bluuebunny/crossref_metadata_2025_split huggingface dataset:
Thymidylate synthase inhibitors in cancer therapy: direct and indirect inhibitors.
Authors: Rustum Y M , Harstrick A , Cao S , Vanhoefer U , Yin M B , Wilke H , Seeber S 
Published: February 2017

PURPOSE AND METHODS Although fluoropyrimidines, in particular, fluorouracil (5-FU) and fluorodeoxyuridine (FdUrd), are active alone and in combination with other agents in a variety of human malignancies, therapeutic selectivity, resistance, and efficacy have been a major limitation in cancer therapy. Preclinical and clinical results in advanced and adjuvant colorectal cancers confirmed that the therapeutic efficacy of fluoropyrimidines, with thymidylate synthase (TS) as a primary target, can be improved significantly with leucovorin (LV) modulation. With the recognition that TS is an important therapeutic target, direct and specific inhibitors have been developed and are under intensive preclinical and clinical evaluation, primarily in patients with colorectal cancer, with demonstrable activity. The direct TS inhibitors have been shown to be potent, with a high level of specificity under therapeutic conditions for TS. This includes ZD1694, AG337, and LY231514. To date, although the therapeutic activity of both direct and indirect inhibitors of TS is similar, differences in the magnitude and profile of toxicity have been observed. A phase III comparative evaluation of a direct inhibitor of TS (ZD1694) with an indirect inhibitor (5-FU/LV) has been completed and showed similar activity but reduced toxicity in favor of ZD1694. RESULTS Recognition that greater than 95% of the injected dose of 5-FU is rapidly inactivated by dihydropyrimidine dehydrogenase (DPD) to therapeutically inactive products, but with toxicity to normal tissues, led to the development of inhibitors of this enzyme with the aim to modify the therapeutic index of 5-FU. Several inhibitors in combination with 5-FU are under preclinical and clinical evaluation, including uracil and 5-chloro-2,4-dihydroxy pyridine, as modulators of 5-FU derived from its prodrug tegafur and 5-ethynyluracil as a modulator of 5-FU. CONCLUSION In this review, an update of the present status of direct and indirect inhibitors of TS is discussed, as well as the future prospect for new drugs alone and in combination.
Fifteen-year survival and recurrence rates after radiotherapy for localized prostate cancer.
Authors: Eastham J A , Kattan M W , Groshen S , Scardino P T , Rogers E , Carlton C E , Lerner S P 
Published: February 2017

PURPOSE To determine 15-year survival and recurrence rates after radiotherapy for localized prostate cancer. METHODS One hundred thirty-six patients with clinically localized prostate cancer treated from 1966 to 1974 with interstitial gold seed and external-beam irradiation were evaluated to determine the probability of recurrence and survival > or = 15 years after therapy. All patients were surgically staged with pelvic lymphadenectomy and none received hormonal therapy before relapse. RESULTS Overall, 60 patients (44%) have never recurred, although 57% (34 of 60) of these same patients have died of causes other than prostate cancer. Local progression developed in 39% of patients and distant metastases in 42%. At 15 years, the probability of dying of prostate cancer was 33%+/-8% (% +/- 2SE) and of all causes was 72%+/-8%. In clinical stage A2 and B, 29%+/-9% of patients died of their cancer within 15 years, compared with 57%+/-21% in stage C1, while only 18%+/-8% with clinical stage A2 and B and negative lymph nodes died of cancer within this period. In contrast, the prostate cancer mortality rate at 15 years was high for patients with positive nodes regardless of the stage of the primary tumor (73% for A2 and B; 71% for C1). Patients with nodal metastases, poorly differentiated tumors, and advanced local disease all had a significantly (P < .0001) increased risk of cancer death. CONCLUSION The cancer-specific mortality rate for patients with stage A2 and B tumors and negative nodes compares favorably with other series of patients treated with radiation therapy and > or = 15 years' follow-up evaluation. While local progression rates are high and associated with a substantial risk of prostate cancer death, many patients live with the disease and ultimately die of causes other than prostate cancer.
Quantitation of intratumoral thymidylate synthase expression predicts for disseminated colorectal cancer response and resistance to protracted-infusion fluorouracil and weekly leucovorin.
Authors: Leichman C G , Lenz H J , Leichman L , Danenberg K , Baranda J , Groshen S , Boswell W , Metzger R , Tan M , Danenberg P V 
Published: February 2017

