bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I and Pharmacokinetic Study of the Differentiating Agent Vesnarinone in Combination With Gemcitabine in Patients With Advanced Cancer
Authors: Patnaik Amita , Rowinsky Eric K. , Tammara Brinda K. , Hidalgo Manuel , Drengler Ronald L. , Garner Allison M. , Siu Lillian L. , Hammond Lisa A. , Felton Sally A. , Mallikaarjun Suresh , Von Hoff Daniel D. , Eckhardt S. Gail 
Published: February 2017

PURPOSE: To evaluate the maximum-tolerated dose, dose-limiting toxicities (DLTs), and pharmacokinetic profile of vesnarinone given once daily in combination with gemcitabine. PATIENTS AND METHODS: Twenty-six patients were treated with oral vesnarinone once daily on a continuous schedule at doses of 60, 90, 120, 150, and 180 mg in combination with intravenous (IV) gemcitabine at a dose of 1,000 mg/m2 on days 1, 8, and 15 every 4 weeks. To determine whether biologically relevant concentrations were being achieved, predose concentrations (Cmin) of vesnarinone were obtained weekly. Plasma gemcitabine and 2′,2′-difluorodeoxyuridine concentrations were obtained during courses 1 and 2. RESULTS: Twenty-six patients were treated with 92 courses of vesnarinone/gemcitabine. The principal toxicities of the regimen consisted of neutropenia and thrombocytopenia, which were dose-limiting in two of eight heavily pretreated new patients treated at the 90 mg/1,000 mg/m2 dose level and one of 10 minimally pretreated new patients at the 120 mg/1,000 mg/m2 dose level. None of three patients treated with 15 courses at the vesnarinone/gemcitabine dose levels of 60 mg/1,000 mg/m2 experienced DLT. Pharmacokinetic studies of vesnarinone revealed significant interpatient variability at any given dose level. There was evidence of a linear relationship between vesnarinone dose and mean Cmin at dosages of vesnarinone less than 150 mg, with plateauing of mean Cmin values at higher dosages. There was no impact of vesnarinone on gemcitabine concentrations, and the vesnarinone pharmacokinetics did not change with gemcitabine between weeks 1 and 2. Two partial responses occurred in patients with refractory breast and non–small-cell lung carcinoma. CONCLUSION: When combined with gemcitabine, the recommended dose of vesnarinone for phase II evaluations is 90 mg orally once daily with gemcitabine 1,000 mg/m2 IV on days 1, 8, and 15 every 4 weeks. There is no evidence of pharmacokinetic interaction between vesnarinone and gemcitabine. Further studies of vesnarinone as a single agent or in combination with gemcitabine and other antineoplastic agents are warranted.
Long-Term Outcome for Patients With Nonmetastatic Osteosarcoma of the Extremity Treated at the Istituto Ortopedico Rizzoli According to the Istituto Ortopedico Rizzoli/Osteosarcoma-2 Protocol: An Updated Report
Authors: Bacci Gaetano , Ferrari Stefano , Bertoni Franco , Ruggieri Pietro , Picci Piero , Longhi Alessandra , Casadei Roberto , Fabbri Nicola , Forni Cristiana , Versari Michela , Campanacci Mario 
Published: February 2017

PURPOSE: To provide an estimate of long-term prognosis for patients with osteosarcoma of the extremity treated in a single institution with neoadjuvant chemotherapy and observed for at least 10 years. PATIENTS AND METHODS: Patients with nonmetastatic osteosarcoma of the extremity were preoperatively treated with high-dose methotrexate, cisplatin, and doxorubicin (ADM). Postoperatively, good responders (90% or more tumor necrosis) received the same three drugs used before surgery, whereas poor responders (less than 90% tumor necrosis) received ifosfamide and etoposide in addition to those three drugs. RESULTS: For the 164 patients who entered the study between September 1986 and December 1989, surgery was a limb salvage in 136 cases (82%) and a good histologic response was observed in 117 patients (71%). At a follow-up ranging from 10 to 13 years (median, 11.5 years), 101 patients (61%) remained continuously free of disease, 61 relapsed, and two died of ADM-induced cardiotoxicity. There were no differences in prognosis between good and poor responding patients. ADM-induced cardiotoxicity (six patients), male infertility (10 of the 12 assessable patients), and second malignancies (seven patients) were the major complications of chemotherapy. Despite the large number of limb salvages performed, only four local recurrences (2.4%) were registered. CONCLUSION: With an aggressive neoadjuvant chemotherapy, it is possible to cure more than 60% of patients with nonmetastatic osteosarcoma of the extremity and amputation may be avoided in more than 80% of them. Because local or systemic relapses, myocardiopathies, and second malignancies are possible even 5 years or more after the beginning of treatment, a long-term follow-up is recommended for these patients.
Symptoms of Posttraumatic Stress in Young Adult Survivors of Childhood Cancer
Authors: Hobbie Wendy L. , Stuber Margaret , Meeske Kathleen , Wissler Kathryn , Rourke Mary T. , Ruccione Kathy , Hinkle Andrea , Kazak Anne E. 
Published: February 2017

