tbuckley/cabot-search huggingface dataset:
Exposure-response relationships of AMG 386 in combination with weekly paclitaxel in advanced ovarian cancer: Population pharmacokinetic/pharmacodynamic (PK/PD) modeling to facilitate phase III dose selection.
Authors: J. Lu, E. Rasmussen, L. Navale, M. Kuchimanchi, E. Hurh, B. Y. Karlan, I. B. Vergote, D. E. Stepan, D. M. Weinreich, Y. Sun
Journal: Journal of Clinical Oncology (2010)

5042 Background: The exposure-response relationships of AMG 386 (an investigational peptide-Fc fusion protein that neutralizes the interaction between the Tie2 receptor and angiopoietin-1 and -2) plus paclitaxel in patients (pts) with advanced ovarian cancer enrolled in a phase II study were evaluated using population PK/PD to facilitate phase III dose selection. Methods: 161 pts with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer were randomized 1:1:1 to paclitaxel (80 mg/m2 IV QW, 3 wk on/1 wk off) plus AMG 386 (3 or 10 mg/kg IV QW) or placebo and treated until disease progression, toxicity, or death. Population PK analysis for AMG 386 was performed using PK data from the first-in-human study and the phase II study. Cox regression was used to evaluate the effect of AUC at steady state (AUCss) on progression-free survival (PFS). Kaplan-Meier estimates for PFS and safety were evaluated for pts with high exposure (AUCss ≥ 9.6 mg·h/mL [75th percentile]) vs. low exposure (AUCss < 9.6 mg·h/mL). Monte Carlo simulations based on a parametric survival model were used to evaluate PFS with the different dose regimens. Results: Cox regression analysis showed prolonged PFS with an increase of AUCss for all pts (HR, 0.97, p = 0.095) and the 10 mg/kg arm (HR, 0.89, p = 0.073). Pts with AUCss ≥ 9.6 mg·h/mL (n = 26) had longer PFS (8.1 mo; HR, 0.67) than either pts (n = 79) with AUCss < 9.6 mg·h/mL (5.7 mo; HR, 0.81) or pts who received placebo (4.6 mo). No association between AUCss and safety was observed. Simulations using a parametric survival model predicted that a dose of 15 mg/kg (which provides AUCss ≥ 9.6 mg·h/mL coverage for >90% of patients) would result in a median PFS of 8.3 months compared to 5.0 months for the placebo group (HR, 0.55). Based on the population PK analysis, creatinine clearance was significantly associated with AMG 386 clearance. Conclusions: Population PK/PD analyses demonstrate an association between exposure and PFS and suggest that although the primary endpoint (PFS) was met the maximum benefit in PFS was not reached at an AMG 386 dose of 10 mg/kg QW. Higher doses should be explored in future studies. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen Amgen Amgen
Minimal role of xanthine oxidase and oxygen free radicals in rat renal tubular reoxygenation injury.
Authors: R B Doctor, L J Mandel
Journal: Journal of the American Society of Nephrology (1991)

The role of xanthine oxidase and oxygen free radicals in postischemic reperfusion injury in the rat kidney remains controversial. Proximal tubules, the focal segment affected by ischemic renal injury, were isolated in bulk, assayed for xanthine oxidase activity, and subjected to 60 min of anoxia or hypoxia and 60 min of reoxygenation to evaluate the participation of xanthine oxidase and oxygen radicals in proximal tubule reoxygenation injury. The total xanthine oxidase in isolated rat proximal tubules was 1.1 mU/mg of protein, approximately 30% to 40% of the activity found in rat intestine and liver. Lactate dehydrogenase release, an indicator of irreversible cell damage, increased substantially during anoxia (39.8 +/- 2.3 versus 9.8 +/- 1.8% in controls) with an additional 8 to 12% release during reoxygenation. Addition of 0.2 mM allopurinol, a potent xanthine oxidase inhibitor, and dimethylthiourea, a hydroxyl radical scavenger, failed to protect against the reoxygenation lactate dehydrogenase release. Analysis of xanthine oxidase substrate levels after anoxia and flux rates during reoxygenation indicates that hypoxanthine and xanthine concentrations are in a 15-fold excess over the enzyme Km and 0.3 mU/mg of protein of xanthine oxidase activity exists during reoxygenation. Hypoxic tubule suspensions had a minimal lactate dehydrogenase release during hypoxia and failed to demonstrate accelerated injury upon reoxygenation. In conclusion, although xanthine oxidase is present and active during reoxygenation in isolated rat proximal tubules, oxygen radicals did not mediate reoxygenation injury.
How is <i>KRAS</i> testing associated with treatment and supportive care for patients with metastatic colorectal cancer? VA national assist project.
Authors: Aparna Raj Parikh, Benjamin Kim, Philip Pantoja, Diana M. Tisnado, Sangeeta C Ahluwalia, Anne M. Walling, Steven M Asch, Karl Lorenz
Journal: Journal of Clinical Oncology (2013)

