tbuckley/cabot-search huggingface dataset:
A new IV busulfan fixed dosing for better exposure targeting in children undergoing allogeneic or autologous hematopoietic stem cell transplantation
Authors: G. Vassal, G. Michel, J.-C. Gentet, H. Espérou, F. Doz, F. Méchinaud, C. Galambrun, A. Fischer, H. Zouabi, C. Puozzo
Journal: Journal of Clinical Oncology (2005)

8535 Background: Oral busulfan (Bu) clearance is highly variable in children and increased in the youngest. Thus, higher doses in children ≤4 y allowed to reach a similar exposure (AUC). Nevertheless, therapeutic drug monitoring (TDM) and dose-adjustments are needed to control the Bu AUC variability. An IV Bu form was developed. In a first trial, 24 children received an IV Bu dosing equivalent to the oral one (1.0 mg/kg ≤ 4 y, 0.8 mg/kg > 4 y). A retrospective pharmacokinetic (PK) modelling demonstrated body weight (BW) better than age for dose calculation. A new dosing was developed. [Nguyen L. et al., BMT 2004] Methods: It was evaluated in a representative pediatric population receiving Bu/Melphalan or Bu/Cyclophosphamide as a conditioning regimen before autologous or allogeneic transplantation, respectively. No dose adjustment was allowed and PK was performed at doses 1, 9 and 16. Bayesian Bu AUCs were calculated. Results: Today’s results (55 patients, median age 6 y [0.3 - 17.2], 20 patients ≤ 4 y) demonstrated the dosing performance to target the “therapeutic window”. All AUCs were >847 μM.min (engraftment threshold), 84% <1500 μM.min (hepatic veno-occlusive disease threshold) and all <2100 μM.min. Advantage of this new dosing over the previous age-based one is obvious. Large inter-patient variability (CV = 50%) on Bu clearance was confirmed but similar AUCs were achieved whatever the age. AUC inter-patient variability was 2.5-fold-reduced (CV ≤ 20%). Low intra-patient variability enabled reproducible exposure without the constraining and invasive use of TDM in children. Preliminary clinical results supported the PK benefit of the new IV Bu dosing: all patients engrafted, no death at Day+100 post-transplant, no severe HVOD (McDonald criteria). Conclusions: Body-weight-based calculation of IV Bu fixed dose can successfully target a therapeutic AUC in children without any dose-adjustment and PK monitoring. No significant financial relationships to disclose.
Racial differences in the use of contralateral prophylactic mastectomy among women undergoing BRCA1/BRCA2 genetic testing
Authors: K. Ready, A. M. Gutierrez-Barrera, J. Litton, F. Meric-Bernstam, A. M. Gonzalez-Angulo, G. Hortobagyi, B. Arun
Journal: Journal of Clinical Oncology (2009)

6542 Background: Patients often use both positive and negative BRCA1/BRCA2 genetic test results to aid in surgical management decisions, but little is known about the existence of racial/ethnic differences in the use of genetic test results. The objective of this study was to evaluate differences in rates of contralateral prophylactic mastectomy (CPM) by race. Methods: A retrospective chart review was performed. Women with a personal history of breast cancer who underwent genetic testing for the BRCA1 and BRCA2 genes at our institution between 1996 and 2008 and were eligible for CPM were included in the study. Genetic test result, race/ethnicity as reported by the patient, years of follow-up since receipt of test result, and decision regarding CPM were recorded. Pearson chi square analyses and Fisher's exact tests were performed to test for significance. Results: 881 women were included in the study. Twenty percent (n = 180) were found to have a BRCA1 or BRCA2 mutation, while 80% (n = 701) were found to have an uninformative negative result. The study population was 87% (n = 771) Caucasian; 7% (n = 58) African American; and 6% (n = 52) Hispanic. Median follow up time was 3 years. There were no significant differences in either follow up time or percentages of BRCA positivity, based on race/ethnicity. Among those with a positive result, 45% (67/149) of Caucasians, 33% (5/15) of African Americans, and 50% (8/16) of Hispanics underwent CPM, but this was not statistically significant. Caucasians and Hispanics with positive results were significantly more likely than their counterparts with negative results to undergo CPM (Caucasians, 45%; 67/149 vs. 16%; 101/622; p&lt;.001; Hispanics, 50%; 8/16 vs. 11%; 4/36; p = 0.004), but this same trend was not observed among African Americans (positive results, 33%; 5/15 vs. negative results, 14%; 6/43; p = 0.10). Conclusions: Among those with a BRCA1/BRCA2 mutation, there does not appear to be any significant difference in the use of CPM based on race/ethnicity. However, Caucasians and Hispanics appear to be more likely than African Americans to use the results of genetic testing to make surgical management decisions. No significant financial relationships to disclose.
Abstract 9200: Targeted Delivery of Slow-Releasing Form of A Prostacyclin Analogue, ONO-1301®, Enhances Recruitment of Bone Marrow Derived Cell and Yields Functional Benefits in Acute Myocardial Infarction in Mice
Authors: Yukiko Imanishi, Shigeru Miyagawa, Satsuki Fukushima, Kazuhiko Ishimaru, Atsuhiro Saito, Yoshiki Sakai, Yoshiki Sawa
Journal: Circulation (2011)

