tbuckley/cabot-search huggingface dataset:
Treatment of adults with newly diagnosed glioblastoma multiforme or anaplastic astrocytoma with surgery, gliadel wafers and limited field radiation plus concomitant temozolomide followed by adjuvant temozolomide
Authors: T. Ryken, T. Carlisle, J. Buatti, P. Kirby, J. Maley, R. Hohl, B. J. Smith, J. Greenlee, M. Frees, M. Rogers
Journal: Journal of Clinical Oncology (2008)

13003 Background: Improved survival of patients with newly diagnosed malignant glioma has been acheived with the addition of either intracavitary carmustine (BCNU) chemotherapy or oral temozolomide to surgical resection and external radiotherapy. This study prospectively evaluates the safety and preliminary efficacy of combining surgical resection with implantable BCNU, oral temozolomide and external beam radiotherapy in patients with newly diagnosed malignant glioma. Methods: Adult patients with newly diagnosed intracranial lesions suspected to be primary malignant tumors felt to be candidates by their surgeon for cytoreductive surgery were included. Patients with a final diagnosis of either glioblastoma or anaplastic astrocytoma who received implantable chemotherapy at the time of surgery went on to receive concomitant temozolomide during a course of 6 weeks of external beam radiotherapy followed by adjuvant temozolomide for 12 months. Results: At the time of this analysis 21 patients were enrolled with a median age of 60.8 years (range 49 to 78 years) and included 9 females and 12 males. Estimated six month survival was 0.815 (81.5%) (95% CI 0.622–1.00) and 12-month survival was 0.724 (72.4 %) (95% CI 0.485–0.964). There were 9 Grade 3 or greater toxicities in 5 patients judged either possibly or definitely related to the overall course of treatment. This included one death from multi-organ system failure (Grade5), nausea (Grade 4), vomiting (Grade 4), seizure (Grade 4), dyspnea (Grade 4), pulmonary embolus (Grade 4), liver toxicity (2 patients Grade 3) and thrombocytopenia (Grade 3). Based on the timing of the occurrence, none of theses toxicities appeared related specifically to the addition of implantable BCNU to the combination of radiotherapy and temozolomide. Conclusions: The combination of cytoreductive surgery with implantable BCNU combined with concomitant temozolomide and radiotherapy does not appear to increase the toxicity of treatment above what would be expected with either alone. The potential for an additive or synergistic effect on survival is promising but must await a randomized multi-arm trial. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration MGI Pharma MGI Pharma, Schering-Plough
Early results from Children's Oncology Group (COG) ARST0431: Intensive multidrug therapy for patients with metastatic rhabdomyosarcoma (RMS).
Authors: B. Weigel, E. Lyden, J. R. Anderson, A. Galster, C. A. Arndt, J. Michalski, D. S. Hawkins, W. H. Meyer
Journal: Journal of Clinical Oncology (2010)

9503 Background: The outcome for patients with metastatic RMS has remained approximately 30% survival for several decades. The COG phase 3 trial, ARST0431 aimed to 1) improve early disease control using interval compressed therapy of known active agents: vincristine, doxorubicin, and cyclophosphamide (VDC) alternating with ifosfamide, etoposide (IE) and 2) to determine the feasibility and toxicity of vincristine/irinotecan (VI) given concurrently with radiation therapy. Methods: We conducted a phase 3, single arm study. Previously untreated patients <50 yrs with metastatic RMS and adequate organ function were eligible for enrollment. Patients received 54 wks of therapy: blocks of therapy with VI (wks 1-6, 20-25, 47-52), interval compression with VDC/IE (wks 7-19 and 26-34) and vincristine, actinomycin D and cyclophosphamide (VAC) (wks 38-46). Radiation therapy occurred at wk 20-25 (primary) but was also permitted at wk 1-6 (for intracranial or paraspinal extension) and wk 47-52 (for extensive metastatic sites). Results: The study enrolled 109 eligible pts from 7/2006 and 6/2008. 