tbuckley/cabot-search huggingface dataset:
Evaluation of Src Tyr419 as a predictive biomarker in a neoadjuvant trial using dasatinib in resectable malignant pleural mesothelioma.
Authors: A. S. Tsao, I. I. Wistuba, R. J. Mehran, J. Gil, M. Nunez, J. Lee, H. Lin, S. M. Lippman, W. K. Hong
Journal: Journal of Clinical Oncology (2010)

7042 Background: Preclinical studies in malignant pleural mesothelioma (MPM) have shown that dasatinib, a multitargeted Src kinase/PDGFR inhibitor, has antitumor activity. We designed a novel biomarker-based neoadjuvant trial using dasatinib in resectable MPM. Methods: Untreated MPM patients undergo extended surgical staging (ESS) with multiple biopsies along the future surgical incision line to account for tumor heterogeneity. If deemed a surgical candidate for either P/D or EPP, patients receive 4 weeks of oral dasatinib (70 mg BID) followed by P/D or EPP. If a radiographic response is seen, an additional 2 years of dasatinib maintenance after adjuvant radiotherapy and chemotherapy is given. Serum/blood/platelets/pleural effusion are collected for exploratory analysis of peripheral surrogate biomarkers. Primary endpoint is biomarker modulation of Src Tyr419 in tumor tissue. Secondary endpoints: response, survival, safety/toxicity, and peripheral biomarker modulation. Results: 15 patients enrolled on the trial (4/08–1/10) have successfully completed ESS, neoadjuvant dasatinib, and P/D (n=10) or EPP (n=5). 13 epitheliod and 2 biphasic histology, 12 men: 3 women. The dasatinib main side effects were grade 1-2: anemia, nausea, vomiting, anorexia, fatigue, and anxiety. Grade 3 toxicities included fluid retention, infection (pneumonia), and hypoxia. There are no grade 4-5 toxicities. Post-surgical grade 3 toxicity included anemia, arrhythmia, HTN, and pleural effusion; 1 grade 4 episode of hyperglycemia. After 4 weeks of neoadjuvant dasatinib therapy, there was 1 PD, 12 SD and 2 minor responses. In the initial analysis of Src Tyr419 in 13 patients, higher baseline levels of p-Src Tyr419 predicted for an improved PFS with dasatinib therapy (p=0.008). Also, patients who had significant modulation of p-Src Tyr419 after dasatinib therapy had improved PFS (p=0.008). Conclusions: There is preliminary evidence that a subgroup of MPM patients gain clinical benefit from dasatinib therapy and that baseline p-Src Tyr419 levels in MPM tumor tissue may be predictive of PFS. This is the first targeted therapy neoadjuvant trial to potentially identify a predictive biomarker in MPM. No significant financial relationships to disclose.
Transfusion trends in chemotherapy-induced anemia: Observation from the Medicare 5% Sample, 1992–2005
Authors: S. C. Dunning, D. T. Gilbertson, J. P. Ebben, S. Li, T. J. Arneson, A. J. Collins
Journal: Journal of Clinical Oncology (2008)

6541 Background: The primary indication for ESA use in chemotherapy-induced anemia (CIA) is transfusion reduction based on randomized clinical trials. Little information is available on trends in transfusion requirements for CIA patients in clinical practice. Therefore, we analyzed transfusion events in Medicare patients with cancer diagnoses, chemotherapy (chemo) with and without ESA treatment, between 1992 and 2005. Methods: Using the Medicare 5% sample from 1992–2005, we included Medicare primary beneficiaries, surviving the calendar year. Cancer diagnoses were defined from ICD9-CM diagnosis codes within the year. Chemotherapy was identified using HCPCS, CPT and ICD9 procedure codes. Transfusion events were identified using ICD9 procedure codes, value codes from Institutional claims or CPT codes. ESA use was identified from HCPCS codes. Patients with End Stage Renal Disease (ESRD) or chronic kidney disease (CKD) were defined separately as it is unclear whether ESA treatment was due to cancer or kidney disease. We then calculated the percent of patients receiving transfusions within a year. Results: From 1992–2005, the percent of patients with transfusions in those with both chemo claims and ESA claims, though highest of all the groups, consistently decreased over time from 52.0% to 28.6%. In contrast, the percent of all cancer patients receiving at least one transfusion during the calendar year was stable between 5.5% and 6.6% from 1992 to 2005. Similarly stable, were the percent of cancer patients, excluding ESRD and CKD, and the percent of cancer patients receiving chemo with at least one transfusion, ranging from 4.7%-5.6% and 9.3%-12% respectively. Conclusions: Transfusion experience in the Medicare CIA population treated with ESA has consistently declined from 1992–2005, consistent with the indication for ESA treatment, while the overall cancer and CIA trends have remained nearly constant. Additional research is needed to assess possible differences over time in characteristics of CIA patients receiving ESAs and the impact of those differences on observed decreases in transfusion experience. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Amgen Amgen Amgen
Risk Factors for Recurrence of Thrombotic Thrombocytopenic Purpura.
