bluuebunny/crossref_metadata_2025_split huggingface dataset:
Autografting Followed by Nonmyeloablative Immunosuppressive Chemotherapy and Allogeneic Peripheral-Blood Hematopoietic Stem-Cell Transplantation as Treatment of Resistant Hodgkin’s Disease and Non-Hodgkin’s Lymphoma
Authors: Carella Angelo M. , Cavaliere Marina , Lerma Enrica , Ferrara Raimondo , Tedeschi Lucilla , Romanelli Antonella , Vinci Maria , Pinotti Graziella , Lambelet Paola , Loni Carlo , Verdiani Simonetta , De Stefano Francesco , Valbonesi Mauro , Corsetti Maria Teresa 
Published: February 2017

PURPOSE: To investigate the use of a nonmyeloablative fludarabine-based immunosuppressive regimen to allow engraftment of HLA-sibling donors’ mobilized stem cells and induction of a graft-versus-lymphoma effect for patients with advanced resistant Hodgkin’s disease and non-Hodgkin’s lymphoma. PATIENTS AND METHODS: Fifteen patients with Hodgkin’s disease (n = 10) and non-Hodgkin’s lymphoma (n = 5) were studied. All patients received cyclophosphamide and granulocyte colony-stimulating factor to mobilize autologous hematopoietic stem cells (HSCs). Subsequently, they received high-dose therapy with carmustine, etoposide, cytarabine, and melphalan and reinfusion of HSCs. At a median of 61 days after engraftment, patients were given fludarabine 30 mg/m2 with cyclophosphamide 300 mg/m2 daily for 3 days. Donor-mobilized HSC collections were prepared for fresh infusion and were not T-cell depleted. Methotrexate and cyclosporine were used to prevent graft rejection and as graft-versus-host disease (GVHD) prophylaxis. RESULTS: Combined treatment was well tolerated. After mini-allografting, hematologic recovery was prompt. Thirteen patients had 100% donor cell engraftment. Eleven patients achieved complete remission (CR) after the combined procedure. Nine patients, who were in partial remission after autografting, achieved CR after mini-allografting. Seven patients developed ≥ grade 2 acute GVHD (aGVHD) and two developed extensive chronic GVHD (cGVHD). Three patients who received the highest number of donor lymphocyte infusions (DLIs) developed grade 3 GVHD (two patients) and extensive cGVHD (one patient). Ten patients are currently alive, and five are in continuous CR. Seven patients received DLI, with five CRs. Five patients died: one of progressive disease, two of progressive disease combined with aGVHD or cGVHD, one of extensive cGVHD, and one of infection. CONCLUSION: Fludarabine/cyclophosphamide was well tolerated and allowed consistent engraftment in lymphoma allografted patients. Response rates were high in this group of refractory and heavily pretreated patients. This dual procedure seems to be most promising in patients with end-stage malignant lymphomas.
p53 Gene Status and Response to Platinum/Paclitaxel-Based Chemotherapy in Advanced Ovarian Carcinoma
Authors: Lavarino Cinzia , Pilotti Silvana , Oggionni Maria , Gatti Laura , Perego Paola , Bresciani Gianluigi , Pierotti Marco A. , Scambia Giovanni , Ferrandina Gabriella , Fagotti Anna , Mangioni Costantino , Lucchini Valeria , Vecchione Francesca , Bolis Giorgio , Scarfone Giovanna , Zunino Franco 
Published: February 2017

