, 29.8% v 16.0%, P < .01). Patients estimated a greater potential for benefit (59.8% v 36.8%, P < .01) and less potential for toxicity (29.8% v 45.6%, P = .01) for experimental therapy, compared with standard therapy. Short Form- 36 general health perception correlated with patient perception of potential benefit from experimental therapy (r = .48, P = .01). CONCLUSION: Participants in phase I clinical trial have high expectations regarding the success of experimental therapy and discount potential toxicity. Patient QOL may affect the expectation of benefit from experimental therapy and, ultimately, treatment choice. Understanding the interactions between QOL and patient expectations may guide the development of improved strategies to present appropriate information to patients considering early-phase clinical trials.
Safety and Efficacy Results of a Randomized Trial Comparing Adjuvant Toremifene and Tamoxifen in Postmenopausal Patients With Node-Positive Breast Cancer
Authors: Holli Kaija , Valavaara Ritva , Blanco Guillermo , Kataja Vesa , Hietanen Päivi , Flander Martti , Pukkala Eero , Joensuu Heikki ,   for the Finnish Breast Cancer Group
Published: February 2017

PURPOSE: In this multicenter trial, toremifene 40 mg/d was compared with tamoxifen 20 mg/d, both given orally for 3 years to postmenopausal, axillary node–positive women after breast surgery. PATIENTS AND METHODS: The first 899 patients (toremifene, n = 459; tamoxifen, n = 440) of the total of 1,480 patients accrued to the trial were included in this scheduled safety analysis. The mean follow-up time was 3.4 years. RESULTS: The two treatment groups were well balanced with respect to patient and disease characteristics. The subjective side-effect profile was similar in both treatment groups. Slightly more vascular complications (deep vein thromboses, cerebrovascular events, and pulmonary embolisms) were seen among tamoxifen-treated patients (5.9%) as compared with toremifene-treated patients (3.5%) (P = .11), whereas bone fractures (P = .09) and vaginal leukorrhea (P = .05) were more common in the toremifene group. The number of subsequent second cancers was similar. The breast cancer recurrence rate was 23.1% (n = 106) in the toremifene group and 26.1% (n = 115) in the tamoxifen group (P = .31). When only patients with estrogen receptor (ER)–positive cancer were considered (n = 556), the risk for breast cancer recurrence was nonsignificantly lower among the toremifene-treated women, with a hazards ratio of 0.74 (90% confidence interval, 0.52 to 1.04; P = .14). The mean time to breast cancer recurrence and overall survival were similar in both groups. CONCLUSION: The side-effect profile of toremifene resembles that of tamoxifen. The efficacy of toremifene seems to be no less than that of tamoxifen. The trend for fewer breast cancer recurrences in the ER-positive subgroup is encouraging, but a longer follow-up is needed to confirm this.
Phase I Trial of Carmustine Plus O6-Benzylguanine for Patients With Recurrent or Progressive Malignant Glioma
Authors: Friedman Henry S. , Pluda James , Quinn Jennifer A. , Ewesuedo Reginald B. , Long Lina , Friedman Allan H. , Cokgor Ilkcan , Colvin O. Michael , Haglund Michael M. , Ashley David M. , Rich Jeremy N. , Sampson John , Pegg Anthony E. , Moschel Robert C. , McLendon Roger E. , Provenzale James M. , Stewart Elizabeth S. , Tourt-Uhlig Sandra , Garcia-Turner Ana M. , Herndon James E. , Bigner Darell D. , Dolan M. Eileen 
Published: February 2017

