bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical Significance of Apoptosis-Related Factors p53, Mdm2, and Bcl-2 in Advanced Ovarian Cancer
Authors: Baekelandt M. , Kristensen G. B. , Nesland J. M. , Tropé C. G. , Holm R. 
Published: February 2017

PURPOSE: To investigate the prognostic and predictive relevance of p53, Mdm2, and Bcl-2 protein expression in advanced ovarian cancer. PATIENTS AND METHODS: Tumor biopsy specimens from 185 consecutive and homogeneously treated patients with stage III ovarian cancer were examined immunohistochemically for expression of p53, Mdm2, and Bcl-2 proteins. Both uni- and multivariate analyses of prognostic factors were performed, and correlations with classical clinicopathologic parameters and response to chemotherapy were examined. RESULTS: Forty-nine percent and 39% of cases were considered positive for expression of p53 and Bcl-2, respectively. p53 expression was correlated with loss of histologic differentiation and Bcl-2 expression with smaller residual disease after primary surgery. The absence of p53 expression and the presence of Bcl-2 expression were associated with improved survival but not with overall response to chemotherapy, although a positive correlation was found between Bcl-2 expression and the possibility of obtaining a completely negative second-look laparotomy. Expression of Mdm2 was found in 17% of cases. Although correlations were found with known favorable clinicopathologic factors, no prognostic significance was demonstrated for Mdm2 in this patient group. In multivariate analyses, histologic type, degree of differentiation, residual disease, and p53 alone or combined with Bcl-2 expression were found to be independently associated with overall survival. CONCLUSION: p53, and especially the combination of p53 and Bcl-2 expression data, represents an independent prognostic predictor in stage III ovarian cancer. Despite their role in the apoptotic process, p53 and Bcl-2 do not seem to be clinically useful predictors of response to combination chemotherapy in these patients.
Conservative Treatment for Girls With Nonmetastatic Rhabdomyosarcoma of the Genital Tract: A Report From the Study Committee of the International Society of Pediatric Oncology
Authors: Martelli Hélène , Oberlin Odile , Rey Annie , Godzinski Jan , Spicer Richard D. , Bouvet Nathalie , Haie-Meder Christine , Terrier-Lacombe Marie-Josée , Sanchez de Toledo José , Spooner David , Sommelet Danielle , Flamant Françoise , Stevens Michaël C.G. 
Published: February 2017

PURPOSE: To report the results of a conservative multimodal approach in girls with nonmetastatic rhabdomyosarcoma (RMS) of the genital tract, treated in International Society of Pediatric Oncology (SIOP) Malignant Mesenchymal Tumors 84 and 89 protocols. PATIENTS AND METHODS: From 1984 to 1994, 38 girls with RMS of the genital tract (vulva, vagina, uterus) were treated in SIOP protocols. With the exception of patients with rare small tumors, which were resected at the start of the studies, all patients received initial chemotherapy (CHT) (ifosfamide, vincristine, and actinomycin D). Local treatment including surgery, brachytherapy (BT), and external-beam radiotherapy (ERT) was given only to girls who did not achieve complete remission (CR) with CHT or who subsequently relapsed. RESULTS: The primary tumor originated in the vulva or vagina in 27 girls and in the uterus in 11. The overall survival rate (± SE) was 91% ± 6% at 5 years, and the event-free survival rate was 78% ± 7%. At a median follow-up of 5 years, 30 girls were alive and in first CR and five were alive and in second CR. Four patients treated with complete resection of the tumor at diagnosis received less CHT. Thirteen patients were treated with CHT alone. In 17 patients, local treatment was necessary to achieve complete local control, for a residual mass after initial CHT (10 patients), for viable tumor on biopsy (three patients), or for local relapse (four patients). The local treatment used was radiotherapy (RT) (ERT in three patients, BT in seven), radical surgery with uterine ablation (three patients), RT and radical surgery (three patients), and conservative surgery with RT (one patient). CONCLUSION: Girls with nonmetastatic RMS of the genital tract have an excellent prognosis. We found no difference in outcome between uterine and vulvovaginal RMS. Local treatment does not seem necessary in patients who have a complete response to CHT. When a local treatment is needed, BT may be an alternative to radical surgery or ERT.
Gemcitabine and Paclitaxel: Pharmacokinetic and Pharmacodynamic Interactions in Patients With Non–Small-Cell Lung Cancer
Authors: Kroep Judith R. , Giaccone Giuseppe , Voorn Daphne A. , Smit Egbert F. , Beijnen Jos H. , Rosing Hilde , van Moorsel Catharina J.A. , van Groeningen Cornelis J. , Postmus Pieter E. , Pinedo Herbert M. , Peters Godefridus J. 
Published: February 2017