64 Background: EGFR monoclonal antibody (mAb) therapies improve quality of life and outcomes for metastatic colorectal cancer (mCRC), but only wild-type KRAS benefit from treatment. We evaluated KRAS testing and pharmacogenetic-guided treatment and supportive and end of life (EOL) care. Methods: Among a national random sample of 265 veterans diagnosed with mCRC in 2008 we evaluated KRAS testing, EGFR mAb therapy, supportive care using the Cancer Quality ASSIST indicators, and healthcare use. Three oncology nurses abstracted charts for care received 2008-2011. We linked chart to VA and Medicare administrative data and compared care received by KRAS testing and results. Results: 227/265 (85%) veterans died within 3 years and received an average of 48% of recommended supportive care processes. 96 / 265 (36%) underwent KRAS testing, of whom 41, 42, and 13 had wild-type, mutant, and indeterminant/unknown KRAS. 27/41 (66%) wild-type KRAS patients received an EGFR mAb; 18/45 (40%) patients receiving an EGFR mAb had mutant, indeterminant/unknown, or untested KRAS. KRAS testing was associated with increased systemic therapy but not differences in supportive care or intensity of care at the EOL. KRAS tested vs. not tested received hospice or palliative care (67 vs. 73%, p=0.55); any systemic therapy (96 vs. 40%, p&lt;0.001) including new regimen in last month (0 vs. 6%); any chemotherapy in last 14 days of life (9 vs. 7%); and any acute care in last month of life (28 vs. 32%, p=0.78). Conclusions: KRAS testing was not performed for most veterans with mCRC in 2008, and EGFR mAb therapy was administered to many without wild-type KRAS. KRAS-tested patients were more likely to receive systemic treatments, and testing was not associated with greater intensity or inappropriate EOL care, and rates of such care were low among veterans.
A phase I, open-label study of lapatinib plus chemoradiation in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN)
Authors: K. J. Harrington, J. Bourhis, C. M. Nutting, D. Rosine, A. M. Theodosiou, S. Gardiner, M. S. Berger, A. P. Beelen, A. G. Stead, I. A. El-Hariry
Journal: Journal of Clinical Oncology (2006)

5553 Background: Lapatinib is a selective and potent dual, competitive inhibitor of EGFR and ErbB2. A high level of expression of EGFR is reported in SCCHN (ranging from 55% to 90%), which is a negative prognostic factor, whereas ErbB2 expression ranges between 40% to 60%. The rationale for EGFR inhibition in combination with fractionated radiotherapy is to enhance radiosensitivity and inhibit cellular proliferation, including accelerated repopulation, during treatment. Methods: Patients (pts) with locally advanced SCCHN were enrolled at escalating dose levels of lapatinib (500–1,500 mg/d) in combination with radiotherapy (66–70 Gy/6–7 weeks given 5 days a week in 2 Gy daily fractions) and intravenous cisplatin (100 mg/m 2 , days 1, 22 and 43 of radiotherapy). Each cohort was to include 3 pts, with expansion to 6 in the event of dose-limiting toxicity (DLT). Main eligibility criteria were confirmed SCCHN, excluding nasopharynx, stage III, IVa,b, and adequate organ function. Regular safety assessments were performed during therapy and follow-up period. Cardiac assessments using MUGA or ECHO scans were also performed. Results: Seventeen pts were treated (500 mg - 7; 1,000 mg - 7; 1,500 mg - 3; expanded cohort of 9 additional pts is currently recruiting). The most common side effects were Grade 1-3 dysphagia, mucositis and dermatitis, typically observed with cisplatin and radiotherapy in this population. Lapatinib-related adverse events were minor. In the 500mg cohort: 2 pts had diarrhea (Gr 1), 1 pt had tinnitus (Gr 1); in the 1,000mg cohort: 2 pts had nausea (Gr 2) and vomiting (Gr 2), 1 pt had transient elevated liver enzymes (Gr 3); in the 1,500mg cohort 2 pts had nausea (Gr 1) and 3 pts vomiting (1 pt Gr 1, and 2 pts Gr 2). One DLT was reported both at 500 mg and 1,000 mg dose levels; no further DLT were reported at the final 1,500 mg dose level. The optimally tolerated regimen was lapatinib 1,500 mg OD, given concurrently with conventional radiotherapy and cisplatin. Preliminary evidence of clinical activity was encouraging. Conclusions: The combination of lapatinib and concomitant chemoradiation is well tolerated, has demonstrated encouraging clinical activity in this population of locally advanced SCCHN patients, and warrants phase II studies in this disease. [Table: see text]
Discontinuation and dose modification of imatinib in clinical practice
Authors: M. Y. Hamdan, L. Sanders, S. Oliveria, U. Campbell, V. Willey, I. Hirji, C. Davis, M. Ulcickas Yood
Journal: Journal of Clinical Oncology (2007)