PURPOSE Response rates to fluorouracil (5-FU)-based therapy remain low. As new, active agents are being tested, information regarding specific intratumoral genetic determinants of chemotherapy sensitivity or resistance can be used to plan therapy rationally. Intratumoral thymidylate synthase (TS) quantitation may be among the most important determinants of sensitivity or resistance to 5-FU. MATERIALS AND METHODS Forty-six disseminated colorectal cancer patients had measurable tumor biopsies for polymerase chain reaction (PCR)-based determination of TS mRNA pretreatment. Protracted infusion of 5-FU 200 mg/m2/d for 21 days with weekly intravenous leucovorin 20 mg/m2 each cycle was given. After two cycles, responses were evaluated. Response data were correlated with independently determined intratumoral ratios of TS/beta-actin mRNA for each patient. RESULTS TS/beta-actin ratios were successfully obtained for 42 patients (91%). TS/beta-actin ratios ranged from 0.3 x 10(-3) to 18.2 x 10(-3) (median, 3.5 x 10[-3]). Twelve patients (26%) responded to treatment (median TS/beta-actin ratio, 1.7 x 10[+3]). Thirty-four patients did not respond (median TS/beta-actin ratio, 5.6 x 10[-3]). No patient with a TS mRNA level greater than 4.1 x 10(-3) responded. The median TS/beta-actin ratio (3.5 x 10[-3]) significantly segregated responders from nonresponders (P = .001). Median survival for patients with TS/beta-actin ratios < or = 3.5 x 10(-3) was 13.6 months; for patients with TS/beta-actin ratios greater than 3.5 x 10(-3), it was 8.2 months (P = .02). CONCLUSION For this cohort, the intratumoral TS/beta-actin ratio had a statistically significant association with response and survival. This relationship for other 5-FU schedules remains unknown. Confirmation of these data in a larger patient population could lead to determination of therapy for disseminated colorectal cancer based on a specific intratumoral molecular parameter.
High-dose cyclophosphamide for poor-prognosis and recurrent pediatric brain tumors: a dose-escalation study.
Authors: Yule S M , Foreman N K , Mitchell C , Gouldon N , May P , McDowell H P 
Published: February 2017

PURPOSE To determine the maximum-tolerated dose (MTD) of cyclophosphamide (CTX) when administered over 2 consecutive days followed by hematopoetic stem-cell rescue given as two sequential courses to children with glioblastoma multiforme, poor-prognosis pontine gliomas, and other recurrent CNS tumors. PATIENTS AND METHODS Two identical doses of CTX were administered 24 hours apart to 14 children and followed by hematopoetic stem-cell rescue. This treatment was repeated immediately following hematologic recovery. The starting dose of CTX was 2.5 g/m2/d with increments of 0.5 g/m2/d. CTX pharmacokinetics and metabolism were measured during 22 courses of treatment. Toxicity and tumor response were recorded. RESULTS There were two toxic deaths at the dose level of 4 g/m2/d. These were not clearly related to cardiac toxicity and may have been due to generalized capillary leak syndrome. Thus, the MTD of CTX was 3.5 g/m2/ d. There were six complete responses (CRs) (46%; (95% confidence interval [CI], 19% to 73%) and four partial responses (PRs) (31%; 95% CI, 6% to 56%), and one patient achieved stable disease. All children with intracranial primitive neuroectodermal tumors (PNETs) improved following CTX. The median duration of tumor response was 6 months (range, 4 to 29) and only one patient remains disease-free following CTX alone. Overall survival is 21% (95% CI, 13% to 29%) at a median follow-up time of 27 months (range, 12 to 34). CONCLUSION The MTD of CTX when followed by hematopoetic stem-cell rescue is 3.5 g/m2 administered on each of 2 consecutive days. This treatment was tolerable in children with poor-prognosis brain tumors and produced complete responses in children with recurrent PNETs.
Phase II trial of docetaxel in non-Hodgkin's lymphomas: a study of the Cancer and Leukemia Group B.
Authors: Budman D R , Petroni G R , Johnson J L , Cooper M R , Schlossman D M , Barcos M , Peterson B A 
Published: February 2017

