bluuebunny/crossref_metadata_2025_split huggingface dataset:
Second Allogeneic Bone Marrow Transplantation in Acute Leukemia: Results of a Survey by the European Cooperative Group for Blood and Marrow Transplantation
Authors: Bosi Alberto , Laszlo Daniele , Labopin Myriam , Reffeirs Josy , Michallet Mauricette , Gluckman Eliane , Alessandrino Paolo Emilio , Locatelli Franco , Vernant Jean Paul , Sierra Jorge , Jouet Jean Pierre , Frassoni Francesco ,   for the Acute Leukemia Working Party of the European Blood and Marrow Transplant Group
Published: February 2017

PURPOSE: Leukemic relapse is the most frequent cause of treatment failure after allogeneic hematopoietic stem-cell transplantation (HSCT). To identify prognostic factors affecting the outcome of second HSCT, we performed a retrospective study on patients with acute leukemia (AL) undergoing second HSCT who reported to the Acute Leukemia Working Party of the European Cooperative Group for Blood and Marrow Transplantation registry. PATIENTS AND METHODS: One hundred seventy patients who received second HSCTs for AL experienced relapse after first HSCTs were performed from 1978 to 1997. Status at second HSCT, time between first and second HSCT, conditioning regimen, source of stem cells, treatment-related mortality (TRM), acute graft-versus-host disease (aGVHD), leukemia-free survival (LFS), overall survival (OS), and relapse were considered. RESULTS: Engraftment occurred in 97% of patients. Forty-two patients were alive at last follow-up, with a 5-year OS rate of 26%. The 5-year probability for TRM, LFS, and relapse was 46%, 25%, and 59%, respectively. Grade ≥ 2 aGVHD occurred in 59% of patients, and chronic GVHD occurred in 32%. In multivariate analysis, diagnosis, interval to relapse after first HSCT > 292 days, aGVHD at first HSCT, complete remission status at second HSCT, use of total-body irradiation at second HSCT, acute GVHD at second HSCT, and use of bone marrow as source of stem cells at second HSCT were associated with better outcome. CONCLUSION: Second HSCT represents an effective therapeutic option for AL patients relapsed after allogeneic HSCT, with a 3-year LFS rate of 52% for the subset of patients who experienced relapse more than 292 days after receiving the first HSCT and who were in remission before receiving the second HSCT.
Impact of Surgical and Pathologic Variables in Rectal Cancer: A United States Community and Cooperative Group Report
Authors: Stocchi Luca , Nelson Heidi , Sargent Daniel J. , O’Connell Michael J. , Tepper Joel E. , Krook James E. , Beart Robert ,   the North Central Cancer Treatment Group
Published: February 2017

PURPOSE: Substantial and successful effort has been focused on decreasing the risk of local failure after rectal cancer surgery through the use of adjuvant therapies. Our study examined data from studies conducted by United States cooperative groups to investigate the impact of surgical and pathologic variables in rectal cancer outcomes. PATIENTS AND METHODS: Surgical and pathologic reports from 673 patients with stage II/III rectal cancer enrolled onto three adjuvant clinical trials were reviewed for tumor and surgical variables. Additional information on individual institutions and operating surgeon was collected. Variables were tested for association with 5-year local recurrence and survival after adjustment for adjuvant treatments and other important prognostic factors. RESULTS: Five-year local recurrence and survival rates were 16% and 59%, respectively. Surgeons treating more than 10 study cases had lower local recurrence rates than those treating ≤ 10 (11% v 17%, P = .02). Free radial margins also correlated with local recurrence (P = .01). Type of surgery, distal margins, and tumor radial spread were not significant. Tumor adherence to adjacent structures predicted local recurrence (35% v 14%, P < .001) and survival (30% v 63%, P < .001), regardless of en bloc resection. Although T and N classification predicted survival (P < .001), only N classification correlated with local recurrence. The number and percentage of positive nodes correlated with survival, but only the percentage independently predicted local recurrence. Several pathologic and surgical variables were reported suboptimally. CONCLUSION: Moderate variability in outcomes among surgeons was detected in this high-risk population. Efforts to improve surgical results will require changes in reporting practices to allow for more accurate assessment of the quality of surgery.
Does Histologic Grade Have a Role in the Management of Head and Neck Cancers?
Authors: Fortin André , Couture Christian , Doucet René , Albert Michele , Allard Josée , Tetu Bernard 
Published: February 2017