Authors: Flora Peyvandi, Silvia Lavoretano, Roberta Palla, Hendrik B. Feys, Tullia Battaglioli, Carla Valsecchi, Maria T. Canciani, Fabrizio Fabris, Pier M. Mannucci
Journal: Blood (2006)
The impact of pharmacotherapy on depression and quality of life in patients undergoing a bone marrow transplant (BMT).
Authors: P. B. Mumby, C. Garcia, R. Trivedi-Purohit, R. Gourvitz, K. Rychlik, T. Rodriguez, S. E. Smith, A. A. Toor, M. Rao, P. J. Stiff
Journal: Journal of Clinical Oncology (2010)

9132 Background: Depression and decreased quality of life (QL) develop frequently in BMT patients. We conducted a prospective randomized trial to assess whether pretreatment of BMT patients with the antidepressant sertraline (SER) reduces depression and improves QL. Methods: 123 BMT patients were randomized (1:1) in a Phase III double blind study to receive SER 50 mg daily or placebo (PL), starting at admission for BMT, for 12 weeks. Depression (Beck Depression Inventory-II, BDI-II) and QL (Functional Assessment of Cancer Therapy-BMT, FACT-BMT; and FACT Trial Outcome Index which includes Physical, Functional and BMT subscales, TOI-BMT) were assessed prior to BMT, and weekly to week 12; scores were evaluated at weeks 8 and 12. Clinically depressed patients were ineligible. Results: Participants were: 82% caucasian; 76% married; 65% male; mean age 48 ± 12 years; years education 14 ± 3; 39% underwent autologous, 61% allogeneic BMT. No significant differences in baseline medical/psychosocial variables were found between treatment groups. BDI-II scores decreased from baseline to week 8 for all patients (n=85; p=.007; attrition=69%); no significant differences were found between treatment groups (baseline: PL = 7.77, ± 4.3, SER = 8.61, ± 5.2; week 8: PL = 6.89, ± 5.1, SER = 6.39, ± 5.7, p=.24). At week 12, TOI QL scores were significantly better in the SER group (PL [n=30] 49.4 ± 7.9, SER [n=35] 53.8 ± 7.9, p=0.029). In multiple logistic regression analyses, younger age (p=.029) and lower social support (p=.04) at baseline were significantly associated with higher BDI-II scores. At week 8, only lower social support (p=.007) predicted depression. Conclusions: The administration of SER was associated with better QL at week 12 and the TOI-BMT proved sensitive to clinical change. Social support was significantly associated with depression and may serve to buffer depression during BMT. Depression improved over time for all patients, with no added benefit seen for SER. Therefore, we recommend that antidepressants be reserved for BMT patients with clinically significant depression until additional randomized trials can confirm the effects of antidepressants on QL and depression in BMT patients. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer
HER2 expression/amplification: Frequency, clinicopathologic features, and prognosis in 713 patients with esophageal adenocarcinoma (EAC).