7045 Background: Imatinib mesylate induces response in most patients with chronic myelogenous leukemia (CML). Although recent evidence shows benefit from a starting dose of 800mg/day, the recommended starting dose is 400 mg/day for chronic phase patients and 600 mg/day for accelerated phase/blast crisis patients. This study describes trends in imatinib dosing and reasons for dose changes in CML patients. Methods: Using medical and pharmacy claims in the HealthCore Managed Care Database, we identified all patients with CML from 1/1/00–3/31/04. Chart review supplemented claims and confirmed CML diagnosis, obtained phase, treatment, and clinical outcomes through 3/31/05. Results: Among 216 patients receiving imatinib, 87% were diagnosed in chronic phase, 5% in accelerated phase, 1% in blast phase; 7% were unable to be determined. Among 156 patients (72%) with a starting imatinib dose of 400mg/day, 21% had a subsequent dose reduction of at least 100mg/day. The most common reasons for dose reduction were neutropenia, anemia, and nausea/vomiting. Among 29 patients (13%) with a starting dose of at least 600mg/day, 59% had a subsequent dose reduction; the most common reasons for dose reduction in these patients were thrombocytopenia and gastrointestinal bleeding. Among 9 patients (4%) with a starting imatinib dose of at least 800mg/day, 67% had a subsequent dose reduction; the most common reason for dose reduction was myelosuppression. Imatinib therapy was suspended in sixty-two patients (29%), most often because of anemia (11%) or thrombocytopenia (11%); 46 patients (74%) restarted imatinib therapy following a median time of 21 days and the remaining 16 (26%) patients were permanently discontinued. Of the 64 patients (30%) who experienced a dose escalation of at least 100mg/day over starting dose, 34% patients had a subsequent dose decrease; the most common reason for dose reduction among these patients was neutropenia (18%). Conclusions: Among CML patients treated with imatinib, discontinuation and dose changes occurred frequently; the most common reason was myelosuppression. More than 50% of patients starting at higher doses required dose reductions and 1/3 of those receiving dose escalations did not remain on higher doses. No significant financial relationships to disclose.
Defining Best Practices on Supportive Care During Chemo-Radiotherapy for Head and Neck Cancer with a Formal Systematic Methodology
Authors: P. Bossi, E. Russi, G. Numico, V. De Sanctis, N. Denaro, M.G. Ghi, A. Mirabile, F. Moretto, C.I. Ripamonti, M. Buglione, M. Airoldi, J.B. Vermorken, B. Murphy, J. Langendijk, J.E. Raber Durlacher, L. Licitra
Journal: Annals of Oncology (2014)
Clonal history of a cord blood donor cell leukemia with prenatal somatic JAK2 V617F mutation
Authors: P Hirsch, A C Mamez, R Belhocine, S Lapusan, R Tang, L Suner, D Bories, C Marzac, F Fava, O Legrand, M Mohty, L Douay, F Delhommeau
Journal: Leukemia (2016)
BRM promoter insertion/deletion polymorphisms in hepatocellular carcinoma risk and survival.
Authors: Kit Man Wong, Geoffrey Liu, Jonghun John Lee, Osvaldo Espin-Garcia, Yonathan Brhane, Dangxiao Cheng, Zhuo Chen, Devalben Patel, Catherine Brown, Amy Wong, David Reisman, Wei Xu, Jennifer J. Knox, Sean P. Cleary, Rayjean J Hung
Journal: Journal of Clinical Oncology (2014)

