tbuckley/cabot-search huggingface dataset:
Increasing 4'-epidoxorubicin and fixed ifosfamide doses plus granulocyte-macrophage colony-stimulating factor in advanced soft tissue sarcomas: a pilot study.
Authors: S Frustaci, A Buonadonna, E Galligioni, D Favaro, A De Paoli, G Lo Re, R Sorio, S Tumolo, S Monfardini
Journal: Journal of Clinical Oncology (1997)

PURPOSE To determine the maximum-tolerated dose (MTD) of 4'-epidoxorubicin (EPI) in combination with full dose of ifosfamide (IFO) when granulocyte-macrophage colony-stimulating factor (GM-CSF) was used, to estimate its clinical efficacy, and to evaluate the mobilization of hematopoietic progenitors. PATIENTS AND METHODS Previously untreated advanced patients were treated with fixed doses of IFO at 1.8 g/m2/d for 5 days and escalating doses of EPI. The starting dose level of EPI was 50 mg/m2 bolus on days 1 and 2; subsequent levels were 60 mg/m2 and 70 mg/ m2 given on days 1 and 2. GM-CSF (5 micrograms/kg/d) was administered from days +6 to +19. Clinical evaluation of response was performed after three consecutive cycles. Mobilization of hematopoietic progenitors was evaluated as day 14 CFU-GM after the first cycle only. RESULTS Overall, six, 18, and 13 assessable patients were entered onto each EPI dose level, respectively. The first and the second EPI level were considered feasible. Conversely, at the third level, only six of 13 patients [46%] tolerated full EPI doses at the scheduled time. Therefore, the dose-intensity of the three levels was 100%, 99.7%, and 86.1%, respectively. Overall, 20 of 37 patients (54%) obtained an objective response. The response rates for the three EPI dose levels were significantly different [17%, 33%, and 100%, respectively; test for trend, P &lt; .001]. Considering only lung metastases, the overall response rate was 72% (20%, 66%, and 100% for the three EPI levels, respectively). The most relevant mobilization effect was obtained at the third EPI level, when both GM-CSF and IL-3 were used as in vitro-stimulating factors. CONCLUSION The third EPI level (70 mg/m2 on days 1 and 2) is the MTD of this program, since it was administered, without dose reduction or treatment delay, for three consecutive cycles in less than half of the patients. Nevertheless, this level proved to be interesting with regard to response rate (13 of 13 objective responses) and in mobilization of the hematopoietic progenitors.
Oxaliplatin or Paclitaxel in Patients With Platinum-Pretreated Advanced Ovarian Cancer: A Randomized Phase II Study of the European Organization for Research and Treatment of Cancer Gynecology Group
Authors: Martine J. Piccart, John A. Green, Angel Jimenez Lacave, Nick Reed, Ignace Vergote, Pierluigi Benedetti-Panici, Andrea Bonetti, Vera Kristeller-Tome, Cesar Mendiola Fernandez, Desmond Curran, Martine Van Glabbeke, Denis Lacombe, Marie-Claire Pinel, Serge Pecorelli
Journal: Journal of Clinical Oncology (2000)

PURPOSE: This was a multicentric, open, randomized, phase II study of single-agent paclitaxel and oxaliplatin to evaluate the efficacy of oxaliplatin in a relapsing progressive ovarian cancer patient population and to analyze the safety profile and impact of both agents on quality of life, time to progression, and survival. PATIENTS AND METHODS: Eighty-six patients with platinum-pretreated advanced ovarian cancer were randomly assigned to two arms: 41 received paclitaxel at 175 mg/m 2 over 3 hours every 3 weeks, and 45 received oxaliplatin at 130 mg/m 2 over 2 hours every 3 weeks. For inclusion, patients had to have a performance status of 0 to 2 and to have received at least one and no more than two prior cisplatin- and/or carboplatin-containing chemotherapy regimens within the last 12 months. RESULTS: Seven confirmed responses were observed in each arm, for an