Authors: H. H. Yoon, Q. Shi, W. R. Sukov, A. E. Wiktor, M. Khan, C. A. Sattler, A. Grothey, T. Wu, R. B. Diasio, R. B. Jenkins, F. Sinicrope
Journal: Journal of Clinical Oncology (2011)

4012 Background: HER2 testing in EAC is now routine after regulatory approval of trastuzumab in advanced gastroesophageal cancer. But in EAC the frequency of HER2 expression (exp), its correlation with gene amplification (amp), clinicopathologic features, and prognosis are unknown. Methods: We examined HER2 exp (HercepTest, immunohistochemistry [IHC]) in resection specimens (n = 713) from our institution (1980–97). No patient had neoadjuvant therapy. HER2 amp (fluorescent in situ hybridization [FISH]) was assessed in all 172 IHC2+ and in an unselected subset of IHC3+/0-1+ cases. Per gastric cancer guidelines, amp+ was defined as HER2/CEP17 ratio ≥2.0; and HER2-positive (pos) status (using IHC and FISH) was defined as IHC3+, or IHC2+ plus amp+. Cox models were used. Results: Tumors were 65% T3-4 and 71% node-positive. By location, 35% were esophageal and 65% gastroesophageal junction [GEJ]/cardia. Frequency of HER2 exp and its correlation with amp are shown (Table). In IHC2+ cases, 15% (25/172) were amp+. Using IHC and FISH data, the HER2-posrate was 17% (119/713). HER2 exp and amp had high agreement (κ = .89 [95% CI 0.75 – 1.0]). HER2-pos frequency was higher in esophageal versus GEJ/cardia subsites (21% vs. 15%; p=.03). HER2-pos (vs. -negative) status was associated with lower grade (p<.0001), absence of signet rings (p=.009), lower T stage (p=.03), and fewer malignant nodes (p=.006). HER2-pos status was associated with favorable overall (hazard ratio [HR] 0.75 [0.59 – 0.97]; p=.02) and disease-specific survival (HR 0.79 [0.62 – 1.01]; p=.06), but not after covariate adjustment (p=.18). Conclusions: In the largest study of HER2 in EAC to date, we found HER2-pos frequency was 17%, with high agreement between exp and amp. In IHC2+ tumors, 15% were amp+. In contrast to breast cancer, HER2-pos status in EAC is not associated with adverse survival. The equivalent frequency of HER2 exp/amp in nonmetastatic EAC with that in metastatic gastric cancer may inform future evaluation of trastuzumab therapy in EAC. n = 713 3+ High n = 94 2+ Medium n = 172 0 – 1+ Absent – low n = 447 HER2 protein exp 13% 24% 63% HER2 Amp tested 18 172 20 HER2 Amp+ 94% (17) 15% (25) 5% (1)
Role of CYP3A4 phenotyping by midazolam clearance in predicting irinotecan pharmacokinetics
Authors: F. A. De Jong, R. H. J. Mathijssen, E. R. Lepper, R. H. Van Schaik, L. Friberg, P. De Bruijn, W. J. Graveland, W. D. Figg, J. Verweij, A. Sparreboom
Journal: Journal of Clinical Oncology (2004)

2007 Background: Variability in the pharmacokinetics of irinotecan and its active metabolite, SN-38, is extensive and largely unexplained. Irinotecan is mainly eliminated by a cytochrome P450 isoform 3A (CYP3A)-mediated oxidation and by an esterase-cleavage to form SN-38, which is further conjugated by uridine-diphosphate glucuronosyltransferase (UGT) isozymes. Here, we prospectively explored the relationships between CYP3A phenotype and enzyme and transporter genotypes with the disposition of irinotecan. Methods: Thirty Caucasian patients with cancer were eligible, and received irinotecan as a 3-weekly 90-minute infusion (dose, 600 mg), and pharmacokinetic data were obtained using NONMEM. Four to eight days prior to the first and second cycle, patients underwent the erythromycin breath test (ERMBT; a substrate for CYP3A4 and ABCB1) and the midazolam clearance test (MCT; a substrate for CYP3A4 and CYP3A5), as putative phenotyping probes. Genomic DNA was isolated and screened for 11 known genetic variants in genes encoding ABCB1, CYP3A4, CYP3A5, and UGT1A1. Results: The mean irinotecan clearance and the relative extent of conversion to SN-38 were 31.8 L/h [coefficient of variation (CV), 28.1%] and 3.01% (CV, 42.4%), respectively. CYP3A activity as determined by various ERMBT and MCT parameters varied up to 10-fold. ERMBT parameters