tbuckley/cabot-search huggingface dataset:
Liver Transplantation in the Super Morbidly Obese: a Single Center Experience; Section of Abdominal Transplantation, Ochsner Clinic Foundation, New Orleans, La
Authors: Scott Seals, Nigel Girgrah, Ari J. Cohen, Ian C. Carmody, Margaret A. Davidson, Humberto E. Bohorquez, David Bruce, Shobha Joshi, Brian Parker, George E. Loss
Journal: Hepatology (2009)
Phase II trial of thalidomide (T), bevacizumab (Bv), and docetaxel (Doc) in patients (pts) with metastatic castration-refractory prostate cancer (mCRPC)
Authors: Y. M. Ning, P. M. Arlen, J. L. Gulley, W. D. Stein, A. T. Fojo, L. Latham, J. J. Wright, H. Parnes, W. D. Figg, W. L. Dahut
Journal: Journal of Clinical Oncology (2008)

5000 Background: Angiogenesis has a vital role in progression of mCRPC. We hypothesized that combining the mechanistically different anti-angiogenic agents, T and Bv, with Doc would block multiple angiogenic pathways and lead to potent anti-tumor activity. Methods: Pts have progressive mCRPC and no prior chemotherapy for CRPC. Treatment regimen: Doc 75 mg/m2 + Bv 15 mg/kg day 1, q 21 days as a cycle (C), plus T 200 mg qhs and prednisone 10 mg qd. Enoxaparin for thrombosis prevention and pegfilgrastim after grade >3 neutropenia. PSA assay q C and staging studies at C 0, C 2, & then q 3 Cs. Results: All 60 pts have enrolled as planned, median age 66 [44- 79], Gleason score 8 [66% Gs 10∼8, 34% Gs 7∼5], on-study PSA 99 ng/ml [6.0–4,399], and pre-study PSA doubling time 1.6 months [0.3–18.2, 81 % < 3 months]. 2 pt had disease of no PSA activity. Median treatment Cs is 11 [2–46]. 51 pts (88%) had PSA declines of >50%, with median >50% PSA-duration 11 Cs [0∼45]. 5 pts had PSA declines <50%. 2 pts had no PSA decline. 41 pts (71%) had a >80% PSA decline. 32 pts with measurable disease were evaluable: 2 CR, 18 PR, 11 SD, & 1 PD, with 63 % ORR. The current estimated median PFS is 18.2 months. PSA-based concomitant rates of tumor regression and tumor growth (growth rate constant, g) are explored with a validated two-phase equation that shows a correlation of g with OS. The pretreatment g (10-1.885 in days-1) was reduced by > 10-fold to 10-3.155 on therapy, superior to prior Doc-containing therapies analyzed in this setting, with g values one third that of other regimens. Significant toxicities: febrile neutropenia (5/60), syncope (5/60), GI perforation or fistula (3/60), thrombosis (3/60), grade 3 bleeding (2/60). Conclusions: T and Bv with Doc are associated with high response rates, 88% in PSA and 63% in measurable disease, with expected toxicities. The regimen elicits a > 10-fold reduction in pre-treatment g values with projected better OS. The median estimated PFS of 18.2 months is very encouraging in this population of patients with unfavorable prognostic factors. These results suggest that combining T and Bv with Doc is worthy of further study for treatment of mCRPC. No significant financial relationships to disclose.
Cationic liposomal paclitaxel in combination with gemcitabine in patients with advanced pancreatic cancer: A phase II trial
Authors: M. Loehr, G. Bodoky, U. Fölsch, A. Märten, M. Karrasch, C. Lilla, I. Meyer, D. Osinsky, J. Szanto, M. Lutz
Journal: Journal of Clinical Oncology (2009)