PURPOSE: The p53 gene plays a critical role in cellular response to DNA damage and has been implicated in the response to platinum compounds in ovarian carcinoma patients. Because taxanes could induce p53-independent apoptosis, we assessed the relevance of p53 gene status to response in ovarian carcinoma patients receiving paclitaxel and platinum-containing chemotherapy. PATIENTS AND METHODS: Forty-eight previously untreated patients with advanced disease received standard paclitaxel/platinum-based chemotherapy. In tumor specimens collected at the time of initial surgery, before therapy, p53 gene status and expression were examined by single-strand conformation polymorphism, sequence analysis, and immunohistochemical analysis. Microsatellite instability analysis was performed on available samples from 30 patients. RESULTS: Thirty-four (71%) of the 48 patients had a clinical response. Pathologic complete remission was documented in 13 (27%) of 48 patients. p53 mutations were detected in 29 (60%) of 48 tumors. Among the patients with mutant p53 tumors, 25 patients (86%) responded to chemotherapy. Only nine (47%) of 19 patients with wild-type p53 tumors responded to the same treatment. The overall response rate and the complete remission rate were significantly higher among patients with mutant p53 tumors than among patients with wild-type p53 tumors (P = .008). Most of the tested tumors not associated with complete remission (10 of 12 tumors) were also characterized by microsatellite instability. The complete remission rate was higher among patients with tumors without microsatellite instability (five of seven patients). CONCLUSION: In contrast to the limited efficacy of treatment with paclitaxel in combination with standard platinum doses against wild-type p53 ovarian tumors, patients with mutant p53 ovarian tumors were more responsive to paclitaxel-based chemotherapy. The pattern of response to chemotherapy containing paclitaxel is different from that associated with high-dose cisplatin therapy. Determining p53 mutational status can be useful in predicting therapeutic response to drugs effective in ovarian carcinoma.
Phase I and Pharmacokinetic Trial of Weekly Oral Fluorouracil Given With Eniluracil and Low-Dose Leucovorin to Patients With Solid Tumors
Authors: Grem Jean L. , Harold Nancy , Shapiro Jeremy , Bi Dao-Qin , Quinn Mary G. , Zentko Suzanne , Keith Bruce , Hamilton J. Michael , Monahan Brian P. , Donavan Sean , Grollman Frank , Morrison Geraldine , Takimoto Chris H. 
Published: February 2017

PURPOSE: Fluorouracil (5-FU) given as a weekly, high-dose 24-hour infusion is active and tolerable. We evaluated an oral regimen of eniluracil (which inactivates dihydropyrimidine dehydrogenase [DPD]), 5-FU, and leucovorin to simulate this schedule. PATIENTS AND METHODS: Patients received a single 24-hour infusion of 5-FU (2,300 mg/m2 on day 2) with leucovorin (15 mg orally [PO] bid on days 1 through 3) to provide reference pharmacokinetic data. Two weeks later, patients began treatment with eniluracil (20 mg) and leucovorin (15 mg) (PO bid on days 1 through 3) and 5-FU (10 to 15 mg/m2 PO bid on day 2). RESULTS: Dose-limiting toxicity (diarrhea, neutropenia, and fatigue) was seen with 5-FU 15 mg/m2 PO bid on day 2 given weekly for either 6 of 8 weeks or 3 of 4 weeks, whereas five of seven patients tolerated 5-FU 10 mg/m2 PO bid given weekly for 3 of 4 weeks. Eniluracil led to a 35-fold reduction in 5-FU clearance. Fluoro-beta-alanine, a 5-FU catabolite, was not detected in plasma during oral 5-FU–eniluracil therapy. DPD activity was markedly suppressed in all patients during eniluracil therapy; the inactivation persisted after the last eniluracil dose; percentages of baseline values were 1.8% on day 5, 4.5% on day 12, and 23.6% on day 19. CONCLUSION: The recommended oral dosage of 5-FU (10 mg/m2 PO bid) given with eniluracil and leucovorin is approximately 115-fold lower than the reference dosage for 24-hour infusional 5-FU. This difference is greater than expected given the reduction in 5-FU clearance. DPD inactivation persisted for several weeks after completion of eniluracil therapy.
Phase I Study in Advanced Cancer Patients of a Diversified Prime-and-Boost Vaccination Protocol Using Recombinant Vaccinia Virus and Recombinant Nonreplicating Avipox Virus to Elicit Anti–Carcinoembryonic Antigen Immune Responses
Authors: Marshall John L. , Hoyer Robert J. , Toomey Mary Ann , Faraguna Kristen , Chang Ping , Richmond Ellen , Pedicano James E. , Gehan Edmund , Peck Ronald A. , Arlen Philip , Tsang Kwong Y. , Schlom Jeffrey 
Published: February 2017

