bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparative Effects of Three Cytokine Regimens After High-Dose Cyclophosphamide: Granulocyte Colony-Stimulating Factor, Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF), and Sequential Interleukin-3 and GM-CSF
Authors: Ballestrero Alberto , Ferrando Fabio , Garuti Anna , Basta Palma , Gonella Roberta , Stura Paola , Mela Giuseppe Sandro , Sessarego Mario , Gobbi Marco , Patrone Franco 
Published: February 2017

PURPOSE: To compare the toxicity and effects on hematologic recovery and circulating progenitor cell mobilization of three cytokine regimens administered after high-dose cyclophosphamide (HD-CTX; 6 g/m2), given as the first step of a high-dose sequential chemotherapy. PATIENTS AND METHODS: Forty-eight patients with breast cancer or non-Hodgkin's lymphoma were randomized to receive granulocyte colony-stimulating factor (G-CSF) alone (arm 1), granulocyte-macrophage colony-stimulating factor (GM-CSF) alone (arm 2), or sequential interleukin-3 (IL-3) and GM-CSF (arm 3). Cytokines were administered as a single daily subcutaneous injection at a dose of 5 to 6 μg/kg/d. Progenitor cells were evaluated in peripheral blood as well as in apheretic product as both CD34+ cells and granulocyte-macrophage colony-forming units (CFU-GM). RESULTS: Neutrophil recovery was faster in arm 1 as compared with arms 2 and 3 (P < .0001); no significant differences were observed between arms 2 and 3. In arm 3, a moderate acceleration of platelet recovery was observed, but it was statistically significant only as compared with arm 1 (P = .028). The peak of CD34+ cells was hastened in a median of 2 days in arm 1 compared with arms 2 and 3 (P = .0002), whereas the median peak value of CD34+ cells and CFU-GM was similar in the three patient groups. Administration of IL-3 and GM-CSF resulted in more significant toxicity requiring pharmacologic treatment in 90% of patients. CONCLUSION: The three cytokine regimens administered after HD-CTX are comparably effective in reducing hematologic toxicity and mobilizing the hematopoietic progenitor cells. G-CSF accelerates leukocyte recovery and progenitor mobilization. Although G-CSF–treated patients have somewhat slower platelet recovery, they definitely have fewer side effects.
Analysis of the p53/BAX Pathway in Colorectal Cancer: Low BAX Is a Negative Prognostic Factor in Patients With Resected Liver Metastases
Authors: Sturm Isrid , Köhne Claus-Henning , Wolff Gerhard , Petrowsky Henrik , Hillebrand Timo , Hauptmann Steffen , Lorenz Matthias , Dörken Bernd , Daniel Peter T. 
Published: February 2017

PURPOSE: To determine the prognostic value of the central downstream apoptosis effector BAX in relation to its upstream regulator p53 in R0-resected hepatic metastases of colorectal cancer. PATIENTS AND METHODS: Retrospective analysis of 41 patients who underwent potentially curative resection of liver metastases from colorectal cancer was performed. Tumor DNA was screened for p53 mutations by single-stranded conformational polymorphism polymerase chain reaction and for BAX frameshift mutations by fragment length analysis. Protein expression of BAX, p21, and p53 was investigated by immunohistochemistry. RESULTS: Overall median survival was 40.2 months. Tumors with BAX frameshift mutations were considered microsatellite mutator phenotype–positive and were excluded from further prognostic analyses. Patients with high BAX protein expression had a median survival of 53.6 months compared with 35.4 months for patients with low BAX expression (P < .05). The negative prognostic value of low BAX expression was more evident in those patients with wild-type p53 (median survival, 54.0 v 23.3 months for BAX-negative tumors; P < .01). Low BAX expression was an independent negative prognostic marker in multivariate regression analysis for all patients independent of the p53 status (relative risk, 3.03, P = .03), especially for p53 wild-type tumors (relative risk, 8.21; P = .0095). CONCLUSION: We conclude that low BAX expression is an independent negative prognostic marker in patients with hepatic metastases of colorectal cancer. The best survival was seen in patients with an intact p53-to-BAX pathway; ie, wild-type p53- and BAX-positive tumors. Thus, analysis of apoptosis signaling pathways (here, p53 in concert with its downstream death effector, BAX) might yield more prognostic power in future studies as compared with analysis of single genes such as p53 alone.
Infusional Paclitaxel and Weekly Vinorelbine Chemotherapy With Concurrent Filgrastim for Metastatic Breast Cancer: High Complete Response Rate in a Phase I-II Study of Doxorubicin-Treated Patients
Authors: Ellis Georgiana K. , Gralow Julie R. , Pierce H. Irving , Williams Margaret A. , Livingston R. B. 
Published: February 2017