PURPOSE: High histologic grade is usually associated with a greater propensity to distant metastases (DM). Its role to predict DM in head and neck cancer is not yet defined. The aim of this study is to evaluate the role of histologic grade as an independent predictor of DM and to determine a subgroup of patients who may benefit from systemic chemotherapy. PATIENTS AND METHODS: This is a retrospective study of 1,266 consecutive patients treated by definitive or postoperative radiotherapy between 1989 and 1997. All patients received at least 50 Gy. All stages and subsites of head/neck were included. DM rates were evaluated by the Kaplan-Meier method with a subsequent Cox analysis. RESULTS: There is a strong correlation of grade with N stage (P < .000001). The metastases-free survival (MFS) was 98%, 90%, and 72% for grades 1, 2, and 3, respectively (P < .000001). In patients with N0 stage, MFS is always greater than 90%, whatever the grade. In the 222 N1 patients, MFS was more than 90% in grade 1 and 2 but dropped to 75% for grade 3 (P = .001). In patients with N2 and N3, MFS was 91%, 79%, and 59% for grades 1, 2, and 3, respectively (P = .008). The same conclusion is applicable when only patients with neck control are analyzed. In a Cox model, grade was an independent predictor of DM (P = .000001) as well as T stage (P = .003), N stage (P = .000001), and neck failure (P = .0003). Higher grade was also an independent predictor of survival (P = .02). CONCLUSION: Patients with histologic grade 1 and grade 2 (except N3) are at low risk of DM. Patients with grade 2 and N3 or patients with grade 3 and N1 to N3 have a higher risk of distant metastases and should be considered for systemic treatment.
MCM2 Is an Independent Predictor of Survival in Patients With Non–Small-Cell Lung Cancer
Authors: Ramnath Nithya , Hernandez Francisco J. , Tan Dong-Feng , Huberman Joel A. , Natarajan Nachimuthu , Beck Amy F. , Hyland Andrew , Todorov Ivan T. , Brooks John S.J. , Bepler Gerold 
Published: February 2017

PURPOSE: Minichromosome maintenance protein 2 (MCM2) is a component of the prereplicative complex. It is essential for eukaryotic DNA replication and is only expressed in proliferating cells. The prognostic utility of MCM2 compared with Ki-67, another marker of proliferating cells, on survival of patients with non–small-cell lung cancer (NSCLC) was studied. PATIENTS AND METHODS: We examined the immunohistochemical expression of MCM2 and Ki-67 in primary pathologic tumor specimens from 221 NSCLC patients. For each marker, the fraction of tumor cells with positive staining was assessed as a percentage and categorized into four groups: 0% to 24%, 25% to 49%, 50% to 74%, and ≥ 75%. MCM2 and Ki-67 immunoreactivities were compared with each other, and associations with pathologic and clinical parameters predictive of survival were analyzed with the χ2 test. Cox regression models were used to assess associations between MCM2 and Ki-67 and survival while controlling for confounders. RESULTS: Independent variables significantly associated with survival were tumor stage, performance status, and staining category. Patients with less than 25% MCM2 immunoreactivity had a longer median survival time than patients with ≥ 25% MCM2 immunoreactivity (46 v 31 months; P = .039) and a lower relative risk (RR) of death (RR, 0.55, 95% confidence interval, 0.34 to 0.88). There was no significant association between survival and Ki-67 expression. CONCLUSION: Immunostaining of tumor cells for MCM2 is an independent prognostic parameter of survival for patients with NSCLC. Interpretable results can be obtained on more than 96% of paraffin-embedded specimens, and approximately 35% will be in the favorable subgroup, with less than 25% positively stained tumor cells. Whether MCM2 is predictive of response to therapy needs to be studied.
Troxacitabine, A Novel Dioxolane Nucleoside Analog, Has Activity in Patients With Advanced Leukemia
Authors: Giles Francis J. , Cortes Jorge E. , Baker Sharyn D. , Thomas Deborah A. , O’Brien Susan , Smith Terry L. , Beran Miloslav , Bivins Carol , Jolivet Jacques , Kantarjian Hagop M. 
Published: February 2017