Background: Prostacyclin is an endogenous factor having a variety of protective effects against ischemic pathologies. We have generated ONO-1301®, which is a synthetic prostacyclin analog characterized by chemically stable structure and enhances stromal cell derived factor-1 (SDF-1), hepatocyte growth factor (HGF), and vascular endothelial growth factor (VEGF) secretion. Here, we hypothesized that sustained delivery of ONO-1301® may induce therapeutic effects mediated by the recruited bone marrow derived cells into the injured myocardium in acute MI mouse. Methods and Results: ONO-1301® was conjugated with poly-DL-lactic-co-glycolic acid microsphere to generate a biodegradable controlled-release form. Either the atelocollagen-sheet with ONO-1301® microsphere eluted (ONO group; n=28) or ONO-1301® free microsphere eluted (control group; n=40) was implanted on the left ventricular anterior wall at 15 minutes following permanent LCA occlusion in C57BL6/N mice (male, 8-weeks old). ONO-1301® was still present in the plasma at 1 month (134±26 pg/ml; n=5). Expression levels of SDF-1, HGF, and VEGF in the infarct-border area were significantly elevated for 1 month in the ONO group. Recruitment of bone marrow cell induced by ONO-1301® was investigated using the acute-MI model in GFP-expressing bone marrow-transplanted chimera mice. Two months after LCA ligation followed by ONO-1301® treatment, there was a greater retention of the GFP+ cells in the infarct area. Some of the GFP+ cells were differentiated into the capillary components. In the ONO-1301® treated hearts, LV anterior wall thickness was significantly greater and infarct size was lower at 1 month. Cardiac performance was significantly greater in the ONO group (fractional area change: 24±1%; n=18) than the control group (20±1%; n=22; P=0.011), associated with greater 1 month survival in the ONO group (61±9 vs. 36±8%; P=0.052). Conclusions: Targeted delivery of the slow-releasing form of ONO-1301® possibly up-regulates protective factors, and recruits bone marrow cells into the infarct area, leading to the functional and survival benefits, indicating promising strategy to be translated into the clinical arena.
Single-agent capecitabine use in patients age 70 or older with colorectal cancer.
Authors: Marcia Hall, Daniel Krell, Robert Glynne-Jones
Journal: Journal of Clinical Oncology (2015)

764 Background: Colorectal cancer (CRC) is primarily a disease of the elderly, with a median age at diagnosis of 71. Administration of chemotherapy treatment in elderly patients with CRC is challenging due to multiple factors, including co-morbidities and a decline in organ function and is often associated with more toxicities and hospitalisations. Capecitabine monotherapy is an effective treatment in CRC but is associated with toxicities, commonly necessitating dose reduction (DR) in elderly patients. We present an audit of capecitabine prescribing in patients with CRC over the age of 70. Methods: The medical records of 43 patients over 70 receiving capecitabine monotherapy for CRC in our unit between November 2012 and August 2014 were analysed. The starting dose of capecitabine was established, and dose reductions prior to initial treatment were noted. Subsequent dose reductions, and toxicities necessitating such reductions were recorded. Results: 74 patients (37 male;37 female) were treated, 47 adjuvantly and 27 palliatively. The median age at treatment was 78. Patients received an average of 4.3 cycles (range 1-8), at an average starting dose of 1800mg (range 1000-2700mg). 43/74 (58%) patients received a DR from 1250mg/m2, prior to cycle one, with an average DR of 22% (range 0%-60%). The primary reason for DR was frailty (62%), inadequate GFR (35%), and poor performance status (3%). Secondary reasons included ischaemic heart disease and other comorbidities. 12/43 (28%) patients required a DR at subsequent cycles, due to diarrhoea (50%), fatigue (33%) and PPE (17%). 3/43 (7%) patients terminated their treatment early due to angina, PPE and diarrhoea respectively. 2/27 (9%) metastatic patients received capecitabine (625mg/m2) in combination with bevacizumab. Conclusions: Real-life dosing of capecitabine in the over 70’s, selected as fit but frail is more conservative than the guidelines recommend and was associated with considerable toxicity precluding dose escalation. Even at reduced starting doses toxicity was substantial and a third required a further dose reduction which questions the efficacy of adjuvant chemotherapy in this age group, despite a proactive education patient programme about diarrhoea and PPE.
Phase II study of irinotecan, 5-fluorouracil (5-FU) and leucovorin combination chemotherapy in taxane and cisplatin-based chemotherapy-refractory metastatic gastric cancer
Authors: J. Yoon, S. Cho, W. Bae, J. Hwang, H. Shim, I. Chung
Journal: Journal of Clinical Oncology (2009)