PURPOSE: To assess possible pharmacokinetic and pharmacodynamic interactions between gemcitabine and paclitaxel in a phase I/II study in non–small-cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: Eighteen patients with advanced NSCLC received the following in a 3-week schedule: gemcitabine 1,000 mg/m2 (30 minutes, days 1 and 8) and paclitaxel 150 (n = 9) or 200 mg/m2 (n = 9) before gemcitabine (3 hours, day 1). Plasma pharmacokinetics and pharmacodynamics in mononuclear cells were studied. RESULTS: Gemcitabine did not influence paclitaxel pharmacokinetics at 150 and 200 mg/m2 (area under the concentration-time curve [AUC], 7.7 and 8.8 μmol/ L · h, respectively; maximum plasma concentration [Cmax], 3.2 and 4.0 μmol/L, respectively), and paclitaxel did not influence that of gemcitabine (Cmax, 30 ± 3 μmol/L) and 2′,2′-difluorodeoxyuridine. Paclitaxel, however, dose-dependently increased the Cmax of gemcitabine triphosphate (dFdCTP), the active metabolite of gemcitabine, from 55 ± 10 to 106 ± 16 pmol/106 cells. No significant difference in the AUC of dFdCTP was observed. Moreover, the gemcitabine-paclitaxel combination significantly increased ribonucleotide levels, most pronounced for adenosine triphosphate (six- to seven-fold). Postinfusion paclitaxel AUC was related to pretreatment hepatic function (bilirubin: r = 0.79; P < .001) and to the percentage decrease in platelets (r = 0.61; P = .009). The latter was also related to the duration of paclitaxel concentration above 0.1 μmol/L (r = 0.62; P = .007). Gemcitabine Cmax was related to the percentage decrease in platelets (r = 0.58; P = .01), pretreatment hepatic function (bilirubin: r = 0.77; P < .001), and to plasma creatinine (r = 0.5; P = .03). The pharmacokinetics and pharmacodynamics were not related to response or survival. CONCLUSION: Gemcitabine and paclitaxel pharmacokinetics were related to the percentage decrease in platelets. Paclitaxel did not affect the pharmacokinetics of gemcitabine, nor did gemcitabine affect the pharmacokinetics of paclitaxel, but paclitaxel increased dFdCTP accumulation. This might enhance the antitumor activity of gemcitabine.
Randomized 2 × 2 Trial Evaluating Hormonal Treatment and the Duration of Chemotherapy in Node-Positive Breast Cancer Patients: An Update Based on 10 Years’ Follow-Up
Authors: Sauerbrei W. , Bastert G. , Bojar H. , Beyerle C. , Neumann R. L. A. , Schmoor C. , Schumacher M. ,   for the German Breast Cancer Study Group
Published: February 2017

PURPOSE: In 1984, the German Breast Cancer Study Group started a multicenter randomized trial to compare six versus three cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF) starting perioperatively and to investigate the additional effect of tamoxifen as adjuvant treatment in node-positive breast cancer patients treated with mastectomy. PATIENTS AND METHODS: From 1984 to 1989, 473 patients were randomized from 41 institutions. After a median follow-up of approximately 10 years for overall survival (OS) and 9 years for event-free survival (EFS), the treatment groups were compared with respect to OS and EFS. Results based on a median follow-up of 56 months have been published earlier. RESULTS: Estimated cumulative locoregional incidence rate after 10 years was 19.9%; the corresponding rate of distant recurrences was 41.3%. Concerning duration of chemotherapy, we did not find any difference between six and three cycles of CMF (EFS: relative risk [RR] in multivariate analysis = 0.95; 95% confidence interval [CI], 0.74 to 1.21 OS: RR = 0.90; 95% CI, = 0.69 to 1.18). Treatment with tamoxifen resulted in an improvement in outcome (EFS: RR = 0.81; 95% CI, 0.61 to 1.07, OS: RR = 0.74; 95% CI, 0.55 to 1.0) although it proved not significant. Number of positive lymph nodes and progesterone receptor were the dominant prognostic factors. CONCLUSION: In this study, we observed some tendency in favor of hormonal treatment, which is in agreement with the literature. Concerning duration of chemotherapy, the results of this study provide further evidence that a reduction to three cycles of CMF is possible without increasing the risk of recurrence or death. For a definitive conclusion, however, further investigations are required.
Treatment of Leptomeningeal Metastases Evaluated by Interphase Cytogenetics
Authors: van Oostenbrugge R.J. , Hopman A.H. N. , Arends J.W. , Ramaekers F.C. S. , Twijnstra A. 
Published: February 2017