PURPOSE: We investigated 96-hour paclitaxel infusion combined with weekly (days eight and 15) vinorelbine as salvage therapy for metastatic breast cancer in anthracycline-exposed patients. All patients received scheduled support with granulocyte colony-stimulating factor (G-CSF; filgrastim). Tumor response, toxicity, time to progression (TTP), and survival were assessed. PATIENTS AND METHODS: This single-center nonrandomized trial enrolled 32 patients. Anthracycline exposure and subsequent progression were common to all patients. Paclitaxel and vinorelbine were escalated over three dosing levels, stratified by liver function. RESULTS: Seven patients (22%) achieved a complete response and nine patients achieved a partial response for an overall response rate of 50%. The median TTP was 6.1 months, and median survival time was 14.1 months. Dose-limiting toxicity was neutropenia, with dose delay or reduction in seven of 32 patients. Febrile neutropenia requiring hospitalization was uncommon (three of 32 patients; 9%). There were no treatment-related deaths. Grade 3/4 thrombocytopenia occurred in two patients (6%), and 13 patients (41%) required RBC transfusions for anemia. Grade 3 nausea and vomiting was seen in one patient, who was found to be Addisonian. Despite potentially overlapping neurologic toxicities of the two agents, only two patients (6%) were removed from the study because of progressive peripheral neuropathy. CONCLUSION: Administration of 96-hour paclitaxel infusion and subsequent weekly vinorelbine with G-CSF support is well tolerated. The response rate, TTP, and survival data are encouraging for therapy given to anthracycline pretreated patients with metastatic breast cancer. If these results can be verified in multi-institution trials, this or a similar combination of drugs would merit investigation as first-line therapy in this patient population.
Postoperative Nomogram for Disease Recurrence After Radical Prostatectomy for Prostate Cancer
Authors: Kattan Michael W. , Wheeler Thomas M. , Scardino Peter T. 
Published: February 2017

PURPOSE: Although models exist that place patients into discrete groups at various risks for disease recurrence after surgery for prostate cancer, we know of no published work that combines pathologic factors to predict an individual's probability of disease recurrence. Because clinical stage and biopsy Gleason grade only approximate pathologic stage and Gleason grade in the prostatectomy specimen, prediction of prognosis should be more accurate when postoperative information is added to preoperative variables. Therefore, we developed a postoperative nomogram that allows more accurate prediction of probability for disease recurrence for patients who have received radical prostatectomy as treatment for prostate cancer, compared with the preoperative nomogram we previously published. PATIENTS AND METHODS: By Cox proportional hazards regression analysis, we modeled the clinical and pathologic data and disease follow-up for 996 men with clinical stage T1a-T3c NXM0 prostate cancer who were treated with radical prostatectomy by a single surgeon at our institution. Prognostic variables included pretreatment serum prostate-specific antigen level, specimen Gleason sum, prostatic capsular invasion, surgical margin status, seminal vesicle invasion, and lymph node status. Treatment failure was recorded when there was either clinical evidence of disease recurrence, a rising serum prostate-specific antigen level (two measurements of 0.4 ng/mL or greater and rising), or initiation of adjuvant therapy. Validation was performed on this set of men and a separate sample of 322 men from five other surgeons' practices from our institution. RESULTS: Cancer recurrence was noted in 189 of the 996 men, and the recurrence-free group had a median follow-up period of 37 months (range, 1 to 168 months). The 7-year recurrence-free probability for the cohort was 73% (95% confidence interval, 68% to 76%). The predictions from the nomogram appeared to be accurate and discriminating, with a validation sample area under the receiver operating characteristic curve (ie, a comparison of the predicted probability with the actual outcome) of 0.89. CONCLUSION: A postoperative nomogram has been developed that can be used to predict the 7-year probability of disease recurrence among men treated with radical prostatectomy.
Expression of MUC-1 Epitopes on Normal Bone Marrow: Implications for the Detection of Micrometastatic Tumor Cells
Authors: Brugger Wolfram , Bühring Hans-Jörg , Grünebach Frank , Vogel Wichard , Kaul Sepp , Müller Robert , Brümmendorf Tim H. , Ziegler Benedikt L. , Rappold Irene , Brossart Peter , Scheding Stefan , Kanz Lothar 
Published: February 2017