e15599 Background: The role of the second line chemotherapy in advanced gastric cancer was not clear, but possibility of prolongation of survival is open question. Irinotecan is promising agents in gastric cancer and this phase II study evaluated the efficacy and safety of combination chemotherapy with irinotecan, high dose of 5-fluorouracil (5-FU) and leucovorin in taxane and cisplatin based chemotherapy refractory metastatic gastric cancer. Methods: Eligible criteria were as followed; histologic confirmed adenocarcinoma of stomach, previously treated with taxane and cisplatin, age≥18, Eastern Clinical Oncology Group (ECOG) performance status of 1 or less, adequate organ function. Irinotecan (150 mg/m 2 ) as a 30-min infusion and leucovorin (200 mg/m 2 ) as a 15-min infusion were given on day 1, followed by 5-FU 400 mg/m 2 bolus infusion then 5-FU 2,400 mg/m 2 as a 48-hour continuous infusion. This cycle was repeated every 2 weeks until disease progression or unacceptable toxicities. Results: Thirty-four patients were enrolled. The median age was 57 years (range 27–73 years), and the ECOG performance status of all patients was 1. All patients were evaluable for safety and survival and twenty seven patients (79.4%) were evaluable for tumor response. The overall response rate was 18.5% (95% CI: 3.9–33.1). The median progression free survival and overall survival were 4.6 (95% CI: 2.4–6.9) and 9.3 months (95% CI: 5.2–13.4), respectively. Greater than grade 3 haematological toxicities were neutropenia in nine (26.5%), febrile neutropenia in one (2.9%) and thrombocytopenia in one patient (2.9%). The major non-haematological toxicity was asthenia, but most of patients showed grade 1 or 2. Greater than grade 3 non- haematological toxicities were elevated AST/ALT in four (11.8%), hyperbilirubinemia in two (5.9%), nausea in two patients (5.9%). Conclusions: This results showed that the combination chemotherapy with irinotecan, 5-FU and leucovorin was well tolerated and active in taxane and cisplatin refractory patients. No significant financial relationships to disclose.
Radio-induced esophageal cancer (RI-EC): Case-control study on behalf of the Rare Cancer Network
Authors: G. Crehange, F. Bonnetain, R. Miller, E. Morineaux, B. OEI, Y. Kirova, F. N'guyen, P. Maingon
Journal: Journal of Clinical Oncology (2008)