PURPOSE: Although cytologic examination of CSF is the primary method for the evaluation of response to therapy for leptomeningeal metastases (LMMs), the procedure’s sensitivity decreases throughout the course of protracted therapy. We studied whether this response could be monitored more accurately through the detection of numerical chromosomal aberrations by interphase cytogenetics, using fluorescence in situ hybridization (FISH). PATIENTS AND METHODS: Seven patients treated for LMMs and with a known numerical aberration for chromosome 1 in their pretreatment CSF were included in this study. Up to 16 consecutive CSF samples were analyzed by means of the fluorescence in situ hybridization (FISH) technique for cells with aberrant chromosome 1 content. The results of routine cytology and FISH analyses were compared and were correlated with each patient’s neurologic status. RESULTS: Routine cytology detected malignancies in only 24 of the 76 samples, all of which were classified as chromosomally abnormal by FISH (except for two samples that could not be evaluated). Moreover, FISH demonstrated aneusomic cells in 32 additional samples, which could therefore be classified as malignant. The FISH results correlated better with patient neurologic status in that more malignant cells were detected in the CSF of neurologically deteriorating patients. CONCLUSION: Using FISH in addition to performing routine cytologic examination of CSF led to a more accurate evaluation of response to treatment in patients treated for LMMs.
Phase I-II Study of Paclitaxel, Cisplatin, and Gemcitabine in Advanced Transitional-Cell Carcinoma of the Urothelium
Authors: Bellmunt J. , Guillem V. , Paz-Ares L. , González-Larriba J.L. , Carles J. , Batiste-Alentorn E. , Sáenz A. , López-Brea M. , Font A. , Nogué M. , Bastús R. , Climent M.A. , de la Cruz J.J. , Albanell J. , Banús J.M. , Gallardo E. , Diaz-Rubio E. , Cortés-Funes H. , Baselga J. ,   for the Spanish Oncology Genitourinary Group
Published: February 2017

PURPOSE: To determine the maximum-tolerated dose and the antitumor activity of a combination of paclitaxel, cisplatin, and gemcitabine in advanced transitional-cell carcinoma (TCC) of the urothelium. PATIENTS AND METHODS: Patients with measurable, previously untreated, locally advanced or metastatic TCC and with Eastern Cooperative Oncology Group performance status ≤ 2 and creatinine clearance ≥ 55 mL/min were eligible. Cisplatin was given on day 1 at a fixed dose of 70 mg/m2. Paclitaxel and gemcitabine were given on days 1 and 8 at increasing dose levels. Cycles were repeated every 21 days to a maximum of six cycles. RESULTS: Sixty-one patients were registered. In phase I, 15 patients were entered at four different dose levels. Dose-limiting toxicity consisted of early onset (after the first cycle) grade 2 asthenia (two of six patients) and grade 3 asthenia (one of six patients) at dose level 4. A paclitaxel dose of 80 mg/m2 and gemcitabine 1,000 mg/m2 was recommended for phase II, and 46 additional patients were entered at this level for a total of 49 patients. Main nonhematologic toxicity was grade 2 asthenia in 18 patients, with early onset in five patients, and grade 3 in four patients. Grade 3/4 neutropenia and thrombocytopenia occurred in 27 (55%) and 11 (22%) patients, respectively. Overall, febrile neutropenia was seen in 11 patients, and one toxic death occurred because of neutropenic sepsis. The combination was active at all dose levels. In total, 58 of 61 eligible patients were assessable for response; 16 complete responses (27.6%) and 29 partial responses (50%) were observed for an overall response rate of 77.6% (95% confidence interval, 60% to 98%). The median survival time (MST) available for the phase I part of the study is 24.0 months. MST has not been reached for the whole group with the current follow-up. CONCLUSION: This combination of paclitaxel, cisplatin, and gemcitabine is feasible and highly active in patients with advanced TCC of the urothelium. Further evaluation of this regimen in patients with TCC is warranted.
Improving Survival Without Reducing Quality of Life in Small-Cell Lung Cancer Patients by Increasing the Dose-Intensity of Chemotherapy With Granulocyte Colony-Stimulating Factor Support: Results of a British Medical Research Council Multicenter Randomized Trial
Authors: Thatcher Nicholas , Girling David J. , Hopwood Penelope , Sambrook Robert J. , Qian Wendi , Stephens Richard J. ,   for the Medical Research Council Lung Cancer Working Party
Published: February 2017