PURPOSE: The major mechanism of resistance to alkylnitrosourea therapy involves the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT), which removes chloroethylation or methylation damage from the O6 position of guanine. O6-benzylguanine (O6-BG) is an AGT substrate that inhibits AGT by suicide inactivation. We conducted a phase I trial of carmustine (BCNU) plus O6-BG to define the toxicity and maximum-tolerated dose (MTD) of BCNU in conjunction with the preadministration of O6-BG with recurrent or progressive malignant glioma. PATIENTS AND METHODS: Patients were treated with O6-BG at a dose of 100 mg/m2 followed 1 hour later by BCNU. Cohorts of three to six patients were treated with escalating doses of BCNU, and patients were observed for at least 6 weeks before being considered assessable for toxicity. Plasma samples were collected and analyzed for O6-BG, 8-oxo-O6-BG, and 8-oxoguanine concentration. RESULTS: Twenty-three patients were treated (22 with glioblastoma multiforme and one with anaplastic astrocytoma). Four dose levels of BCNU (13.5, 27, 40, and 55 mg/m2) were evaluated, with the highest dose level being complicated by grade 3 or 4 thrombocytopenia and neutropenia. O6-BG rapidly disappeared from plasma (elimination half-life = 0.54 ± 0.14 hours) and was converted to a longer-lived metabolite, 8-oxo-O6-BG (elimination half-life = 5.6 ± 2.7 hours) and further to 8-oxoguanine. There was no detectable O6-BG 5 hours after the start of the O6-BG infusion; however, 8-oxo-O6-BG and 8-oxoguanine concentrations were detected 25 hours after O6-BG infusion. The mean area under the concentration-time curve (AUC) of 8-oxo-O6-BG was 17.5 times greater than the mean AUC for O6-BG. CONCLUSION: These results indicate that the MTD of BCNU when given in combination with O6-BG at a dose of 100 mg/m2 is 40 mg/m2 administered at 6-week intervals. This study provides the foundation for a phase II trial of O6-BG plus BCNU in nitrosourea-resistant malignant glioma.
Phase I Study of Preoperative Oral Uracil and Tegafur Plus Leucovorin and Radiation Therapy in Rectal Cancer
Authors: Hoff Paulo M. , Janjan Nora , Saad Everardo D. , Skibber John , Crane Christopher , Lassere Yvonne , Cleary Karen R. , Benner Steve , Randolph Jacqueline , Abbruzzese James L. , Pazdur Richard 
Published: February 2017

PURPOSE: Preoperative combined-modality therapy for rectal cancermay allow for sphincter preservation, while decreasing recurrencerates and improving the overall prognosis. Oral chemotherapy withuracil and tegafur (UFT) plus leucovorin (LV) may reduce costs andcomplications associated with protracted infusions offluorouracil. Our goal was to evaluate the safety of UFT plus LVcombined with preoperative radiation and determine themaximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of UFTplus LV in this setting. PATIENTS AND METHODS: Patients with tumor-node-metastasis stage II or III rectalcancer received escalating doses of UFT (starting at 250mg/m2/d, with50-mg/m2/d increments between consecutivecohorts) and fixed doses of LV (90 mg/d). The UFT and LV combinationwas given 5 days per week concurrently with a 5-week course ofpreoperative radiation totaling 45 Gy (1.8 Gy/fraction). Surgery wasperformed 4 to 6 weeks after radiation and was followed by four 35-daycycles of fixed doses of UFT and LV (28 days of therapy eachcycle). RESULTS: Fifteen patients weretreated, and 13 received the full preoperative chemotherapy. Allplanned radiation was delivered successfully. The MTD of UFT withradiation was 350 mg/m2/d with 90 mg/d ofLV. Diarrhea was the DLT. Sphincter-preserving surgery was performedin 12 of 14 patients. One patient had progressive disease beforesurgery. Pathologic evaluation of 14 resected specimens showed acomplete response in three cases. CONCLUSION: Preoperative chemoradiation with oral UFT plus LV isfeasible and well tolerated and should be furtherinvestigated.
MYCN Expression Is Not Prognostic of Adverse Outcome in Advanced-Stage Neuroblastoma With Nonamplified MYCN
Authors: Cohn Susan L. , London Wendy B. , Huang Donghui , Katzenstein Howard M. , Salwen Helen R. , Reinhart Todd , Madafiglio Janice , Marshall Glenn M. , Norris Murray D. , Haber Michelle 
Published: February 2017