PURPOSE: To investigate the toxicity profile, activity, and pharmacokinetics of a novel l-nucleoside analog, troxacitabine (BCH-4556), in patients with advanced leukemia. PATIENTS AND METHODS: Patients with refractory or relapsed acute myeloid (AML) or lymphocytic (ALL) leukemia, myelodysplastic syndromes (MDS), or chronic myelogenous leukemia in blastic phase (CML-BP). Troxacitabine was given as an intravenous infusion over 30 minutes daily for 5 days. The starting dose was 0.72 mg/m2/d (3.6 mg/m2/course). Courses were given every 3 to 4 weeks according to toxicity and antileukemic efficacy. The dose was escalated by 50% until grade 2 toxicity was observed, and then by 30% to 35% until the dose-limiting toxicity (DLT) was defined. RESULTS: Forty-two patients (AML: 31 patients; MDS: six patients [five MDS + one CMML]; ALL: four patients; CML-BP: one patient) were treated. Median age was 61 years (range, 23 to 79 years), and 29 patients were males. Stomatitis and hand-foot syndrome were the DLTs. The MTD was defined as 8 mg/m2/d. The pharmacokinetic behavior of troxacitabine is linear over the dose range of 0.72 to 10.0 m/m2. Approximately 69% of troxacitabine was excreted as unchanged drug in the urine. Marrow hypoplasia occurred between days 14 and 28 in 73% of AML patients. Three complete remissions and one partial remission were observed in 30 assessable AML patients. One MDS patient achieved a hematologic improvement. A patient with CML-BP achieved a return to chronic phase disease. CONCLUSION: Troxacitabine has a unique metabolic and pharmacokinetic profile and significant antileukemic activity. DLTs were stomatitis and hand-foot syndrome. Troxacitabine merits further study in hematologic malignancies.
Phase Ib Trial of Intravenous Recombinant Humanized Monoclonal Antibody to Vascular Endothelial Growth Factor in Combination With Chemotherapy in Patients With Advanced Cancer: Pharmacologic and Long-Term Safety Data
Authors: Margolin K. , Gordon M. S. , Holmgren E. , Gaudreault J. , Novotny W. , Fyfe G. , Adelman D. , Stalter S. , Breed J. 
Published: February 2017

PURPOSE: Tumor angiogenesis mediated by vascular endothelial growth factor (VEGF) is inhibited by the recombinant humanized (rhu) monoclonal antibody (MAb) rhuMAbVEGF, which has synergy with chemotherapy in animal models. The present study was designed to assess the safety and pharmacokinetics of weekly intravenous (IV) rhuMAbVEGF with one of three standard chemotherapy regimens. PATIENTS AND METHODS: Twelve adult patients were enrolled four on each combination. rhuMAbVEGF, 3 mg/kg IV, was administered weekly for 8 weeks with (1) doxorubicin 50 mg/m2 every 4 weeks; (2) carboplatin at area under the curve of 6 plus paclitaxel 175 mg/m2 every 4 weeks; and (3) fluorouracil (5-FU) 500 mg/m2 with leucovorin 20 mg/m2 weekly, weeks 1 to 6 every 8 weeks. RESULTS: The median number of rhuMAbVEGF doses delivered was eight (range, four to eight doses). Grade 3 toxicities were diarrhea (one 5-FU patient), thrombocytopenia (two patients on carboplatin plus paclitaxel), and leukopenia (one patient on carboplatin plus paclitaxel). These toxicities were likely attributable to the chemotherapy component of the regimen. The mean (± SD) peak serum level of rhuMAbVEGF was 167 ± 46 μg/mL, and the mean terminal half-life was 13 days. Total (free plus bound) serum VEGF levels increased from 51 ± 39 pg/mL (day 0) to 211 ± 112 (day 49) pg/mL. Three responding patients continued treatment with rhuMAbVEGF and chemotherapy, receiving the equivalent of 36, 20, and 40 total rhuMAbVEGF doses with no cumulative or late toxicities. CONCLUSION: rhuMAbVEGF can be safely combined with chemotherapy at doses associated with VEGF blockade and without apparent synergistic toxicity. Its contribution to the treatment of advanced solid tumors should be evaluated in randomized treatment trials.
Phase I and Pharmacokinetic Study of the Oral Farnesyl Transferase Inhibitor SCH 66336 Given Twice Daily to Patients With Advanced Solid Tumors
Authors: Eskens Ferry A.L.M. , Awada Ahmad , Cutler David L. , de Jonge Maja J.A. , Luyten Gré P.M. , Faber Marije N. , Statkevich Paul , Sparreboom Alex , Verweij Jaap , Hanauske Axel-R. , Piccart Martine 
Published: February 2017