PURPOSE: The treatment of small-cell lung cancer patients with good performance status aims to improve survival. Dose-intensification could be a way to achieve improved survival but can be limited by neutropenia and thrombocytopenia. Preliminary, nonrandomized feasibility studies showed that doxorubicin, cyclophosphamide, and etoposide (ACE) could be given every 2 (instead of the usual 3) weeks with granulocyte colony-stimulating factor (G-CSF) (lenograstim; Chugai-Rhône-Poulenc, Tokyo, Japan) support. The present multicenter randomized trial was designed to examine whether such dose-intensification improves survival while maintaining acceptable toxicity levels. PATIENTS AND METHODS: All patients were randomized to receive six cycles of ACE either every 3 weeks (control [C] group) or every 2 weeks with G-CSF (G group). The standard dose-intensity of ACE was increased by 50% in group G. RESULTS: Four hundred and three patients (G group: n = 201; C group: n = 202) were randomized. The received dose-intensity was 34% higher in the G group than in the C group. Complete response rates were 40% for the G group and 28% for the C group (P = .02), and overall rates were 78% for the G group and 79% for the C group. Survival was longer in the G group (hazard ratio = 0.80; 95% confidence interval, 0.65 to 0.99; P = .04), survival rates for the G and C groups being 47% and 39% at 12 months and 13% and 8% at 24 months, respectively. Metastasis-free survival, nonhematologic toxicity, and quality of life were similar in the two groups. In the G group, there was less neutropenia but more thrombocytopenia and more frequent blood and platelet transfusions. CONCLUSION: Increasing the dose-intensity of ACE with G-CSF support improved survival while maintaining acceptable toxicity.
Treatment of Patients With Metastatic Renal Carcinoma With a Combination of Subcutaneous Interleukin-2 and Interferon Alfa With or Without Fluorouracil
Authors: Négrier Sylvie , Caty Armelle , Lesimple Thierry , Douillard Jean-Yves , Escudier Bernard , Rossi Jean-François , Viens Patrice , Gomez Frédéric ,   for the Groupe Français d’Immunothérapie, Fédération Nationale des Centres de Lutte Contre le Cancer
Published: February 2017

PURPOSE: Subcutaneous recombinant interleukin-2 (rIL-2) and recombinant interferon alfa-2a (rIFNα-2a) have been used extensively in the treatment of metastatic renal cancer. Most results, coming from noncontrolled phase II trials, showed inconsistent rates of response. More recently, the addition of fluorouracil (FU) was proposed to improve the efficacy of these regimens. PATIENTS AND METHODS: The role of a subcutaneous combination of rIL-2 and rIFNα-2a with or without FU was investigated. Patients were randomly assigned to receive a combination of rIL-2 and rIFNα-2a at weeks 1, 3, 5, and 7 or the same combination together with a continuous infusion of FU at weeks 1 and 5. The major end points of this multicenter, randomized trial were progression-free survival, response rate, and toxicity. Overall survival was a secondary end point. Tumor responses were reviewed by an independent committee. Analysis of the results was performed on an intention-to-treat basis. RESULTS: One hundred thirty-one patients were enrolled. There was no difference in toxicity between the arms, and no toxic death was observed. One partial response was observed in arm A and five in arm B. Progression-free survival did not differ between the arms, and rates at 1 year were 12% and 15% in arms A and B, respectively. No statistically significant differences were detected in any end point. CONCLUSION: The subcutaneous combination of rIL-2 and rIFNα-2a with or without FU does not benefit patients with metastatic renal carcinoma. Neither of these regimens can be recommended as standard treatment. The results of the subcutaneous cytokine regimen seem disappointing.
What Threshold for Adjuvant Therapy in Older Breast Cancer Patients?
Authors: Extermann Martine , Balducci Lodovico , Lyman Gary H. 
Published: February 2017

