tbuckley/cabot-search huggingface dataset:
N0733: Phase II trial of capecitabine and lapatinib plus or minus cixutumumab in HER2-positive breast cancer.
Authors: P. Haluska, M. M. Reinholz, A. C. Dueck, H. M. Linden, W. L. Lingle, A. M. Bernath, M. C. Arbushites, H. Youssoufian, H. X. Chen, E. A. Perez
Journal: Journal of Clinical Oncology (2010)

TPS129 Background: Insulin-like growth factor (IGF) signaling has been implicated as a mechanism of resistance to therapies targeting the HER2 pathway in breast cancer, such as trastuzumab and lapatinib. Cixutumumab (IMC-A12) is an IgG1 monoclonal antibody that binds IGF-1 receptor (IGF-1R), blocking ligand activation of the IGF system and stimulating receptor down-regulation. The addition of cixutumumab to capecitabine and lapatinib in HER2+ breast cancer may improve the clinical benefit of this regimen. Methods: N0733 is CTEP-sponsored, NCCTG-led, multicooperative group supported randomized phase II trial investigating the clinical activity of capecitabine plus lapatinib ± cixutumumab. Patients with advanced or metastatic HER2+ breast cancer treated previously with trastuzumab and an antracycline and/or a taxane with measureable disease and adequate organ function are eligible for participation. Following an initial safety cohort testing the safety and tolerability of cixutumumab in combination with capecitabine and lapatinib, the next stage is for patients to be randomized in a 2:1 ratio to either: 1) capecitabine at 825 mg/m2 twice daily by mouth on days 1-14, lapatinib 1,000 mg daily by mouth, and cixutumumab 6 mg/kg intravenously day 1, 8, 15, or 2) capecitabine at 1,000 mg/m2 twice daily on days 1-14, lapatinib 1,250 mg daily. Cycles are 21 days. Primary endpoint is progression-free survival; approximately 154 patients will be needed to complete the trial. Correlative studies include pre- and post-treatment analysis of phospho-epitopes for IGF-1R and HER2 on circulating tumor cells and serum-based determinant of IGF signaling, including IGF binding proteins, IGF-1, insulin, and growth hormone. We will also explore the insulin receptor isoform and erbB family receptors expression in archived tissue for correlation with benefit from study treatment. Quality-of-life assessments will be performed to test for differences between the treatments arms. The study has completed a safety analysis of the three-agent combination and is accruing to the randomized portion of the trial via the CTSU. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline, ImClone Systems ImClone Systems GlaxoSmithKline GlaxoSmithKline, ImClone Systems
Turnover of Human Cardiomyocytes
Authors: Olaf Bergmann, Ratan D. Bhardwaj, Samuel Bernard, Sofia Zdunek, Fanie Barnabe-Heider, Stuart Walsh, Joel Zupicich, Kanar Alkass, Bruce A. Buchholz, Henrik Druid, Stefan Jovinge, Jonas Frisen
Journal: Circulation Research (2008)
Fractionated radioimmunotherapy (RAIT) for enhanced cumulative radiation delivery in the treatment of advanced pancreatic cancer (APC).