PURPOSE: This study assessed the prevalence of posttraumatic stress symptoms in young adult survivors of childhood cancer and the association of posttraumatic stress with anxiety, adjustment, perceptions of illness and treatment, and medical data extracted from oncology records. PATIENTS AND METHODS: Seventy-eight young adults (ages 18 to 40 years) who had been treated for childhood cancer completed questionnaires and psychiatric interviews assessing posttraumatic stress, anxiety, perceptions of their illness and treatment, and symptoms of psychologic distress. Data on treatment intensity and severity of medical late effects were collected via chart review. RESULTS: Of the patient sample, 20.5% met American Psychiatric Association Diagnostic and Statistical Manual criteria for posttraumatic stress disorder (PTSD) at some point since the end of their treatment. Clinically significant levels of intrusive (9%) and avoidant (16.7%) symptoms were reported. Participants also reported elevated state and trait anxiety. Participants with PTSD reported higher perceived current life threat, more intense treatment histories, and higher (and clinically significant) levels of psychologic distress than those who did not have PTSD. CONCLUSION: One-fifth of this sample of young adult survivors of childhood cancer met criteria for a diagnosis of PTSD, with clinically significant symptoms of intrusion and avoidance reported. As in other samples, PTSD in young adult survivors was associated with anxiety and other psychologic distress. Survivors’ perceptions of treatment and its effects were more highly associated with posttraumatic stress than were more objective medical data. The data suggest that cancer-related posttraumatic stress may emerge in young adulthood and may affect the achievement of developmental milestones and orientation toward health care.
Molecular and Clinical Features of Non-Burkitt’s, Diffuse Large-Cell Lymphoma of B-Cell Type Associated With the c-MYC/Immunoglobulin Heavy-Chain Fusion Gene
Authors: Akasaka Takashi , Akasaka Hiroshi , Ueda Chiyoko , Yonetani Noboru , Maesako Yoshitomo , Shimizu Akira , Yamabe Hirohiko , Fukuhara Shirou , Uchiyama Takashi , Ohno Hitoshi 
Published: February 2017

PURPOSE: t(8;14)(q24;q32) and/or c-MYC/immunoglobulin heavy-chain (IGH) fusion gene have been observed not only in Burkitt’s lymphoma (BL) but also in a proportion of non-BL, diffuse large-cell lymphoma of B-cell type (DLCL). We explored molecular features of DLCL with c-MYC/IGH fusion and the impact of this genetic abnormality on clinical outcome of DLCL. PATIENTS AND METHODS: A total of 203 cases of non-BL DLCL were studied. Genomic DNA extracted from tumor tissues was subjected to long-distance polymerase chain reaction (LD-PCR) using oligonucleotide primers for exon 2 of c-MYC and for the four constant region genes of IGH. RESULTS: Twelve cases (5.9%) showed positive amplification; one had a c-MYC/Cμ, nine had a c-MYC/Cγ, and two had a c-MYC/Cα fusion sequence. Restriction and sequence analysis of the LD-PCR products, ranging from 2.3 to 9.4 kb in size, showed that breakage in the 12 cases occurred within a 1.5-kb region that included exon 1 of c-MYC in combination with breakpoints at the switch regions of IGH (10 of 12). In 10 cases, Myc protein encoded by the fusion genes demonstrated mutations and/or deletions. Six cases had additional molecular lesions in BCL-2 or BCL-6 and/or p53 genes. The age range of the 12 patients was 44 to 86 years, with a median age of 65.5 years. Five patients had stage I/II disease, and seven had stage III/IV disease. Lactate dehydrogenase was elevated in nine of 11 subjects. Seven showed involvement of the gastrointestinal tract. All patients were treated by surgery and/or chemoradiotherapy; six died of the disease within 1 year, resulting in the poorest 1- and 2-year survival rates among DLCL subgroups. CONCLUSION: The c-MYC/IGH fusion gene of DLCL is identical to that of the sporadic type of BL (sBL). DLCL with c-MYC/IGH shares clinical features with sBL but is characterized further by an older age distribution.
Plasma d-Dimer Levels in Operable Breast Cancer Patients Correlate With Clinical Stage and Axillary Lymph Node Status
Authors: Blackwell Kimberly , Haroon Zishan , Broadwater Gloria , Berry Donald , Harris Lyndsay , Iglehart J. Dirk , Dewhirst Mark , Greenberg Charles 
Published: February 2017