PURPOSE: This trial sought to determine, for the first time, the validity in human vaccinations of using two different recombinant vaccines in diversified prime-and-boost regimens to enhance T-cell responses to a tumor antigen. PATIENTS AND METHODS: Eighteen patients with advanced tumors expressing carcinoembryonic antigen (CEA) were randomized to receive either recombinant vaccinia (rV)-CEA followed by three avipox-CEA vaccinations, or avipox-CEA (three times) followed by one rV-CEA vaccination. Subsequent vaccinations in both cohorts were with avipox-CEA. Immunologic monitoring was performed using a CEA peptide and the enzyme-linked immunospot assay for interferon gamma production. RESULTS: rV-CEA followed by avipox-CEA was superior to the reverse order in the generation of CEA-specific T-cell responses. Further increases in CEA-specific T-cell precursors were seen when local granulocyte-macrophage colony-stimulating factor (GM-CSF) and low-dose interleukin (IL)-2 were given with subsequent vaccinations. The treatment was extremely well tolerated. Limited clinical activity was seen using vaccines alone in this patient population. Antibody production against CEA was also observed in some of the treated patients. CONCLUSION: rV-CEA was more effective in its role as a primer of the immune system; avipox-CEA could be given up to eight times with continued increases in CEA T-cell precursors. Future trials should use rV-CEA first followed by avipox-CEA. Vaccines specific to CEA are able to generate CEA-specific T-cell responses in patients without significant toxicity. T-cell responses using vaccines alone may be inadequate to generate significant anticancer objective responses in patients with advanced disease. Cytokines such as GM-CSF and IL-2 may play a key role in generating such responses.
Germline BRCA1/2 Mutations and p27Kip1 Protein Levels Independently Predict Outcome After Breast Cancer
Authors: Chappuis Pierre O. , Kapusta Linda , Bégin Louis R. , Wong Nora , Brunet Jean-Sébastien , Narod Steven A. , Slingerland Joyce , Foulkes William D. 
Published: February 2017

PURPOSE: Decreased levels of the cyclin-dependent kinase inhibitor p27Kip1 in breast cancer are associated with a poor outcome. The prognostic significance of BRCA1/2 mutations is less clear, and the relationship between BRCA1/2 mutation status, p27Kip1 protein levels, and outcome has not been studied. PATIENTS AND METHODS: Pathology blocks from 202 consecutive Ashkenazi Jewish women with primary invasive breast cancer were studied. Tumor DNA was tested for the three common BRCA1/2 founder mutations present in Ashkenazi Jews, and p27Kip1 expression was evaluated by immunohistochemistry. The median follow-up was 6.4 years. RESULTS: Thirty-two tumors (16%) were positive for a BRCA1/2 mutation. Low p27Kip1 expression was seen in 110 tumors (63%) and was significantly associated with BRCA1/2 mutations (odds ratio, 4.0; 95% confidence interval [CI], 1.4 to 11.1; P = .009). BRCA1/2 mutation carriers had a significantly worse 5-year distant disease-free survival (DDFS) compared with women without BRCA1/2 mutations (58% v 82%; P = .003). Similar results were seen for women whose tumors expressed low levels of p27Kip1, compared with those with high levels (5-year DDFS, 68% v 93%; P < .0001). In a multivariate analysis, both BRCA1/2 mutation and low p27Kip1 expression were associated with a shorter DDFS (relative risk [RR], 2.1; 95% CI, 1.0 to 4.3; P = .05; and RR, 3.9; 95% CI, 1.4 to 11.1; P = .01, respectively). CONCLUSION: In this study, we showed that BRCA1/2 mutations were associated with low levels of p27Kip1 in breast cancer. Both BRCA1/2 and p27Kip1 status were identified as independent prognostic factors.
Familial Invasive Breast Cancers: Worse Outcome Related to BRCA1 Mutations
Authors: Stoppa-Lyonnet Dominique , Ansquer Yan , Dreyfus Hélène , Gautier Chantal , Gauthier-Villars Marion , Bourstyn Edwige , Clough Krishna B. , Magdelénat Henri , Pouillart Pierre , Vincent-Salomon Anne , Fourquet Alain , Asselain Bernard 
Published: February 2017

PURPOSE: Although all studies confirm that BRCA1 tumors are highly proliferative and poorly differentiated, their outcomes remain controversial. We propose to examine, through a cohort study, the pathologic characteristics, overall survival, local recurrence, and metastasis-free intervals of 40 patients with BRCA1 breast cancer. PATIENTS AND METHODS: A cohort of 183 patients with invasive breast cancer, treated at the Institut Curie and presenting with a familial history of breast and/or ovarian cancer, were tested for BRCA1 germ-line mutation. Tumor characteristics and clinical events were extracted from our prospectively registered database. RESULTS: Forty BRCA1 mutations were found among the 183 patients (22%). Median follow-up was 58 months. BRCA1 tumors were larger in size (P = .03), had a higher rate of grade 3 histoprognostic factors (P = .002), and had a higher frequency of negative estrogen (P = .003) and progesterone receptors (P = .002) compared with non-BRCA1 tumors. Overall survival was poorer for carriers than for noncarriers (5-year rate, 80% v 91%, P = .002). Because a long time interval between cancer diagnosis and genetic counseling artificially increases survival time due to unrecorded deaths, the analysis was limited to the 110 patients whose diagnosis-to-counseling interval was less than 36 months (19 BRCA1 patients and 91 non-BRCA1 patients). The differences between the BRCA1 and non-BRCA1 groups regarding overall survival and metastasis-free interval were dramatically increased (49% v 85% and 18% v 84%, respectively). Multivariate analysis showed that BRCA1 mutation was an independent prognostic factor. CONCLUSION: Our results strongly support that among patients with familial breast cancer, those who have a BRCA1 mutation have a worse outcome than those who do not.
Quantitative Tumor Cell Content of Bone Marrow and Blood as a Predictor of Outcome in Stage IV Neuroblastoma: A Children’s Cancer Group Study
Authors: Seeger Robert C. , Reynolds C. Patrick , Gallego Richard , Stram Daniel O. , Gerbing Robert B. , Matthay Katherine K. 
Published: February 2017