Authors: D. M. Goldenberg, S. J. Goldsmith, T. Manzone, M. Holt, N. Hall, A. Sheikh, A. N. Serafini, H. Horne, R. M. Sharkey, W. A. Wegener
Journal: Journal of Clinical Oncology (2010)

e14502 Background: A single dose of 90Y-labeled anti-mucin humanized mAb, clivatuzumab tetraxetan (90Y-hPAM4), showed transient objective antitumor activity in APC, but hematological toxicity limited 90Y to 20 mCi/m2. Fractionated RAIT may deliver higher total 90Y doses for enhanced outcome with acceptable hematological toxicity. Methods: A phase I/II trial in untreated, inoperable, stage 3/4 APC administered 200 mg/m2 Gem once-weekly × 4 with 90Y-hPAM4 on wks 2-4 and 111In-hPAM4 on wk 1 for radiation dosimetry estimates. The 90Y-dose was escalated by a 3+3 cohort design, with tumor responses assessed after each cycle, and cycles repeated until progression or unacceptable NCI-CTCv3 toxicity. Radiation doses determined by MIRD methods were compared to standard limits of 2-3,000 cGy for liver, kidney, lung and 300 cGy for red marrow. Results: Twenty-seven pts (10F/17M, 40-75 yrs, ECOG 0-1, 24 stage 4) received 90Y doses of 6.5 (n = 4), 9 (n = 4), 12 (n = 14) and 15 (n = 5) mCi/m2 × 3, including 11 pts retreated with 1-3 additional cycles. Fractionation allowed cumulative 90Y doses up to 45 mCi/m2 with cycle 1 and 90 mCi/m2 with repeated cycles, a 2- and 4-fold increase, respectively, over that achieved previously with a single dose. Treatment was well-tolerated with few non-hematological side effects. Median estimated cumulative radiation doses were below standard limits for liver, lungs and kidneys, but elevated for red marrow (range, 547- 597 cGy). Grade 3-4 plts or ANC developed in 10/23 (43%) pts now evaluated after cycle 1 and 9/9 (100%) retreated pts after their last cycle. Hematologic suppression was reversible without major infections or bleeding events, except for 3 pts after repeated cycles, one with extensive marrow tumor infiltration. Of 22 pts now with responses assessed by CT, 5 pts (23%) achieved PRs by RECIST criteria, while 10 pts (45%) had SD as best response. Conclusions: Fractionated 90Y-hPAM4, given as an outpatient treatment, allowed delivery of total 90Y doses several-fold higher than as a single dose, including repeated treatments. In combination with low-dose Gem, there was therapeutic activity, with manageable hematological toxicity in most pts, even after 4 cycles. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Immunomedics Immunomedics Immunomedics
Functional proteomic-based predictor of pathologic complete response to neoadjuvant chemotherapy with paclitaxel/FAC-FEC in breast cancer
Authors: A. M. Gonzalez-Angulo, B. T. Hennessy, Z. Ju, F. Meric-Bernstam, P. Lajos, W. F. Symmans, K. R. Coombes, G. N. Hortobagyi, G. B. Mills
Journal: Journal of Clinical Oncology (2008)

11078 Background: Different chemotherapy regimens are used in the treatment of breast cancer, but not all regimens are equally effective for all patients. Complete pathologic response (pCR) to neoadjuvant therapy is an accepted surrogate of prolonged recurrence-free survival after chemotherapy in breast cancer. Currently, there are transcriptional profiles that can predict for pCR. We report the discovery of a functional proteomics profile that predicts pCR after neoadjuvant weekly paclitaxel followed by FAC/FEC sequential chemotherapy (T/FA- EC). Methods: Reverse phase protein arrays were applied to 96 breast cancer fine needle aspirates using 87 different antibodies. A resampling approach was applied to repeatedly (100 times) split the samples into training (72) and test (24) sample sets so as to identify functional proteomic signatures that predict for pCR. Trained signatures were defined using principal component analysis (PCA) after dendrogram construction using Pearson correlation and then tested 100 times using the resampling approach with Chi square analysis. The predictive accuracy of the model was calculated using cross-validation. Results: 26/96 (27%) patients achieved pCR. The 96-sample dendrogram identified 8 breast tumor clusters and PCA was performed on each protein cluster to define 8 different signatures. One signature containing 5 proteins was found to significantly predict for pCR. After resampling, this signature could significantly identify patients in the pCR group 88/100 times. The prediction accuracy for pCR varied between 69% and 80% (mean, 75%) in the 100 resamplings. Conclusion: The proteomic signature was able to predict pCR to neoadjuvant T/FA-EC with an accuracy of 75%. Studies are ongoing to determine whether proteomic profiling may also assist in selection targeted agents to use in combination therapy in patients predicted to not obtain pCR with standard regimens. No significant financial relationships to disclose.