20 pts received irinotecan on the protracted daily × 5 for two consecutive wks schedule before a protocol amendment, and 89 pts received irinotecan on the shorter daily × 5 schedule. The majority of pts were between ages 10-20 (56%), male (55%), with alveolar histology (59%), primary tumors ≥5cm (80%) and had regional lymph nodal involvement (60%). Toxicity was comparable to the prior COG study with VI and VAC, D9802, as was the early response rate (RR) after VI for 6 wks (CR 7%, PR 57%). The early response rate was also similar by histology (RR for embyronal RMS: 58%; alveolar RMS: 66%). At 18 mos, the failure-free survival (FFS) and OS rates are 66% (55-75%, 95% CI) and 80% (70-87%, 95% CI), respectively. A comparable pooled analysis of metastatic RMS pts from European and North American clinical trials (J Clin Oncol 2008;26:2384-9) had an 18 mo FFS of 41% for all pts, and 45% when restricted to North American pts only. Conclusions: Pts with metastatic RMS treated on ARST0431 experienced similar toxicity compared to prior COG trials. Early outcome data appear promising, with a FFS at 18 mos 20% higher than prior studies. Longer follow up is required. No significant financial relationships to disclose.
Effect of nitric oxide (NO) inhibitors 1400W, aminoguanidine and L-NAME in oral mucositis induced by 5-fluorouracil (5FU) in animals
Authors: R. A. Ribeiro, R. F. Carvalho, R. O. Sant’ana, F. D. B. Macedo, E. A. L. Bellaguarda, L. R. Silva, C. B. Diogenes, G. A. C. Brito
Journal: Journal of Clinical Oncology (2005)

8140 Background: Oral mucositis induced by antineoplastic drugs is an important, dose-limiting and costly side effect of cancer therapy. It has been well established the role of cytokines in pathogenesis of oral mucositis, and it was reported that these pro-inflammatory mediators are important inducers of NO synthesis, suggesting a possible role for NO on the inflammatory response of mucosítis. The aim of this study was to investigate the role of the non-selective NO inhibitor Nφ-Nitro-L-Arginine Methyl Ester (L-NAME) and the inducible NO synthase (iNOS) selective inhibitors 1400W, and aminoguanidine on oral mucositis induced by 5-FU. Methods: Oral mucositis was induced by two intraperitoneal (i.p) injections of 5-FU in the first and second days of the experiment (60 and 40 mg/Kg respectively) in male Golden Sirian hamsters, followed by check pouches mechanical trauma in the 4th day. L-NAME (5, 10 or 20mg/Kg, s.c.), aminoguanidine (5 or 10 mg/Kg, s.c.), 1400W (1 mg/Kg, s.c.) or saline (positive control) were administered one hour before the injections of 5-FU and daily until sacrifice, on the 10th day. Macroscopic and histopathological analyses were evaluated and graded. The MPO activity was also determined. Results: AG (10 mg/Kg) and 1400W reduced both macroscopic (p<0.05; n=8: AG=score 2 (1–3); 1400W=1(1–3) vs Saline=3(2–3)) and histological parameters (p<0.05; n=8: AG=score 1.5(1–3); 1400W=1(1–3) vs Saline=3(1–3)) of oral mucositis, associated with a reduction in MPO activity and increase of the animal survival when compared to the group of animals subjected to oral mucositis that received saline. In contrast, the administration of L-NAME (5, 10 or 20 mg/Kg) did not significantly reverse the inflammatory alterations induced by experimental mucositis. Conclusion: The results presented in this study suggest a role of NO on the pathogenesis of oral mucositis induced by 5-FU, via iNOS. However, the mechanisms of actions of NO in inflammatory events of mucositis still deserves further investigation. Financial support: CNPq No significant financial relationships to disclose.