were not significantly related to irinotecan or SN-38 pharmacokinetics. In contrast, midazolam clearance was highly correlated to irinotecan clearance (R = .75; P < .001). The homozygous (TA)nTAA repeat in the UGT1A1 promoter (UGT1A1*28) was associated with a significantly increased area under the curve of SN-38 [435 (6/6; N=12) vs 631 (6/7; N=16) vs 1,343 ng×h/mL (7/7; N=3); P = .008, trend analysis] and a diminished relative extent of glucuronidation [9.27 vs 5.79 vs 3.48; P = .010]. Conclusions: CYP3A phenotype as determined by the MCT and UGT1A1*28 genotype are significant predictors of irinotecan and SN-38 pharmacokinetics, respectively. A study to prospectively validate the usefulness of these phenotyping and genotyping strategies to individualize chemotherapeutic treatment with irinotecan is currently ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis
A phase II study of pemetrexed, carboplatin and thoracic radiation with or without cetuximab in patients with locally advanced unresectable non-small cell lung cancer: CALGB 30407—Early evaluation of feasibility and toxicity
Authors: R. Govindan, J. Bogart, X. Wang, D. Liu, R. A. Kratzke, E. E. Vokes
Journal: Journal of Clinical Oncology (2008)

7518 Background: Less than one-third of patients with unresectable stage III non-small cell lung cancer (NSCLC) are cured with concurrent chemoradiation. Administering systemic doses of novel chemotherapy agents along with thoracic radiation, adding molecularly targeted agents and increasing the dose of thoracic radiation are current investigational approaches to improve outcomes. Methods: The Cancer and Leukemia Group B (CALGB) conducted a randomized phase II study of thoracic radiation (70 Gy) along with carboplatin (AUC 5) and pemetrexed 500 mg/m2 on days 1 administered intravenously every 21 days for 4 cycles (arm A) or the same chemotherapy regimen along with cetuximab with a loading dose of 400 mg/m2 followed a week later by 250 mg/m2 weekly for additional 6 weeks (arm B). Subsequently all patients received four additional cycles of pemetrexed (500 mg/m2 every 21 days) as consolidation therapy. Eligibility criteria: previously untreated stage III NSCLC performance status 0–1, no significant weight loss and adequate organ functions. The primary endpoint was the percentage of patients who lived longer than 18 months after initial treatment. Secondary endpoints were failure free survival and response rates. We planned to study the regimen (s) further if the 18 month survival rates equaled or exceeded 55%. Results: Characteristics of the 106 eligible pts (54 in arm A and 52 arm B) enrolled from 09/05 to 12/07: male 61%, median age 64.5 years (range 32–81). The most common histological type was adenocarcinoma (39%). Preliminary toxicity data (grade 3 or greater, %) by arms (arm A/arm B) for 106 pts: neutropenia 36/37; febrile neutropenia 5/7, thrombocytopenia 30/34, nausea/vomiting 10/12, esophagitis 35/22, skin rash 3/23 and fatigue 22/18. One patient died of fatal hemoptysis. Updated data on treatment delivery and toxicity will be available in May 2008. Conclusions: The combination of thoracic radiation with pemetrexed, carboplatin with or without cetuximab is feasible and is fairly well tolerated. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Lilly Oncology
Two-fraction carbon ion radiotherapy for hepatocellular carcinoma: Preliminary results of a phase I/II clinical trial
Authors: H. Kato, S. Yamada, S. Yasuda, K. Yamaguchi, H. Kitabayashi, T. Kamada, J.-E. Mizoe, M. Ohto, H. Tsujii
Journal: Journal of Clinical Oncology (2005)