PURPOSE: This study investigated the prognostic value of quantifying tumor cells in bone marrow and blood by immunocytology in children with high-risk, metastatic neuroblastoma. PATIENTS AND METHODS: Patients with stage IV neuroblastoma (N = 466) registered on Children’s Cancer Group study 3891 received five cycles of induction chemotherapy and were randomized either to myeloablative chemoradiotherapy with autologous purged bone marrow rescue or to nonmyeloablative chemotherapy. Subsequently, they were randomized to 13-cis-retinoic acid or no further treatment. Immunocytologic analyses of bone marrow and blood were performed at diagnosis, week 4, week 12, bone marrow collection, and end induction and were correlated with tumor biology, clinical variables, treatment regimen, and event-free survival (EFS). RESULTS: Immunocytology identified neuroblastoma cells in bone marrow of 81% at diagnosis, 55% at 4 weeks, 27% at 12 weeks, 19% at bone marrow collection, and 14% at end induction. Tumor cells were detected in blood of 58% at diagnosis and 5% at collection. There was an adverse effect on EFS of increasing tumor cell concentration in bone marrow at diagnosis (P = .04), at 12 weeks (P = .006), at bone marrow collection (P < .001), and at end induction (P = .07). Positive blood immunocytology at diagnosis was associated with decreased EFS (P = .003). The prognostic impact of immunocytology was independent of morphologically detected bone marrow disease, MYCN status, and serum ferritin level in bivariate Cox analyses. CONCLUSION: Immunocytologic quantification of neuroblastoma cells in bone marrow and blood at diagnosis and in bone marrow during induction chemotherapy provides prognostic information that can identify patients with very high-risk disease who should be considered for experimental therapy that might improve outcome.
Phase I Dose-Finding Study of a New Taxane, RPR 109881A, Administered as a One-Hour Intravenous Infusion Days 1 and 8 to Patients With Advanced Solid Tumors
Authors: Gelmon Karen A. , Latreille Jean , Tolcher Anthony , Génier Luc , Fisher Bryn , Forand Dominique , D’Aloisio Susan , Vernillet Laurent , Daigneault Luc , Lebecq Ann , Besenval Michele , Eisenhauer Elizabeth 
Published: February 2017

PURPOSE: To define the maximum-tolerated dose, recommended phase II dose (RD), dose-limiting toxicity (DLT), and pharmacokinetics of a novel taxane, RPR 109881A, administered on days 1 and 8 of a 21-day cycle. PATIENTS AND METHODS: Twenty-nine patients were enrolled and treated according to a modified continual reassessment method from a starting dose of 7.5 mg/m2 to 52.5 mg/m2. Detailed pharmacokinetic analyses of blood and urine were performed on days 1 and 8 of the first cycle. Toxicity was monitored weekly. RESULTS: DLT consisting of grade 3 or 4 diarrhea was seen in three of six patients at 52.5 mg/m2. Grade 3 or 4 granulocytopenia was also seen in five of six patients treated at this dose (four of six in the first cycle). At the next lower dose level, 45 mg/m2 toxicity was moderate, with only one of 12 patients experiencing severe diarrhea and grade 4 granulocytopenia with associated infection. Drug concentrations were consistent with a three-compartment open model. The total-body clearance suggests a linear dose-concentration relationship. RPR 109881A has a high clearance (mean, 42.6 L/h/m2), a large volume of distribution (mean, 952 L/m2), and a long terminal half-life (mean, 24 hours). There was no drug accumulation between days 1 and 8. One partial response was seen in a patient with renal cell carcinoma. CONCLUSION: The RD of RPR 109881A given as a 1-hour infusion on days 1 and 8 of a 21-day cycle is 45 mg/m2. At this dose the drug is well tolerated and should be further studied.
Randomized Trial of Omeprazole or Ranitidine Versus Placebo in the Prevention of Chemotherapy-Induced Gastroduodenal Injury
Authors: Sartori Sergio , Trevisani Lucio , Nielsen Ingrid , Tassinari Davide , Panzini Ilaria , Abbasciano Vincenzo 
Published: February 2017