PURPOSE: A single-agent dose-escalating phase I and pharmacokinetic study on the farnesyl transferase inhibitor SCH 66336 was performed to determine the safety profile, maximum-tolerated dose, and recommended dose for phase II studies. Plasma and urine pharmacokinetics were determined. PATIENTS AND METHODS: SCH 66336 was given orally bid without interruption to patients with histologically or cytologically confirmed solid tumors. Routine antiemetics were not prescribed. RESULTS: Twenty-four patients were enrolled onto the study. Dose levels studied were 25, 50, 100, 200, 400, and 300 mg bid. Pharmacokinetic sampling was performed on days 1 and 15. At 400 mg bid, the dose-limiting toxicity (DLT) consisted of grade 4 vomiting, grade 4 neutropenia and thrombocytopenia, and the combination of grade 3 anorexia and diarrhea with reversible grade 3 plasma creatinine elevation. After dose reduction, at 300 mg bid, the DLTs consisted of grade 4 neutropenia, grade 3 neurocortical toxicity, and the combination of grade 3 fatigue with grade 2 nausea and diarrhea. The recommended dose for phase II studies is 200 mg bid, which was found feasible for prolonged periods of time. Pharmacokinetic analysis showed a greater than dose-proportional increase in drug exposure and peak plasma concentrations, with increased parameters at day 15 compared with day 1, indicating some accumulation on multiple dosing. Plasma half-life ranged from 4 to 11 hours and seemed to increase with increasing doses. Steady-state plasma concentrations were attained at days 7 through 14. A large volume of distribution at steady-state indicated extensive distribution outside the plasma compartment. CONCLUSION: SCH 66336 can be administered safely using a continuous oral bid dosing regimen. The recommended dose for phase II studies using this regimen is 200 mg bid.
Effectiveness of Breast Cancer Surveillance in BRCA1/2 Gene Mutation Carriers and Women With High Familial Risk
Authors: Brekelmans C.T.M. , Seynaeve C. , Bartels C.C.M. , Tilanus-Linthorst M.M.A. , Meijers-Heijboer E.J. , Crepin C.M.G. , van Geel A.N. , Menke M. , Verhoog L.C. , van den Ouweland A. , Obdeijn I.M. , Klijn J.G.M. 
Published: February 2017

PURPOSE: Women with a high breast cancer risk due to a familial predisposition may choose between preventive surgery and regular surveillance. The effectiveness of surveillance in high-risk women and especially BRCA1/2 mutation carriers is unknown. We present first results from a single large family cancer clinic. PATIENTS AND METHODS: Women with breast cancer risk over 15% were examined by physical examination every 6 months and mammography every year. Detection rates and screening parameters were calculated for the total group and separately for different age and genetic risk groups. RESULTS: At least one examination was performed in 1,198 women: 449 moderate and 621 high-risk women and 128 BRCA1/2 mutation carriers. Within a median follow-up of 3 years, 35 breast cancers were detected (four ductal carcinoma-in-situ; 31 invasive tumors); the average detection rate was 9.7 per 1,000. Detection rates (95% confidence interval) for moderate and high-risk women and BRCA1/2 carriers were 3.3 (1.1 to 8.6), 8.4 (5.4 to 13.2), and 33 (17 to 63) per 1,000 person-years, respectively. The ratio of observed cases versus breast cancers expected in an average-risk population of comparable age was 2.7, 7.0 and 23.7 respectively. Overall, node negativity was 65%; 34% of primary tumors were less than 10 mm; sensitivity was 74%. Results with respect to tumor stage and sensitivity were less favorable in BRCA1/2 carriers and in women under the age of 40. CONCLUSION: It is possible to identify young women at high risk for breast cancer. The number of cancers detected was significantly greater than expected in an age-matched average-risk population and related to the risk category. Overall, screening parameters were comparable to population screening data, with less favorable results in the youngest age group (< 40) and BRCA1/2 carriers.
Phase I Study of Paclitaxel Given by Seven-Week Continuous Infusion Concurrent With Radiation Therapy for Locally Advanced Squamous Cell Carcinoma of the Head and Neck
Authors: Rosenthal David I. , Lee Jason H. , Sinard Robert , Yardley Denise A. , Machtay Mitchell , Rosen D. Marc , Egorin Merrill J. , Weber Randal S. , Weinstein Gregory S. , Chalian Ara A. , Miller Linda K. , Frenkel Eugene P. , Carbone David P. 
Published: February 2017

