tbuckley/cabot-search huggingface dataset:
Cancer survival: Which low molecular weight heparin (LMWH) is best?
Authors: J. E. Spahr, W. Akerley, G. M. Rodgers
Journal: Journal of Clinical Oncology (2007)

19624 Background: The role of LMWH in cancer survival is controversial. There have been 6 randomized trials specifically evaluating cancer survival with LMWH. The objective of this study was to determine which LMWH is best for cancer survival, based on literature data. Methods: We performed a review of the literature for studies published from 1990 - 2007. Results: We identified 14 studies that included data on cancer survival and the use of LMWH, even if the primary endpoint was not cancer survival. We found studies for 5 LMWH products (See Table ). Conclusions: Based on our analysis, dalteparin is the most well studied LMWH in cancer. The 4 best designed trials looking at cancer survival were performed using dalteparin with over 1190 patients. The magnitude of benefit appears to be greatest in patients with better up-front estimated survival, and absence of metastatic disease. The estimated survival benefit was 25%. The second best studied LMWH appears to be nadroparin, with 5 trials with over 480 patients, including the MALT trial, and the most recently published Icli trial. Unfortunately, nadroparin is currently not available in the US. The studies of the other LMWH lack evidence to draw significant conclusions. The results of this study must be interpreted with caution. As there have been no randomized clinical trials comparing one LMWH against another in cancer survival, the studies we compared were not always similar in design or LMWH dosing, and cannot be compared head-to-head. No significant financial relationships to disclose. [Table: see text]
Gemcitabine and vinorelbine as third-line therapy in elderly patients (pts) with advanced breast cancer (ABC) pretreated with taxanes and anthracyclines
Authors: H. G. Botto, M. E. Botto
Journal: Journal of Clinical Oncology (2007)

1110 Background: Gemcitabine (G) and vinorelbine (V) combinations are active in ABC pts. In this trial our purpose was to study in elderly pts with ABC and pretreated with T and A, the response rate (RR), the time to progression (TTP), the overall survival (OS) and the tolerance, with G and V as third line therapy. Methods: Sixteen pts with ABC pretreated with T and A combinations, median age 69 years (range 66–81 y). PS: 0=7, 1=8, 2=1, with normal organic functions, sites of disease: hepatic 8, bone 7, lung 5, soft tissue 3; two or three sites of disease 9 pts, more than three sites 7 pts. Treatment: G/1,200 mg/m 2 and V 35 mg/m 2 , day 1, every 21 days. Median N° of cycles 4 (range 2–8). Total N° of cycles 71. All pts were evaluated for RR, OS and toxicity. Results: PR 25%, SD 37%. All PR pts and one SD pt, have previously showed response to T and A combinations. The total median TTP was 4 months (range 2–20 m), the total overall survival was 7 months (range 3–36 m). In non responders and responders pts to previous T and A combinations, the median TTP was 3 and 5 months respectively, and the median OS was 5 and 10 months respectively. Tocixity, neutropenia Gr.3–4: 6 pts, Gr.2: 10 pts, anemia Gr.2: 7 pts, thrombocitopenia Gr.2: 3 pts. Conclusions: In this trial the gemcitabine and vinorelbine as third line therapy, in elderly pts with ABC, pretreated with T and A combinations, showed good response rate, good overall survival and acceptable toxicity. Pts who have responded to the previous T and A regimens obtained better response than pts who have not responded. No significant financial relationships to disclose.
Prognostic role of FOXP3/CD4 ratio in resectable NSCLC.
Authors: Marta Usó, Rafael Sirera, Eloisa Jantus-Lewintre, Elena Sanmartin, Sandra Gallach, Ana Blasco, Nieves Martinez, Cristina Hernando, Santiago Figueroa, Christian Diego Rolfo, Miguel Martorell, Ricardo Guijarro, Carlos Camps
Journal: Journal of Clinical Oncology (2012)