PURPOSE: To investigate the relationship between preoperative plasma d-dimer levels and extent of tumor involvement in operable breast cancer patients. PATIENTS AND METHODS: A total of 140 preoperative plasma specimens were obtained from women scheduled to undergo diagnostic breast biopsies. Ninety-five patients in the initial group went on to undergo axillary lymph node dissection. Of the 140 patients from whom plasma samples were obtained, 102 were subsequently diagnosed with invasive breast carcinoma, nine were subsequently diagnosed with ductal carcinoma-in-situ, and 20 were subsequently diagnosed with benign breast disease. Plasma d-dimer levels were quantitated using a commercially available immunoassay kit (DIMERTEST; American Diagnostica, Greenwich, CT). The relationships between plasma d-dimer and other prognostic variables (tumor size, estrogen receptor, progesterone receptor, nuclear grade, histologic grade, lymphovascular invasion, and clinical stage grouping) were then examined using univariate and multivariate linear and logistic regression analyses. RESULTS: Median plasma d-dimer levels were significantly higher in patients with invasive carcinoma than those patients with either benign breast disease or carcinoma-in-situ (P = .0001). A significant relationship existed between the presence of elevated d-dimer (> 100 ng/mL) and involved axillary lymph nodes (χ2 test; P = .001). Elevated d-dimer levels predicted positive lymph node involvement in both univariate regression (P = .0035) and multivariate linear regression (P = .012) models. In addition, elevated d-dimer levels predicted the presence of lymphovascular invasion in univariate logistic regression (P = .0025) and multivariate logistic regression analysis (P = .0053). Quantitative d-dimer levels were highly correlated with clinical stage grouping (analysis of variance test; P = .002). CONCLUSION: Plasma d-dimer levels were markers of lymphovascular invasion, clinical stage, and lymph node involvement in operable breast cancer. This correlation suggests that detectable fibrin degradation, as measured by plasma d-dimer, is a clinically important marker for lymphovascular invasion and early tumor metastasis in operable breast cancer.
Overexpression of Her-2 in Patients With Poorly Differentiated Carcinoma or Poorly Differentiated Adenocarcinoma of Unknown Primary Site
Authors: Hainsworth John D. , Lennington Wayne J. , Greco F. Anthony 
Published: February 2017

PURPOSE: To determine the frequency of Her-2 overexpression in patients with poorly differentiated carcinoma or poorly differentiated adenocarcinoma of unknown primary site. PATIENTS AND METHODS: Tumor specimens from 100 patients with poorly differentiated carcinoma or poorly differentiated adenocarcinoma were stained for the Her-2 protein using the Dako immunohistochemical method. Clinical and pathologic characteristics of patients with and without Her-2 overexpression were compared. RESULTS: Staining for Her-2 overexpression was successful in 94 of 100 patients. Ten (11%) of 94 tumor specimens overexpressed Her-2. Eight of 10 overexpressors had poorly differentiated adenocarcinoma, and all overexpressors had predominant tumor location above the diaphragm, usually in the mediastinum or lungs. CONCLUSION: Her-2 overexpression occurs in a minority of patients with poorly differentiated carcinoma/adenocarcinoma of unknown primary site. Because most overexpressors had poorly differentiated adenocarcinoma, further evaluation of patients with adenocarcinoma of unknown primary site is necessary to determine the frequency of Her-2 overexpression in this common subgroup. Evaluation of the efficacy of trastuzumab in Her-2 overexpressors with carcinoma of unknown primary site is indicated.
Preoperative Chemoradiation for Patients With Pancreatic Cancer: Toxicity of Endobiliary Stents
Authors: Pisters Peter W. T. , Hudec Wayne A. , Lee Jeffrey E. , Raijman Isaac , Lahoti Sandeep , Janjan Nora A. , Rich Tyvin A. , Crane Christopher H. , Lenzi Renato , Wolff Robert A. , Abbruzzese James L. , Evans Douglas B. 
Published: February 2017