Clinical correlates of JAK2V617F allele burden in essential thrombocythemia
Authors: J. Kittur, R. A. Knudson, T. L. Lasho, C. M. Finke, N. Gangat, A. P. Wolanskyj, C. Li, W. Wu, R. P. Ketterling, A. Pardanani, A. Tefferi
Journal: Journal of Clinical Oncology (2007)

7030 Background: JAK2V617F occurs in approximately 50% of patients with essential thrombocythemia. Qualitative studies of mutation analysis have previously reported an association between JAK2V617F and advanced age, higher hemoglobin level, higher leukocyte count, and lower platelet count. A possible association with thrombotic complication has also been considered. Methods: Allele-specific, quantitative PCR analysis for JAK2V617F was performed on 176 patients with ET, using genomic DNA from archived bone marrow, which was collected within one year (n=72), between 1 and 5 years (n=64), or after 5 years (n=40) of diagnosis. Results: JAK2V617F was detected in 96 patients (55%), in whom mutant allele burden ranged from 1% to 100% (median 6.3%). Neither mutational frequency (p=0.37) nor mutant allele burden (p=0.62) was affected by the timing of bone marrow sample collection. Presence of JAK2V617F was significantly associated with higher hemoglobin level (p&lt;0.0001), lower platelet count (p=0.001), higher leukocyte count (p=0.008), increased incidence of venous thrombosis occurring after diagnosis (p=0.02), and older age at diagnosis (p=0.03). All but age retained significance in multivariable analysis. In mutation-positive patients (n=96), JAK2V617F allele burden clustered between 1% and 22% in 94 cases, in whom it correlated directly and significantly with platelet and leukocyte counts, palpable splenomegaly at diagnosis, and venous thrombosis occurring after diagnosis. Conclusions: JAK2V617F allele burden imparts additional phenotypic effects in ET. No significant financial relationships to disclose.
Patients with initially irresectable colorectal liver metastases: Is there a possibility of cure by an oncosurgical approach?
Authors: R. Adam, D. A. Wicherts, R. J. de Haas, O. Ciacio, F. Lévi, B. Paule, M. Ducreux, D. Azoulay, D. Castaing
Journal: Journal of Clinical Oncology (2008)

4023 Background: Although improved oncosurgical strategies for patients with irresectable colorectal liver metastases (CLM) have lead to increased survival, the potential of cure is still questionned. The objective was to evaluate long-term outcome after combining downsizing chemotherapy and rescue surgery to define prognostic factors of cure. Methods: All patients with initially irresectable CLM that underwent rescue surgery and had a minimum follow-up of 5 years were included. Irresectability was stated as the impossibility to resect all metastases while saving 30% of normal liver. Cure was defined as a disease-free interval >5 years from last hepatic or extrahepatic resection until last follow-up. Results: Mean age of 184 resected patients (April 1988-July 2002) was 56.9 years. Patients had a mean number of 5.3 liver metastases (bilobar in 76%), associated to extrahepatic disease in 27%. Surgery was possible after first (74%) or subsequent line (26%) of chemotherapy. Five- and 10-year overall survival were 33% and 27%. Of 148 patients with a follow-up >5 years, 24 (16%) were considered cured (mean follow-up 118.6 months), 6 of which (25%) after repeat resection of recurrence. Twelve “cured” patients (50%) had a disease-free interval >10 years. Cured patients more often presented with <3 metastases <30 mm (P=0.03), responding to first line chemotherapy (Table). Multivariate analysis identified maximum size of metastases <30 mm at diagnosis, number of metastases at liver resection <3, and complete pathological response as independent predictors of cure. Conclusions: Cure can be achieved overall in 16% of patients with initially irresectable CLM resected after downsizing chemotherapy. Comparison of patient characteristics between cured and non-cured patients Cured (n=24) Non-cured (n=112) P Synchronous 14(58%) 82(73%) 0.15 Number ≤3 >3 13(54%) 11(46%) 34(34%) 66 (66%) 0.07 Size (mm) <30 ≥30 7(30%) 16(70%) 12(12%) 85(88%) 0.03 Bilobar 16(67%) 89(80%) 0.18 Extrahepatic disease 4(17%) 36(32%) 0.13 No. of chemotherapy lines <2 ≥2 21(88%) 3(13%) 75(67%) 37(33%) 0.05 No. of chemotherapy cycles (mean+SD) 10.6+6.3 10.9+5.3 0.85 Complete pathological response 5(21%) 1(1%) <0.001 No significant financial relationships to disclose.
