tbuckley/cabot-search huggingface dataset:
Nelarabine in combination with intensive modified BFM AALL00P2: A pilot study for the treatment of high risk T-ALL a report from the Children’s Oncology Group
Authors: K. Dunsmore, M. Devidas, M. J. Borowitz, N. Winick, S. P. Hunger, W. L. Carroll, B. M. Camitta
Journal: Journal of Clinical Oncology (2008)

10002 Background: Nelarabine has substantial clinical activity in relapsed T-ALL, but has been associated with significant neurotoxicity. Historically, children with high risk T-ALL, based on prednisone response or high-end induction MRD, have fared poorly with less than 50% cured with chemotherapy leading some groups to recommend allogeneic stem cell transplant in first remission for these patients. AALL00P2 was a two-stage pilot study designed to assess the feasibility and safety of adding Nelarabine to an intensive modified BFM regimen in children with newly-diagnosed T-ALL with high risk features. Methods: Ninety-two patients (89 eligible) were accrued from April 2001 to October 2005. In stage 1, patients with a slow early response (SER), defined as > 1000 peripheral blood blasts on day 8 of a prednisone prephase or MRD >1% at day 36 of induction therapy, were assigned to receive chemotherapy that included 5-day courses of Nelarabine at 400mg/m2/day; other patients received chemotherapy without Nelarabine. In stage 2, all patients received therapy with six courses of Nelarabine, at either 650mg/m2/day (SER patients, n=10) or 400mg/m2/day (others, n=51). Results: The 3-year EFS for stage 1 SER patients assigned to Nelarabine 400mg/m2 is 75% + 13% (n= 12), versus 75% + 11% for 16 good responders receiving no Nelarabine. Three-year EFS for all NCI high risk patients receiving Nelarabine 400mg/m2 (n=50) is 85%; 650mg/m2 (n=10) is 70%; and for no Nelarabine (n=13) 69%. There were no differences in either targeted or non-targeted toxicities among patients treated ± Nelarabine (Dunsmore et. al, Blood 108: 528a, 2006). Conclusions: In this pilot study, T-ALL patients with high-risk features and previously very poor outcomes, attained a 3-year EFS of >70% with intensive chemotherapy plus Nelarabine, without excess toxicity, and SER patients appeared to fare as well as good responding patients. These preliminary results have led the COG to randomize patients with T-ALL to intensive chemotherapy ± Nelarabine. AALL0434 will define the role of Nelarabine in patients with newly diagnosed T-ALL. No significant financial relationships to disclose.
Interleukin-21 activates natural killer cell activity against cetuximab-coated pancreatic tumor cells
Authors: Elizabeth L McMichael, Alena Cristin Jaime-Ramirez, Kristan Guenterberg, Eric Luedke, Lakhvir Atwal, William E Carson
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Natural killer (NK) cells are large granular lymphocytes that play a critical role in anti-cancer mechanisms. These effector cells mediate antibody-dependent cellular cytotoxicity (ADCC) and produce IFN-γ in response to antibody-coated targets. The monoclonal antibody cetuximab
Trabectedin for advanced sarcomas failing doxorubicin: Analysis of 189 unreported patients in a compassionate use program
Authors: J. Blay, N. Penel, A. Italiano, F. Duffaud, M. Rios, O. Collard, F. Bertucci, N. Isambert, L. Chaigneau, P. Zintl
Journal: Journal of Clinical Oncology (2009)