overall response rate in the total treated population of 17% (95% confidence interval [CI], 7% to 32%) in the paclitaxel arm and 16% (95% CI, 7% to 29%) in the oxaliplatin arm. Median time to progression was 14 weeks and 12 weeks, and overall survival was 37 weeks and 42 weeks in the paclitaxel and oxaliplatin arms, respectively. Among 63 patients with a 0- to 6-month progression-free, platinum-free interval, there were five objective responses with paclitaxel in 31 patients and two objective responses with oxaliplatin in 32 patients. Nine patients (22%) in the paclitaxel arm had grade 3 or 4 neutropenia (National Cancer Institute of Canada [NCIC] Common Toxicity Criteria). Two patients (4%) experienced grade 3 thrombocytopenia in the oxaliplatin arm. Maximum grade (grade 3) NCIC neurosensory toxicity was experienced by three patients (7%) in the paclitaxel arm and by four patients (9%) in the oxaliplatin arm. CONCLUSION: Single-agent oxaliplatin at 130 mg/m 2 every 3 weeks is active with moderate toxicity in patients with cisplatin-/carboplatin-pretreated advanced ovarian cancer.
OPTIMOX study: FOLFOX 7/LV5FU2 compared to FOLFOX 4 in patients with advanced colorectal cancer
Authors: A. De Gramont, A. Cervantes, T. Andre, A. Figer, G. Lledo, M. Flesch, L. Mineur, G. Russ, E. Quinaux, P.-L. Etienne
Journal: Journal of Clinical Oncology (2004)

3525 Background: FOLFOX4 has shown superiority over LV5FU2 and IFL in first line therapy. Limiting toxicities are neutropenia mainly due to 5FU bolus and cumulative sensory neurotoxicity which imposes to stop oxaliplatin (ox). OPTIMOX is a phase III study in pts with conventional inclusion criteria (526 pts), and two exploratory studies in pts not included in previous studies (37 pts > 75 yrs, 63 pts Alk Ph > 3xUNV) of a new strategy with ox stop and go: FOLFOX7 (high-dose ox and 5FU infusion, 6 cy) followed by 12 cy simplified (s) LV5FU2 and later FOLFOX7 reintroduction. Methods : 526 pts ≤ 75 yrs and/or Alk Ph ≤ 3xUNL were randomized Arm A FOLFOX4 (Ox 85mg/m2 d1, LV 200mg/m2, 5FU bolus 400mg/m2 and 22h 600mg/m2 d1–2, q2w) or Arm B FOLFOX7 x 6 cy (ox 130mg/m2 d1, LV 400mg/m2, 5FU 46h 2.4g/m2, q2w) followed by sLV5FU2 x 12 cy (LV 400mg/m2, 5FU bolus 400mg/m2 d1 and 46-h infusion 2.4g/m2, q2w) then FOLFOX7 reintroduction. Results : Arm A, 262 pts: M/F 58/42%, PS 0/1–2 55/45%, median age 63 yrs; Arm B, 264 pts: M/F 62/38%, PS 0/1–2 56/44%, median age 63 yrs. 3514 cy (2938 with ox, median DI 41.9mg/m2/wk) were administered in arm A and 4107 cy (2076 with ox, median DI 62.2mg/m2/wk) in arm B. Grade 3–4 toxicity (pts %) was in arm A/B : neutrophils 33.2/21.9, platelets 3.1/10.6, nausea 5.7/9.4, mucositis 3.1/6.5, diarrhea 11.1/11.8, neuro 18.7/13.3, maximal 54.6/49.2. RR was 58.8% in arm A and 59.5% in arm B. 28 pts arm A and 26 pts arm B had complete resection of metastasis. In arm A and B, median PFS were 9.2 and 9.0 months (P=0.47), median OS were 20.7 and 21.4 months (P=0.75), respectively. The primary endpoint is time of disease control (TDC=PFS first FOLFOX+PFS reintroduction if PR or SD), median TDC was 9.9 arm A and 11.3 months arm B (P=0.61). Ox was reintroduced in 8.4% pts arm A and 42% arm B. Reintroduction achieved 11.6% RR, 33.9% SD. Post study, in arm A 17.6% pts received ox-based and 58.3% irinotecan-based regimen, in arm B 13.3% received ox-based and 58.3% irinotecan-based regimens. Conclusions : The optimox stop and go strategy is a convenient alternative to FOLFOX4 in first-line therapy. Further studies will use a lower oxaliplatin dose-intensity to improve the reintroducction rate and evaluate lack of sLV5FU2 maintenance. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Sanofi-Synthelabo Sanofi-Synthelabo
Phase I trial of liposomal muramyl tripeptide phosphatidylethanolamine in cancer patients.