7058 Background: Tregs play a critical role in immune tolerance to tumor cells and have been related to prognosis. The aim of this study was to determine the expression of Tregs makers genes by RT-PCR and to correlate them with clinico-pathological and prognostic variables in NSCLC. Methods: RNA was isolated from frozen lung specimens (tumor and normal lung) from resectable NSCLC patients (n=175). RT-PCR was performed to analyze the expression of: CD4, CD8A, CTLA-4, FoxP3, IL-10, CD25, CD127 and TGFβ-1. Relative expression was normalized by an endogenous gene (GUSB) using the Pfaffl formulae. Statistical analyses were considered significant at p&lt;0.05. Results: Tumor samples had significantly lower expression of CD127 (x0.45) and a tendency toward higher expression of CD25 (x1.81), FoxP3 (x1.57) and CTLA-4 (x1.53) compared to normal lung tissues, reflecting a Treg phenotype infiltrating the tumor. Survival analyses revealed that patients with higher FoxP3 expression had reduced OS (median 29.8 vs 67 months, p= 0.026). We also found that those patients with high levels FoxP3/CD4 ratio had worse TTP and OS (median 22.1 months vs NR, p= 0.021 and 29.8 vs NR months, p=0.003, respectively). A multivariable Cox regression model for TTP and OS was built using variables that were found significant in the univariate analysis (nodal involvement, histology, tumor size, PS, and FoxP3/CD4 ratio). This analysis revealed that FoxP3/CD4 ratio was an independent prognostic marker for both TTP and OS (see table). Conclusions: FoxP3 is a transcription factor necessary and sufficient for induction of the immunosuppressive functions in Tregs. In concordance, our results indicate that higher levels of FoxP3/CD4 ratio in tumor samples is a poor prognostic markers for TTP and OS. Furthermore, the multivariable COX regression analysis showed that FoxP3/CD4 ratio is an independent prognostic marker. Therefore, this ratio could be used as a new biomarker of prognosis in resectable NSCLC. Supported by grants PS09-01149 and RD06/0020/1024 from ISCIII. [Table: see text]
Phase II trial of a 3-hour infusion of paclitaxel in previously untreated patients with advanced non-small-cell lung cancer.
Authors: M J Millward, J F Bishop, M Friedlander, J A Levi, D Goldstein, I N Olver, J G Smith, G C Toner, D Rischin, D R Bell
Journal: Journal of Clinical Oncology (1996)

To determine the antitumor activity and toxicity of paclitaxel administered as a 3-hour infusion in patients with advanced non-small-cell lung cancer (NSCLC).Fifty-one patients with advanced measurable or assessable NSCLC and performance status 0 to 2 who had not received prior chemotherapy were treated with paclitaxel 175 mg/m2 over 3 hours with premedication. Cycles were repeated every 3 weeks for a maximum of nine cycles. Most patients had prior radiotherapy (57%), extrathoracic metastatic disease (65%), and measurable disease (75%). Twenty-two percent had previously untreated stage III disease.The objective response rate was five of 51 (10%; 95% confidence interval, 3% to 21%). No subgroup with a higher response rate could be identified. There were no complete responses (CRs) and all responses lasted less than 5 months. Treatment was well tolerated with brief World Health Organization (WHO) grade IV neutropenia in only 16% of patients. Grade III/IV myalgia/athralgia occurred in 22% of patients. No significant hypersensitivity reactions occurred.The antitumor activity of this dose and schedule appears inferior to that reported in previously published phase II trials in NSCLC that used higher doses of paclitaxel infused over 24 hours, although confidence intervals for response overlap. Determining the optimal dose and schedule for using paclitaxel in NSCLC requires further investigation, and these results should caution against using shorter infusions outside appropriate clinical trials.
Correlation of LPL/ADAM-29 expression ratio with IGVH mutational status, ZAP-70 and clinical outcome in patients with chronic lymphocytic leukemia
Authors: R. T. Ignatius, F. Khan, I. A. Jaiyesimi, V. Douglas-Nikitin, S. M. Wills, J. Boura, X. Meng, D. Crisan
Journal: Journal of Clinical Oncology (2008)