PURPOSE: Anticancer drugs may induce acute mucosal injury to stomach and duodenum. This study was planned to evaluate the efficacy of omeprazole or ranitidine in preventing such an injury. PATIENTS AND METHODS: Two hundred twenty-eight cancer patients with normal stomach and duodenum or with less than three erosions, who were selected to be treated with cyclophosphamide, methotrexate, and fluorouracil (90 breast carcinoma patients) or fluorouracil alone (138 colon carcinoma patients), were randomly assigned to treatment with omeprazole 20 mg, ranitidine 300 mg, or one placebo tablet a day. Seven days after the second course of chemotherapy (CT), the patients underwent a further esophagogastroduodenoscopy to evaluate the mucosal injury. Endoscopic findings were quantified on the basis of an arbitrary score, and the occurrence of epigastric pain or heartburn was assessed weekly. RESULTS: A significant difference was found among the three groups (P = .0032), as well as between pre- and postCT endoscopic findings (P = .00001). Endoscopic scores after CT were significantly higher than pretreatment scores in the placebo (P = .003) and ranitidine (P = .003) groups but not in the omeprazole group (P = .354). Acute ulcers were significantly less frequent in patients receiving omeprazole or ranitidine than in those receiving placebo (P = .0001 and P = .0315, respectively). Epigastric pain and/or heartburn were significantly less frequent in patients receiving omeprazole (P = .00124) or ranitidine (P = .038) than in those receiving placebo. CONCLUSION: Omeprazole is effective in preventing chemotherapy-induced gastroduodenal injury. Ranitidine is effective in reducing the frequency of ulcers and upper gastrointestinal symptoms but is not effective in preventing the global endoscopic worsening caused by chemotherapy. The different efficacy of omeprazole and ranitidine can be explained by their different pharmacodynamics.
High-Dose Therapy With Autologous Bone Marrow Support as Consolidation of Remission in Follicular Lymphoma: Long-Term Clinical and Molecular Follow-Up
Authors: Apostolidis John , Gupta Rajnish K. , Grenzelias Demetrios , Johnson Peter W. M. , Pappa Vassiliki I. , Summers Karin E. , Salam Ashiq , Adams Keith , Norton Andrew J. , Amess John A. L. , Matthews Janet , Bradburn Mike , Lister T. Andrew , Rohatiner Ama Z. S. 
Published: February 2017

PURPOSE: To evaluate the long-term results of high-dose therapy (HDT) in follicular lymphoma, with specific emphasis on the prognostic significance of polymerase chain reaction (PCR)–detectable Bcl-2/IgH rearrangements.PATIENTS AND METHODS: Between June 1985 and October 1995, 99 patients with follicular lymphoma received HDT as consolidation of second or subsequent remission. Bone marrow was treated in vitro with anti–B-cell antibodies and complement.RESULTS: Sixty-five patients remained alive, 49 treatment-failure free, with a median follow-up of 5.5 years (range, 1.5 to 12.5 years). Four “early” and 10 “late” deaths occurred from treatment-related causes; seven of the latter were due to secondary myelodysplasia (s-MDS) or secondary acute myeloblastic leukemia. Overall, 12 (12%) of the 99 patients developed s-MDS or acute myeloblastic leukemia. Kaplan-Meier estimates of freedom from recurrence (FFR) and survival rates at 5 years were 63% (95% confidence interval [CI], 52% to 72%) and 69% (95% CI, 58% to 78%), respectively. For all 99 patients, in multivariate analysis, absence of the Bcl-2/IgH rearrangement at the time of diagnosis (hazards ratio [HR], 0.39; P = .04) and three or fewer treatment episodes before HDT (HR, 0.03; P = .001) were significant prognostic factors for improved survival. For patients bearing Bcl-2/IgH rearrangements, in univariate and multivariate analyses, absence of a PCR-detectable Bcl-2/IgH rearrangement during follow-up was associated with a significantly lower risk of recurrence (adjusted HR, 0.13; P < .001) and death (HR, 0.25; P = .02), whereas the PCR status of the reinfused bone marrow did not correlate with outcome.CONCLUSION: Prolonged FFR can be achieved in patients with follicular lymphoma after HDT, but as yet there is no survival advantage compared with conventional treatment. These results confirm that elimination of cells bearing the Bcl-2/IgH rearrangement is highly desirable and should be attempted. The incidence of s-MDS is of increasing concern in this setting.