Authors: James L. Murray, Eugenie S. Kleinerman, Joan E. Cunningham, Janet R. Tatom, Kathe Andrejcio, Jose Lepe-Zuniga, Lamk M. Lamki, Michael G. Rosenblum, Heiner Frost, Jordan U. Gutterman, Isaiah J. Fidler, Irwin H. Krakoff
Journal: Journal of Clinical Oncology (1989)

Twenty-eight evaluable patients with metastatic cancer refractory to standard therapy received escalating doses of muramyl tripeptide phosphatidylethanolamine (MTP-PE) (.05 to 12 mg/m2) in phosphatidylserine (PC):phosphatidylcholine (PS) liposomes (lipid:MTP-PE) ratio 250:1). Liposomal MTP-PE (L-MTP-PE) was infused over 1 hour twice weekly; doses were escalated within individual patients every 3 weeks as tolerated for a total treatment duration of 9 weeks. Routine clinical laboratory parameters, acute phase reactants and various immunologic tests were monitored at various time points during treatment. Toxicity was moderate (less than or equal to grade II) in 24 patients with chief side effects being chills (80% of patients), fever (70%), malaise (60%), and nausea (55%). In four patients L-MTP-PE treatment was deescalated due to severe malaise and recurrent fever higher than 38.8 degrees C. The maximum-tolerated dose (MTD) was 6 mg/m2. Significant (P less than .05) increases in WBC count, absolute granulocyte count, ceruloplasmin, beta 2-microglobulin, c-reactive protein, monocyte tumoricidal activity, and serum IL-1 beta were found. Significant decreases in serum cholesterol were also observed. Clearance of intravenously (iv)-infused technetium-99 (99mTc)-labeled liposomes containing MTP-PE in four patients was biphasic; gamma camera scans revealed uptake of radiolabel in liver, spleen, lung, nasopharynx, thyroid gland, and tumor (two patients). No objective tumor regression was seen. In view of its definite immunobiologic activity and lack of major toxicity, additional phase II and adjuvant trials of L-MTP-PE are warranted.