225 Background: MEF2D and HDAC9 regulate the expression of BRM, the catalytic subunit of SWI/SNF (chromatin remodeling complex). MEF2D binding sites are created in the BRM promoter by two germline insertion/deletion polymorphisms (BRM-741, BRM-1321), which mediate epigenetic silencing. We recently identified BRM as a potential drug target and a susceptibility gene for lung and head and neck cancers, while others reported its association with HCC risk in Asians. BRM also correlates with prognosis in lung and esophageal cancers (ASCO 2013; abstracts 11057, 4077). In this analysis, we assessed the effects of the BRM promoter variants on risk and overall survival (OS) in HCC from a North American centre (Toronto). Methods: We conducted a case-control study with 266 histologically confirmed HCC cases and 536 age/sex distribution-matched healthy controls. Survival of the cases was obtained from medical records. Association between the BRM polymorphisms and HCC risk was analyzed by multivariate logistic regression adjusted for age, sex, race, smoking and BMI; their impact on OS was evaluated by Cox proportional hazard regression adjusted for age, sex, treatment intent and Hepatitis B status. Results: Median age was 62 years; 83% were male. Hepatitis B and C infections affected 34% and 31% of cases, respectively. 83% of patients were Child Pugh A at diagnosis, and 66% received initial curative therapy (surgical resection rate 32%). There were 13% deaths at a median follow-up of 24.1 months. There was no significant association between BRM polymorphisms and HCC risk: the adjusted risk odds ratios of the homozygous BRM variants, relative to wild-type, were 0.87 (95% CI: 0.53-1.45; BRM-741) and 1.01 (95% CI: 0.78-1.29; BRM-1321), and 0.94 (95% CI: 0.48-1.86) for the double homozygotes vs. double wild-type. The adjusted hazard ratios for OS were 5.77 (95% CI: 2.9-11.5; BRM-741) and 4.09 (95% CI: 2.2-7.5; BRM-1321) for each variant allele; the double homozygotes were also highly associated with OS compared to double wild-type (p&lt;0.0001). Conclusions: Two functional BRM promoter polymorphisms did not increase the risk of HCC. However, they were strongly associated with OS despite short median follow-up. SPC and RH are co-senior authors.
The relative value of conventional staging procedures for developing prognostic models in extensive-stage small-cell lung cancer.
Authors: R G Sheehan, E P Balaban, J V Cox, E P Frenkel
Journal: Journal of Clinical Oncology (1990)

Published prognostic models for small-cell lung cancer (SCLC) have either combined limited- and extensive-stage patients or have not included standard anatomic staging information to assess the relative value of the knowledge of specific sites and number of sites of metastases in predicting survival in extensive-stage disease. We studied 136 extensive-stage patients in whom traditional staging procedures were performed and in whom other previously demonstrated significant pretreatment variables were determined. Using the Cox proportional hazards model, when all data were included, three variables were significant: performance status (PS) (P = .0001), number of sites of metastases (P = .0010), and age (P = .0029). A prognostic algorithm was developed using these variables, which divided the patients into three distinct groups. When the anatomic staging data were omitted, the serum albumin (P = .0313) was the only variable in addition to PS (P = .0001) and age (P = .0064) that was significant. An alternative algorithm using these three variables was nearly as predictive as the original. Therefore, in extensive-stage patients, reasonable pretreatment prognostic information can be obtained without using the number or specific sites of metastases as variables once the presence of distant metastases has been demonstrated.
Efficacy and safety of sorafenib in patients with alcohol-related hepatocellular carcinoma: A sub-analysis from the SHARP trial
Authors: A. Craxi, C. Porta, A. Sangiovanni, J. Seitz, M. Moscovici, M. Shan, A. Nadel, D. Voliotis, J. Bruix, J. M. Llovet
Journal: Journal of Clinical Oncology (2008)