Incidence and risk factors for biliary sclerosis following adjuvant hepatic arterial infusion with floxuridine after hepatectomy for metastatic colorectal cancer.
Authors: K. Ito, H. Ito, N. E. Kemeny, M. Gonen, P. Allen, Y. Fong, R. P. DeMatteo, L. H. Blumgart, W. R. Jarnagin, M. I. D'Angelica
Journal: Journal of Clinical Oncology (2010)

3556 Background: Adjuvant hepatic arterial infusion pump chemotherapy (HAIPC) with floxuridine (FUDR) contributes to the prolonged progression-free survival of patients with resected colorectal cancer liver metastases (CRCLM). The most significant adverse event following HAIPC is biliary sclerosis (BS). We analyzed factors associated with the risk of BS. Methods: 293 consecutive pts who underwent hepatectomy followed by HAIPC and dexamethasone plus systemic therapy for CRCLM from 1991-2008 were analyzed. The incidence, demographics, clinico-pathologic factors and chemotherapy details were analyzed for their association with BS. Results: Median disease specific survival (DSS) was 83.9 months (95% CI 59.9–107.8). The incidence of BS was 5.5% (16/293). In the patients who developed BS, the median interval between the initiation of HAIPC and the development of BS was 119 days (range 13–252). The common hepatic duct was the most common site (87.5%). All patients who developed BS underwent biliary stenting with resolution of jaundice. Factors associated with BS are shown in the Table. Type of hepatectomy, type of systemic chemotherapy, portal lymph node dissection, hepatic arterial anatomy, vessels in which catheter was placed, and vessels ligated were not associated with BS. There was no difference in the median DSS between patient with BS and without BS (87.8 vs. 83.9 months, respectively p=0.707). Actual median follow-up period was 61.0 months (range 16.2–171.6) in patients with BS and 47.2 months (range 2.4–200.8) in patients without BS (p=0.316). Conclusions: BS is uncommon complication following adjuvant HAIPC and did not compromise patient survival if adequately salvaged. Technical factors related to postoperative infection and abnormal flow as well as the dose of FUDR per cycle increase the risk of BS. Factors associated with BS Patients who developed BS (n=16) Patients who did not develop BS (n=277) P value Abnormal flow scan 5 (18.8%) 3 (1.8%) 0.006 Postoperative infectious complication 8 (50.0%) 41 (14.8%) 0.002 Dose/cycle/BSA of FUDR, mg/cycle/kg, median, range 2.6 (1.4-4.9) 2.0 (0.7-3.8) 0.025 No significant financial relationships to disclose.
Delineation of<i>MGMT</i>Hypermethylation as a Biomarker for Veliparib-Mediated Temozolomide-Sensitizing Therapy of Glioblastoma
Authors: Shiv K. Gupta, Sani H. Kizilbash, Brett L. Carlson, Ann C. Mladek, Felix Boakye-Agyeman, Katrina K. Bakken, Jenny L. Pokorny, Mark A. Schroeder, Paul A. Decker, Ling Cen, Jeanette E. Eckel-Passow, Gobinda Sarkar, Karla V. Ballman, Joel M. Reid, Robert B. Jenkins, Roeland G. Verhaak, Erik P. Sulman, Gaspar J. Kitange, Jann N. Sarkaria
Journal: JNCI Journal of the National Cancer Institute (2015)

Sensitizing effects of poly-ADP-ribose polymerase inhibitors have been studied in several preclinical models, but a clear understanding of predictive biomarkers is lacking. In this study, in vivo efficacy of veliparib combined with temozolomide (TMZ) was evaluated in a large panel of glioblastoma multiforme (GBM) patient-derived xenografts (PDX) and potential biomarkers were analyzed. The efficacy of TMZ alone vs TMZ/veliparib was compared in a panel of 28 GBM PDX lines grown as orthotopic xenografts (8–10 mice per group); all tests of statistical significance were two-sided. DNA damage was analyzed by γH2AX immunostaining and promoter methylation of DNA repair gene O6-methylguanine-DNA-methyltransferase (MGMT) by Clinical Laboratory