10574 Background: Between 2005 and 2008, 387 patients (pts) with advanced sarcoma failing doxorubicin were treated in a compassionate use program (ATU) of trabectedin in France using the standard 1.5mg/m2/CI 24h q21d regimen. The purpose of this study was to assess the outcome of pts treated in this program. Methods: From 2005 to 2008, 87 centers (ctrs) included at least 1 pt in the ATU program. Inclusion criteria were those of the EORTC trial (J Clin Oncol, 2005;23:5276), with no restriction on the previous number of lines. A simple CRF with 22 items was used to collect pts characteristics and outcome. One hundred eighty-nine pts files were collected as of December 20, 2008. Univariate and multivariate analyses of prognostic factors was performed. Results: Two hundred thirty-five pts were included in the 17 ctrs in which &gt;4 pts were treated. Forty-four ctrs treated only 1 pt. Fifty-two percent were female; major histological subgroups were leiomyosarcoma (29%) and liposarcoma (20%). All pts had been treated with doxorubicin and ifosfamide, 3 (1.5%) in adjuvant setting only. Trabectedin was given in 1st, 2nd, 3rd, or 4th line in metastatic phase in n=8, 69, 66, 42 pts respectively (median: 3rd line). The median number of courses were 3 (range 1–24). Best response reported were PR, n=15 (8%), SD, n=68 (36%) and PD, n=94 (50%), NE, n=11 (6%). With a median follow-up of 805 days (d), median PFS and OS were 91 d and 309 d respectively. 27/127 (20%) evaluable pts had to be hospitalized for treatment related side effects. PFS was superior in myxoid liposarcoma (MyxLPS) (median 192 d vs 69 d, p=0.003), retroperitoneal sarcomas (median 104 d vs 69 d, p=0.006), and grade 1 tumors (median 141 d vs 70 d, p=0.01). In multivariate analysis (Cox model), tumor site, grade 1, histotype were the only independent prognostic factors for PFS. For OS, favorable prognostic factors in univariate analysis were histotypes (MyxLPS, MFH), grade 1 lesions, retroperitoneal site, no hospitalisation for toxicity (p&lt;0.01 all) while Cox model identified female gender, tumor site, histotype as the only independent prognostic factors for OS. Conclusions: In this compassionate use program for heavily pretreated pts with advanced sarcomas, trabectedin yielded PFS and OS close to those observed in phase II and III trial. PFS and OS are superior in myxLPS, retroperitoneal sarcomas, and grade 1 tumors. [Table: see text]
Phase II trial of imatinib maintenance therapy after irinotecan and cisplatin in patients with c-kit positive extensive-stage small cell lung cancer (ES SCLC)
Authors: B. J. Schneider, S. Gadgeel, N. Ramnath, F. P. Worden, A. Wozniak, J. Ruckdeschel, G. P. Kalemkerian
Journal: Journal of Clinical Oncology (2006)

17089 Background: The prognosis for patients (pts) with ES SCLC is poor, with a median survival of 9 mo. This trial was designed to evaluate the efficacy and toxicity of cisplatin plus irinotecan followed by maintenance imatinib (Gleevec) in pts with c-kit positive ES SCLC. Methods: Immunohistochemistry for c-kit was performed on paraffin-embedded tissue prior to enrollment. Treatment consisted of irinotecan 65 mg/m 2 IV on days 1 and 8 plus cisplatin 60 mg/m 2 IV on day 1 repeated every 21 days for 4 cycles. If no evidence of disease progression was identified, Gleevec was given at 400 mg orally BID until disease progression or unacceptable toxicity. Results: 14 pts have been enrolled: median age 61 yrs (range 47–73); 9 men: 5 women; PS 0/1/2 = 3/10/1. 6 pts did not begin Gleevec due to disease progression (4), persistent grade 3 emesis (1), and referral for radiation therapy (1). 8 pts had a PR with cisplatin/irinotecan and received Gleevec. Median number of wks on Gleevec was 6.1 (range 4.6–25.1). Reasons for discontinuation of Gleevec were disease progression (7) and persistent neutropenia (1). Median progression-free survival was 4.7 mo. (range 0.7–16.3) for all pts and 5.5 mo. (range 4.7–16.3) for pts receiving Gleevec. There were no objective responses to Gleevec, but 3 pts (21%) had stable disease for 12, 15 and 25 wks. Median survival was 8.1 mo. (range 3.7–19.6) for all pts and 10.0 mo. (range 7.1–19.6) for those receiving Gleevec. Myelosuppression was mild (grade 1–2 ANC 13%, anemia 76%, platelets 13%) with one pt with grade 3 neutropenia. Non-heme toxicity included grade 1–2 nausea 76%, diarrhea 51% and peripheral edema 75%. Conclusions: Gleevec did not appear to maintain disease stability after response to chemotherapy in the majority of pts despite c-kit tumor positivity. Although disease stability with Gleevec was noted in 3 pts (12–25 wks) and therapy was well tolerated, this approach does not appear to warrant further clinical study. Supported by Novartis Pharmaceuticals. No significant financial relationships to disclose.
TLC388, a novel topoisomerase-1 inhibitor with antihypoxia inducible factor-1 alpha activity: A phase I and pharmacokinetic study in patients with advanced solid malignancies.
Authors: C. Lin, S. A. Ghamande, B. J. Dezube, M. H. Silverman, K. Fong, M. Kuo, W. Mach, Y. Tseng, S. Hsu, S. Goel
Journal: Journal of Clinical Oncology (2010)