Prospective study evaluating the relative sensitivity of 18F-NaF PET/CT for detecting skeletal metastases from renal cell carcinoma in comparison to multidetector CT and 99mTc-MDP bone scintigraphy, using an adaptive trial design
Authors: E.L. Gerety, E.M. Lawrence, J. Wason, H. Yan, S. Hilborne, J. Buscombe, H.K. Cheow, A.S. Shaw, N. Bird, K. Fife, S. Heard, D.J. Lomas, A. Matakidou, D. Soloviev, T. Eisen, F.A. Gallagher
Journal: Annals of Oncology (2015)

BackgroundThe detection of occult bone metastases is a key factor in determining the management of patients with renal cell carcinoma (RCC), especially when curative surgery is considered. This prospective study assessed the sensitivity of 18F-labelled sodium fluoride in conjunction with positron emission tomography/computed tomography (18F-NaF PET/CT) for detecting RCC bone metastases, compared with conventional imaging by bone scintigraphy or CT.Patients and methodsAn adaptive two-stage trial design was utilized, which was stopped after the first stage due to statistical efficacy. Ten patients with stage IV RCC and bone metastases were imaged with 18F-NaF PET/CT and 99mTc-labelled methylene diphosphonate (99mTc-MDP) bone scintigraphy including pelvic single photon emission computed tomography (SPECT). Images were reported independently by experienced radiologists and nuclear medicine physicians using a 5-point scoring system.ResultsSeventy-seven lesions were diagnosed as malignant: 100% were identified by 18F-NaF PET/CT, 46% by CT and 29% by bone scintigraphy/SPECT. Standard-of-care imaging with CT and bone scintigraphy identified 65% of the metastases reported by 18F-NaF PET/CT. On an individual patient basis, 18F-NaF PET/CT detected more RCC metastases than 99mTc-MDP bone scintigraphy/SPECT or CT alone (P = 0.007). The metabolic volumes, mean and maximum standardized uptake values (SUVmean and SUVmax) of the malignant lesions were significantly greater than those of the benign lesions (P < 0.001).Conclusions18F-NaF PET/CT is significantly more sensitive at detecting RCC skeletal metastases than conventional bone scintigraphy or CT. The detection of occult bone metastases could greatly alter patient management, particularly in the context when standard-of-care imaging is negative for skeletal metastases.
A randomized trial of chemotherapy followed by pelvic radiation therapy in stage IIIB carcinoma of the cervix.
Authors: L Souhami, R A Gil, S E Allan, P C Canary, C M Araújo, L H Pinto, T R Silveira
Journal: Journal of Clinical Oncology (1991)

Because of the poor results in stage III B carcinoma of the cervix with standard treatment using radiotherapy alone, we designed a randomized trial to determine whether administration of chemotherapy before pelvic irradiation would improve survival. Between May 1984 and August 1986, 107 patients with previously untreated squamous cell carcinoma were randomly assigned, after stratification by age (less than 50 v greater than 50 years), extent of parametrial involvement (unilateral v bilateral), and lymphangiographic findings (negative v positive) to pelvic radiotherapy (RT; arm A) or three cycles of chemotherapy (CT; bleomycin, vincristine, mitomycin, and cisplatin [BOMP]), followed by the same radiotherapy regimen (CT + RT; arm B). The groups were balanced by age, performance status, extent of parametrial involvement, bulkiness of cervical disease, nodal involvement, and presence of hydronephrosis. Minimal follow-up is 34 months. A complete local response was observed in 32.5% of the patients in arm A and in 47% of the patients in arm B (P = .19). Overall 5-year survival rates were 39% for the RT arm and 23% for the CT + RT approach (P = .02). Toxicity was severe in arm B and included fatal pulmonary toxicity in four patients. Locoregional and distant failures were similar in both groups. We conclude that, despite a satisfactory response rate, neoadjuvant BOMP chemotherapy adversely affects survival in stage III B cervical cancer and is associated with unacceptable toxicity.
