bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chemoradiotherapy with or without granulocyte-macrophage colony-stimulating factor in the treatment of limited-stage small-cell lung cancer: a prospective phase III randomized study of the Southwest Oncology Group.
Authors: Bunn P A , Crowley J , Kelly K , Hazuka M B , Beasley K , Upchurch C , Livingston R , Weiss G R , Hicks W J , Gandara D R 
Published: February 2017

PURPOSE This phase III randomized trial was designed to determine if granulocyte-macrophage colony-stimulating factor (GM-CSF) reduces the hematologic toxicity and morbidity induced by chemoradiotherapy in limited-stage small-cell lung cancer (SCLC). METHODS This multicenter prospective trial randomized 230 patients to receive chemotherapy and radiotherapy (RT) with or without GM-CSF given on days 4 to 18 of each of six cycles. The primary end point was hematologic toxicity. Secondary end points included the following: nonhematologic toxicities; days of (1) fever, (2) antibiotics, (3) hospitalization, and (4) infection; number of transfusions; drug doses delivered; and response rates and survival. RESULTS There was a statistically significant increase in the frequency and duration of life-threatening thrombocytopenia (P < .001) in patients randomized to GM-CSF. GM-CSF patients had significantly more toxic deaths (P < .01), more nonhematologic toxicities, more days in hospital, a higher incidence of intravenous (IV) antibiotic usage, and more transfusions. Patients randomized to GM-CSF had higher WBC and neutrophil nadirs (P < .01), but no significant difference in the frequency of grade 4 leukopenia or neutropenia. Patients randomized to GM-CSF had a lower complete response rate (36% v 44%), but the differences were not significant (P = .29). There were no significant differences in survival (median, 14 months on GM-CSF and 17 months on no GM-CSF; P = .15). CONCLUSION GM-CSF, as delivered in this study, should not be included with concurrent chemoradiotherapy treatment programs for limited-stage SCLC. The simultaneous use of hematopoietic colony-stimulating factors (CSFs) and chemoradiotherapy should be performed only in experimental settings. Chemoradiotherapy programs with cisplatin and etoposide ([VP-16] PE) and simultaneous chest RT produce grade 4 neutropenia and thrombocytopenia in a small-enough proportion of patients that prophylactic hematopoietic growth factors are clinically unnecessary.
Results of a salvage treatment program for relapsing lymphoma: MINE consolidated with ESHAP.
Authors: Rodriguez M A , Cabanillas F C , Velasquez W , Hagemeister F B , McLaughlin P , Swan F , Romaguera J E 
Published: February 2017

PURPOSE We report the results of a prospective trial in which patients with relapsing non-Hodgkin's lymphomas were sequentially treated with two regimens (mesna, ifosfamide, mitoxantrone, and etoposide [MINE], and etoposide, methylprednisolone, cytarabine, and cisplatin [ESHAP]) if they had no history of disease resistance to these drugs. PATIENTS AND METHODS Ninety-two patients received MINE (mesna 4 g/m2, ifosfamide 4 g/m2, mitoxantrone 8 mg/m2, and etoposide 195 mg/m2) for a maximum of six courses followed by ESHAP (etoposide 240 mg/m2, methylprednisone 500 mg/d, high-dose cytarabine 2 g/m2, and cisplatin 100 mg/m2) for three courses to consolidate complete response (CR) or for a maximum of six cycles after a partial response (PR) or no response to MINE. Pretreatment serum levels of lactate dehydrogenase (LDH) and beta 2-microglobulin (beta 2M) were documented in 80 of 92 patients. RESULTS The response rate to MINE-ESHAP was 69% (48% CRs and 21% PRs), with a median survival time of 24 months and median time to treatment failure of 12 months. The median time to treatment failure according to histology was as follows: low-grade histologies, 16 months; low-grade transformed to intermediate-grade, 8 months; and intermediate-grade, 5 months. The most serious complication was myelosuppression, which resulted in two deaths due to neutropenic sepsis. A risk factor model based on beta 2M and LDH levels before salvage treatment showed three categories of risk, with 36-month survival rates as follows: low (beta 2M < 3 mg/dL and LDH normal), 61%; intermediate (beta 2M > or = 3 mg/dL or LDH above normal), 23%; and high (beta 2M > or = 3 mg/dL and LDH above normal), 0%. CONCLUSION MINE-ESHAP is an effective salvage strategy for patients with recurrent lymphoma. Toxicity was acceptable. Factors that determine prognostic categories at relapse merit further study.
Extramedullary myeloid cell tumors in acute nonlymphocytic leukemia: a clinical review.
Authors: Byrd J C , Edenfield W J , Shields D J , Dawson N A 
Published: February 2017