Haplotype analysis of UGT1A1 and UGT1A9 gene polymorphisms related to the glucuronidation of SN-38, the active metabolite of irinotecan
Authors: W. Liu, F. Innocenti, P. X. Chen, A. Desai, C. Grimsley, A. Di Rienzo, S. Das, M. Ratain
Journal: Journal of Clinical Oncology (2004)

2085 Background: There are 9 unique UGT1A enzymes with overlapping specificity and tissue-specific expression, which are generated from a single gene by alternative splicing of individual exons 1 with common exons 2–5. The TA repeat polymorphism in UGT1A1and other UGT1A1 variants have been suggested to play a role in increased risk of severe toxicity of irinotecan. In addition to UGT1A1, UGT1A9 enzyme has also been proposed to inactivate SN-38, and a T indel in the 5' untranslated region has been associated with altered gene expression. As UGT1A1-UGT1A9 haplotypes might have a different phenotypic effect compared to single variants, we sought to determine the haplotype map of UGT1A1 and UGT1A9functional variants. Asian (n=150) and Caucasian (n=66) samples were used to evaluate interethnic differences in haplotype structure. Methods: DNA samples were genotyped for variants in UGT1A9 (-11810T/9T) and UGT1A1 [-3279G>T, -3156G>A, -53TA5–8, 211G>A, 686C>A]. Results: In both populations, significant linkage disequilibrium (LD) was present among all variants (p<0.05) except between -11810T/9T and 686C>A. Stronger LD was found in Caucasians compared to Asians. In Asians, 13 haplotypes (1–13) were found, 8 of them being present in Caucasians. In Asians, common haplotypes (q>0.10) were 10TG6GC (1, q=0.44), 9GG6GC (2, q=0.22), and 9TG6AC (3, q=0.12), and common diplotypes were 1,1 (0.19), 1,2 (0.18), and 1,3 (0.13). In Caucasians, 211G>A was invariant and one 686C>A heterozygote was found; common haplotypes were 10TG6GC (1, q=0.35), 9GA7GC (9, q=0.28), 9TG6GC (4, q=0.19), and 9GG6GC (2, q=0.10); common diplotypes were 1,9 (0.20), 1,4 (0.17), 1,1 (0.12), and 9,9 (0.11). Significantly different haplotype frequencies were observed between Asians and Caucasians (chi-square 97.4, p<0.0001). Conclusions: The haplotype map of UGT1A1 and UGT1A9is different between Asians and Caucasians. These results provide the knowledge basis for the correct design of prospective clinical trials of irinotecan (and other UGT1A substrates) pharmacogenetics with respect to UGT1A1 andUGT1A9in patients of Asian and Caucasian ethnic background. No significant financial relationships to disclose.
Dasatinib dose-optimization study in chronic phase chronic myeloid leukemia (CML-CP): Three-year follow-up with dasatinib 100 mg once daily and landmark analysis of cytogenetic response and progression-free survival (PFS)
Authors: R. M. Stone, D. W. Kim, H. M. Kantarjian, P. Rousselot, A. Hochhaus, P. E. Dorlhiac-Llacer, J. Milone, Y. Matloub, A. Lambert, N. P. Shah
Journal: Journal of Clinical Oncology (2009)

7007 Background: The recommended dosing regimen of dasatinib for CML-CP is now 100 mg once daily (QD) (previously 70 mg twice daily [BID]), based upon a phase III dose-optimization study (CA180–034) that enrolled patients (pts) with CML-CP with resistance, intolerance, or suboptimal response to imatinib. While therapeutic milestones have been established for pts with CML-CP treated with imatinib, they have not been well established for pts treated with second-line TKIs. Methods: Pts were randomized using a 2 × 2 factorial design to one of four treatment arms: 100 mg QD (n = 167), 70 mg BID (n = 168), 140 mg QD (n = 167), or 50 mg BID (n = 168). Details of study design and endpoints have been described previously. Results: After a minimum of 24 months of follow-up, the 24-month PFS rate with 100 mg QD was 80% (vs. 75%-76% in other arms) and the overall survival rate was 91% (vs. 88%-94%). In