PURPOSE To evaluate the new anticancer agent, docetaxel, with a novel mechanism of action in patients with non-Hodgkin's lymphoma International Working Formulation (IWF) A through H, to determine the response rate by histologic group and the toxicities of this agent in this population. PATIENTS AND METHODS Sixty-eight patients previously treated for non-Hodgkin's lymphoma with two prior cytotoxic regimens for low-grade and one prior regimen for intermediate-grade lymphoma were entered onto this phase II trial. Central pathologic review was required. Twenty-four IWF A to C and 31 IWF D to H patients with normal hepatic and renal function, performance status (PS) 0 to 2, and adequate hematologic function were eligible. Patients received docetaxel 100 mg/m2 intravenously over 1 hour without corticosteroid premedications every 3 weeks with weekly hematologic monitoring, and tumor assessment every 3 weeks. For grade 3 or 4 hematologic toxicity, the docetaxel dosage was lowered to 75 mg/m2. Patients received a maximum of six cycles of therapy. RESULTS The major response rate was 13% (95% confidence limits, 3% to 32%) for IWF A to C and 16% (95% confidence limits, 5% to 34%) for IWF D to H; response durations ranged from 1.4 to 20 months. Time to response ranged from 1.3 to 2.8 months. Patients refractory to previous chemotherapy were less apt to respond to docetaxel, but the differences were not statistically different in this small sample size. Twelve percent of IWF A to C and 6% of IWF D to H patients discontinued treatment because of toxicity. The major toxicity was granulocytopenia (grade 3 to 4), which occurred in virtually all patients during the first course of therapy. CONCLUSION This study confirms that docetaxel has limited but definite activity in patients with non-Hodgkin's lymphoma and suggests that the previously reported responses with taxanes can not be attributed solely to the use of corticosteroid premedications.
Intensive weekly chemotherapy for advanced gastric cancer using fluorouracil, cisplatin, epi-doxorubicin, 6S-leucovorin, glutathione, and filgrastim: a report from the Italian Group for the Study of Digestive Tract Cancer.
Authors: Cascinu S , Labianca R , Alessandroni P , Marcellini M , Silva R R , Pancera G , Testa E , Martignoni G , Barni S , Frontini L , Zaniboni A , Luporini G , Cellerino R , Catalano G 
Published: February 2017

PURPOSE A multiinstitutional trial was performed to confirm the clinical activity, in terms of response rate and toxicity (primary objectives) and duration of responses and survival (secondary objectives), of an intensive weekly regimen in advanced gastric cancer. PATIENTS AND METHODS Patients with measurable unresectable and/or metastatic gastric carcinoma received 1-day per week administration of cisplatin (CDDP) 40 mg/m2, fluorouracil (5FU) 500 mg/m2, epi-doxorubicin (epi-ADR) 35 mg/m2, 6S-stereoisomer of leucovorin 250 mg/m2, and glutathione 1.5 g/m2. On the other days, filgrastim was administered by subcutaneous injection at a dose of 5 mg/kg. One cycle of therapy consisted of eight 1-week treatments. Patients who showed a response or stable disease received a further 6 weeks of therapy. RESULTS Of 105 enrolled patients, 11 had locally advanced unresectable disease only; 33 had primary nonresected and metastatic disease; 48 had metastatic disease and primary tumor resected; 10 had locoregional recurrence and metastatic disease; and three had locoregional recurrence only. After one cycle, 18 complete responses (CRs) and 47 partial responses (PRs) were achieved, for an overall response rate of 62% (95% confidence interval [CI], 53% to 71%). Twenty patients had stable disease and 20 progressed on therapy. The median survival duration of all 105 patients was 11 months, with 1- and 2-year survival rates of 42% and 5%, respectively. World Health Organization (WHO) grade III to IV toxicity, in terms of anemia, neutropenia, thrombocytopenia, and mucositis, was experienced by 40 patients (38%). There were no treatment-related deaths. CONCLUSION These data support the results of the pilot study and confirmed the high activity of the regimen, with acceptable toxicity. This schedule deserves evaluation in the adjuvant setting.
CD30 ligand in lymphoma patients with CD30+ tumors.
Authors: Younes A , Consoli U , Snell V , Clodi K , Kliche K O , Palmer J L , Gruss H J , Armitage R , Thomas E K , Cabanillas F , Andreeff M 
Published: February 2017