15543 Background: RI-EC is a rare but well identified disease. Treatment strategy remains uncertain as surgery or reirradiation are often not possible in such second cancers. Methods: RI-EC was defined as a tumor with a different histology than the primary tumor, occurring in previous treatment fields, at least 5 years after a primary irradiation according to the Cahan criteria. A case - control study with control patients matched according to sex, age and year of diagnosis was performed. 74 patients were included in the study. We report preliminary results on survival for 60 patients. Survivals were estimated using Kaplan Meier estimations and compared using Log Rank tests. Results: Mean age was 63 years (range, 30–90 years). 19 pairs were women (63%) and 11 pairs were men (34%). Among RI-EC patients(pts), 14 pts were initially treated with radiotherapy (RT) for breast cancer (46.7%), 11 pts for lymphoma (36.7%), 2 patients for testicular cancer (6.7%), 2 pts for head and neck cancer (6.7%) and 1 pt for mediastinal astrocytoma. Median dose of primary RT was 45 Gy (range, 30 Gy - 60 Gy) in 20.5 fractions (range, 13 - 30). Histology was SCC in 76.7% of RI-C pts and in 66.7% of control pts, adenocarcinoma in 10% of RI-C pts and in 30% of control pts. 2 RI-EC pts were diagnosed with lymphoma and 2 pts with sarcomatoïd SCC. 1 control pt had an undifferenciated carcinoma. Patients with RI-EC were more likely to be treated with surgery (58.4%) and control pts with chemo-RT (63.4%). Resection was not curative for 16.7% of the RI-EC pts (R1) and 3.3% of pts (R2). 15 local relapses and 45 deaths were observed. Control vs. RI-EC patients: median relapse-free survival was 22.6 months and not reached, respectively (p= 0.021), median overall survival was 12.5 months vs. 14.8 months (p= 0.78). Conclusion: RI-EC is a rare iatrogenic entity with an overall survival similar to that of alcohol, smoking or Barrett-related carcinomas. Local control for RI-EC was significantly decreased, probably secondary to incomplete resections in an irradiated field or a decision to pursue palliative care. No significant financial relationships to disclose.
The importance of ongoing nutritional assessment in advanced colorectal cancer
Authors: J. Grutsch, D. Gupta, C. A. Lammersfeld, P. G. Vashi, C. G. Lis
Journal: Journal of Clinical Oncology (2004)

3691 Background: Previously, we reported that well-nourished status versus moderate to severe malnourished status at baseline identifies patients with better survival outcomes in advanced colorectal cancer. The goal of this investigation was to evaluate if nutritional status after three months of therapy provides ongoing prognostic information in advanced colorectal cancer. Methods: A consecutive case series of 63 newly diagnosed stages III-IV colorectal cancer patients treated at Cancer Treatment Centers of America (CTCA) at Midwestern Regional Medical Center between January 1995 and March 2001 were identified from the tumor registry. The Patient Generated Subjective Global Assessment (PG-SGA) was used to evaluate the nutritional status following three months of therapy (N=53). Patients were classified as either well nourished (low PG-SGA score, 0–4), or moderate-severely malnourished (high PG-SGA score, 5+). Kaplan-Meier survival analysis was used to calculate survival, which was defined as the time interval between date of patient visit at 3 months from diagnosis and date of death from any cause or date of last contact. The Log-Rank test statistic was used to evaluate survival differences across strata. Results: Patients with low PG-SGA scores had a median survival of 29.8 months (95% CI, 18.4 to 41.1; n = 40) while those with high PG-SGA scores had a median survival of 13.6 months (95% CI, 9.6 to 17.7; n = 13), the difference being statistically significant (p = .03) Conclusions: These results indicate that nutritional status provides useful prognostic information even after three months of therapy for advanced colorectal cancer. As a result, ongoing nutritional assessment deserves serious consideration in the management of patients with advanced colorectal cancer. No significant financial relationships to disclose.
Royal colleges express concern over junior doctors’ contract as petition calls for strike
Authors: Tom Moberly
Journal: BMJ (2015)

More than 50 000 people have signed an online petition urging doctors to take strike action against the imposition of a new junior doctor contract.1

Junior doctors are concerned about proposed changes to their contract that they say will lead to an effective pay cut and increase their workload. The BMA said that the proposed changes were “bad for patients, bad for junior doctors, and bad for the NHS” and that it would resist their imposition.2

Medical royal colleges have also raised concerns about the potential impact …
Effects of Butylated Hydroxyanisole, Butylated Hydroxytoluene, and NaCl on Gastric Carcinogenesis Initiated With <italic>N</italic>-Methyl-<italic>N</italic>'-nitro-<italic>N</italic>-nitrosoguanidine in F344 Rats<xref ref-type="fn" rid="FN2">2</xref>
Authors: T Shirai, S Fukushima, M Ohshima, A Masuda, N Ito
Journal: JNCI Journal of the National Cancer Institute (1984)