Abstract 1134: N-Myc promotes glutamine anaplerosis and aggressive tumor progression through direct GLS2 activation
Authors: Daibiao Xiao, Ping Ren, Hexiu Su, Ming Yue, Ruijuan Xiu, Lei Gan, Hudan Liu, Guoliang Qing
Journal: Cancer Research (2015)

Abstract Elevated glutamine metabolism is an essential feature for malignant transformation. Glutaminase-catalyzed deamidation of glutamine to glutamate is a key step in both glutaminolysis and synthesis of ROS-scavenging glutathione. Two predominant human isozymes of glutaminase, kidney-type GLS1 (also called GLS) and liver-type GLS2, are involved in regulation of glutaminolysis. It has been shown the Myc family member, c-Myc, specifically potentiates elevated expression of GLS1 and promotes the downstream utilization of glutamine carbon in anaplerosis in liver cancer, whereas p53 tumor suppressor specifically activates GLS2 to support cellular defense against oxidative stress, suggesting GLS1 promoted tumorigenesis whereas GLS2 may inhibited it. However, whether cancer cells of different origins use a common or unique signal pathways to regulate glutamine metabolism remains largely unexplored. Using MYCN-amplified neuroblastoma as a model system, we identified GLS2 expression dramatically increased while that of GLS1 substantially decreased in the tumorigenic process of N-Myc transformed neuroblastoma. GLS2 depletion profoundly inhibited glutaminolysis concomitant with a substantial decrease in cell proliferation and viability in vitro and inhibition of tumorigenesis in vivo. Mechanistically, N-Myc, but not p53, selectively activates GLS2 transcription by direct binding to a conserved Myc-binding site within GLS2 promoter. In support of this notion, we found significant elevation of GLS2 expression concomitant with considerable GLS1 down-regulation in primary tumors obtained from MYCN-amplified neuroblastoma patients (invariably with poor prognosis) in comparison with those from MYCN non-amplified patients. In aggregate, these studies suggest that the metabolic regulation of c-Myc induced liver tumors differs from that of N-Myc induced neuroblastoma tumors which is likely to depend on both the genotype and the tissues of origin and have implications regarding the design of selective therapies targeting tumor metabolism. Citation Format: Daibiao Xiao, Ping Ren, Hexiu Su, Ming Yue, Ruijuan Xiu, Lei Gan, Hudan Liu, Guoliang Qing. N-Myc promotes glutamine anaplerosis and aggressive tumor progression through direct GLS2 activation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1134. doi:10.1158/1538-7445.AM2015-1134
Comparison of the Genomic Landscape Between Primary Breast Cancer in African American Versus White Women and the Association of Racial Differences With Tumor Recurrence
Authors: Tanya Keenan, Beverly Moy, Edmund A. Mroz, Kenneth Ross, Andrzej Niemierko, James W. Rocco, Steven Isakoff, Leif W. Ellisen, Aditya Bardia
Journal: Journal of Clinical Oncology (2015)

African American women are more likely to die as a result of breast cancer than white women. The influence of somatic genomic profiles on this racial disparity is unclear. We aimed to compare the racial distribution of tumor genomic characteristics and breast cancer recurrence.We assessed white and African American women with stage I to III breast cancer diagnosed from 1988 to 2013 and primary tumors submitted to The Cancer Genome Atlas from 2010 to 2014. We used Cox proportional hazards models to evaluate the association of race and genetic traits with tumor recurrence.We investigated exome sequencing and gene expression data in 663 and 711 white and 105 and 159 African American women, respectively. African Americans had more TP53 mutations (42.9% v 27.6%; P = .003) and fewer PIK3CA mutations (20.0% v 33.9%; P = .008). Intratumor genetic heterogeneity was greater in African American than white tumors overall by 5.1 units (95% CI, 2.4 to 7.7) and within triple-negative tumors by 4.1 units (95% CI, 1.4 to 6.8). African Americans had more basal tumors by the 50-gene set predictor using the predication analysis of microarray method (PAM50; 39.0% v 18.6%; P < .001) and fewer PAM50 luminal A tumors (17.0% v 34.7%; P < .001). Among triple-negative subtypes, African Americans had more basal-like 1 and mesenchymal stem-like tumors. African Americans had a higher risk of tumor recurrence than whites (hazard ratio, 2.22; 95% CI, 1.05 to 4.67). Racial differences in TP53 mutation, PAM50 basal subtype, and triple-negative tumor prevalence but not intratumor genetic heterogeneity influenced the magnitude and significance of the racial disparity in tumor recurrence.African Americans had greater intratumor genetic heterogeneity and more basal gene expression tumors, even within triple-negative breast cancer. This pattern suggests more aggressive tumor biology in African Americans than whites, which could contribute to racial disparity in breast cancer outcome.