PURPOSE To discuss the predisposing risk factor for all forms of extramedullary leukemia (EML) and to review the clinical features, prognostic significance, and treatment strategies for primary EML and leukemia cutis (LC)/granulocytic sarcomas (GS) in the setting of acute nonlymphocytic leukemia (ANLL). METHODS A review of all reports published since 1965 related to all forms of extramedullary leukemia (LC, GS, gingival hypertrophy, and meningeal leukemia [ML]). RESULTS Several factors, including chromosomal abnormalities [t(8;21), inv(16)], cell-surface markers (CD56, CD2, CD4, CD7), French-American-British (FAB) subtype (M2, M4, M5), blast differentiation and maturation, patient nutritional status, age, cellular immune dysfunction, high presenting leukocyte count, and decreased blast Auer rods, have been associated with a higher incidence of EML. Of 154 published cases of primary EML identified, 71 (46%) were initially misdiagnosed. The addition of immunohistochemical stains can assist in preventing such misdiagnoses and should be included in all atypical lymphoma/carcinoma cases. Only one of the patients (3%) with primary EML did not progress to ANLL in the absence of chemotherapy. In contrast, 66% of patients who received chemotherapy for the primary EML never developed ANLL. The prognostic significance of EML at presentation and medullary relapse of ANLL is uncertain. Isolated extramedullary recurrence of ANLL always heralds bone marrow relapse and should be treated with reinduction chemotherapy. Close clinical follow-up observation is necessary to insure resolution of EML. Radiation therapy is an effective local treatment for resistant or symptomatic EML. CONCLUSION Many advances in diagnoses and treatment of EML have been made. Future investigations are needed to define the clinical significance of EML in patients with ANLL treated with modern chemotherapy or bone marrow transplantation.
Expression of p53 oncoprotein in non-small-cell lung cancer: a favorable prognostic factor.
Authors: Lee J S , Yoon A , Kalapurakal S K , Ro J Y , Lee J J , Tu N , Hittelman W N , Hong W K 
Published: February 2017

PURPOSE Mutation of the p53 gene is one of the most common genetic abnormalities found in lung cancer. The purpose of this study was to evaluate the prognostic value of p53 oncoprotein expression in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS We studied 156 resected primary NSCLCs by the immunohistochemical staining technique, using the p53 antibody DO7. There were 81 adenocarcinomas, 16 large-cell carcinomas, and 59 squamous cell carcinomas; stages were I in 67, II in 30, and III in 59 cases. For each tumor, the percentage of p53 positivity was calculated by scoring a minimum of 1,000 cells on an arbitrary intensity scale of 0 to 3+. RESULTS Overall, 103 (66%) tumors expressed p53 in more than 0.1% of cells, and squamous cell carcinomas tended to express more p53 than adenocarcinomas. Since 50% positivity marked the most distinct change in overall survival duration (P = .0008), we divided the cases into three groups, as follows: p53-negative (< or = 0.1%, n = 53), low p53 (0.1% to 50%, n = 54), and high p53 (> 50%, n = 49). Overall, patients in the high-p53 group survived longer than those in the low or negative groups, with respective median survival durations of more than 65, 26, and 33 months (P = .002). The survival difference among the three groups was statistically significant for non-squamous cell (P = .008), but not for squamous cell (P = .17) carcinomas. Among lymph node-negative patients, the survival difference between groups was not statistically significant. However, among lymph node-positive patients (n = 78), more than 65% of the high-p53 group survived for more than 70 months, while the median survival durations for the low and negative groups were 21 and 18 months, respectively (P = .001). A Cox regression analysis with multiple covariates showed that p53 positivity in more than 50% of tumor cells was an independent prognostic factor for better outcome. CONCLUSION These results suggest that high expression of the p53 oncoprotein is a favorable prognostic factor in a subset of patients with NSCLC.
Phase I/II trial of dexverapamil plus vinblastine for patients with advanced renal cell carcinoma.
Authors: Motzer R J , Lyn P , Fischer P , Lianes P , Ngo R L , Cordon-Cardo C , O'Brien J P 
Published: February 2017