4526 Background: EndoTAG-1 is a novel cationic liposomal formulation of paclitaxel being developed for the treatment of solid malignancies. It acts by targeting activated negatively charged endothelial cells of tumor blood vessels. We present safety and efficacy data of a randomized, controlled phase II trial in pancreatic cancer (PC). Methods: 200 patients with advanced PC were randomized to 1 st line treatment with weekly gemcitabine (GEM: 1000 mg/m 2 ) and twice weekly infusions of EndoTAG-1 (E) at 3 different dose levels (E low : 11 mg/m 2 , E med : 22 mg/m 2 , E high : 44 mg/m 2 ) or GEM monotherapy. Patients were treated for 7 weeks and followed up for overall survival (OS) for at least 1 year. After finishing study treatment, any anti-tumor therapy was allowed. A subgroup of patients had the option to receive repeated cycles of combination therapy in case of at least stable disease according to RECIST until disease progression. Results: Median OS was substantially higher in the GEM+E med and GEM+ E high groups than the GEM monotherapy group. Adjusted hazard ratios for OS were 0.72 (95% CI 0.46–1.13) and 0.67 (0.43–1.07). In patients receiving &gt;1 treatment cycle, median OS was 11.5 months (GEM+E high ); in the GEM+E med group 75% of patients were alive at 1 year. Treatment with EndoTAG-1 and gemcitabine was generally well tolerated. A trend for increasing adverse event frequency with EndoTAG-1 dose was observed for infusion-related reactions associated with chills and pyrexia, and thrombocytopenia. The overall frequency of serious adverse events in the GEM+E groups was low, the most frequent SAE being pyrexia in 4 (8%) patients in the GEM+E high group. There was no indication for significant organ toxicity associated with EndoTAG-1, even in patients receiving multiple treatment cycles. Conclusions: This phase II trial indicates a considerable survival benefit for patients with advanced PC receiving EndoTAG-1 in combination with gemcitabine and a favourable safety profile warranting further development of EndoTAG-1 in this indication. [Table: see text]
Efficacy of lapatinib in patients with high tumor EGFR expression: Results of a phase III trial in advanced renal cell carcinoma (RCC)
Authors: A. Ravaud, J. Gardner, R. Hawkins, H. Von der Maase, N. Zantl, P. Harper, F. Rolland, B. Audhuy, J. Machiels, I. El-Hariry
Journal: Journal of Clinical Oncology (2006)

4502 Background: Lapatinib is an orally-active, reversible inhibitor of EGFR/ErbB2 tyrosine kinases. In Phase I/II trials, lapatinib has demonstrated activity in patients (pts) with advanced breast cancer. We report the first results of a randomized open-label Phase III trial ( EGF20001 ) of lapatinib vs. hormone therapy (HT) in pts with advanced RCC that express EGFR and/or ErbB2 by immunohistochemistry (IHC). The main endpoints were time to progression (TTP) and overall survival (OS). Methods: Pts with advanced RCC of any histology who had failed first-line cytokine therapy were stratified by Karnofsky performance score (KPS) and number of metastatic sites. Pts were randomized to receive oral lapatinib 1250 mg OD or HT. The primary efficacy endpoint was TTP, with 90% power to detect a 50% increase (i.e. 4 vs. 6 months) at a two-sided 5% significance level. All pt scans were interpreted by independent radiologic review. Results: At the time of the TTP analysis, 417 pts were randomized and 298 TTP events were reported. Demographic and baseline characteristics were similar between both arms; pooled results were: median age: 61 yrs; Stage IV disease: 97%, KPS 90–100: 59%, metastatic sites &gt;2: 49%, prior nephrectomy: 94%, prior interferon therapy: 64%. No unexpected toxicities were observed, and drug-related AE (all grades) for lapatinib vs. HT included rash (44%:3%), diarrhoea (40%:3%). When results from all pts were analysed, median TTP was 15.3 weeks for lapatinib vs. 15.4 weeks for HT (hazard ratio (HR) = 0.94; p = 0.60), and median OS was 46.9 weeks for lapatinib vs. 43.1 weeks for HT (HR=0.88; p=0.29). In the major subgroup of 241 pts with EGFR overexpressed disease (3+ by IHC), median TTP was 15.1 weeks for lapatinib vs. 10.9 weeks for HT (HR = 0.76; p = 0.06), and median OS was 46.0 weeks for lapatinib vs. 37.9 weeks for HT (HR = 0.69; p = 0.02). These results were confirmed by Cox Regression analysis, and additional biomarker evaluation, including FISH, is underway. Conclusions: The EGFR/ErbB2 dual targeted inhibitor, lapatinib, appears to prolong overall survival compared to hormone therapy in advanced RCC pts with overexpressed EGFR who failed prior therapy. [Table: see text]
Contribution of NGR and TNF portions of NGR-TNF to tumor vessel-specific homing and apoptosis in vivo.
Authors: G. Rizzardi, C. Traversari, B. Valentinis, P. Di Matteo, L. Alberici, M. Cota, C. Bordignon
Journal: Journal of Clinical Oncology (2010)