7082 Background: The expression of LPL/ADAM-29 in the peripheral blood has been reported to correlate with IGVH (Immunoglobulin heavy chain) mutational status and survival in CLL (Chronic lymphocytic leukemia) patients. We studied the correlation between IGVH, ZAP 70(Zeta associated protein), LPL/ADAM 29 expression (L/A) ratio and clinical outcome in patients diagnosed with CLL. Methods: 50 CLL ( Binet stage A= 31, stage B+C= 19) patients were identified through tumor registry at William Beaumont Hospital from 1988- 2007.Information about age, sex, time to treatment, progression and death were collected. RNA was isolated from peripheral blood, cDNA was synthesized and PCR was performed for detection of transcripts for the LPL/ADAM29 ratio. For IGVH status, DNA was isolated from peripheral blood and PCR amplified with VH specific primers and the amplified product was sequenced. The degree of homology to the germline VH sequence is expressed as % value. ZAP-70 expression on the CLL lymphocytes was determined by evaluation of the percentage of neoplastic cells in comparison with the matched isotype control. ZAP-70 expression was evaluated using Alexa-488 antibody (Cal tag). For all statistical analyses we used SAS® version 9.1.3, Cary, NC. Results: L/A ratio had a sensitivity of 94%, negative predictive value (NPV) of 96% and specificity of 70% when compared to IGVH status. ZAP-70 and L/A ratio together had a sensitivity of 93%, a NPV of 86% and specificity of 72%. Multivariate analyses showed patients with stages B or C (p=0.02), advanced age (p=0.04) and UM-IGVH status (p=0.035) had a higher likelihood of having lower EFS in the whole cohort. Conclusions: LPL/ADAM 29 expression ratio better corroborated with IGVH status in patients with CLL than ZAP-70 or ZAP-70 combined with L/A ratio. L/A ratio is a valuable addition to a panel of tests for CLL prognostication. Correlation between IGVH,L/A ratio,ZAP-70 and event free survival in patients with CLL Tests CLL stage A+B+C B+C A IGVH (MT vs. UM) 18.3 vs. 9.3 (p=0.18) 26.7 vs. 9.9 (p=0.77) 12.8 vs. 7.3 (p=0.16) L/A(<1 vs. >1) 15 vs. 11 (p=0.59) 20.3 vs 11.8 (p=0.53) 11.8 vs 11.02 (p=0.84) ZAP-70(Neg vs. Pos) 10.6 vs. 9.9 (p=0.76) 10.1 vs 9.9 (p=0.95) 10.8 vs. 9.9 (p=0.81) No significant financial relationships to disclose.
Phase II study of dose-intense temozolomide in recurrent glioblastoma.
Authors: S. Hammond, A. D. Norden, G. J. Lesser, J. Drappatz, C. E. Fadul, T. Batchelor, E. C. Quant, R. Beroukhim, A. Muzikansky, A. S. Ciampa, L. M. Doherty, D. C. LaFrankie, S. Ruland, C. A. Bochacki, K. Griffin, M. Gerard, C. Sceppa, M. R. Rosenfeld, P. Y. Wen
Journal: Journal of Clinical Oncology (2011)

2038 Background: Most GBM patients relapse within 1 year from diagnosis. Among patients who progress on standard temozolomide, the optimal therapy is unknown. Resistance to temozolomide is partially mediated by the DNA repair enzyme, O6-methylguanine-DNA methyltransferase (MGMT). Since MGMT may be depleted by prolonged temozolomide administration, dose-intense schedules may overcome resistance in patients with recurrent GBM. Methods: This is a phase 2 single arm study of temozolomide 75-100 mg/m2/day for 21 days of each 28-day cycle. Patients have GBM in first recurrence following standard therapy, including at least 2 cycles of adjuvant temozolomide. The primary endpoint is 6-month progression-free survival (PFS6). Results: Forty-eight participants have been accrued, one of whom withdrew prior to treatment. There are 26 men (55%), median age 57 (range 25-74), median KPS 90 (range 60-100). Of 40 patients with MGMT methylation results, 7 are methylated (17.5%). There were 6 (13%) partial responses (PR). Eighteen patients (38%) achieved stable disease (SD). Median PFS was 10 weeks (95% CI: 8-17) and PFS6 23%. Median OS was 13 months (95% CI: 8-not reached). Patients with methylated MGMT had median PFS 7.4 months (95% CI 1.9-15.6), and unmethylated promoters 2 months (95% CI 1.9-3.8; p=0.08). Median OS in methylated patients was 16 months (95% CI 16-not yet reached), unmethylated 11.5 months (95% CI 8-not yet reached; p=0.05). The probability of achieving PR/SD was higher in patients with MGMT methylation (p=0.03). Response, PFS, and OS did not depend on the number of prior temozolomide cycles or the time off temozolomide. Treatment was well tolerated with limited Grade 3 neutropenia (n=3) or thrombocytopenia (n=4). Conclusions: Dose-intense temozolomide on a 21/28 day schedule is a safe regimen for patients with GBM in first recurrence. Updated efficacy results will be presented.
Modified cisplatin, etoposide (or vinblastine) and ifosfamide salvage therapy for male germ-cell tumors. Long-term results
Authors: G. Pizzocaro, R. Salvioni, L. Piva, M. Faustini, N. Nicolai, L. Gianni
Journal: Annals of Oncology (1992)