all arms, high response rates were achieved in pts with or without a baseline BCR-ABL mutation. Dasatinib 100 mg QD was well tolerated and rates of key side effects showed only a minimal increment from 12 to 24 months. Among the four treatment arms, significant differences were observed in rates of drug-related pleural effusion (all grades: p = 0.049) and cytopenia (p = 0.003 for grade 3/4 thrombocytopenia), with lowest rates observed for 100 mg QD. Dasatinib 100 mg QD treatment resulted in the lowest rates of treatment interruption, reduction, and discontinuation. In addition to providing 36-month follow-up, the likelihood of achieving long-term endpoints based on cytogenetic status at 6, 12, and/or 18 months will be presented. Conclusions: Dasatinib 100 mg once daily remains the optimal dosing schedule for pts with CML-CP. The landmark analyses to be presented should provide useful information to clinicians treating imatinib-resistant, -suboptimally responding, or -intolerant CML-CP pts with dasatinib 100 mg once daily based on cytogenetic response at key intervals. [Table: see text]
Characterization, resource use, and the economic impact of low-risk myelodysplastic syndrome (MDS) at an MDS specialty center
Authors: M. A. Sekeres, T. Jin, J. Maciejewski, M. E. Kalaycio, S. Brown, A. Advani, A.-R. Golshayan, R. Sobecks, M. W. Kattan
Journal: Journal of Clinical Oncology (2005)

6098 Background: MDS is diagnosed in 12–20,000 people annually in the U. S., making it the most common bone marrow disorder. While the first chemotherapy agent has been approved this year for the treatment of MDS, and others are at advanced stages of development, little is known about resource use in this population, a crucial component of decision-making about therapy initiation. Methods: We retrospectively examined 134 MDS patients seen for clinical trial enrollment at the Cleveland Clinic Foundation (CCF) from November, 2002 through September, 2004. Of these, 78 (58.2%) had low-risk disease, which we defined as having <5% bone marrow blasts. Economic impact was calculated using CCF charges. Results: Thirty low-risk patients (38.5%), with a median age of 72 years (range, 48–87), were followed long-term at our institution, of whom 5 (16.7%) had secondary MDS. They fell into the following IPSS risk groups: 11 Low, 15 Int-1, and 4 Int-2. Seventeen patients (56.7%) had received prior chemotherapy: 13 (76.5%) immune (including immunosuppressants and IMIDs); 2 (11.8%) cytotoxic, and 5 “other” (amifostine, Vitamin D derivatives), with some patients receiving more than one. For supportive therapy, 22 patients (73.3%) had used erythropoietin growth factors, with 14 treated for a total of 279 weeks in the year preceding consultation, while 8 (26.6%) had used granulocyte stimulating growth factors, with 3 treated for a total of 23 weeks in a one-year period. In the 6 months prior to consultation, patients received a mean of 5.3 (S.D. 6.4) RBC transfusions and 0.4 (S.D. 1.1) platelet transfusions. Transfusions increased in the 6 months post-consultation, to a mean of 8.2 (S.D. 7.6) and 2.4 (S.D. 5.4), respectively. During the same time period, 22 patients (73.3%) were hospitalized, for a mean length of stay of 9.9 (S.D. 9.3) days. Supportive care charges for a low-risk MDS patient, including hospitalizations, was $30,033 over the one-year time period prior to consultation. Conclusions: Low-risk MDS patients incur substantial health care costs even prior to initiating therapy on a clinical trial. These numbers should be considered in a decision analysis of when therapy should be initiated. No significant financial relationships to disclose.
A phase I/II and pharmacologic study of MM-111 in patients with advanced, refractory HER2-positive (HER2+) cancers.