PURPOSE CD30 ligand (CD30L), which is expressed on resting B and activated T lymphocytes, can induce cell death in several CD30+ cell lines. Patients with CD30+ tumors (Hodgkin's disease and Ki-1+ non-Hodgkin's lymphoma) frequently have elevated soluble CD30 (sCD30) levels in their serum, which correlates with a poor prognosis. The role of sCD30 in protecting tumor cells from CD30L-mediated cell death and the pattern of CD30L expression on human peripheral-blood lymphocytes (PBLs) of normal donors and patients with CD30+ tumors are investigated. MATERIALS AND METHODS CD30L surface protein expression was determined by two-color flow cytometry on PBLs of patients with CD30+ tumors and normal individuals. CD30L levels were determined on subsets of PBLs before and after stimulation with phytohemagglutinin (PHA), anti-CD3 antibody, or CD40L. sCD30 was measured by enzyme-linked immunosorbent assay (ELISA). The apoptotic activity of membrane-bound CD30L was tested in a CD30+ cell line by the annexin V-binding method. RESULTS Unstimulated T lymphocytes of normal donors and patients with lymphoma rarely expressed CD30L surface protein, but were able to express it after stimulation with PHA or anti-CD3 antibody. Resting B cells of patients with CD30+ tumors had lower levels of detectable surface CD30L compared with normal donors (mean, 55% and 80.6%, respectively; P = .0008). Patients with high levels of serum sCD30 had lower detectable levels of CD30L on their PBLs (R2 = .72, P = .0008) and exogenous sCD30 blocked membrane-bound CD30L-mediated apoptosis in a CD30+ cell line. CONCLUSION In patients with CD30+ tumors, sCD30 can decrease the availability of CD30L on PBLs. Blocking the apoptosis-inducing activity of CD30L by its soluble receptor may explain how CD30+ tumors escape immunosurveillance and may be related to the reported poor prognosis of patients who have elevated sCD30 levels.
Randomized placebo-controlled study of recombinant human interleukin-11 to prevent chemotherapy-induced thrombocytopenia in patients with breast cancer receiving dose-intensive cyclophosphamide and doxorubicin.
Authors: Isaacs C , Robert N J , Bailey F A , Schuster M W , Overmoyer B , Graham M , Cai B , Beach K J , Loewy J W , Kaye J A 
Published: February 2017

PURPOSE Thrombocytopenia may compromise cancer treatment, causing chemotherapy dose reductions, schedule alterations, or the need for platelet transfusions. We evaluated the efficacy and safety of recombinant human interleukin-11 (rhIL-11; Neumega, Genetics Institute, Inc, Cambridge, MA), a novel thrombopoietic growth factor, in reducing the need for platelet transfusions in patients who undergo dose-intensive chemotherapy. PATIENTS AND METHODS Women with advanced breast cancer received cyclophosphamide (3,200 mg/m2) and doxorubicin (75 mg/m2) plus granulocyte colony-stimulating factor (G-CSF; 5 microg/kg/d). Patients were randomized to blinded treatment with placebo or 50 microg/kg/d rhIL-11 subcutaneously for 10 or 17 days after the first two chemotherapy cycles. RESULTS Seventy-seven patients were randomized and constitute the intent-to-treat (ITT) population. Sixty-seven patients (the assessable subgroup) either completed both cycles without a major protocol violation (n = 62) or received a platelet transfusion before treatment was discontinued after the first cycle. In the ITT population, rhIL-11 significantly decreased the requirement for platelet transfusions; 27 of 40 (68%) patients who received rhIL-11 did not require transfusions, compared with 15 of 37 (41%) in the placebo group (P = .04). Treatment with rhIL-11 significantly reduced the total number of platelet transfusions required in the assessable subgroup (P = .03) and the time to platelet recovery to more than 50,000/microL in the second cycle (P = .01). Most adverse events associated with rhIL-11 were reversible, mild to moderate in severity, and likely related to fluid retention. CONCLUSION rhIL-11 is safe and effective in reducing treatment-associated thrombocytopenia and the need for platelet transfusions in patients who undergo dose-intensive chemotherapy, and thus may permit chemotherapy to be administered as planned at intended doses and thereby maximize the potential for a successful outcome.
Randomized trial of chemotherapy and radiation therapy with or without warfarin for limited-stage small-cell lung cancer: a Cancer and Leukemia Group B study.
Authors: Maurer L H , Herndon J E , Hollis D R , Aisner J , Carey R W , Skarin A T , Perry M C , Eaton W L , Zacharski L L , Hammond S , Green M R 
Published: February 2017

