bluuebunny/crossref_metadata_2025_split huggingface dataset:
Response of children with high-risk acute lymphoblastic leukemia treated with and without cranial irradiation: a report from the Children's Cancer Group.
Authors: Nachman J , Sather H N , Cherlow J M , Sensel M G , Gaynon P S , Lukens J N , Wolff L , Trigg M E 
Published: February 2017

PURPOSE Intensified intrathecal (i.t.) chemotherapy without cranial radiation therapy (CRT) prevents CNS relapse in children with low-risk and intermediate-risk acute lymphoblastic leukemia (ALL). In the current study, high-risk ALL patients who achieved a rapid early response (RER) to induction chemotherapy were randomized to receive intensive systemic chemotherapy and presymptomatic CNS therapy that consisted of either i.t. methotrexate (MTX) and CRT or intensified i.t. MTX alone. PATIENTS AND METHODS Children (n = 636) with high-risk ALL (aged 1 to 9 years and WBC count > or = 50,000/microL or age > or = 10 years, excluding those with lymphomatous features) who achieved an RER (< or = 25% marrow blasts on day 7) to induction therapy and lacked CNS disease at diagnosis were randomized to receive systemic therapy with either i.t. MTX and CRT (regimen A, n = 317) or intensified i.t. MTX alone (regimen B, n = 319). RESULTS Interim analysis in July 1993 revealed 3-year event-free survival (EFS) estimates of 82.1% +/- 4.0% (SD)and 70.4% +/- 4.2% for patients treated on regimens A and B, respectively (P = .004). As of January 1996, outcome had changed: 5-year EFS estimates were 69.1% +/- 3.4% and 75.0% +/- 2.7% for regimens A and B, respectively (P = 0.50). Marrow relapses comprised 57 events on regimen A and 43 events on regimen B. Fewer late events occurred on regimen B. CONCLUSION For high-risk pediatric ALL patients who show an RER to induction therapy and are treated with systemic Children's Cancer Group (CCG)-modified Berlin-Frankfurt-Munster (BFM) chemotherapy, presymptomatic CNS therapy that consists of either i.t. MTX plus CRT or intensified i.t. MTX alone results in a similar 5-year EFS outcome. Furthermore, intensified i.t. MTX may protect against late bone marrow relapse.
Phase I study of topotecan in combination with cyclophosphamide in pediatric patients with malignant solid tumors: a Pediatric Oncology Group Study.
Authors: Saylors R L , Stewart C F , Zamboni W C , Wall D A , Bell B , Stine K C , Vietti T J 
Published: February 2017

PURPOSE To determine the maximum-tolerated dose (MTD) and dose-limiting toxicity of topotecan when combined with cyclophosphamide in pediatric patients with recurrent or refractory malignant solid tumors. PATIENTS AND METHODS A total of 33 patients received cyclophosphamide (250 mg/m2/dose) followed by topotecan in escalating doses (0.6 to 0.75 mg/m2/dose), each given as a 30-minute infusion daily for 5 days. A total of 154 fully assessable treatment courses were given to these patients. RESULTS Neutropenia was the dose-limiting toxicity of the therapy at both topotecan dose levels. The addition of filgrastim allowed escalation of the topotecan dose to the 0.75-mg/m2 level with acceptable neutropenia. Other significant toxicities were anemia and thrombocytopenia. Nonhematopoietic toxicity of grades > or = 3 was not observed. Responses were reported in patients with Wilms' tumor (one complete response [CR], one partial response [PR]), neuroblastoma (one CR, one PR), rhabdomyosarcoma (one PR), and osteosarcoma (one PR). Pharmacokinetic studies indicate that cyclophosphamide administered on the schedule used in this study did not alter topotecan disposition on day 5. As with previous studies, a pharmacodynamic relation between systemic exposure and myelosuppression was noted. CONCLUSION The combination of topotecan and cyclophosphamide shows activity in a wide variety of pediatric solid tumors and can be given with acceptable hematopoietic toxicity with the use of filgrastim support. We recommend that pediatric phase II trials use cyclophosphamide 250 mg/m2 followed by topotecan 0.75 mg/m2 daily for 5 days with filgrastim for amelioration of neutropenia.
Randomized comparison of cisplatin and etoposide and either bleomycin or ifosfamide in treatment of advanced disseminated germ cell tumors: an Eastern Cooperative Oncology Group, Southwest Oncology Group, and Cancer and Leukemia Group B Study.
Authors: Nichols C R , Catalano P J , Crawford E D , Vogelzang N J , Einhorn L H , Loehrer P J 
Published: February 2017