Authors: C. S. Denlinger, M. Beeram, A. W. Tolcher, L. J. Goldstein, W. J. Slichenmyer, J. Murray, C. McDonagh, K. Andreas, V. M. Moyo
Journal: Journal of Clinical Oncology (2010)

TPS169 Background: The ErbB2/ErbB3 oncogenic heterodimer is the most potent ErbB receptor pairing with respect to strength of interaction, ligand–induced tyrosine phosphorylation, and downstream signaling through mitogen-activated protein kinase and phosphoinositide-3 kinase pathways. Recently, ErbB3 signaling has emerged as an important hypothesized mechanism of resistance to ErbB2 (HER2) targeted agents in clinical use (Sergina et al. Nature 2007; Garrett et al. SABCS 2009 abstract 63). MM-111 is a novel bispecific antibody fusion protein that specifically targets the ErbB2/ErbB3 heterodimer and blocks ligand binding to ErbB3. In HER2+ gastric, breast, ovarian, and lung cancer cell lines and xenografts, MM-111 inhibits ligand-induced ErbB3 phosphorylation, tumor cell cycle progression, and tumor growth. This first-in-human phase I-II study evaluates the safety and tolerability of MM-111 and provides preliminary efficacy data in HER-2+ advanced breast cancer (ABC). Methods: Patients (pts) aged ≥ 18 years with histologically confirmed HER2+ advanced solid tumors that have progressed or recurred on standard therapy or for which no standard therapy exists, and adequate performance status, bone marrow reserve, and organ function, are eligible for the phase I portion. Phase II is restricted to pts with HER2+ ABC who have progressed on prior trastuzumab or lapatinib therapy. Pts with stable central nervous system lesions are eligible. Phase I employs a standard 3 + 3 dose escalation design. Once the maximum tolerated (MTD) or feasible dose (MFD) is determined, up to 25 additional pts with HER2+ ABC will be enrolled, for a planned total of 40-49 pts in both phases. Primary endpoints are determination of MTD/MFD (phase I) and 6-month progression-free survival (phase II). Secondary endpoints include determination of dose-limiting toxicity, adverse event, pharmacokinetic, and immunogencity profiles of MM-111, as well as overall response and clinical benefit rates of MM-111 in HER2+ ABC. MM-111 is administered intravenously weekly in 4-week cycles. 8 pts have been enrolled in the phase I portion (7 ABC, 1 advanced gastric cancer), and enrollment in the phase I portion is ongoing. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merrimack Pharmaceuticals Merrimack Pharmaceuticals Merrimack Pharmaceuticals Chemotherapy Foundation Merrimack Pharmaceuticals Merrimack Pharmaceuticals
Registro central venous devices (CVD) - Polonord
Authors: G. Aondio, D. Fagnani, C. Porta, A. Bertolini, M. Giordano, A. Scanni, A. Ardizzoia, R. Franchi, C. Cimminiello
Journal: Journal of Clinical Oncology (2005)

8153 Background: The use of CVD (advantages and complications) has been studied with an observational prospective study, called "Registro CVD - PoloNord", collecting all patients (pts) having placed a CVD, in the PoloNord Group Oncology Services (Abs. 8239 ASCO 2004). We reported the update after 20 months follow-up. Methods: Starting from January 2003, and for a total of three years, the pts data are collected in a computer-assisted log, running into a web server technology. CVD model, patient medical history and relationships with drug therapy including antithrombotic prophylaxis, CVD related adverse events, thromboembolic events (TE) and patient outcome were recorded. Results: On 09.04, 938 CVD (Port-a-cath 74%, CVC 14%, PICC 12%) were placed in 885 pts: 732 pts were followed-up for at least four months. We noticed a frequency of 13% (100) CVD-related complications (mainly infections, catheter thrombosis, misplacement and breakage), giving a CVD removal in 50 pts (7%); the complications-related removals were more elevated in PICC (17%) vs Port-a-cath (6%). We found 56 TE (7.6%), with 15 CVD-site DVT (2%). Median time to the first occurring CVD-related complication and TE was 86 and 87 days respectively. Furthermore we have to point out an elevated frequency of catheter and CVD-site thrombosis among pts with tip catheter placed in giugular and succlavia (9% e 5%) vs superior vena cava and right atrium (2%), among pts with gastric cancer (8%) vs other cancer (2%) and among metastatic (3.3%) vs non-metastatic disease (1%). 299 pts (40%) were given an antithrombotic prophylaxis (mainly low-dose warfarin), without any benefit on the incidence of ET (7.7%) and CVD-site thrombosis (4%). Conclusions: CVD use is tied with an elevated safety rate (mainly for Port-a-cath), but careful must be due to some item like misplaced tip cateter, gastric cancer and metastatic disease, correlated with CVD-site thrombosis; antitrombotic prophylaxis seems to be useless. No significant financial relationships to disclose.