e13554 Background: NGR-TNF is a new peptide-targeted agent coupling CNGRCG peptide (NGR), homing to angiogenic blood vessels, and tumor necrosis factor alpha (TNF), presently in clinical development (phase II studies in MPM, HCC and CRC). Methods: To further elucidate its mechanism of action, we studied NGR-TNF homing and downstream effects with doses comparable to those used in clinical trials. Results: Using NGR-quantum dots in vivo, NGR specifically targets the CD13 expressed in neoangiogenic vessels, sparing CD13+ normal tissues. Using CD13-specific shRNAs we showed that target cell CD13-expression is essential but not sufficient for NGR binding. For the first time, we formally demonstrated the physical interaction between NGR and CD13 by pool-down experiments using NGR-biotinylinated peptides. Although molecular characterization of the NGR-binding complex is still ongoing, microvesicles released by NGR-binding cells are able to transfer the NGR-binding capability to NGR-non-binder cells, suggesting that the binding complex associates on the target cell before NGR engages CD13. The in vivo activity of NGR-TNF may be due to target cell homing determining an increased affinity for TNF receptor (TNFR), and/or to CD13 cell signaling. Our data support the contribution of both mechanisms. First, using a recombinant tagged-human TNF as a probe along with NGR-TNF and TNF as competitors, NGR-TNF has an NGR-mediated higher affinity for TNFR than TNF. Second, in TNF-activated endothelial cells, NGR-TNF inhibits Mek, Erk1/2, and Akt, and activates caspases 3, 8, and 9, resulting in tumor endothelial cells apoptosis in vivo. Of note, these pathways are similarly activated also using NGR and TNF as separate molecules engaging CD13 and TNFR, respectively, indicating that both NGR and TNF portions contribute to the activation of signaling pathways by NGR-TNF. Conclusions: The binding of NGR to CD13 determines not only the “mere homing” of NGR-TNF but also a) the stabilization of the NGR-CD13/TNF-TNFR interaction and b) a direct effect of CD13, leading to a highly selective homing on tumor blood vessels and apoptosis of angiogenic endothelial cells in vivo, thus significantly contributing to the control of tumor growth. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration MolMed MolMed
SANDPIPER: Phase III study of the PI3-kinase (PI3K) inhibitor taselisib (GDC-0032) plus fulvestrant in patients (pts) with estrogen receptor (ER)-positive, HER2-negative locally advanced or metastatic breast cancer (BC) enriched for pts with <i>PIK3CA-</i>mutant tumors.
Authors: Jose Baselga, Javier Cortes, Michele De Laurentiis, Veronique Dieras, Nadia Harbeck, Jerry Y. Hsu, Vivian Ng, Frauke Schimmoller, Timothy R. Wilson, Young-Hyuck Im, William Jacot, Ian E. Krop, Sunil Verma
Journal: Journal of Clinical Oncology (2016)

TPS617 Background: PIK3CA mutations are one of the most frequent genomic alterations in BC, being present in ~40% of ER-positive, HER2-negative breast tumors. PIK3CA mutations promote growth and proliferation of tumors and can mediate resistance to endocrine therapies in BC. Taselisib is a potent and selective PI3K inhibitor that displays greater selectivity for mutant PI3Kα than wild-type PI3Kα. Taselisib has enhanced activity against PIK3CA-mutant BC cell lines, and clinical data include confirmed partial responses in pts with PIK3CA-mutant BC treated with taselisib either as a single agent or in combination with fulvestrant. SANDPIPER, a double-blind, placebo-controlled, randomized, phase III study, is designed to evaluate efficacy and safety of taselisib plus fulvestrant in postmenopausal pts with ER-positive, HER2-negative, PIK3CA-mutant locally advanced or metastatic BC. Methods: Pts with disease recurrence or progression during or after aromatase inhibitor treatment will be randomized 2:1 to receive either taselisib (4 mg qd) or placebo in combination with fulvestrant (500 mg intramuscular on Days 1 and 15 of Cycle 1, and on Day 1 of each subsequent 28-day cycle). Randomization will be stratified by visceral disease, endocrine sensitivity, and geographical region. The study enriches for pts with PIK3CA-mutant tumors who will be randomized separately from pts with non-mutant tumors; a valid PIK3CA-mutation result in tumor tissue via central assessment is required prior to enrollment. The primary efficacy endpoint is investigator-assessed progression-free survival in pts with PIK3CA-mutant tumors. Other endpoints include overall survival, objective response rate, clinical benefit rate, duration of objective response, safety, pharmacokinetics, and patient-reported outcomes. Target enrollment is 600 pts; > 100 patients have been enrolled onto study, and enrollment is ongoing. Clinical trial information: NCT02340221.
Breast cancer in young women aged 35 or less
Authors: U. Euler, B. Knopf, A. H. Tulusan
Journal: Journal of Clinical Oncology (2004)