PURPOSE: The expression of the carcinoma-associated mucin MUC-1 is thought to be restricted to epithelial cells and is used for micrometastatic tumor cell detection in patients with solid tumors, including those with breast cancer. Little is known, however, about the expression of MUC-1 epitopes in normal hematopoietic cells. MATERIALS AND METHODS: MUC-1 expression was analyzed by flow cytometry and immunocytology on bone marrow (BM) mononuclear cells and purified CD34+ cells from healthy volunteers, using different anti-MUC-1–specific monoclonal antibodies. In addition, Western blotting of MUC-1 proteins was performed. RESULTS: Surprisingly, 2% to 10% of normal human BM mononuclear cells expressed MUC-1, as defined by the anti–MUC-1 antibodies BM-2 (2E11), BM-7, 12H12, MAM-6, and HMFG-1. In contrast, two antibodies recognizing the BM-8 and the HMFG-2 epitopes of MUC-1 were not detected. MUC-1+ cells from normal BM consisted primarily of erythroblasts and normoblasts. In agreement with this, normal CD34+ cells cultured in vitro to differentiate into the erythroid lineage showed a strong MUC-1 expression on day 7 proerythroblasts. Western blotting of these cells confirmed that the reactive species is the known high molecular weight MUC-1 protein. CONCLUSION: Our data demonstrate that some MUC-1 epitopes are expressed on normal BM cells and particularly on cells of the erythroid lineage. Hence the application of anti–MUC-1 antibodies for disseminated tumor cell detection in BM or peripheral blood progenitor cells may provide false-positive results, and only carefully evaluated anti–MUC-1 antibodies (eg, HMFG-2) might be selected. Furthermore, MUC-1–targeted immunotherapy in cancer patients might be hampered by the suppression of erythropoiesis.
Plasmablastic Morphology Is an Independent Predictor of Poor Survival After Autologous Stem-Cell Transplantation for Multiple Myeloma
Authors: Rajkumar S. Vincent , Fonseca Rafael , Lacy Martha Q. , Witzig Thomas E. , Therneau Terry M. , Kyle Robert A. , Litzow Mark R. , Gertz Morie A. , Greipp Philip R. 
Published: February 2017

PURPOSE: To study the prognostic value of plasmablastic morphology after autologous stem-cell transplantation for relapsed or primary refractory myeloma. PATIENTS AND METHODS: Seventy-five patients were studied. Investigators blinded to the clinical details of the individual cases reviewed bone marrow aspirate slides to determine plasmablastic classification. Plasmablasts were defined using strict, well-described criteria. Plasmablastic morphology was considered to be present (plasmablastic myeloma) when 2% or more plasmablasts were present in the plasma-cell population. RESULTS: Patients underwent transplantation 5 to 88 months (median, 20 months) after the initial diagnosis of myeloma. Twenty-eight percent of patients had plasmablastic morphology. A significantly greater proportion of patients with plasmablastic morphology had abnormal cytogenetics compared with those with nonplasmablastic classification (73% v 31%, respectively; P = .003). The overall survival rate measured from the time of transplantation was significantly worse in patients with plasmablastic morphology compared with those without (median survival time, 5 months v 24 months, respectively; P < .001). Progression-free survival time was shortened also, with a median time of 4 months compared with 12 months, respectively (P < .001). In the multivariate analysis, plasmablastic classification was the most powerful prognostic factor after transplantation for both overall (P = .001) and progression-free survival rates (P < .001). We also identified three risk groups based on plasmablastic morphology: plasma-cell labeling index, lactate dehydrogenase, and cytogenetics. The median overall survival time was 38 months when none of these factors was abnormal, 17 months with one abnormal factor, and 8 months with two or more abnormal factors (P < .001). CONCLUSION: Plasmablastic morphology is a powerful independent predictor of poor survival rate after autologous stem-cell transplantation for relapsed or primary refractory myeloma.
Oral Medroxyprogesterone Acetate in the Treatment of Advanced or Recurrent Endometrial Carcinoma: A Dose-Response Study by the Gynecologic Oncology Group
Authors: Thigpen J. Tate , Brady Mark F. , Alvarez Ronald D. , Adelson Mark D. , Homesley Howard D. , Manetta Alberto , Soper John T. , Given Fred T. 
Published: February 2017