PURPOSE: To consider the question of when to prescribe adjuvant treatment for elderly breast cancer patients, particularly when comorbidities are present. Knowledge of the threshold relapse risks above which adjuvant treatment is worth prescribing would enhance decision making. PATIENTS AND METHODS: A Markov analysis of data from the medical literature was conducted. Patients aged 65 to 85 years were considered, along with three levels of comorbidity. The threshold risk of relapse at 10 years (RR10), at which time treatment provides absolute reduction or reduction of an absolute 1% in relapse or mortality, was evaluated. RESULTS: The threshold RR10 for an absolute reduction in mortality risk by adjuvant treatment was low through the age of 85 years. However, for an absolute 1% reduction, the effect of treatment on relapse and the effect of treatment on mortality increasingly diverged. The threshold RR10 for an absolute 1% reduction in relapse risk remained fairly low (5% to 6% for tamoxifen, 12% to 19% for chemotherapy). The threshold RR10 for an absolute 1% reduction in mortality risk, although starting close to the RR10 for an absolute 1% reduction in relapse risk, rose sharply. For tamoxifen, the difference between the two was 4% for an average 65-year-old, 6% at the age of 75 years, and 15% at the age of 85 years. For chemotherapy, the differences were 6%, 12%, and 30%, respectively. Similarly, thresholds increased with increasing comorbidity. In older and sicker patients, the maximum benefit was reached after 5 years rather than 10 years. CONCLUSION: Older breast cancer patients can expect a reduction in relapse that is fairly similar to that of younger patients. However, the effect on mortality diverges markedly, and attention should be paid to this difference in clinical decision making. Comorbidity should be considered in recommendations for adjuvant treatment, including clinical practice guidelines.
Bone Marrow Features Improve Prognostic Efficiency in Multivariate Risk Classification of Chronic-Phase Ph1+ Chronic Myelogenous Leukemia: A Multicenter Trial
Authors: Kvasnicka Hans Michael , Thiele Juergen , Schmitt-Graeff Annette , Diehl Volker , Zankovich Rudolf , Niederle Norbert , Leder Lutz-Dietrich , Schaefer Hans Eckart 
Published: February 2017

PURPOSE: Multivariate risk classifications for chronic (stable)-phase Ph1+ chronic myelogenous leukemia (CML) are generally focused on hematologic variables, and the putative prognostic property of bone morphology has been neglected or even contested so far. PATIENTS AND METHODS: A total of 510 consecutively recruited patients in first chronic phase Ph1+ CML and pretreatment bone marrow biopsy specimens were entered onto this multicenter observational trial to evaluate the effect of bone marrow histopathology. According to generally accepted criteria, patients with any signs of accelerated disease were excluded. Treatment modalities included administration of interferon alfa-2b (IFN) and chemotherapy with hydroxyurea (HU) or busulfan. Immunohistochemical and morphometric techniques were applied to identify marrow cells and to quantify fiber density. Patients were separated into learning and validation samples, and classification and regression tree (CART) analysis was performed to establish a prognostic decision tree. RESULTS: CART analysis of the validation sample (123 patients with HU therapy) revealed the amount of erythroid precursors in the bone marrow, myelofibrosis, and splenomegaly as the most important prognostic features. Three risk profiles with significantly different survival patterns were established, with median survival times ranging from 33 to 108 months (two-sided log-rank test, P = .0001). The new score was confirmed by application to the learning sample with IFN therapy (two-sided log-rank test, P = .0002). Furthermore, risk status defined by the new score was significantly correlated with the occurrence of blast transformation. CONCLUSION: Our data strongly implicate that prognostic classification of chronic-phase Ph1+ CML can be significantly improved by the inclusion of morphologic parameters. The variables of the presented scoring system may be easily assessed by routinely processed aspirates and bone marrow trephines.