PURPOSE Studies by the Veterans Administration Cooperative Studies Program and Cancer and Leukemia Group B (CALGB) suggested that the addition of warfarin to chemotherapy might enhance response and/or survival in small-cell lung cancer (SCLC). This randomized study evaluated the effect of warfarin with chemotherapy and radiation therapy in limited-stage SCLC. PATIENTS AND METHODS Patients were randomized to receive warfarin or no warfarin. All patients received three cycles of doxorubicin, cyclophosphamide, and etoposide (ACE). Cycles 4 and 5 (cisplatin, cyclophosphamide, and etoposide [PCE]) were given concurrently with radiation therapy. Three cycles of ACE were given after chemoradiation therapy, but were discontinued due to a high rate of pulmonary toxicity. RESULTS There were no significant differences in response rates, survival, failure-free survival, disease-free survival, or patterns of relapse between the warfarin-treated and control groups. In patients treated according to the initial design, an increase in failure-free survival seen with warfarin treatment approached significance (P = .07). Preamendment results, while not significant, did not have superimposable treatment survival curves. A landmark analysis at 8 months showed a median survival time after the landmark for complete responders of 33 months with warfarin treatment compared with < or = 13.75 months for complete or partial responders not treated with warfarin (P = .05). Differences between the complete responders in this preamendment population were not significant (P = .103). CONCLUSION Warfarin does not appear to improve outcome significantly in limited-stage SCLC. However, the differences in some variables between populations before the protocol amendment correspond to the favorable effects of anticoagulants observed in previous studies.
Serum tissue polypeptide antigen in bladder cancer as a tumor marker: a prospective study.
Authors: Maulard-Durdux C , Toubert M E , Hennequin C , Housset M 
Published: February 2017

PURPOSE Tissue polypeptide antigen (TPA) is a differentiation and proliferation tissue marker of epithelia. Increased serum levels were found in some patients with invasive bladder cancer. We present the results of a prospective study that evaluated the role of serum TPA (S-TPA) in bladder carcinoma. PATIENTS AND METHODS The series included 167 patients treated for invasive bladder cancer between 1989 and 1996. S-TPA concentrations were measured by radioimmunoassay before treatment, at the end of treatment, and during follow-up evaluation. The upper normal limit of the test was set at 80 UI/L. RESULTS With a specificity of 100%, the diagnostic sensitivity was 46%. Pretherapeutic S-TPA levels were significantly correlated with tumor stage (T2 v T3 and T4; P = .02), with nodal stage (N0 v N1 and N2; P = .00001), and with metastatic stage (M0 v M1; P = 10[-6]), but not with histologic grading (grade 1 and 2 v 3). In the subset of patients with normal pretherapeutic S-TPA levels, 95% had no residual disease at the end of treatment, compared with 53% of patients with initial elevated S-TPA (P = 10[-8]). Among patients who achieved a complete response, 27% experienced a relapse, with an increase of S-TPA in 72% of cases. The mean follow-up time was 20 +/- 17 months. For patients with normal pretherapeutic S-TPA levels, 3-year overall survival and disease-free survival rates were 76% and 67% respectively. These were 46% (P = .001) and 25% (P = 10[-7]), respectively, for patients with high pretherapeutic S-TPA. Multivariate analysis showed that S-TPA was an independent prognostic factor for survival (P = .03). CONCLUSION In invasive bladder cancer, S-TPA level is correlated with initial tumor stage. It is a valuable parameter for follow-up evaluation and appears to be a prognostic factor in multivariate analysis.
Chronologic changes in the clinicopathologic findings and survival of gastric cancer patients.
Authors: Kitamura K , Yamaguchi T , Sawai K , Nishida S , Yamamoto K , Okamoto K , Taniguchi H , Hagiwara A , Takahashi T 
Published: February 2017

PURPOSE To determine the chronologic changes in the clinicopathologic features of gastric cancer patients. PATIENTS AND METHODS The clinicopathologic findings of 1,795 patients with gastric cancer were examined retrospectively from hospital records obtained between 1969 and 1995. The patients were divided into three generations on the basis of chronologic order. The first generation included patients treated over the period 1969 to 1977; the second generation, 1978 to 1986; and the third generation, 1987 to 1995. RESULTS The chronologic changes in the clinicopathologic findings for all gastric cancers included increases in the superficial type based on macroscopic appearance (P < .005), small-sized tumor (P < .025), superficial depth of invasion (P < .005), and earlier histologic stages (P < .005), in addition to a decrease in lymph node metastasis (P < .005). Overall, the postoperative survival rate has improved over time in gastric cancer patients, with 5-year survival rates of 36.0%, 53.3%, and 68.6% in the first, second, and third generations, respectively. In stages 1,2, and 3, the survival rate in the third generation was the highest of the three generations, whereas in stage 4, the survival rate did not differ between the three generations. Patients who underwent a D2 dissection showed a higher survival rate than those with D1 or D3 dissections, but there was no statistical difference in the survival of patients with D1, D2, and D3 dissections when stage 4 patients were excluded. CONCLUSION The chronologic changes in gastric cancer patients over the past 27 years have included an increase in the incidence of earlier-staged gastric cancers, which has had a significant impact on the improved postoperative survival rate.