Six-minute walk distance targets in elderly IPAH patients - Consideration of predicted values
Authors: Tobias Lange, Angela Keller, Michael Arzt, Michael Pfeifer
Journal: European Respiratory Journal (2013)

Background and aims  The number of elderly patients diagnosed with idiopathic pulmonary arterial hypertension (IPAH) is increasing. As exercise capacity is naturally decreasing with age, treatment goals for elderly patients might be different from those established for younger patients. Therefore, the aim of the present study was to determine the prognostic value of six-minute walk distance targets with respect to age at diagnosis.  Methods  Consecutive adult patients diagnosed with IPAH between 1/2005 and 7/2012 were retrospectively included. Survival analysis was performed according to six-minute walk distance targets (in meters and % predicted) reached after initiation of IPAH therapy.  Results  The mean (± SD) six-minute walk distances in 23 patients aged > 65 years at diagnosis compared to 22 younger patients were significantly lower at baseline (262 ± 69 vs. 356 ± 128 m; p=0.011) and first follow-up (310 ± 75 vs. 377 ± 137 m; p=0.045), while the corresponding % predicted values were similar (62 ± 16% vs. 63 ± 21%; p=0.854, and 74 ± 16% vs. 68 ± 21%; p=0.267). All 9 patients who died on follow-up (5 elderly, 4 younger) had six-minute walk distances ≤ 380 m on first follow-up, but this threshold was exceeded by only 13% of elderly compared to 46% of younger patients (p=0.016). In contrast, the corresponding value of more than 77% predicted was achieved by 48% and 46% of elderly and younger patients, respectively. All elderly patients who exceeded that target survived during follow-up.  Conclusion  In the targeted treatment of elderly patients with IPAH, % predicted of six-minute walk distances should be considered and may be superior to absolute values for prognostic assessment.
Use of 2 agonists in sport: are the present criteria right? * Commentary
Authors: J Naranjo Orellana, R A Centeno Prada, M D Carranza Márquez
Journal: British Journal of Sports Medicine (2006)

Background: The regulations for doping control prohibit the use of β 2 agonist bronchodilators (salbutamol, salmeterol, formoterol, and terbutaline) unless the subject follows the procedure known as abbreviated therapeutic use exemption (ATUE). Objective: To highlight how the interest in discovering possible cheats may result in damage to athletes who really need bronchodilator treatment. Methods: Thirty one high level athletes (18 men and 13 women) with a previous diagnosis of asthma were examined in our laboratory in order to obtain an ATUE for β 2 agonists. All the subjects underwent spirometry at rest. If the results were normal, the subjects underwent an effort test and, if negative, a methacholine test inhaling progressive doses of methacholine until a fall of 20% in forced expiratory volume in one second (FEV 1 ) was achieved. The international anti-doping regulations require that the fall in FEV 1 occurs with a concentration of methacholine (PC20) lower than 2 mg/ml (4 mg/ml for Torino 2006). In clinical practice, a test is positive if the response occurs with a PC20 lower than 8 mg/ml. Results: Only one subject met the criterion for the bronchodilation test at rest. The remaining 30 athletes underwent an effort test, which was positive in nine of them. In 21 cases (13 men and 8 women) the effort test was negative so a methacholine test was carried out. Seven (33%) were negative for ATUE with a PC20 higher than 8 mg/ml, seven (33%) were positive for ATUE with a PC20 less than 2 mg/ml, in four (19%) the PC20 was 2–4 mg/ml, and in three (14%) it was 4–8 mg/ml. Conclusions: Strict vigilance of fair play should be pursued, but excessive control can lead to situations of inequality for asthmatic athletes such that a third of athletes cannot be treated with β 2 agonists. Therefore under current regulations, asthmatic athletes are often denied the most effective therapeutic option.