PURPOSE To compare standard therapy with bleomycin, etoposide, and cisplatin (BEP) to experimental therapy with etoposide, ifosfamide, and cisplatin (VIP) as primary treatment of men with advanced, disseminated germ cell tumors. PATIENTS AND METHODS A total of 304 men with advanced disseminated germ cell tumors were randomly allocated to receive four courses of BEP or VIP. Two hundred ninety-nine patients were assessable for toxicity and 286 were assessable for response. Complete response rates, favorable response (complete remission, surgical free of disease, continuous partial remission for 2+ years), time to treatment failure, and overall survival were assessed. RESULTS Overall complete remission rate (VIP, 37%; BEP, 31%), favorable response rate (VIP, 63%; BEP, 60%), failure-free at 2 years (VIP, 64%; BEP, 60%), and 2-year overall survival (VIP, 74%; BEP, 71%) were not significantly different between the two treatments. Grade 3 or worse toxicity, particularly hematologic and genitourinary toxicity, was significantly more common in patients who received VIP. CONCLUSION BEP and VIP produce comparable favorable response rate and survival in patients with poor-risk germ cell tumors. The substitution of ifosfamide for bleomycin, however, was associated with significantly greater toxicity. Four courses of BEP remain the standard treatment for advanced disseminated germ cell tumors.
Correlation of p34cdc2 cyclin-dependent kinase overexpression, CD44s downregulation, and HER-2/neu oncogene amplification with recurrence in prostatic adenocarcinomas.
Authors: Kallakury B V , Sheehan C E , Ambros R A , Fisher H A , Kaufman R P , Muraca P J , Ross J S 
Published: February 2017

PURPOSE To test whether p34cdc2 overexpression, CD44s downregulation, and HER-2/neu amplification correlate with disease recurrence after radical prostatectomy, and to evaluate a possible biologic association between p34cdc2 and HER-2/neu expression. MATERIALS AND METHODS Immunohistochemical (IHC) detection of both p34cdc2 cyclin-dependent kinase (CDK) and CD44s expression and fluorescence in situ hybridization (FISH)-based analysis of HER-2/neu gene status were performed on formalin-fixed, paraffin-embedded sections of 106 prostatic adenocarcinomas (PACs). Findings were correlated with Gleason grade, pathologic stage, DNA ploidy, and postsurgical biochemical disease recurrence. RESULTS CDK overexpression correlated with tumor grade (P = .001), DNA ploidy (P = .001), pathologic stage (P = .04), and disease recurrence (P = .01). CD44s downregulation correlated with grade (P = .03), ploidy (P = .01), and recurrence (P = .02). HER-2/neu amplification correlated with grade (P = .001), ploidy (P = .001), and recurrence (P = .01). On multivariate analysis, CDK overexpression independently predicted recurrence (P = .001) after prostatectomy. CDK expression correlated with HER-2/neu status with 32 of 65 (49%) tumors that overexpressed CDK and showed concomitant HER-2/neu amplification (P = .04). CONCLUSION This study showed that p34cdc2, CD44s, and HER-2/neu are variably expressed or amplified in prostatic carcinoma and that such alteration may affect tumor behavior. In addition, CDK overexpression and HER-2/neu amplification may be biologically related.
Phase II trial of paclitaxel, ifosfamide, and cisplatin in patients with recurrent head and neck squamous cell carcinoma.
Authors: Shin D M , Glisson B S , Khuri F R , Ginsberg L , Papadimitrakopoulou V , Lee J J , Lawhorn K , Gillenwater A M , Ang K K , Clayman G L , Callender D L , Hong W K , Lippman S M 
Published: February 2017