754 Background: Breast cancer (BC) in young women is often associated with aggressive tumor features and poor prognosis. The incidence of disease seems to increase. Therefore, a retrospective review was undertaken for pathological and biologic factors and the outcome was analyzed. Methods: 47 patients (pts) aged 35 and younger were treated for BC between 1994 and 2003. Mean age was 31,6. 24 pts received neoadjuvant, 22 pts adjuvant chemotherapy (CH). The adjuvant treatment was individual tailored. 6 pts received CMF. 23 pts were treated with anthracycline-based, 7 with taxane-based CH, 4 with a combination of both. 45 pts underwent radiation after CH. Tissue from tumorectomy was analyzed for ER, PgR, p53, Ki67, Her2-neu, EGRF, UPA and PAI1. Results: In 79% the initial tumor was more than 2cm. All pts with T3 and T4 tumors were treated with neoadjuvant CH. Nearly half of the pts (49%) presented with lymph node metastases. 81% of all tumors were invasive ductal. 60% were classified as grade 3. 67% of all tumors were ER+ and 53% PgR+. P53 was mutated in 42%(n=31), Her2neu positive in 55%(n=40), a high Ki67(>18%)(n=31)was found in 68%. EGRF status was negative in 80%(n=20), UPA was positive in 81%(n=21), PAI1 positive in 91%(n=21). 37 pts (79%) received breast conserving therapy (BCT), 6 combined with oncoplastic surgery. 6 pts (16%) with BCT suffered a local relapse, 1(10%) relapse seen with mastectomy. In 70% of pts without local relapse and BCT the tumor was 20mm or less. 65% of all pts have no metastases, 81,4% are still with no evidence of tumor, 83% are still alive. The mean follow-up is 44 months. Conclusions: More than 80% of the pts are still alive despite the aggressiveness and poor reputation of tumors in younger women. A higher rate of local relapses in pts with BCT could be seen, but smaller tumors seem to have a lower risk of recurrence. However, individual treatment adapted to each pt is necessary and important. No significant financial relationships to disclose.
Incidence of Veno-Occlusive Disease with IV in Busulfan Children Is Higher Than Expected: Preliminary Results of the VOD-DF Trial.
Authors: Selim Corbacioglu, Simone Cesaro, Maura Faraci, Bernd Gruhn, Jaap Jan Boelens, Cornelio Uderzo, Netty Hewitt, Johanna Schrum, Ingo Mueller, Ansgar S Schulz, Jerry Stein, Robert Wynn, Johann Greil, Susanne Matthes, Karl-Walter Sykora, Monika Fuehrer, Jacek Toporski, Petr Sedlacek, Rainer Muche, Friederike Rohlmann, Christina Peters
Journal: Blood (2009)
Secondary acute myeloid leukemia in children with acute lymphoblastic leukemia treated with etoposide.
Authors: N J Winick, R W McKenna, J J Shuster, N R Schneider, M J Borowitz, W P Bowman, D Jacaruso, B A Kamen, G R Buchanan
Journal: Journal of Clinical Oncology (1993)

PURPOSE To describe the occurrence of secondary acute myeloid leukemia (AML) in children with acute lymphoblastic leukemia (ALL) treated with etoposide (VP-16). PATIENTS AND METHODS Two hundred five consecutive children with early B-lineage ALL were treated according to the Dallas/Fort Worth (DFW) protocol between January 1986 and July 1, 1991. Therapy included a four-drug induction followed by consolidation and continuation phases of nightly oral mercaptopurine (6-MP) and repetitive courses of divided-dose oral methotrexate (dMTX) and asparaginase (L-asp). Three doses of VP-16 and cytarabine (Ara-C) were given during consolidation and later, during continuation, two doses were given 3 to 4 days apart, every 9 weeks. Intrathecal (IT) chemotherapy was given throughout the treatment period. RESULTS Two hundred three of the 205 patients entered remission. Only eight of these 203 children have had a bone marrow relapse (ALL). However, 10 other children have developed secondary AML 23 to 68 months following the diagnosis of ALL. Overall event-free survival (EFS) at 4 years is 79.3% +/- 5.1%, with a risk of secondary AML at 4 years of 5.9% +/- 3.2%. CONCLUSION This experience provides strong evidence for a link between epipodophyllotoxin therapy and secondary AML since none of these children received alkylating agent therapy or irradiation. This serious complication raises concern as to the appropriate use of epipodophyllotoxins in the treatment of childhood ALL.
Efficacy and safety of low dose versus full dose anticoagulation for prevention of thalidomide-related venous thromboembolism
Authors: S. Y. Farhan, J. Vega, A. Hanbali, P. Kuriakose, N. Janakiraman
Journal: Journal of Clinical Oncology (2008)