4124 Background: We reported that the 4-fraction/1-week carbon ion radiotherapy, that had been conducted from April 2001 to February 2003 within a phase II clinical study, appeared to be safe and to have a promising potential as a new, radical, and minimally invasive therapeutic option for hepatocellular carcinoma (HCC) at the last ASCO annual meeting. The next clinical trial of 2-fraction/2-day carbon ion radiotherapy is going on within a phase I/II study from April 2003. Patients and Methods: Twenty-five patients with histologically proven HCC were treated with 2-fraction/2-day carbon ion radiotherapy of 32.0GyE in 6, 33.6GyE in 7, 35.2GyE in 6, and 37.0GyE in 6 in a step-wise dose-escalation study from April 2003 to August 2004. Common Toxicity Criteria, RTOG/EORTC criteria were used for evaluation of toxicity. Serial changes in Child-Pugh score were investigated after the start of therapy to evaluate its invasiveness to the liver. Anti-tumor effect was evaluated by the tumor response and directly- calculated local control rate. Results: During a median follow-up of 12.1 (3.9–19.5) months, no severe adverse effects and no treatment-related deaths occurred. In the early phase, no change in the Child-Pugh score was observed in 79% (19/24), only a 1-point increase in 17% (4/24), and 2-point increase in 4% (1/24) of the patients. In the late phase, similar observations were made in 75% (12/16), 6% (1/16), and 19% (3/16), respectively. The overall tumor response rate was 96% (24/25) at 6 months after the therapy. Local control rates were 96% (24/25) and 93% (13/14) at 6 and 12 months, respectively. Overall survival rates were 100% at 6 and 12 months, respectively. There were preliminarily no differences between the results in the current study and those in the 4-fraction carbon ion radiotherapy. Conclusion: Two-fraction carbon ion radiotherapy for HCC appears preliminarily to be safe and effective. However, further observation is needed to confirm its clinical usefulness. No significant financial relationships to disclose.
MVA-MUC1-IL2 vaccine immunotherapy for advanced non small cell lung cancer <b>(NSCLC)</b>: Interim phase II data
Authors: P. Squiban, T. Velu, B. Mennecier, M. Pless, V. Morel, E. Levy, V. Richard, T. Maciejewska, N. Bizouarne, E. Quoix
Journal: Journal of Clinical Oncology (2004)

2544 Background: Over-expression, non-polarity and under-glycosylation of the mucin glycoprotein molecule, MUC1, are associated with many cancers, making MUC1 an attractive target antigen for vaccine immunotherapy of cancer. MVA (Modified Vaccinia Ankara), a highly attenuated Vaccinia virus, is non-propagative in most mammalian cells and has an excellent safety profile. We have produced a recombinant MVA expressing MUC1 and IL2 (TG4010). Murine studies have shown that TG4010 can induce a MUC1 specific immune response associated with the elimination of MUC1 expressing tumors. In a Phase I study of TG4010 in patients with late stage, MUC1 expressing cancers, TG4010 was well tolerated and showed some evidence of efficacy. We have initiated a Phase II study in which TG4010 is assessed alone or in combination with chemotherapy in NSCLC patients. Methods: A randomized, two stage Simon design, two arm (18 / 33 patients stage 1 / 2 per arm ), phase II study in stage IIIb / IV NSCLC is described . Arm 1: TG4010 is combined upfront with cisplatin and vinorelbine. Arm 2: patients are treated with TG4010 alone, followed by TG4010 + cisplatin and vinorelbine upon disease progression. Results: A this time 45 patients (9 stage IIIb- 36 stage IV) have been enrolled. In arm 1, interim data show an objective response rate (ORR) of 5 / 12 patients so far validated by independent central review (response duration 114–195 days). ORR already satisfies the criteria to move forward to the second stage of the study. In Arm 2, disease control is observed in 4 / 15 patients with TG4010 alone, and to date, an ORR of 1 / 8 in subsequent combination with chemotherapy is observed. TG4010 is well tolerated. Injection site reaction is the most frequent adverse event. Conclusions: TG4010, combined with standard chemotherapy, is being evaluated further in stage 2 of the study. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Transgene Transgene Transgene
Pharmacokinetics (PK) of oxaliplatin (OX) after intraperitoneal (IP) and intravenous (IV) administration in patients with gynecological malignancies.