PURPOSE: Progestins have definite activity against advanced or recurrent endometrial carcinoma. Both parenteral and oral progestins yield similar serum levels and response rates, which range from 18% to 34%. The one major study that used oral medroxyprogesterone acetate (MPA) noted a response rate at the lower end of the range (18%) and much poorer progression-free and overall survival times (4 and 10.5 months, respectively) than previously reported. The present study sought to confirm this earlier study of oral MPA, to assess the importance of prognostic factors such as histologic grade and receptor levels, and to determine whether a higher dose of MPA would yield a higher response rate. PATIENTS AND METHODS: Two hundred ninety-nine eligible women with advanced or recurrent endometrial carcinoma were randomized to receive oral MPA either 200 mg/d or 1,000 mg/d until unacceptable toxicity intervened or their disease progressed. RESULTS: Among 145 patients receiving the low-dose regimen, there were 25 complete (17%) and 11 partial (8%) responses for an overall response rate of 25%. The 154 patients receiving the high-dose regimen experienced 14 (9%) complete and 10 (6%) partial responses for an overall response rate of 15%. Median durations of progression-free survival were 3.2 months and 2.5 months for the low-dose and high-dose regimens, respectively. Median survival durations were 11.1 months and 7.0 months, respectively. The adjusted relative odds of responding to the high-dose regimen compared with the low-dose regimen was 0.61 (90% confidence interval, 0.36 to 1.04). Prognostic factors having a significant impact on the probability of response included initial performance status, age, histologic grade, and progesterone receptor concentration. Compliance with oral therapy was documented with serum levels 1 month after starting therapy, when possible. MPA levels were commensurate with the assigned dose and schedule. CONCLUSION: Oral MPA is active against endometrial carcinoma. Response to progestin therapy is more frequent among patients with a well-differentiated histology and positive progesterone receptor status. This study provides no evidence to support the use of MPA 1,000 mg/d orally instead of MPA 200 mg/d orally. In fact, the trends suggest the opposite. The use of oral MPA 200 mg/d is a reasonable initial approach to the treatment of advanced or recurrent endometrial carcinoma, particularly those lesions that are well-differentiated and/or progesterone receptor-positive (> 50 fmol/mg cytosol protein). Patients with poorly differentiated and/or progesterone receptor levels less than 50 fmol/mg cytosol protein had only an 8% to 9% response rate.
Immunohistochemical Quantitation of Thymidylate Synthase Expression in Colorectal Cancer Metastases Predicts for Clinical Outcome to Fluorouracil-Based Chemotherapy
Authors: Aschele Carlo , Debernardis Domizia , Casazza Stefania , Antonelli Giovanna , Tunesi Gianni , Baldo Chiara , Lionetto Rita , Maley Frank , Sobrero Alberto 
Published: February 2017

PURPOSE: To determine whether immunohistochemical thymidylate synthase (TS) quantitation predicts for clinical outcome in patients with advanced colorectal cancer treated by fluorouracil (FUra)-based chemotherapy. PATIENTS AND METHODS: TS levels were measured immunohistochemically on archival specimens of colorectal cancer metastases from 48 patients homogenously treated by bolus FUra plus methotrexate alternating with continuous-infusion FUra plus leucovorin. These measurements were retrospectively correlated with patient characteristics and clinical outcome. RESULTS: A significant correlation was found between intratumoral TS expression and all the parameters of clinical outcome analyzed. In patients whose tumors had low (n = 27) and high (n = 21) TS levels, the overall response rates were 67% and 24%, respectively (P = .003). The percentage of tumor shrinkage after chemotherapy was linearly related to TS immunoreactivity (r = .56, P = .00004), and its mean values were 65% and 14% with low and high TS levels, respectively (P = .0001). By logistic regression analysis, low TS expression was the single best predictor of response to chemotherapy (relative probability, 5.0). In patients with low and high TS expression, the median time to progression was 9.6 months v 6.2 months (P = .005) and the median survival time 18.4 months v 15.4 months (P = .02), respectively. Two- and 3-year survival rates were 41% v 15% and 19% v 0% (P = .02), respectively. CONCLUSION: In this cohort of homogenously treated patients, intratumor TS content was a major predictor of clinical outcome. Immunohistochemical TS quantitation provides a convenient, low-cost technique for identifying patients unresponsive to TS inhibitors who may be candidates for alternative chemotherapy regimens.
Phase II/Pharmacodynamic Trial of Dose-Intensive, Weekly Parenteral Hydroxyurea and Fluorouracil Administered With Interferon Alfa-2a in Patients With Refractory Malignancies of the Gastrointestinal Tract
Authors: Wadler Scott , Damle Snehal , Haynes Hilda , Kaleya Ron , Schechner Richard , Berkenblit Robert , Ladner Robert D. , Murgo Anthony 
Published: February 2017