e13020 Background: To assess the feasibility of administering TLC388, a novel derivative of camptothecin with a unique modification in the lactone ring resulting in a more potent inhibition of topoisomerase I with anti-HIF1 alpha activity. Methods: Patients with chemotherapy-refractory solid malignancies were treated with escalating doses of TLC388 as a 30-minute intravenous infusion weekly x3, repeated every 28 days. Plasma and urine sampling were performed to characterize the pharmacokinetics of TLC388. Results: Thirty-two patients (M:F = 14:18, median age 62, range 33-81) with advanced solid malignancies (colorectal 5, pancreatic / biliary 4, esophageal 3, urothelial 3, ovarian 3, others 14) received 67 courses (range 1-6) of TLC388 at eight dose levels ranging from 1.5 to 40 mg/m2/d. Grade 2 or 3 neutropenia and grade 3 or 4 hyponatremia was observed in 6 and 3 patients, respectively. One dose-limiting toxicity (DLT), grade 4 hyponatremia, was observed in cycle 1 at 40 mg/m2/d resulting in expansion of this cohort to 6 patients. Prolonged stable disease was noted in 5 patients (6 months in sorafenib-refractory hepatocellular carcinoma, anal cancer, one each; 4 months in docetaxel-refractory prostate cancer, gastric cancer, bladder urothelial carcinoma, one each). Pharmacokinetics of TLC388 was dose-independent; mean (SD) values for the volume of distribution at steady-state and clearance were 852 (791) L/m2 for S,R-TLC388 and 1,196 (1,156) L/m2 for S,S-TLC388, and 2,766 (2739) L/h-m2 for S,R-TLC388 and 3777 (3,614) L/h-m2 for S,S-TLC388, respectively. The half-life values averaged 0.36 (0.91) hours for S,R-TLC388 and 0.40 (0.88) hours for S,S- TLC388. Conclusions: TLC388 is safe as a weekly infusion up to 30 mg/m2/d. The DLT of grade 4 hyponatremia is possibly drug-related and is being investigated. Based on preliminary clinical efficacy, further trial of TLC388 in hepatocellular carcinoma is planned. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Taiwan Liposome Company, Ltd. Taiwan Liposome Company, Ltd. Taiwan Liposome Company, Ltd.
Gene expression profile of enzymes involved in gemcitabine (Gem) metabolism in bone marrow mononuclear cells as predictors of myelosuppression
Authors: A. K. Ganti, A. Parr, D. Nguyen, J. L. Grem
Journal: Journal of Clinical Oncology (2006)

2007 Background: The dose-limiting toxicity of gemcitabine (Gem) is hematologic toxicity (heme tox), and there is wide intra-patient variability in the degree of heme tox. This study was done to assess the possible impact of gene expression of enzymes involved in Gem metabolism or mechanism of action on heme tox. Methods: Pre-therapy mononuclear cells were isolated from bone marrow aspirates collected from 71 consenting patients with various advanced malignancies enrolled in an IRB-approved phase I trial in which single agent Gem was given over 30 min weekly for 2 of 3 weeks during cycle 1 at doses ranging from 750–1,560 mg/m 2 . Gene expression of deoxycytidine kinase (DCK), an activating enzyme, cytidine deaminase (CD) and deoxycytidylate deaminase (DCD), deactivating enzymes, and ribonucleotide reductase M2 (RNR), which is inhibited by Gem diphosphate, was measured by real-time RT-PCR. Target gene expression was relative to beta-actin. Heme tox was calculated as the % decrease in white blood cells (WBC), neutrophils (ANC) and platelets (PLT) from baseline. Results: 71 patients (26 females, 35 males) with a median age of 56 years (range: 20–75) were included in the analysis. The median (25 th %, 75 th %) gene expression was as follows (x10e3/beta-actin): DCK, 0.34 (0.19, 0.64); CD, 1.88 (1.33, 2.92); DCD, 2.48 (1.15, 7.78); and RNR, 0.39 (0.19, 0.80). A strong linear correlation was noted only between RNR &amp; DCD gene expression (Pearson r = 0.89). When gene expression was categorized as above or below the median value, only CD appeared to influence heme tox (mean ± std dev) ( Table ). T-test p value is shown. Conclusions: Gem is rapidly metabolized to its inactive metabolite by CD. Subjects with a higher relative gene expression of CD tended to have a lesser degree of heme tox following Gem. Correlation with Gem pharmacokinetics in these subjects is planned. [Table: see text] No significant financial relationships to disclose.
A discussion of "urban sprawl and public health: designing, planning, and building for healthy communities"
Authors: K. Olden
Journal: Environmental Health Perspectives (2005)