PURPOSE To assess the activity and toxicity profile of combined taxol (paclitaxel), ifosfamide, and platinum (cisplatin) (TIP) in patients with recurrent or metastatic squamous cell carcinoma (SCC) of the head and neck. PATIENTS AND METHODS Recurrent or metastatic head and neck SCC patients received paclitaxel 175 mg/m2 in a 3-hour infusion on day 1; ifosfamide 1,000 mg/m2 in a 2-hour infusion on days 1 through 3; mesna 600 mg/m2 on days 1 through 3; and cisplatin 60 mg/m2 on day 1, repeated every 3 to 4 weeks. All were premedicated with dexamethasone, diphenhydramine, and cimetidine. Prophylactic hematopoietic growth factors were not permitted. RESULTS Fifty-two patients were assessable for response and toxicity; 53 for survival (local-regional recurrence alone in 57% and distant metastasis with or without local-regional recurrence in 43%). Overall response rate was 58% (30 of 52) of patients; complete response rate was 17% (nine of 52) of patients, with six complete responses that continued for a median 15.7+ months. Median follow-up of all patients was 17.7 months. Median survival was 8.8 months (95% confidence interval [CI] 8.1 to 17.5 months). Toxicity was relatively well tolerated and caused no deaths. The most frequent moderate-to-severe toxicity (90% of patients) was transient grades 3 to 4 neutropenia; neutropenic fever occurred in 27%. Grade 3 peripheral neuropathy occurred in three patients, none had grade 4. Grade 3 mucositis occurred in only one patient, none had grade 4. CONCLUSION TIP had major activity in this setting, with a 58% objective response rate, 17% complete response rate, durable complete responses (six of nine persisting), and relatively well-tolerated toxicity, with no toxic deaths. The activity of TIP, a novel taxol-cisplatin-based regimen, in recurrent or metastatic head and neck SCC should be confirmed in a phase III trial.
neu/erbB-2 amplification identifies a poor-prognosis group of women with node-negative breast cancer. Toronto Breast Cancer Study Group.
Authors: Andrulis I L , Bull S B , Blackstein M E , Sutherland D , Mak C , Sidlofsky S , Pritzker K P , Hartwick R W , Hanna W , Lickley L , Wilkinson R , Qizilbash A , Ambus U , Lipa M , Weizel H , Katz A , Baida M , Mariz S , Stoik G , Dacamara P , Strongitharm D , Geddie W , McCready D 
Published: February 2017

PURPOSE It remains a challenge to predict which women with axillary node-negative (ANN) breast cancer at greatest risk of relapse may benefit most from adjuvant therapy. Increases in neu/erbB-2 have been implicated in breast cancer prognosis. Although overexpression has been investigated extensively, this study represents the first prospective assessment of the prognostic value of neu/erbB-2 DNA amplification in a cohort of women with newly diagnosed ANN. METHODS A consecutive series of women was monitored for recurrence (median follow-up duration, 36 months) and tumors from 580 individuals were analyzed for amplification. The association of amplification with risk of recurrence was examined in survival analyses with traditional and histologic markers as prognostic factors. RESULTS Neu/erbB-2 was amplified in 20% of cases. We found an increased risk of disease recurrence when neu/erbB-2 was amplified > or = twofold that persisted with adjustment for other prognostic factors (relative risk, 2.36; P = .002). We found some evidence that amplification was more important in patients who received chemotherapy compared with untreated patients. CONCLUSION neu/erbB-2 amplification is an independent prognostic factor for risk of recurrence in ANN breast cancer. Women with tumors without neu/erbB-2 amplification have a good prognosis; aggressive therapy in this group is therefore difficult to justify. On the other hand, even with adjuvant chemotherapeutic treatment, women whose tumors exhibit neu/erbB-2 amplification have an increased risk of recurrence. We encourage a randomized trial to compare more aggressive adjuvant chemotherapy versus standard chemotherapy for ANN women whose tumors exhibit neu/erbB-2 amplification.
Randomized phase II trial of infusional fluorouracil, epirubicin, and cyclophosphamide versus infusional fluorouracil, epirubicin, and cisplatin in patients with advanced breast cancer.
Authors: Eisen T , Smith I E , Johnston S , Ellis P A , Prendiville J , Seymour M T , Walsh G , Ashley S 
Published: February 2017

PURPOSE We previously developed an inpatient regimen that consisted of infusional fluorouracil (5-FU), epirubicin, and cisplatin (ECisF), with a response rate of 86% in advanced breast cancer. The current phase II 2:1 randomized study investigated whether cyclophosphamide can be substituted for cisplatin (ECycloF) to reduce toxicity and allow the regimen to be administered on an outpatient basis without loss of efficacy. PATIENTS AND METHODS Ninety-six women (median age, 49 years; range, 28 to 73) with breast cancer (59 metastatic, 37 locally advanced) received continuous infusional 5-FU (200 mg/m2/d via Hickman line) and six cycles of epirubicin (60 mg/m2 every 21 days) with either cyclophosphamide 600 mg/m2 every 21 days (38 metastatic, 24 locally advanced) or cisplatin 60 mg/m2 every 21 days (21 metastatic, 13 locally advanced). There were no significant differences in patient characteristics between these groups. RESULTS ECycloF was better tolerated than ECisF in terms of lethargy (P = .005), stomatitis (P = .008), plantar palmar erythema (P = .02), constipation (P < .001), thrombosis (P = .0014), and nausea and vomiting (P = .05). Although there was a trend toward more anemia and leukopenia with ECisF (P =. 1), there was no significant difference in the rates of infection. Efficacy was comparable in terms of overall response (69% v 68%), complete response (CR; 13% v 15%), and median progression-free survival (9 v 8 months). CONCLUSION ECycloF is an outpatient regimen with a lower incidence of severe nonhematologic toxicity than inpatient ECisF; it has comparable efficacy and is considerably more economical.
Phase I clinical and pharmacologic study of eniluracil plus fluorouracil in patients with advanced cancer.
Authors: Schilsky R L , Hohneker J , Ratain M J , Janisch L , Smetzer L , Lucas V S , Khor S P , Diasio R , Von Hoff D D , Burris H A 
Published: February 2017