PURPOSE The reduced cardiac toxicity of the dextro-(d-) stereoisomer of verapamil (dexverapamil; Knoll Pharmaceuticals, Whippany, NJ) warrants its study as a potential multidrug-resistance (MDR) reversal agent. PATIENTS AND METHODS Twenty-three patients with advanced renal cell carcinoma (RCC) were treated with vinblastine at a dose of 0.11 mg/kg intravenous (IV) bolus injection on days 1 and 2 every 21 days. Dexverapamil was added to subsequent cycles after resistance had been demonstrated. Dexverapamil treatment was begun 18 hours before day 1 of vinblastine administration and was given orally every 6 hours for 12 doses. Patients in group A were treated with a dose of 120 mg/m2, and those in group B were treated with 180 mg/m2 plus dexamethasone; plasma concentrations achieved in patients were correlated with in vitro effects. RESULTS Toxicities included hypotension, asymptomatic bradycardia, and mild atrioventricular conduction delays, although one patient had dexverapamil discontinued for grade IV congestive heart failure. There were no partial or complete responses. The mean day-1 serum dexverapamil plus norverapamil plasma concentrations were 2,575 ng/mL (range, 697 to 6,015 ng/mL) for group A and 1,654 ng/mL (range, 710 to 4,132 ng/mL) for group B at the time of vinblastine administration. These concentrations were in the range of those that reversed vinblastine resistance in vitro. CONCLUSION The advantage of dexverapamil as an MDR reversal agent is its potential for achieving desired blood levels with substantially less toxicity than the racemic mixture of verapamil. Based on tolerability, it is a suitable drug for further study in clinical trials of malignancies other than RCC that attempt to achieve MDR reversal. The dose of 120 mg/m2 given orally every 6 hours, with dose escalation based on individual tolerance, represents a feasible schedule to be considered for such studies.
Effect of R-verapamil on the pharmacokinetics of paclitaxel in women with breast cancer.
Authors: Berg S L , Tolcher A , O'Shaughnessy J A , Denicoff A M , Noone M , Ognibene F P , Cowan K H , Balis F M 
Published: February 2017

PURPOSE To study the effect of the multidrug-resistance reversal agent R-verapamil on the pharmacokinetic behavior of paclitaxel. METHODS Six women with breast cancer who received paclitaxel as a 3-hour infusion with and without R-verapamil were monitored with frequent plasma sampling up to 24 hours postinfusion. Paclitaxel concentrations were measured using a reverse-phase high-pressure liquid chromatography assay. RESULTS Concomitant administration of R-verapamil resulted in a decrease in mean (+/- SD) paclitaxel clearance from 179 +/- 67 mL/min/m2 to 90 +/- 34 mL/min/m2 (P < .03) and in a twofold increase in paclitaxel exposure (area under the curve [AUC]). The mean end-infusion paclitaxel concentration was also twofold higher: 5.1 +/- 1.8 mumol/L versus 11.3 +/- 4.1 mumol/L (P < .03). CONCLUSION The alteration in paclitaxel pharmacokinetics when paclitaxel and R-verapamil are coadministered complicates the interpretation of response and toxicity data from clinical trials of this drug combination.
Prognostic factors for prolonged progression-free survival with high-dose chemotherapy with autologous stem-cell support for advanced breast cancer.
Authors: Ayash L J , Wheeler C , Fairclough D , Schwartz G , Reich E , Warren D , Schnipper L , Antman K , Frei E , Elias A 
Published: February 2017