Urban Sprawl and Public Health, a timely publication by highly qualified authors, is another wake-up call about public policy decisions with respect to land use, transportation, and community design that adversely affect our health, civic involvement, and quality of life. Its thesis is that the designs of buildings and communities inhibit physical activity and social interactions and promote sedentary lifestyles and environmental pollution or degradation. The authors provide solution-oriented information to professionals, public officials, business and community leaders, and others who are concerned about protecting the environment and human health. They describe sprawl as the way land is used, the way people travel, and the way cities expand over large geographic areas. Such expansion increases distance between places of interest, makes walking and biking impractical, and increases reliance on automobiles for transportation. Although sprawl appears chaotic, the authors point out that it is well orchestrated and supported by public policy through cheap land, favorable tax codes, zoning regulations, lending practices, and the revolution in transportation. The latter made it possible for large numbers of people to live longer distances from work and commercial centers. But now that the forces that spun sprawl (e.g., concerns about sanitation, infectious diseases, noise, crime, industrial pollution, and exposed sewage) no longer represent a nuisance or a threat to safety, it is time to rethink public policies designed to encourage or support migration from urban centers.
Phase I/II study of MK-0646, the humanized monoclonal IGF-1R antibody in combination with gemcitabine or gemcitabine plus erlotinib (E) for advanced pancreatic cancer.
Authors: M. M. Javle, G. R. Varadhachary, R. T. Shroff, P. Bhosale, M. J. Overman, J. Weatherly, R. A. Wolff, J. L. Abbruzzese
Journal: Journal of Clinical Oncology (2010)

4039 Background: MK-0646 binds to IGF-1R and blocks its interaction with IGF-I/ II ligands, enhances gemcitabine (G)-induced apoptosis and inhibits the MEK/Erk and the PI3-kinase/Akt signaling which are important in cellular proliferation, survival and drug resistance in pancreatic cancer. Receptor cross-talk between IGF-1R and EGFR and enhanced IGF-1R-induced activation of the PI3-kinase/Akt pathways mediate resistance to anti- EGFR agents such as E. Methods: Patients with stage IV, previously untreated pancreatic cancer, ECOG performance status (PS) 0-1, adequate hematologic and organ function were enrolled. MK-0646 was escalated in two dose levels using 3+3 statistical design. Uncontrolled hyperglycemia or cardio-respiratory conditions were exclusions. Blood was collected at study entry for IGF-1 and IGFBP-3 levels. Arm A: G 1,000 mg/m2 over 100 min, weekly × 3, MK-0646 over 60 min: 5 or 10 mg/kg, weekly × 4; Arm B: G 1,000 mg/m2 over 100 min, weekly × 3, MK-0646: 5 or 10 mg/kg over 60 min, weekly × 4 + E 100 mg daily. Phase II study uses adaptive randomized design with Arm A, Arm B and Arm C (G + E). Cycles repeated q 4 weeks. Study endpoints: maximal tolerated dose, progression-free survival, response rate, toxicity and overall survival. Results: 28 pts enrolled, 22 males, 2 prior Whipple, 27 PS 1, 1 PS 0. Median of 2 cycles administered (range 1, 12+). Hematologic toxicity: grade 3 or 4 neutropenia (n = 14) or thrombocytopenia (n = 5). Other grade 3 toxicities: hyperglycemia (n = 5), fatigue (n = 5), ALT (n = 4). Dose-limiting toxicity reached in Arm B at dose level 2 (MK-0646 at 10 mg/kg + E + G): febrile neutropenia (n = 1), hepatic transaminitis (n = 1). Radiologic responses: 6 PR (including 1 hepatic CR), 10 PD, 8 SD, 3 too early,1 not treated. 5 sustained PRs (range = 20+, 44+ weeks). Median TTP 8 weeks (range 4, 44+weeks). Ranges for: IGF-1 levels, 28-280 ng/mL; IGFBP-3 levels, 900-4,000 ng/mL. The range of IGF-1:IGFBP-3 ratios for patients with PR and SD was 0.027-0.036 versus .034-.058 for patients with PD. Conclusions: MK-0646 is tolerable in a dose of 10 mg/kg with G 1,000 mg/m2 and at 5 mg/kg with G 1,000 mg/m2 and E 100 mg. Sustained PRs occurred. A randomized phase II study is ongoing. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck
Assessment of diabetes mellitus (DM) as a risk factor for development of cisplatin-induced nephrotoxicity (CIN)
Authors: J. Weese, P. D. Sandhu, A. Mody, H. Ozer, M. Jafari, A. H. Tfayli, K. Kojouri
Journal: Journal of Clinical Oncology (2009)