PURPOSE To determine the highest dose of fluorouracil (5-FU) that could be safely administered with Eniluracil (776C85; Glaxo Wellcome Inc, Research Triangle Park, NC), an inactivator of dihydropyrimidine dehydrogenase (DPD), on a daily schedule for 5 days, and to define the toxicities of the combination and the pharmacokinetics of 5-FU when administered with 776C85. PATIENTS AND METHODS Patients with advanced solid tumors refractory to standard therapy were enrolled at two institutions. The study consisted of three periods designed to evaluate the safety, pharmacokinetics, and pharmacodynamics of 776C85 alone (period 1); the effects of 776C85 on the pharmacokinetics of 5-FU (period 2); and the maximum-tolerated dose (MTD) of 5-FU, with or without leucovorin, that could be safely administered with 776C85 (period 3). Cohorts of at least three patients each received oral 776C85 alone at doses of 3.7 mg/m2/d, 18.5 mg/m2/d and 0.74 mg/m2/d. After a 14-day washout period, each patient then received 776C85 daily for 3 days, with a single intravenous (i.v.) bolus dose of 5-FU 10 mg/m2 on day 2. After a second washout period, patients were treated with 776C85 daily for 7 days and 5-FU i.v. bolus on days 2 through 6. The starting dose of 5-FU 10 mg/m2/d was escalated until the MTD was determined. After determination of the MTD of 5-FU given with 776C85, oral leucovorin 50 mg/d on days 2 through 6 was added to determine the MTD of 5-FU with leucovorin in the presence of 776C85. Near the completion of the study, additional cohorts of patients were treated with 776C85 at 50 mg/d and oral 5-FU with or without leucovorin. RESULTS Sixty-five patients were enrolled onto the study and 60 were assessable for toxicity and response. Bone marrow suppression was the primary and dose-limiting toxicity of this regimen. Other toxicities included diarrhea, mucositis, anemia, anorexia, nausea, vomiting, and fatigue. 776C85 suppressed DPD activity in peripheral-blood mononuclear cells (PBMCs) by at least 90% for at least 24 hours at all dose levels tested. In the presence of 776C85, 5-FU half-life was prolonged, clearance was reduced, and the drug displayed linear pharmacokinetics. Recommended doses for further testing on a daily for 5-day schedule are 776C85 10 mg/d with i.v. 5-FU 25 mg/m2/d; 776C85 10 mg/d with i.v. 5-FU 20 mg/m2/d plus leucovorin 50 mg/d; 776C85 50 mg/d with 5-FU given orally at 15 mg/m2/d with leucovorin at 50 mg/d. CONCLUSION 5-FU can be safely administered with 776C85; however, the MTDs are considerably lower than those conventionally used, caused, at least in part, by marked alterations in 5-FU plasma pharmacokinetics.
Higher levels of thymidylate synthase gene expression are observed in pulmonary as compared with hepatic metastases of colorectal adenocarcinoma.
Authors: Gorlick R , Metzger R , Danenberg K D , Salonga D , Miles J S , Longo G S , Fu J , Banerjee D , Klimstra D , Jhanwar S , Danenberg P V , Kemeny N , Bertino J R 
Published: February 2017