PURPOSE: Combined depletion of pyrimidine and purine DNA precursors has resulted in therapeutic synergism in vitro. The aims of the current study were to test this strategy in patients with refractory tumors and to assess its effects on selected nucleotide pools. PATIENTS AND METHODS: A single-institution phase II trial was initiated in patients with advanced carcinomas of the stomach and pancreas. Patients had measurable disease and had no prior chemotherapy except adjuvant fluorouracil (5FU) or gemcitabine. 5FU was administered by CADD + pump at 2.6 g/m2 intravenously by 24-hour infusion on days 1, 8, 15, 22, 29, and 36. Parenteral hydroxyurea (HU) was administered at 4.3 g/m2 as a 24-hour infusion concurrently with 5FU. Interferon alfa-2a (IFN-α2a) was administered at 9 million units subcutaneously on days 1, 3, and 5 each week. No drug was administered in weeks 7 and 8. Pharmacodynamic studies were performed to assess drug effects on levels of deoxyuridine triphosphate (dUTP) and thymidine triphosphate (TTP) pools in peripheral-blood mononuclear cells (PBMCs) before and 6 hours after treatment using a highly sensitive DNA polymerase assay. RESULTS: There were 53 patients enrolled onto the study (gastric carcinoma, 31; pancreatic carcinoma, 22). The median age was 61 years, with 22% of patients ≥ 70 years old. The predominant grade 3 to 4 toxicities were leukopenia (49%), granulocytopenia (55%), and thrombocytopenia (22%). Severe diarrhea occurred in 12%, mucositis in 0%, and vomiting in 10% of patients. Patients ≥ 70 years had no greater incidence of toxicities. Among the 30 assessable patients with gastric carcinoma, there were two (7%) complete responders and 11 (37%) partial responders (median duration, 7 months). Among the 21 assessable patients with pancreatic carcinoma, there was one responder. Median survival among all patients with gastric carcinoma was 10 months and 13 months for patients with pancreatic carcinoma. Twenty-three patients had samples studied for levels of dUTP and TTP. There was no change in the levels of TTP before and after treatment. Furthermore, dUTP was detected in only five of 28 samples after treatment with no increase in the dUTP/TTP ratio. CONCLUSION: Combination therapy with high-dose, weekly infusional HU and 5FU with IFN-α2a modulation was well-tolerated with activity in gastric cancer. Patients ≥ 70 years tolerated therapy as well as younger patients. This was the first study to correlate levels of TTP and dUTP after treatment with clinical outcome. In PBMCs used as a surrogate tissue, HU abrogated the 5FU-induced increase in dUTP levels without reversing the overall efficacy of the regimen.
Direct Translation of a Protracted Irinotecan Schedule From a Xenograft Model to a Phase I Trial in Children
Authors: Furman Wayne L. , Stewart Clinton F. , Poquette Catherine A. , Pratt Charles B. , Santana Victor M. , Zamboni William C. , Bowman Laura C. , Ma Margaret K. , Hoffer Fredrick A. , Meyer William H. , Pappo Alberto S. , Walter Andrew W. , Houghton Peter J. 
Published: February 2017

PURPOSE: In a preclinical model of neuroblastoma, administration of irinotecan daily 5 days per week for 2 consecutive weeks ([qd × 5] × 2) resulted in greater antitumor activity than did a single 5-day course with the same total dose. We evaluated this protracted schedule in children. PATIENTS AND METHODS: Twenty-three children with refractory solid tumors were enrolled onto a phase I study. Cohorts received irinotecan by 1-hour intravenous infusion at 20, 24, or 29 mg/m2 (qd × 5) × 2 every 21 days. RESULTS: The 23 children (median age, 14.1 years; median prior regimens, two) received 84 courses. Predominant diagnoses were neuroblastoma (n = 5), osteosarcoma (n = 5), and rhabdomyosarcoma (n = 4). The dose-limiting toxicity was grade 3/4 diarrhea and/or abdominal cramps in six of 12 patients treated at 24 mg/m2, despite aggressive use of loperamide. The maximum-tolerated dose (MTD) on this schedule was 20 mg/m2/d. Five patients had partial responses and 16 had disease stabilization. On day 1, the median systemic exposure to SN-38 (the active metabolite of irinotecan) at the MTD was 106 ng-h/mL (range, 41 to 421 ng-h/mL). CONCLUSION: This protracted schedule is well tolerated in children. The absence of significant myelosuppression and encouraging clinical responses suggest compellingly that irinotecan be further evaluated in children using the (qd × 5) × 2 schedule, beginning at a dose of 20 mg/m2. These results imply that data obtained from xenograft models can be effectively integrated into the design of clinical trials.