PURPOSE With a median observation time of 50 months from transplant, 13 (22%) of 62 women with metastatic breast cancer treated with high-dose chemotherapy at the Dana-Farber Cancer Institute (DFCI)/Beth Israel Hospital (BIH) remain progression-free. This study determined factors prognostic for prolonged progression-free survival (PFS). METHODS From June 1988 to January 1992, women who responded to standard chemotherapy received high-dose cyclophosphamide, thiotepa, and carboplatin with autotransplantation. Data encompassing initial breast cancer diagnosis, metastatic presentation, and response to induction treatment were examined for correlations with improved PFS. RESULTS The 5-year PFS rate for the entire group is estimated to be 21% (95% confidence interval [CI], 10% to 32%). For those patients who attained a complete response (CR) to induction therapy, the 5-year PFS rate is estimated to be 31% (95% CI, 0% to 63%). In univariate analyses, a single metastatic site, CR to induction therapy, prolonged interval from primary diagnosis to first metastases, estrogen receptor (ER)-negative tumors, and older age (> or = 40 years) were associated with prolonged PFS. In multivariate analyses, single metastatic site (P = .002) and attainment of a CR to induction chemotherapy (P = .04) were the most significant predictors for PFS, with a strong trend observed for an interval from primary diagnosis to onset of metastatic disease of 24+ months (P = .066). CONCLUSION We and others have shown that 10% to 25% of women with metastatic breast cancer are progression-free after high-dose chemotherapy with autotransplantation. Those with chemosensitive disease, minimal tumor bulk, and a prolonged disease-free interval appear to benefit most. Emphasis should continue to focus on the development of more effective cytotoxic regimens and biologic approaches to increase the percentage of patients who may benefit from this approach.
Detection of occult melanoma cells in blood with a multiple-marker polymerase chain reaction assay.
Authors: Hoon D S , Wang Y , Dale P S , Conrad A J , Schmid P , Garrison D , Kuo C , Foshag L J , Nizze A J , Morton D L 
Published: February 2017

PURPOSE The objective of the study was to develop a sensitive multimarker polymerase chain reaction (PCR) assay to detect circulating melanoma cells in patient blood. The rationale was that malignant melanoma is heterogeneous in regards to antigen expression. PATIENTS AND METHODS A PCR assay that uses four melanoma-associated gene markers (tyrosinase, p97, MUC18, and MAGE-3) was developed. Sensitivity and specificity of the PCR assay for individual markers were assessed using 10 melanoma cell lines and peripheral-blood lymphocytes (PBL) from 39 normal volunteers as controls. The assay's sensitivity and specificity were improved using nested primers and Southern blot analysis. Patients (N = 119) with American Joint Committee on Cancer (AJCC) stages I to IV disease were evaluated for circulating melanoma cells using the four gene markers under optimal conditions. RESULTS All melanoma-associated gene markers were expressed in at least 80% of the melanoma lines, whereas 37 of 39 normal PBL tested negative for all markers; the remaining two PBL were positive for MUC18. Using four markers in the PCR assay was significantly better than using tyrosinase alone. There was a significant correlation between the number of positive PCR markers, AJCC stage of disease, and progression of disease. In all AJCC stages, there were more PCR-positive patients with disease than without disease. CONCLUSION A multimarker PCR assay is more reliable and sensitive than a single-marker assay for detection of melanoma cells in blood of patients. This assay can provide important insight into tumor progression kinetics without major surgical or conventional radiologic diagnostic procedures.
Phase I study of suramin given by intermittent infusion without adaptive control in patients with advanced cancer.
Authors: Kobayashi K , Vokes E E , Vogelzang N J , Janish L , Soliven B , Ratain M J 
Published: February 2017

PURPOSE Suramin is a promising agent for the treatment of hormone-refractory metastatic prostate cancer. However, questions about the relationship of severe neurotoxicity to sustained peak plasma concentrations greater than 300 micrograms/mL raised concerns that this drug could not be safely administered without adaptive control. To test the adaptive-control hypothesis, we designed a phase I study that relied on clinical end points, using a fixed dosing scheme that did not rely on adaptive control. PATIENTS AND METHODS In a phase I dose-escalation study using fixed dosing without adaptive control, gradually decreasing doses of suramin were administered to 63 patients on days 1 (loading dose), 2, 8, and 9 of a 28-day cycle. Fifty-four patients with hormone-refractory metastatic prostate cancer and nine patients with other solid tumors have been treated. RESULTS Doses of 400 mg/m2 to 2,080 mg/m2 on the first day have been administered. The mean peak plasma concentration following the loading dose at a dose level of 1,730 mg/m2 was 933 micrograms/mL (26% coefficient of variation), and the mean trough concentration was 139 micrograms/mL (40% CV) on day 1 of cycle 2 [corrected]. At 1,730 mg/m2, five of 13 patients experienced dose-limiting toxicity (DLT), including malaise, neurotoxicity, pericardial effusion, and coagulopathy. At 2,080 mg/m2, three of five patients experienced DLT. Two patients treated at this dose level died while on study. One of these patients died of a subdural hematoma sustained after a fall and had a prolonged prothrombin time at the time of his death. One patient developed classic suramin neurotoxicity, which led to respiratory failure, for which the patient refused intubation. No significant associations were noted between peak or trough concentrations during either cycles 1 or 2 and the occurrence of neurotoxicity. CONCLUSION (1) Suramin can be safely administered without adaptive control, (2) suramin on this schedule may exhibit significant activity against hormone-refractory metastatic prostate cancer, and (3) based strictly on toxicity considerations, we recommended that a day-1 dose of 1,440 mg/m2 be used in subsequent clinical trials, with a maximum of three cycles. Further studies to establish the optimal empiric dosing regimen are needed.
Pharmacologic variables associated with the development of neurologic toxicity in patients treated with suramin.
Authors: Bitton R J , Figg W D , Venzon D J , Dalakas M C , Bowden C , Headlee D , Reed E , Myers C E , Cooper M R 
Published: February 2017