e13537 Background: DM is the most common cause of kidney disease in the US, and it may increase the risk of CIN. In vivo studies however suggest that DM not only is not a risk factor for CIN, it may even be protective. This may be explained by dysfunction of organic cation transporter-2, the critical transporter for cisplatin uptake in proximal tubules, in diabetic kidneys. We conducted a case-control study to assess the relationship between DM and CIN. Methods: Records of all patients (pts) who received cisplatin between 1/1/00 and 12/31/06 at Oklahoma City VA Hospital were reviewed. DM was diagnosed if pt had (1) been taking anti-diabetic treatment, or (2) Hgb A1C ≥6.5%, or (3) ≥2 fasting outpatient serum glucose levels 126–199 mg/dl, or (4) ≥1 serum glucose level ≥200 mg/dl at any time, prior to receiving cisplatin. CIN was defined as increase in serum creatinine (SCr) by ≥50% above baseline and higher than upper limit of normal, after exclusion of other causes of elevated SCr, during or within 8 weeks of completion of treatment. Continuous variables are reported by means and ranges, and compared using 2-tailed student's t test. Odds ratio (OR) was calculated to compare risk of CIN between diabetics and non-diabetics. Results: Two hundred pts (2 females, 198 males) received cisplatin in the study period, 50 (25%) were diabetic. Distribution of age (years, diabetics: 62 [46–77]; non-diabetics: 60 [26–79], p = 0.18) and baseline SCr (mg/dl, diabetics: 1.0 [0.4–1.5]; non-diabetics: 1.0 [0.5–1.6], p = 0.86) were similar between the two groups. Overall 15% of pts (30 of 200) developed CIN. Risk of CIN was not different between diabetics (8 of 50 pts, 16%) and non-diabetics (22 of 150 pts, 14.7%); OR = 1.11 (95% CI = 0.46 to 2.67) (Table). Conclusions: DM was not shown to be a risk factor for development of CIN. This finding is consistent with in vivo data obtained through animal diabetic models. [Table: see text] No significant financial relationships to disclose.
Temporary ovarian suppression with goserelin for prevention of chemotherapy-induced menopause in young early breast cancer patients: Results of a phase II study
Authors: L. Del Mastro, T. Catzeddu, L. Boni, C. Bighin, S. Pastorino, C. Bell, M. R. Sertoli, M. Clavarezza, D. Testa, M. Venturini
Journal: Journal of Clinical Oncology (2005)

662 Background: Early menopause is a frequent irreversible side-effect induced by chemotherapy(CT) in young patients(pts) and no standard methods for its prevention are available. Preclinical data suggests that LHRH analogs given during CT can decrease gonado-toxicity induced by CT. The aim of this trial was to investigate the ability of Goserelin(G) to prevent CT-induced menopause by a two-step phase II study. Methods: Treatment with G was considered clinically interesting if it was able to prevent menopause in at least 80% of pts whilst the accrual was stopped with a success rate <50%. The planned sample size was 29 pts. End point of the study was resumption of menstrual activity(MA) and/or a FSH value <40IU/L within 12 months after the CT end. FSH, LH and E2 were assessed at 3, 6, 9 and 12 months after the end of CT and then every 6 months. G 3.6 mg was administered at least 1 wk before CT and then every 4 wks until CT completion. Results: From Oct 2001 to Jun 2003, 30 pts were enrolled and 29 were evaluable. Median age was 38(29–47); 11(38%) pts had no previous pregnancy. All but one patient(96%) received FEC regimen; median number of CT cycles: 6(5–8), median number of G doses: 5(2–6). After CT, all ER+ and/or PgR+ pts received tamoxifen. Within 12 months after the end of CT resumption of ovarian activity(OA) was indicated by: 1)both a FSH level ≤40 and resumed MA in 17 pts(58.6%); 2)FSH ≤40 without resumption of MA but with premenopausal E2 level(>20 pg/mL) in 4 pts(13.7%); 3)resumption of MA but not available data on FSH and E2 in 3 pts(10%); 4)FSH ≤40 but without E2 increase and no resumption of MA in 3 pts(10%). One patient with both FSH>40 and E2<20 had a single menstrual mense 12 months after CT end, but no further signs of OA were reported in the follow-up. One patient who stopped CT after 1 cycle and continued G as antitumor therapy was not evaluable and was considered a failure. Median time to menstrual resumption was 164 days(63–362). Conclusions: After treatment with G given prior and during CT a sure ovarian function resumption (FSH ≤40 + MA or FSH ≤40 + increased E2 or MA and FSH and E2 levels unknown) was observed in 83% of pts. Ovarian function resumption was uncertain in 10% pts. No significant financial relationships to disclose.