19518 Background: Thalidomide has been found to be effective in the treatment of Multiple Myeloma. However, its use is associated with an increased risk for venous thromboembolic events (VTE) ranging from 10 to 28% when used in combination with dexamethasone or chemotherapy. VTE prophylaxis should be considered at the initiation of thalidomide treatment. Current practice varies from low dose to full dose warfarin, use of low-molecular weight heparin, or aspirin. Data to guide the clinicians on the most effective VTE prophylaxis strategy are very limited. Methods: To further investigate this topic, we reviewed the records of 74 patients treated with thalidomide in combination with dexamethasone (n=55), chemotherapy (n=13), or both (n=6) in our institution between 1999 and 2007. Thirty patients received low dose anticoagulation, defined as warfarin 1–2 mg (n=11), or enoxaparin 1mg/kg once a day (n=9). Eighteen patients received full dose anticoagulation, defined as warfarin intended to raise the INR to 2–3 (n=17), or enoxaprin 1 mg/kg twice a day (n=1). Twenty- six patients did not receive anticoagulation. Thalidomide-related VTE was defined as deep venous thrombosis or pulmonary embolism occurring while on thalidomide treatment or within 2 weeks of it being stopped. Results: Seven (9.5%) of the 74 patients developed thalidomide-related VTE. Five patients (19%) who were not prescribed prophylactic anticoagulation developed VTE, compared to 2 patients (6.7%) in the low dose anticoagulation group (p=0.23), and none in the high dose anticoagulation group (p=0.068). Two patients (11.1%) in the full dose anticoagulation group experienced bleeding complications (epistaxis, gastrointestinal bleed), compared to none in the low dose anticoagulation and no anticoagulation groups (p=0.16). Conclusions: Full dose anticoagulation might be more effective than low dose anticoagulation in decreasing VTE in patients receiving thalidomide in combination with dexamethasone or chemotherapy, with an acceptable bleeding risk. The absence of statistical significance in this trial could be due to the small number of patients studied. In view of the prevalent lack of consensus, we propose this question be addressed within the context of a formal randomized trial. No significant financial relationships to disclose.
The European Medicines Agency (EMEA) guideline on oncology drug development
Authors: S. Palmeri, J. Bergh, L. Bergmann, S. W. Hansen, J. M. Moraleda, M. Marty, J. H. Schellens, J. Smyth, P. Therasse, A. van Oosterom, B. Jonsson
Journal: Journal of Clinical Oncology (2007)

6636 Background: The scientific assessment and positive opinion of the EMEA is mandatory for the approval of new oncology drugs in the European Union. One of the tasks of the EMEA is to provide guidance on the conduct of the various tests and trials necessary for approval. The EMEA has recently revised its guideline on the clinical development of new anticancer drugs. The revised version includes specific guidance on the development of non-cytotoxic (i.e., cytostatic) agents ( http://www.emea.europa.eu/pdfs/human/ewp/020595en.pdf ). Specific guidance is given about methodological issues using progression-free survival (PFS) as primary endpoint in confirmatory trials for registration ( http://www.emea.europa.eu/pdfs/human/ewp/26757506en.pdf ). Methods: The key elements of the revised guideline are described with particular reference to requirements for approval. Results: The early stages of clinical drug development have to be tailored according to the assumed pharmacology of the individual compound as defined in non-clinical studies. The integration of information from exploratory (phase I-II) and confirmatory (phase III) studies is of primary importance. In general, phase III trials should be designed with the aim of establishing the benefit risk balance of the drug, in a well-characterized target population. These studies should be randomized controlled and, where possible, blinded or include blinded evaluation. Acceptable primary endpoints include overall survival (OS) and PFS or disease-free survival (DFS). It is acknowledged that there are situations where PFS can be considered as a primary endpoint that measures clinical benefit. Adherence to protocol-defined schedules for tumor assessments, typically by imaging techniques, is important and deviations should be reported. Independent, blinded review and confirmation of best tumor response and progression should be undertaken if PFS is the primary endpoint. Conclusions: The current revision of the EMEA guideline provides useful clinical regulatory guidance for the development of cytostatic agents. When recommended guidelines are considered suboptimal, sponsors are encouraged to seek regulatory scientific advice. No significant financial relationships to disclose.