PURPOSE: Paclitaxel is one of the most active agents for squamous cell carcinoma of the head and neck (SCCHN) and an in vitro radiosensitizer. The dose-response relationship for paclitaxel may depend more on exposure duration than on peak concentration. This National Cancer Institute–sponsored phase I trial was designed to determine the feasibility of combining continuous-infusion (CI) paclitaxel with concurrent radiation therapy (RT). PATIENTS AND METHODS: Patients with previously untreated stage IVA/B SCCHN were eligible. Primary end points were determination of the maximum-tolerated dose, dose-limiting toxicity, and pharmacokinetics for paclitaxel given by CI (24 hours a day, 7 days a week for 7 weeks) during RT (70 Gy/7 weeks). RESULTS: Twenty-seven patients were enrolled and assessable for toxicity. Nineteen of the patients who completed ≥ 70 Gy were assessable for response. Grade 3 skin and mucosal acute reactions occurred at 10.5 mg/m2/d, but uninterrupted treatment was possible in five of six patients. At 17 mg/m2/d, skin toxicity required a 2-week treatment break for all three patients. The mean paclitaxel serum concentration at dose levels ≥ 6.5 mg/m2/d exceeded that reported to achieve in vitro radiosensitization. Initial locoregional control was achieved in 14 (58%) of 24 of patients treated to 70 Gy, and control persisted in nine (38%). CONCLUSION: CI paclitaxel with concurrent RT is a feasible and tolerable regimen for patients with advanced SCCHN and good performance status. Preliminary response and survival data are encouraging and suggest that further study is indicated. The recommended phase II dose of paclitaxel by CI is 10.5 mg/m2/d with RT for SCCHN.
Irinotecan in the Treatment of Colorectal Cancer: Clinical Overview
Authors: Vanhoefer Udo , Harstrick Andreas , Achterrath Wolf , Cao Shousong , Seeber Siegfried , Rustum Youcef M. 
Published: February 2017

PURPOSE AND METHODS: For more than three decades, the therapeutic options for patients with advanced colorectal cancer have almost exclusively been based on fluoropyrimidines. With the recognition that topoisomerase-I (TOP-I) is an important therapeutic target in cancer therapy, irinotecan, a semisynthetic TOP-I–interactive camptothecin derivative, has been clinically established in the treatment of colorectal cancer. RESULTS: Irinotecan was investigated as second-line chemotherapy after prior treatment with fluorouracil (FU)-based regimens in two large randomized phase III trials comparing irinotecan with either best supportive care or an infusional FU/leucovorin (LV) regimen. The outcomes of these trials established irinotecan as the standard therapy in the second-line treatment of colorectal cancer. The therapeutic value of irinotecan in the first-line treatment of metastatic colorectal cancer was investigated in two large randomized phase III trials comparing the combination of irinotecan and FU/LV with FU/LV alone. Both trials demonstrated significant superior efficacy for the combination of irinotecan and FU/LV in terms of response rate, median time to disease progression, and median survival time. Consequently, the combination of irinotecan and FU/LV has been approved as first-line chemotherapy for patients with metastatic colorectal cancer and constitutes the reference therapy against which other treatment options must be tested in the future. CONCLUSION: In this review, the clinical rationale and update of the present clinical status of irinotecan in the treatment of colorectal cancer and future prospects of irinotecan-based combinations are discussed.
Hematopoietic Stem-Cell Transplantation for Treatment-Related Leukemia or Myelodysplasia
Authors: Witherspoon Robert P. , Deeg H. Joachim , Storer Barry , Anasetti Claudio , Storb Rainer , Appelbaum Frederick R. 
Published: February 2017

PURPOSE: This report describes results of related or unrelated hematopoietic stem-cell transplants in 111 patients with treatment-related leukemia or myelodysplasia performed consecutively at the Fred Hutchinson Cancer Research Center between December 1971 and June 1998, and identifies patient and treatment characteristics associated with survival and relapse. PATIENTS AND METHODS: At transplantation, 56 patients had treatment-related secondary acute myeloid leukemia (AML), 15 had refractory anemia with excess blasts in transition (RAEB-T), 23 had refractory anemia with excess blasts (RAEB), 15 had refractory anemia (RA), and two had refractory anemia with ringed sideroblasts (RARS). Conditioning regimens were total-body irradiation (TBI) and chemotherapy for 60 patients, busulfan (BU) 14 to 16 mg/kg and cyclophosphamide (CY) 120 mg/kg (BUCY) for 27 patients, BU targeted to 600 to 900 ng/mL plasma steady-state concentration with 120 mg/kg CY (BUCY-t) for 22 patients, and miscellaneous chemotherapy for two patients. The donors were HLA-identical or partially identical family members for 69 patients and unrelated donors for 42 patients. RESULTS: The 5-year disease-free survival was 8% for TBI, 19% for BUCY, and 30% for BUCY-t (P = .006). The 5-year cumulative incidence of relapse was 40% for secondary AML, 40% for RAEB-T, 26% for RAEB, and 0% for RA or RARS (P = .0009). The 5-year cumulative incidence of nonrelapse mortality after TBI was 58%; after BUCY, 52%; and after BUCY-t, 42% (P = .02). CONCLUSION: Patients at risk for treatment-related leukemia or myelodysplasia should be followed closely and be considered for stem-cell transplantation early in the course of myelodysplasia using conditioning regimens such as BUCY-t designed to reduce nonrelapse mortality.