PURPOSE: The clinical significance of MYCN expression in children with neuroblastoma (NB) remains controversial. To determine the prognostic significance of MYCN expression in the absence of MYCN amplification, we analyzed MYCN mRNA and protein expression in tumors from 69 patients. PATIENTS AND METHODS: Sixty-nine NB tumor samples with nonamplified MYCN from patients with stage C or D disease were obtained from the Pediatric Oncology Group Neuroblastoma Tumor Bank. MYCN mRNA was analyzed using a real-time reverse transcriptase polymerase chain reaction assay, and MYCN protein was examined by Western blot analyses. RESULTS: The estimated 5-year event-free survival (EFS) and survival (S) rates plus SE for the cohort were 57% ± 17% and 60% ± 16%, respectively. Infants younger than 1 year had significantly higher rates of EFS and S than children ≥ 1 year of age (P = .003 and P < .001, respectively); patients with stage C disease had better outcome than those with stage D NB (P < .001); and patients with hyperdiploid tumors had better outcome than those with diploid NB (P < .001). Surprisingly, outcome was slightly better for patients with high versus low levels of MYCN mRNA expression (4-year S, 70% ± 13% v 50% ± 16%; P = .290), and for patients with tumors that expressed MYCN protein (4-year S, 73% ± 19% v 53% ± 15%, respectively; P = .171). CONCLUSION: High levels of MYCN expression are not prognostic of adverse outcome in patients with advanced-stage NB with nonamplified MYCN. A trend associating high levels of MYCN expression with improved outcome was observed.
Durable Remission After Aggressive Chemotherapy for Very Late Post–Kidney Transplant Lymphoproliferation: A Report of 16 Cases Observed in a Single Center
Authors: Mamzer-Bruneel M-F. , Lomé C. , Morelon E. , Levy V. , Bourquelot P. , Jacobs F. , Gessain A. , Mac Intyre E. , Brousse N. , Kreis H. , Hermine O. 
Published: February 2017

PURPOSE: Posttransplant lymphoproliferative diseases (PTLDs) represent a group of potentially lethal lymphoid proliferations that may complicate the course of solid organ transplantation. Although early-onset PTLDs frequently have a favorable outcome, late-onset PTLDs behave more alike aggressive lymphoma. We report a monocentric retrospective study that focused on PTLDs occurring later than 1 year after kidney transplantation (very late–onset PTLDs) to define their incidence, clinical presentation, pathologic features, and outcome. We particularly emphasized the follow-up of patients treated with conventional chemotherapy. PATIENTS AND METHODS: The medical histories of all patients who developed very late–onset PTLD in our institution were reviewed, and diagnostic biopsy materials were retrospectively studied. RESULTS: Very late–onset PTLDs were diagnosed in 16 (1.1%) of 1,421 patients. Mean (± SD) time to tumor onset was 103.93 ± 70.88 months. Most tumors were Epstein-Barr virus–related monomorphic large-cell PTLDs of B phenotype. Ten patients received conventional chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone regimen). Two of them died within 2 months, two achieved partial remission, and six achieved definitive complete remission. Overall median survival time was 13 months and rose to 27 months in the treated group. The main cause of mortality was sepsis. None of the treated patients experienced rejection despite withdrawal of immunosuppressive treatment. CONCLUSION: Despite characteristics of aggressive lymphoma, very late–onset PTLDs after renal transplantation may respond to conventional chemotherapy. However, because a high rate of infectious complications occurred, new therapeutic strategies, such as combinations of anti-CD20 monoclonal antibodies and lower doses of chemotherapy, are warranted.
Assessment of Methods for Tissue-Based Detection of the HER-2/neu Alteration in Human Breast Cancer: A Direct Comparison of Fluorescence In Situ Hybridization and Immunohistochemistry
Authors: Pauletti Giovanni , Dandekar Suganda , Rong HongMei , Ramos Lilllian , Peng HongJun , Seshadri Ram , Slamon Dennis J. 
Published: February 2017