15591 Background: The majority of patients with HCC present with advanced disease and are therefore not suitable for curative treatment. The only systemic therapy currently approved for HCC is sorafenib, a multi-kinase inhibitor. Approval of sorafenib by the FDA and EMEA for the treatment of HCC followed results from the phase III Sorafenib HCC Assessment Randomized Protocol (SHARP) trial, which demonstrated that sorafenib 400mg b.i.d. improves overall survival (OS) versus placebo in advanced HCC. The etiological factors most commonly linked to HCC are infection with either hepatitis B virus (HBV) or hepatitis C virus (HCV), and alcohol abuse. Here we report a subgroup analysis of SHARP assessing safety and efficacy of sorafenib in patients with alcohol-related advanced HCC. Methods: In SHARP, 602 patients with advanced, unresectable HCC were randomized to sorafenib 400mg b.i.d. or placebo. In this subanalysis, OS and time to progression (TTP) were evaluated for patients with alcohol-related HCC. Events were independently assessed. Results: In the intent-to-treat population, the number of patients with alcohol as etiology of the underlying liver disease was 79 in the sorafenib group and 80 in the placebo group. Median OS for sorafenib vs placebo was 10.32 vs 7.99 months (HR: 0.76; 95% CI: 0.50, 1.16) and TTP was 5.52 vs 3.94 months (HR: 0.64; 95% CI: 0.40, 1.03). The proportion of patients who had drug-related, treatment-emergent adverse events was 80.8% in the sorafenib group vs 53.8% in the placebo group. The most common drug-related adverse events in the sorafenib group were diarrhea (47.4%), fatigue (20.5%) and hand-foot skin reaction (20.5%); in the placebo group these adverse events occurred at rates of 10%, 12.5% and 6.3%, respectively. Conclusions: This subanalysis included a relatively small number of patients and, therefore, the data must be interpreted with caution. However, the results from patients with alcohol-related advanced HCC suggest a trend of improved OS and TTP in favor of sorafenib and are consistent with the overall results in the SHARP study population, supporting the use of sorafenib as a valid treatment option for a wide range of patients with HCC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bayer Bayer, Biocompatibles, Bristol-Myers Squibb AstraZeneca, Eisai, MDS Nordion, sanofi-aventis Bayer, Biocompatibles, Bracco Bayer
Immunogenetics of HLA-DP — A New View of Permissible Mismatches
Authors: Katharina Fleischhauer
Journal: New England Journal of Medicine (2015)

In this issue of the Journal, Petersdorf and colleagues1 report an association between high-expression HLA-DP variants in patients receiving hematopoietic-cell transplantation for severe blood disorders and acute graft-versus-host disease (GVHD). Acute GVHD is a major hurdle in successful treatment.HLA-DP molecules are immunoglobulin family cell-surface heterodimers encoded by the polymorphic DPA1 and DPB1 loci in the human major-histocompatibility-complex (MHC) class II region on chromosome 6p21.3. To date (IMGT/HLA Release 3.21.0, July 2015; www.ebi.ac.uk/ipd/imgt/hla), 20 DPA1 and 447 DPB1 alleles encoding expressed proteins that differ by at least one amino acid have been reported. Only 2 of the DPA1 and . . .
Treating the anemia of MDS with erythropoietin: Impact of higher dose compared to combination with G/GM-CSF
Authors: V. M. Moyo, P. Lefebvre, M. Duh, B. Yektashenas, S. Mundle
Journal: Journal of Clinical Oncology (2007)

7082 Background: Recombinant human erythropoietin (EPO) is extensively used to improve erythropoiesis and reduce transfusions in anemic MDS pts. The addition of G/GM-CSF to EPO alfa or beta has been associated with higher erythroid response (ER) rates vs. EPO alone. Studies suggest higher ER rates could be achieved with EPO monotherapy if higher initiation doses were used. To study this question a meta-analysis was performed on studies of MDS pts treated with EPO alfa or beta + G/GM-CSF. Methods: Data extraction was performed on studies from PubMed, ASCO and ASH proceedings from 1990–2006 in MDS pts treated with EPO (alfa or beta) ± G/GM-CSF. To allow for cross comparisons, only studies including IWG or IWG-like ER criteria were selected for analysis. Pooled estimates of ER rates were calculated using fixed-effect (F-E) meta-analysis methods. Results were stratified by: (i) EPO-alfa at standard doses, (ii) EPO- alfa at high doses, (iii) EPO-alfa + G/GM-CSF, and (iv) EPO-beta + G/GM-CSF. Results: From 39 studies identified, 19 met inclusion criteria. Most pts (&gt;55%) had RA/RARS. Studies using EPO-alfa at standard doses showed comparable ER rates to studies using EPO- alfa + G/GM-CSF (49.0% vs. 50.6%; p=0.731) ( Table ). Among EPO-alfa studies, those using higher EPO doses had higher ER rates vs. studies using standard EPO doses (p&lt;0.001) or EPO + G/GM-CSF combination (p=0.007). Overall ER rates were not available for studies using EPO- beta + G/GM-CSF, however, 52 pts (37.7%) had major ER, similar to that observed in all EPO-alfa monotherapy studies (195/589=33.1%). Conclusions: These findings suggest increasing EPO-alfa dose may have a greater impact on ER than addition of G/GM-CSF. Further validation is warranted. [Table: see text] [Table: see text]