Improvement Amendments–approved methylation-specific polymerase chain reaction. The combination of TMZ/veliparib statistically significantly extended survival of GBM models ( P < .05 by log-rank) compared with TMZ alone in five of 20 MGMT-hypermethylated lines (average extension in median survival = 87 days, range = 20–150 days), while the combination was ineffective in six MGMT-unmethylated lines. In the MGMT promoter–hypermethylated GBM12 line (median survival with TMZ+veliparib = 189 days, 95% confidence interval [CI] = 59 to 289 days, vs TMZ alone = 98 days, 95% CI = 49 to 210 days, P = .04), the profound TMZ-sensitizing effect of veliparib was lost when MGMT was overexpressed (median survival with TMZ+veliparib = 36 days, 95% CI = 28 to 38 days, vs TMZ alone = 35 days, 95% CI = 32 to 37 days, P = .87), and a similar association was observed in two nearly isogenic GBM28 sublines with an intact vs deleted MGMT locus. In comparing DNA damage signaling after dosing with veliparib/TMZ or TMZ alone, increased phosphorylation of damage-responsive proteins (KAP1, Chk1, Chk2, and H2AX) was observed only in MGMT promoter–hypermethylated lines. Veliparib statistically significantly enhances ( P < .001) the efficacy of TMZ in tumors with MGMT promoter hypermethylation. Based on these data, MGMT promoter hypermethylation is being used as an eligibility criterion for A071102 (NCT02152982), the phase II/III clinical trial evaluating TMZ/veliparib combination in patients with GBM.
The use of an interposed graft during portal vein and/or superior mesenteric vein reconstruction in pancreatic resection for pancreatic cancer.
Authors: Hiroki Yamaue, Seiko Hirono, Manabu Kawai, Ken-Ichi Okada, Motoki Miyazawa, Atsushi Shimizu, Yuji Kitahata, Masaki Ueno
Journal: Journal of Clinical Oncology (2015)

482 Background: Combined portal vein and/or superior mesenteric vein (PV/SMV) resection with pancreatectomy sometimes leads to prolonged survival for patients with periampullary tumors. In this study, we evaluated outcomes of patients with PV/SMV reconstruction, and we considered indications for the use of a graft during this procedure. Methods: We performed PV/SMV resection with pancreatectomy in 128 patients with periampullary tumors, including 14 using grafts. Short and long-term outcomes associated with PV/SMV reconstruction and harvesting venous grafts and reconstructed PV/SMV patency during follow-up were assessed. Results: Of the 128 patients with periampullary tumors, 5 underwent total pancreatectomy, 99 pancreaticoduodenectomy, and 24 distal pancreatectomy. In the 14 patients who underwent PV/SMV reconstruction with grafts, the grafts were harvested from external iliac vein in 10 patients and internal jugular vein in the other 4. Five patients (3.9%) had intraoperative or postoperative acute thrombus or stenosis of reconstructed PV/SMV after direct end-to-end anastomosis. However, PV/SMV patency was excellent after reconstruction using grafts. Among 228 patients with common pancreatic cancer, there were no significant differences in overall survival (OS) between the patients with PV/SMV resection (n=99) and without PV/SMV resection (n=206) (P=0.354), although the lymph node metastasis rates in the patients with PV/SMV resection were higher than those without PV/SMV resection (78.8 vs. 64.6%, P=0.012). Furthermore, the tumor size in the patients with the use of a graft was larger than that without a graft (Mean size; 40.5 vs. 29.3 mm, P=0.047), and the R0 rates and OS were not different between the patients with and without a graft (R0 rates; 50 vs. 73%, P=0.129 and OS; 23.4 vs. 16.6 months, P=0.323). Conclusions: Depending on the length and/or position of the removed PV/SMV segment, an interposed graft may be required for reconstruction in some patients.