PURPOSE: To compare the efficacy of fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) in detecting the HER-2/neu alteration in human breast cancer. PATIENTS AND METHODS: Unselected stage I, II, and III breast cancer patients (N = 900) were tested for HER-2/neu gene amplification by FISH in paraffin-embedded, formalin-fixed archival material. Of these samples, 856 were tested for HER-2/neu overexpression by non–antigen-retrieval IHC with the polyclonal antibody R60, the sensitivity and specificity of which was preliminarily compared with the United States Food and Drug Administration–approved HercepTest (Dako Corp, Carpinteria, CA). Patient survival was analyzed in relation to the presence of the HER-2/neu alteration as determined by these two methodologies. RESULTS: A total of 189 (21%) of 900 patients were positive by FISH and 147 (17.2%) of 856 were positive by IHC. This discrepancy is consistent with expected loss of IHC sensitivity associated with tissue fixation/embedding. The HercepTest did not improve sensitivity and introduced false positives. Comparison of R60-based IHC with FISH demonstrates that patient survival is associated progressively to gene amplification level as determined by FISH, whereas for IHC an association is found only in the highest (3+) immunostaining group. Among FISH-negative tumors, 45 (6.6%) of 678 were IHC-positive, with a survival probability similar to that of FISH-negative/IHC-negative cases; FISH-positive/IHC-negative patients have a survival probability similar to that of FISH-positive/IHC-positive cases. CONCLUSION: IHC does not consistently discriminate patients likely to have a poor prognosis, whereas FISH provides superior prognostic information in segregating high-risk from lower-risk beast cancers. HER-2/neu protein overexpression in the absence of gene amplification occurs infrequently in breast cancer, in which case, patient outcome is similar to that of patients without the alteration.
Phase I Dose-Finding and Pharmacokinetic Study of Paclitaxel and Carboplatin With Oral Valspodar in Patients With Advanced Solid Tumors
Authors: Patnaik Amita , Warner Ellen , Michael Michael , Egorin Merrill J. , Moore Malcolm J. , Siu Lillian L. , Fracasso Paula M. , Rivkin Saul , Kerr Ian , Litchman Manuel , Oza Amit M. 
Published: February 2017

PURPOSE: To evaluate the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic (PK) profile of paclitaxel and carboplatin when administered every 3 weeks with the oral semisynthetic cyclosporine analog valspodar (PSC 833), an inhibitor of P-glycoprotein function. PATIENTS AND METHODS: Fifty-eight patients were treated with escalating doses of paclitaxel ranging from 54 to 94.5 mg/m2 and carboplatin area under the plasma concentration versus time curve (AUC) ranging from 6 to 9 mg·min/mL, every 21 days. The dose of valspodar was fixed at 5 mg/kg every 6 hours for a total of 12 doses from day 0 to day 3. The MTD was determined for the following two groups: (1) previously treated patients, where paclitaxel and carboplatin doses were escalated; and (2) chemotherapy-naïve patients, where paclitaxel dose was escalated and carboplatin AUC was fixed at 6 mg·min/mL. PK studies of paclitaxel and carboplatin were performed on day 1 of course 1. RESULTS: Fifty-eight patients were treated with 186 courses of paclitaxel, carboplatin, and valspodar. Neutropenia, thrombocytopenia, and hepatic transaminase elevations were DLTs. In previously treated patients, no DLTs occurred at the first dose level (paclitaxel 54 mg/m2 and carboplatin AUC 6 mg·min/mL). However, one of 12, two of six, two of four, four of 11, and two of five patients experienced DLTs at doses of paclitaxel (mg/m2)/carboplatin AUC (mg·min/mL) of 67.5/6, 81/6, 94.5/6, 67.5/7.5, and 67.5/9, respectively. In chemotherapy-naïve patients, one of 17 developed DLT at paclitaxel 81 mg/m2 and carboplatin AUC 6 mg/mL·min. There was prolongation of the terminal phase of paclitaxel elimination as evidenced by an increased time that plasma paclitaxel concentration was ≥ 0.05 μmol/L, ranging from 16.6 ± 6.7 hours to 41.5 ± 9.8 hours for paclitaxel doses of 54.5 mg/m2 to 94.5 mg/m2, respectively. CONCLUSION: The recommended phase II dose in chemotherapy-naïve patients is paclitaxel 81 mg/m2, carboplatin AUC 6 mg·min/mL, and valspodar 5 mg/kg every 6 hours. In previously treated patients, the recommended phase II dose is paclitaxel 67.5 mg/m2, carboplatin AUC 6 mg·min/mL, and valspodar 5 mg/kg every 6 hours. The acceptable toxicity profile supports the rationale for performing disease-directed evaluations of paclitaxel, carboplatin and valspodar on the schedule evaluated in this study.