Authors: A. J. Combest, K. K. Zorn, R. P. Edwards, S. K. Hanna, S. Habibi, M. Strange, B. Zamboni, T. C. Krivak, P. Sukurmvanich, W. Zamboni
Journal: Journal of Clinical Oncology (2010)

2584 Background: Combined IV/IP chemotherapy has been associated with improved survival in ovarian cancer patients. Cisplatin is the most common drug used IP but is associated with significant toxicity. OX is a significantly larger molecule and may therefore have improved IP PK as compared to cisplatin IP. We evaluated the PK disposition of IP and IV OX as part of a phase I study. Methods: A phase I study with 2 arms was performed using modified Fibonacci dose escalation in patients (pts) with intraperitoneal ovarian cancer. In arm 1, pts received docetaxel (Doc) 75 mg/m2 IV on day 1 and OX 50 mg/m2 IP (dose level [DL] 1; n = 3) or OX 75 mg/m2 IP (DL2; n = 6) on day 2. In arm 2, pts received OX 75 mg/m2 IV on day 1 and Doc 50 mg/m2 IP (DL1; n = 3) or Doc 75 mg/m2 IP (DL2; n = 1) on day 2. IP fluid and plasma was collected at 0-24 h, 48 h, and 72 h after OX IP. Plasma was collected at 0-24 h after OX IV. Total and ultrafiltrate (UF) platinum (Pt) were measured in plasma and IP fluid via inductively coupled plasma mass spectrometry (ICP-MS). Area under the concentration versus time curve (AUC) and maximum concentration (Cmax) were estimated. Results: The PK of OX IP at 50 mg/m2 and 75 mg/m2 were similar and thus combined in the Table. Conclusions: Total and UF Pt were approximately 1.9- and 10.8-fold higher, respectively, in IP fluid compared with plasma after OX IP. The plasma exposure of UF Pt was approximately 1.5- to 2-fold lower after OX IP as compared with OX IV. The intraperitoneal tumor site has a higher exposure of the active unbound Pt with less systemic exposure following OX IP compared with OX IV. The PK properties of OX IP appear to be superior to OX IV and potentially cisplatin IP. Units IP Plasma Ratio IP:Plasma Arm 1 OX IP (n=9) Total Pt (mean ± SD) UF Pt (mean ± SD) Total Pt (mean ± SD) UF Pt (mean ± SD) Total Pt (mean ± SD) UF Pt (mean ± SD) AUC0–72h μg/mL·h 88.5 ± 58.5 50.9 ± 35.8 46.3 ± 10.6 4.7 ± 1.5 1.9 10.8 AUC0–24h μg/mL·h 60.5 ± 39.4 47.6 ± 34.4 21.1 ± 7.3 3.1 ± 1.0 2.9 15.4 Cmax μg/mL 11.1 ± 5.9 11.8 ± 7.6 1.2 ± 0.6 0.2 ± 0.05 9.4 65.9 Arm 2 OX IV (n=4) AUC0–24h μ g/mL·h — — 32.4 ± 12.3 5.7 ± 3.1 — — Cmax μ g/mL — — 7.0 ± 9.2 1.7 ± 2.6 — — Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration sanofi-aventis
Lack of effect of doxyxyxline on disease activity and pyridinoline excretion rates in rheumatoid arthritis : a double-blind placebo-controlled study: abstract
Authors: W.H. van der Laan, E.T. Molenaar, J.H. Verheijen, F.C. Breedveld, B.A.C. Dijkmans, J.M. TeKoppele
Journal: Annals of the Rheumatic Diseases (2000)
Large Granular Lymphocyte (LGL) Expansions Comprising Oligoclonal T Cell or NK Cell Populations in Dasatinib Treated Patients Are Associated with HLA-A*0201, CMV Reactivation and Enhanced Anti-Leukemic Control.
Authors: Satu Mustjoki, Anna Kreutzman, Carolin Dix, David A Price, Kristin Ladell, Marja Ekblom, Leif Stenke, Hermann Einsele, Kimmo Porkka, Ruth Seggewiss
Journal: Blood (2009)