Promoting activities of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and NaCl and of combinations of these antioxidants with NaCl on gastric carcinogenesis initiated by N-methyl-N'-nitro-N-nitrosoguanidine [(MNNG) (CAS: 70-25-7; 1-methyl-3-nitro-1-nitrosoguanidine] were investigated in male inbred F344 rats. Animals, 6-week old, were given an intragastric administration of MNNG at 150 mg/kg body weight by gastric tube and 1 week later were placed on a diet containing BHA (0.5%), BHT (1.0%), NaCl (5.0%), BHA (0.5%) plus NaCl (5%), or BHT (1.0%) plus NaCl (5.0%) for 51 weeks. Control rats received no further treatment after MNNG administration. A single intragastric application of MNNG to rats induced multiple epithelial tumors of the forestomach and a few epithelial tumors of the glandular stomach after 52 weeks. Squamous cell carcinomas of the forestomach were seen in 2 of 18 effective rats (11.1%) in the control groups, and the incidences in the groups receiving the subsequent treatment were 45.0% with BHA, 15.8% with BHT, 30% with NaCl, 70% with BHA plus NaCl, and 52.9% with BHT plus NaCl. Differences in the incidences of squamous cell carcinoma between the controls and groups given BHA, BHA plus NaCl, and BHT plus NaCl were statistically significant. NaCl given alone after MNNG administration also significantly increased the incidence of papillomas in the forestomach. Incidences of glandular stomach tumors, adenomas and carcinomas were not affected by any of the subsequent treatments. No tumors of the stomach developed in the groups given BHA, BHT, and NaCl without MNNG pretreatment. Thus the present experiment revealed that BHA and NaCl but not BHT exert promoting activity on MNNG-induced forestomach carcinogenesis in rats and that, when BHA and BHT were given with NaCl, promotion was more marked, suggesting a synergistic effect on tumor promotion.
Biomodulation of capecitabine by docetaxel and gemcitabine (mGTX) in patients with metastatic adenocarcinoma of the pancreas (MAP): A dose-escalating phase I study
Authors: M. E. Hill, X. Li, S. Kim, K. Culler, M. M. Zalupski, T. S. Bekaii-Saab
Journal: Journal of Clinical Oncology (2008)

15585 Background: The combination of gemcitabine, docetaxel, and capecitabine (GTX) has been examined retrospectively in advanced pancreas cancer with promising results. Docetaxel leads to upregulation of thymidine phosphorylase activity, a principal determinant of the therapeutic index of capecitabine, beginning 4–6 days after treatment. Gemcitabine inhibits ribonucleotide reductase resulting in enhanced binding of 5-fluorouracil derivatives to thymidylate synthase. With these considerations, we conducted the first prospective analysis of the 3-drug combination with schedule modification (mGTX) to maximize biomodulation of capecitabine. Methods: We conducted a dose escalating study of mGTX in the first line treatment of MAP. There were 3 dose levels (DL 1–3). Patients received docetaxel on days 1 and 8, gemcitabine on days 8 and 15, and capecitabine on days 8 through 21. Gemcitabine dose was fixed at 750 mg/m2 over 75 minutes whereas capecitabine was escalated from 500 mg/m2 to 750 mg/m2 at DL2 and docetaxel from 30 mg/m2 to 36 mg/m2 at DL3. Results: Fifteen patients from The Ohio State University and University of Michigan were enrolled on the study. The most common grade 3/4 toxicities included neutropenia (42%) and fatigue (17%). The dose-limiting toxicity was neutropenia in 1 patient at DL2. We determined the maximum tolerated dose to be DL3. Three patients were considered non-evaluable because they withdrew consent before completing the first cycle for reasons unrelated to toxicity or progression. Tumor growth control rate was 67 % (17% PR; 50% SD with 83% of SD lasting over 3 months). Median time to progression was 7.7 months (range 1.7 to 10+ months). Median overall survival was 9.6 months and the one-year survival rate was 33%. CA 19–9 was elevated at baseline in 73% of patients and decreased >50% from baseline in 40% of patients on therapy. Conclusion: mGTX demonstrates interesting activity and acceptable tolerability in patients with MAP. The recommended doses for phase II studies using this schedule are docetaxel 36 mg/m2 on days 1 and 8, gemcitabine 750 mg/m2 over 75 minutes days 8 and 15, and capecitabine 625 mg/m2 days 8 through 21. Made possible through assistance from NCCN and Roche. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Lilly Oncology, sanofi-aventis Roche, sanofi-aventis
Whither carboplatin?--A replacement for or an alternative to cisplatin?
Authors: D D Von Hoff
Journal: Journal of Clinical Oncology (1987)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1987.5.2.169 Journal of Clinical Oncology - published online before print September 22, 2016 PMID: 3543240 Whither carboplatin?--A replacement for or an alternative to cisplatin? D D Von HoffxD D Von HoffSearch for articles by this author https://doi.org/10.1200/JCO.1987.5.2.169 First Page PDF © 1987 by American Society of Clinical Oncology