PURPOSE To describe pharmacologic variables correlated with the development of neurologic toxicity in patients treated with suramin. METHODS Eighty-one patients were treated with suramin in a phase I study. The rate of drug infusion was continuously adjusted to maintain a preassigned plasma suramin concentration (175, 215, or 275 micrograms/mL) for a fixed duration (2 to 8 weeks). RESULTS Eight patients developed grade III/IV neurologic motor impairment (predominantly motor axonal polyneuropathy). All were treated at the 275-micrograms/mL concentration. One patient treated at the 215-micrograms/mL concentration developed grade II motor dysfunction. In addition, seven of nine patients had sensory symptoms. Pharmacologic variables associated with the development of polyneuropathy included total cumulative suramin dose, duration of exposure to plasma concentrations greater than 200 micrograms/mL, and area under the curve (AUC) greater than 200 micrograms/mL. CONCLUSION Significant neurologic toxicity can result from therapy with suramin, even when dosing is designed to avoid exposure to plasma concentrations greater than 350 micrograms/mL. Future clinical trials of suramin should be designed in such a way as to limit the total cumulative dose to < or = 157 mg/kg given over a period of > or = 8 weeks, limit the period of exposure to plasma suramin concentrations greater than 200 micrograms/mL to < or = 25 days, and limit the AUC greater than 200 micrograms/mL to < or = 48,000 mg.h/AL.
Phase Ia/Ib trial of bispecific antibody MDX-210 in patients with advanced breast or ovarian cancer that overexpresses the proto-oncogene HER-2/neu.
Authors: Valone F H , Kaufman P A , Guyre P M , Lewis L D , Memoli V , Deo Y , Graziano R , Fisher J L , Meyer L , Mrozek-Orlowski M 
Published: February 2017

PURPOSE MDX-210 is a bispecific antibody that binds simultaneously to type I Fc receptors for immunoglobulin G (IgG) (Fc gamma RI) and to the HER-2/neu oncogene protein product. MDX-210 effectively directs Fc gamma RI-positive effector cells such as monocytes and macrophages to phagocytose or kill tumor cells that overexpress HER-2/neu. The goals of this phase Ia/Ib trial were to determine the maximum-tolerated dose (MTD) and/or the optimal biologic dose (OBD) of MDX-210. PATIENTS AND METHODS Patients with advanced breast or ovarian cancer that overexpressed HER-2/neu were eligible for treatment. Cohorts of three patients received a single intravenous (IV) infusion of MDX-210 at increasing dose levels from 0.35 to 10.0 mg/m2. RESULTS Treatment was well tolerated, with most patients experiencing transient grade 1 to 2 fevers, malaise, and hypotension only. Two patients experienced transient grade 3 hypotension at 10.0 mg/m2. Transient monocytopenia and lymphopenia developed at 1 to 2 hours, but no other hematologic changes were observed. Doses of MDX-210 > or = 3.5 mg/m2 saturated > or = 80% of monocyte Fc gamma RI and produced peak plasma concentrations > or = 1 microgram/mL, which is greater than the concentration for optimal monocyte/macrophage activation in vitro. Elevated plasma levels of the monocyte products tumor necrosis factor alpha (TNF alpha), interleukin-6 (IL-6), granulocyte colony-stimulating factor (G-CSF), and neopterin were observed with maximal levels at doses > or = 7.0 mg/m2. Localization of MDX-210 in tumor tissue was demonstrated in two patients. One partial and one mixed tumor response were observed among 10 assessable patients. CONCLUSION MDX-210 is immunologically active at well-tolerated doses. The MTD and OBD is 7 to 10 mg/m2.