PURPOSE: A recent multicenter study of preoperative chemoradiation and pancreaticoduodenectomy for localized pancreatic adenocarcinoma suggested that biliary stent–related complications are frequent and severe and may prevent the delivery of all components of multimodality therapy in many patients. The present study was designed to evaluate the rates of hepatic toxicity and biliary stent–related complications and to evaluate the impact of this morbidity on the delivery of preoperative chemoradiation for pancreatic cancer at a tertiary care cancer center. PATIENTS AND METHODS: Preoperative chemoradiation was used in 154 patients with resectable pancreatic adenocarcinoma (142 patients, 92%) or other periampullary tumors (12 patients, 8%). Patients were treated with preoperative fluorouracil (115 patients), paclitaxel (37 patients), or gemcitabine (two patients) plus concurrent rapid-fractionation (30 Gy; 123 patients) or standard-fractionation (50.4 Gy; 31 patients) radiation therapy. The incidences of hepatic toxicity and biliary stent–related complications were evaluated during chemoradiation and the immediate 3- to 4-week postchemoradiation preoperative period. RESULTS: Nonoperative biliary decompression was performed in 101 (66%) of 154 patients (endobiliary stent placement in 77 patients and percutaneous transhepatic catheter placement in 24 patients). Stent-related complications (occlusion or migration) occurred in 15 patients. Inpatient hospitalization for antibiotics and stent exchange was necessary in seven of 15 patients (median hospital stay, 3 days). No patient experienced uncontrolled biliary sepsis, hepatic abscess, or stent-related death. CONCLUSION: Preoperative chemoradiation for pancreatic cancer is associated with low rates of hepatic toxicity and biliary stent–related complications. The need for biliary decompression is not a clinically significant concern in the delivery of preoperative therapy to patients with localized pancreatic cancer.
Phase I and Pharmacologic Study of Oral Fluorouracil on a Chronic Daily Schedule in Combination With the Dihydropyrimidine Dehydrogenase Inactivator Eniluracil
Authors: Baker Sharyn D. , Diasio Robert B. , O’Reilly Seamus , Lucas V. Sol , Khor Soo Peang , Sartorius Susan E. , Donehower Ross C. , Grochow Louise B. , Spector Thomas , Hohneker John A. , Rowinsky Eric K. 
Published: February 2017

PURPOSE: To determine the maximum-tolerated dose (MTD), toxicities, and pharmacokinetics of oral fluorouracil (5-FU) administered twice daily in combination with oral eniluracil, an inactivator of dihydropyrimidine dehydrogenase, administered for 28 days every 35 days. PATIENTS AND METHODS: Oral 5-FU 1.35 mg/m2 twice daily was administered with oral eniluracil 10 mg daily for 14 to 28 days, followed by a 1-week rest period. Eniluracil was started 1 day before 5-FU. Patients then received escalated doses of oral 5-FU 1.35 to 1.8 mg/m2 twice daily with an increased dose of eniluracil 10 mg twice daily for 28 days. A reduced dose of 5-FU 1.0 mg/m2 with eniluracil 20 mg twice daily was evaluated. RESULTS: Thirty-six patients with solid malignancies were enrolled onto the study. Diarrhea was the principal dose-limiting toxicity of oral 5-FU and eniluracil given on this chronic schedule. The recommended phase II dose is 5-FU 1.0 mg/m2 twice daily with eniluracil 20 mg twice daily. Mean (SD) values for terminal half-life, apparent volume of distribution, and systemic clearance of 4.5 hours (0.83 hours), 19 L/m2 (3.0 L/m2), and 51 mL/min/m2 (13 mL/min/m2), respectively. An average of 77% of 5-FU was excreted unchanged in urine after 28 days of treatment. The mean (range) 5-FU CSS,min values achieved at the 1.0 mg/m2 dose level were 22 ng/mL (8 to 38 ng/mL). CONCLUSION: Chronic oral administration of 5-FU with oral eniluracil is tolerable and produces 5-FU steady-state concentrations similar to those achieved with protracted intravenous administration of 5-FU on clinically relevant dose schedules. Eniluracil provides an attractive means of administering 5-FU on protracted schedules.
Low-Dose 5-Aza-2′-Deoxycytidine, a DNA Hypomethylating Agent, for the Treatment of High-Risk Myelodysplastic Syndrome: A Multicenter Phase II Study in Elderly Patients
Authors: Wijermans P. , Lübbert M. , Verhoef G. , Bosly A. , Ravoet C. , Andre M. , Ferrant A. 
Published: February 2017