The effect of hyperglycemia on survival in patients with glioblastoma multiforme
Authors: R. L. Derr, X. Ye, M. Islas, S. Desideri, S. A. Grossman
Journal: Journal of Clinical Oncology (2008)

2013 Background: Steroid-induced hyperglycemia is rarely carefully managed in patients with glioblastoma multiforme (GBM) unless acute complications of hyperglycemia are present; however epidemiologic and laboratory studies suggest that hyperinsulinemia and/or hyperglycemia may promote tumor growth. We aimed to evaluate whether hyperglycemia was associated with decreased survival in patients with GBM. Methods: 191 patients with newly diagnosed GBM were accrued to New Approaches to Brain Tumor Therapy CNS Consortium trials with similar eligibility criteria between 1999 and 2005, prior to the standard use of temozolomide. 123 patients (64%) had glucose values and glucocorticoid doses recorded every 2 months for at least 6 months after accrual or until death. For each subject, mean glucose and mean glucocorticoid dose were calculated from all available results after weighting each value according to the number of days between it and the next record or the censor date. The primary outcome was survival. Results: The mean age was 55.7 years (SD 11.2 years) and the mean Karnofsky performance score at the time of accrual was 87 (SD 10.2). The median of subjects’ average glucocorticoid dose was 5 mg/day (range 0–64 mg) of dexamethasone or the equivalent. The median average glucose was 110 mg/dl (range 65–459 mg/dl), and 41 patients (21%) had a mean glucose > 140 mg/dl (the cut-off for impaired glucose tolerance). The median survival was longer in subjects with a mean glucose < 140 mg/dl than > 140 mg/dl (372 days versus 230 days, p=0.005). After adjusting for age, sex, race, baseline Karnofsky performance status, and mean glucocorticoid dose, every 10 mg/dl increase in mean glucose was associated with a 3% increase in the risk of death (95% CI: 0%-6%, p=0.034). Conclusions: In a group of patients with GBM and a good baseline performance status, hyperglycemia was associated with shorter survival after controlling for measured confounders. Interventional studies are needed to determine whether intensive management of glucocorticoid-related hyperglycemia in patients with GBM improves survival. No significant financial relationships to disclose.
Phase I dose-escalating study of 24-hour continuous infusion 5-fluorouracil in combination with weekly docetaxel and cisplatin in patients with advanced gastric cancer
Authors: B. Wang, J. Li
Journal: Journal of Clinical Oncology (2008)

15652 Background: In a phase III study (V325), a combination of Docetaxel, Cisplatin and 5-FU (DCF) showed higher efficacy compared to the control arm of the CF regimen, but also higher side effects. We conducted this study to determine the maximum tolerated dose (MTD) of a 24-hour continuous infusion of 5-fluorouracil (5-FU) when administered in combination with a fixed weekly dose of Docetaxel and Cisplatin in patients with advanced gastric cancer. Methods: Patients with advanced gastric adenocarcinoma (n=21) received a weekly regimen of Docetaxel, Cisplatin and 5-FU (DCF) for 3 consecutive weeks every 4 weeks. The doses of Docetaxel and Cisplatin were fixed at 33.3 mg/m2 and 30 mg/m2, respectively. The dose of 5-FU was increased from a starting dose of 1000 mg/m2 to the MTD. Results: A total of 53 cycles of chemotherapy were administered (median = 3 cycles/patient). The MTD of 5-FU was 1750 mg/m2. All patients were assessed for toxicity and 19 (90%) were evaluated. Both grade 3–4 hematologic and non-hematologic toxicities occurred in less than 10% and there were no treatment-related deaths. Among the 19 patients, we observed one complete and four partial responses for an overall response rate of 26% (95% CI: 6–46%). This rate increased to 39% (95% CI: 12- 66%) in 13 chemotherapy-naïve patients. Conclusions: A consecutive weekly DCF regimen at four-week intervals appears effective for advanced gastric cancer and has a tolerable toxicity profile. For a further phase II study, the recommended doses are 33.3 mg/m2 of Docetaxel, 30 mg/m2 of Cisplatin and 1500 mg/m2 of a 24-hour continuous intravenous infusion of 5-FU. No significant financial relationships to disclose.