Long-term survival update of the Scandinavian Prostate Cancer Group 6 study: Bicalutamide 150 mg daily versus placebo in hormone-naïve, non-metastatic prostate cancer.
Authors: Frederik Birkebæk Thomsen, Klaus Brasso, Ib Jarle Christensen, Jan-Erik Johansson, Anders Angelsen, Teuvo L. J. Tammela, Peter Iversen
Journal: Journal of Clinical Oncology (2015)

2 Background: The optimal timing of endocrine therapy in non-metastatic prostate cancer (PCa) is not clear. There is a need for more data from randomized trials. Methods: A randomized, double-blind, parallel-group trial comparing bicalutamide 150 mg once daily with placebo in addition to standard of care in patients with hormone-naïve, non-metastatic PCa. Kaplain-Meier analysis was used to estimate overall survival (OS) and multivariate Cox proportional hazard model was performed to analyse time-to-event (death). Results: 1,218 patients were included into the SPCG-6 study, 607 patients were randomised to bicalutamide and 611 patients to placebo. The majority (81.4%) were managed on watchful waiting. After median 14.6 years follow-up, 866 (71.1%) patients died, 428 (70.5%) in the bicalutamide arm and 438 (71.7%) in the placebo arm, p=0.87. In patients with localised disease (cT1-2, N0/Nx) survival favoured randomisation to the placebo arm (HR=1.19 (95% CI: 1.00-1.43), p=0.056). Bicalutamide significantly improved OS and reduced the risk of death by 23% relative to the placebo arm in patient with locally advanced disease (cT3-4, any N; or any cT, N+) with a median survival difference of 1.8 years (HR=0.77 (95% CI: 0.63-0.94, p=0.01). The survival benefit of bicalutamide in patients with locally advanced PCa was present throughout the study period. In multivariate Cox proportional hazard model OS was dependent on age (HR 1.55 (95% CI:1.20-1.85)), baseline PSA (localised PCa HR for 2 x increase in PSA 1.09 (95% CI:1.02-1.16), locally advanced PCa HR 1.23 (95% CI:1.14-1.33)), WHO histological grade (moderate vs. well HR 1.27 (95% CI:1.08-1.49), poor vs. well HR 1.92 (95% CI:1.51-2.45)), and randomisation to placebo in locally advanced disease (HR=0.76 (95% CI: 0.61-0.95)). Conclusions: The addition of early bicalutamide to standard of care resulted in a significant OS benefit in patients with locally advanced PCa, whereas patients with localised PCa derived no survival benefit from early bicalutamide. The survival benefit of bicalutamide therapy increased with higher baseline PSA. Clinical trial information: NCT00672282.
Effectiveness of Bicycle Safety Helmets in Preventing Head Injuries
Authors: Diane C. Thompson
Journal: JAMA (1996)

The objective of this study is to examine the protective effectiveness of bicycle helmets in 4 different age groups of bicyclists, in crashes involving motor vehicles, and by helmet type and certification standards. Places studied were emergency departments in 7 Seattle, Washington area hospitals between March 1, 1992 and August 31, 1994. There were 3,390 injured bicyclists in the study; 29% of cases and 56% of controls were helmeted. It was concluded that bicycle helmets, regardless of type, provide substantial protection against head injuries for cyclists of all ages involved in crashes, including crashes involving motor vehicles.