PURPOSE: 5-Aza-2′-deoxycytidine (decitabine; DAC) is a DNA hypomethylating agent that has shown a 50% response rate in a small phase II study in elderly patients with high-risk myelodysplastic syndrome. We performed a second, multicenter phase II study in a larger group of patients to confirm our findings and to study the toxicity of DAC. PATIENTS AND METHODS: Between June 1996 and September 1997, 66 patients (median age, 68 years) from seven centers received DAC 45 mg/m2/d for 3 days every 6 weeks. For patients in whom a complete response (CR) was reached after two courses, two further cycles were administered as consolidation therapy. In case of a stable disease situation, improvement, or a partial response (PR), a maximum of six cycles was administered. The primary end points were response rate and toxicity. The secondary end points were response duration, survival from the start of therapy, and overall survival. RESULTS: The observed overall response rate was 49%, with a 64% response rate in the patients with an International Prognostic Scoring System (IPSS) high-risk score. The actuarial median response duration was 31 weeks, with a response duration of 39 weeks and 36 weeks for patients who reached a PR or CR, respectively. The actuarial median survival time from the time of diagnosis was 22 months and from the start of therapy was 15 months. For the IPSS high-risk group, the median survival time was 14 months. The median progression-free survival time was 25 weeks. Myelosuppression was rather common, and the treatment-related mortality rate was 7% and was primarily associated with pancytopenia and infection. Significant responses were observed with regard to megakaryopoiesis, with increases in platelet counts having already occurred after one cycle of DAC therapy in the majority of the responding patients. CONCLUSION: We were able to confirm our previous observation that DAC therapy was effective in half of the studied patients with high-risk myelodysplastic syndrome and is especially active in the patients with the worst prognoses. Myelosuppression was the only major adverse effect observed.
Primary Systemic Therapy in Operable Breast Cancer
Authors: Wolff Antonio C. , Davidson Nancy E. 
Published: February 2017

PURPOSE: Laboratory studies suggest that primary systemic therapy (PST) could improve control of micrometastatic disease and impact on overall survival (OS). This article examines the rationale for and preclinical and clinical data of PST in operable breast cancer and the potential role of intermediate biomarkers as predictive and/or prognostic factors for response and survival. DESIGN AND METHOD: We conducted an extensive literative review (including MEDLINE) on preclinical studies, single-arm feasibility studies, large randomized single- and multi-institutional trials, and laboratory correlate studies of PST in breast cancer. RESULTS: Small trials in locally advanced disease showed high initial rates of response and local control. Six randomized clinical trials (RCTs) of PST for palpable, operable breast cancer have been reported since 1991 (from 204 to 1,523 patients each). These data clearly show a small but significant (less than 10%) absolute increase in the use of breast-conservation treatment (BCT) with similar rates of local control. Although one study showed better disease-free survival (DFS) and another showed better OS, most studies did not show any survival advantage of primary versus adjuvant systemic therapy. Thus far, pathologic complete response seems to be the best predictor of survival, but clinical response assessment correlates poorly with pathologic response. Pilot studies demonstrated feasibility of procuring tissue at diagnosis and after treatment for assays of potential intermediate biomarkers. Initial data suggest a potential correlation between markers of proliferation and apoptosis and in vivo chemotherapy sensitivity. CONCLUSION: Thus far, RCTs of PST versus standard adjuvant therapy have not shown any clear benefit for DFS or OS in early breast cancer. Ongoing trials should determine if specific subsets of patients at risk would benefit from additional systemic therapy and the potential role of intermediate biomarkers in identifying such women. Although PST results in a small increase in the rate of BCT with similar rates of local control, current PST strategies should not replace standard adjuvant approaches. Rather, they represent an acceptable alternative to women with palpable, operable tumors and an excellent arena for clinical trials.