PURPOSE It has been observed previously that the pulmonary metastases of colorectal adenocarcinoma are less responsive to therapy with fluorouracil (FUra) as compared with other sites of metastasis (liver, local). To investigate the basis of this chemoresistance, the levels of thymidylate synthase (TS) mRNA and protein were measured, as TS expression has been shown to be predictive of response to therapy in colorectal cancer. MATERIALS AND METHODS Tumors were obtained from 19 patients with metastatic colorectal cancer (12 hepatic and seven pulmonary). TS expression was measured by quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) and TS protein levels were measured by Western blotting. The presence of TS amplification was assessed by Southern blotting. Levels of p53 protein were determined using immunohistochemistry. RESULTS TS mRNA expression was shown to be significantly higher in the pulmonary metastases (mean TS/beta-actin ratio, 19.7; n = 7) as compared with the hepatic metastases (mean TS/beta-actin ratio, 4.7; n = 11) of colorectal cancer. Lower TS expression was observed in patients with hepatic metastases who had received prior FUra versus patients who had not been treated. High levels of TS expression in some samples was associated with low-level (two to three gene copies) increases in TS gene copy numbers and this was observed more frequently in the pulmonary metastatic samples. The increased gene copy numbers occurred both in samples with wild-type p53 and those with mutant p53 tumor-suppressor gene as determined by immunohistochemistry. CONCLUSION High levels of TS enzyme may be the basis of the lack of response of pulmonary metastases to FUra treatment.
Second-line therapy with paclitaxel and carboplatin for recurrent disease following first-line therapy with paclitaxel and platinum in ovarian or peritoneal carcinoma.
Authors: Rose P G , Fusco N , Fluellen L , Rodriguez M 
Published: February 2017

PURPOSE The combination of paclitaxel and a platinum compound is the most active first-line regimen for advanced ovarian carcinoma. The current study was undertaken to evaluate this combination in the re-treatment of patients with ovarian or peritoneal carcinoma who had disease recurrence > or = 6 months following this combination. METHODS Twenty-five patients with recurrent ovarian or peritoneal carcinoma > or = 6 months after a complete clinical response with first-line paclitaxel and platinum chemotherapy were studied. Recurrent disease was documented by computed tomography (CT), elevated CA 125 level, or surgical findings. Second-line chemotherapy consisted of paclitaxel 135 mg/m2 as a 24 hour infusion and carboplatin at an area under the concentration-time curve (AUC) of 5 to 6 every 21 days. Response to therapy was classified as measurable or assessable. RESULTS The median time to recurrence after first-line therapy was 10 months (range, 6 to 30). Among 20 measurable and assessable patients, 14 (70%) demonstrated a complete clinical response and four (20%) a partial clinical response. The response rate with measurable disease was 91% and with assessable disease was 89%. The median progression-free interval for all patients was 9.0+ months (range, 2 to 15). The median progression-free interval for patients with measurable or assessable disease was 9.0+ months and for nonassessable disease was 7.0+ months. Fifteen patients (60%) have developed recurrence after secondary therapy at a median interval of 9.0 months (range, 2 to 15). Only two patients have died with a median survival after secondary therapy of 10.0+ months (range, 2.0 to 21.0+). CONCLUSION The use of this combination, in this sensitive population, has a high response rate and long progression-free interval. In a chemotherapy-sensitive population, the activity of alternative second-line agents must be interpreted with this perspective.
Demyelination and single-carbon transfer pathway metabolites during the treatment of acute lymphoblastic leukemia: CSF studies.
Authors: Surtees R , Clelland J , Hann I 
Published: February 2017

PURPOSE To investigate the hypothesis that methotrexate causes demyelination due to a deficiency in S-adenosylmethionine (SAM) during the treatment of acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS Twenty-four patients treated on the Medical Research Council United Kingdom ALL trial no. 11 (MRC UKALL XI) were studied. The trial randomized patients at the presymptomatic CNS treatment (PCNS) phase to receive (1) intrathecal methotrexate and cranial radiotherapy (CRTX); (2) high-dose intravenous methotrexate with folinic acid rescue and continuing intrathecal methotrexate (HDMTX); and (3) continuing intrathecal methotrexate alone (ITMTX). Serial CSF samples were collected throughout treatment and concentrations of 5-methyltetrahydrofolate (MTF), methionine (MET), SAM, and myelin basic protein (MBP) were measured. The results were grouped into treatment milestones and compared with an age-matched reference population. RESULTS There was a highly significant effect of both treatment milestones and trial arm on the metabolite and MBP concentrations. CSF MTF reached a nadir during the induction phase of treatment, while SAM and MET reached their nadir during the consolidation phase. CSF MBP mirrored SAM concentration and there was a significant inverse relationship between the two. MTF, SAM, and MBP returned to normal values by the end of treatment, while MET was increased significantly. The effect of treatment was decremental across the ITMTX, HDMTX, and CRTX groups. CONCLUSION Treatment of ALL causes marked abnormalities in the single-carbon transfer pathway and subclinical demyelination. Methotrexate is one cause of this. Whether these abnormalities contribute to the late cognitive deficits requires further study.