Between 1985 and 1989, 36 consecutive male patients with advanced germ-cell tumors, who had failed to be cured with either the cisplatin, vinblastine, bleomycin (PVB) or the cisplatin, etoposide, bleomycin (PEB) combinations, entered either of two modified salvage therapy regimens consisting of cisplatin, etoposide, and ifosfamide (PEI) or cisplatin, vinblastine and ifosfamide (PVI). All patients had evidence of active disease. Ifosfamide was given at the dosage of 2.5 gr/m2 (with mesna protection) on days 1 and 2; etoposide and cisplatin were given at the dosage of 100 mg/m2 and 40 mg/m2, respectively, on days 3 to 5. In the PVI schedule, vinblastine 6 mg/m2 was given on day 3. Overall, 20 (56%, C.I. 39 to 72) patients entered complete response (CR) or achieved disease-free status (NED) with post-chemotherapy surgery. After a follow-up of 2 to 7 years, 15 patients (42%, C.I. 24 to 58) remain alive and free of disease. None of the 9 patients unresponsive to the first-line therapy and/or with extragonadal primaries entered CR or achieved the NED status, versus 20 (74%, C.I. 58 to 91) of the 27 patients with primary testicular tumors who were responsive to the first-line therapy (p less than 0.001). PEI was used in 20 of these 27 patients, with excellent results (90% CR and 70% continuously NED) independently of primary therapy, PVB or PEB. By contrast, only 2 of the 7 patients treated with PVI following PEB entered CR. Toxicity was not life-threatening. Nine (25%) patients suffered granulocytopenic fever and 3 (8%) required platelet transfusions.(ABSTRACT TRUNCATED AT 250 WORDS)
Anti-tumor activity of letrozole in patients with recurrent advanced low malignant potential or low-grade serous ovarian tumors
Authors: J. J. Kavanagh, W. Hu, S. Fu, M. Deavers, C. Moore, R. L. Coleman, C. F. Levenback, D. Shen, G. Zheng H, Li YF, P. Mueller, D. M. Gershenson, H. Zheng, Y. F. Li
Journal: Journal of Clinical Oncology (2007)

5582 Purpose: To evaluate the clinical activity of oral Letrozole in patients with recurrent and advanced low malignant potential or low grade serous ovarian tumors and to determine the impact of steroid receptor expression on this observed activity. Methods: In a phase II design, we recruited patients with confirmed recurrent advanced stage low malignant potential tumors and recurrent low-grade serous carcinomas. Measurable disease was required. Steroid hormone expression (ER and PR), EGFR, and Her2/neu expression were determined on available pathological material by IHC from the initial surgery or at documentation of recurrent disease and blood was obtained before enrollment and every other month while on therapy. Letrozole was administered orally at a dose of 2.5 mg once a day. The endpoints were objective response rate assessed by Response Evaluation Criteria in Solid Tumor. Adverse events were graded using the National Cancer Institute Common Toxicity Criteria. Results: Thirteen patients meeting eligibility have been enrolled are evaluable for response and toxicity. From objective clinical parameters (RECIST) no patients had a CR or PR; five patients (38%) had disease stabilizations, eight patients had progressive disease. However, using criteria for CA 125 response, we obtained a complete serologic response in 2 of 13 patients (15%), and a partial serologic response in 2 additional patients (15%); marker stabilization was seen in 5 other patients (38%). CA125 increased in four patients (31%). We also detected the presence of ER, PR, EGFR, Her-2/Neu by IHC, and estradiol in the plasma by ELISA. No significant correlation was observed between tumor marker response and ER expression alone. However, when we evaluated the co-expression of ER/PR we found 3 of 5 (60%) patients had a serologic response compared to just 1 of 8 patients with ER+/PR- tumors (P=0.07). We observed no severe adverse events. Conclusion: Our preliminary data suggests that oral Letrozole has some antitumor activity in recurrent advanced low grade or borderline ovarian tumors and is well tolerated. The analysis of correlation between objective response and combined prediction markers including phosphorylated ER, PR, AKT, and IGFR is ongoing (Supported by CTRF). No significant financial relationships to disclose.
APR-246, a new class anticancer compound in phase l/lla clinical trials.
Authors: C. Liljebris, N. Mohell, E. Olaisson, T. Uhlin, K. G. Wiman, S. Lehmann
Journal: Journal of Clinical Oncology (2010)

TPS183 Background: APR-246 belongs to a new class of small molecules that is currently being tested in a phase I/IIa clinical trial. The goal of the study is to evaluate safety and pharmacokinetic (PK) properties of APR-246, but efficacy parameters will also be included. APR-246 has been shown to restore nonfunctional p53 by promoting its correct folding (Lambert et al. Cancer Cell 15, 2009). This represents a new strategy with potential to treat patients resistant to conventional chemotherapy. APR- 246 has been tested in a full nonclinical safety package and has shown no toxicity at predicted therapeutic plasma levels. This profile is further supported by the tumor specificity of APR-246 demonstrated in ex vivo studies with primary cells. Methods: The ongoing phase I/IIa trial was initiated in June 2009 and is an open labeled, dose-escalating study on refractory hematological malignancies and prostate cancer. The study will comprise approximately 25 patients, and is performed at 7 sites in Sweden. Each patient receives APR-246 treatment on 4 consecutive days as a 2 h daily intravenous infusion. The treatment phase is followed by a 17-day follow-up phase to reveal any late adverse events. The total duration of one treatment cycle is 21 days. The primary objective is to determine the highest feasible dose of intravenously administered APR-246. As secondary endpoints tumor burden and apoptosis are measured. The study is estimated to be reported in Q3 2010. In parallel with the ongoing phase I/IIa clinical study, planning for a proceeding phase II, proof-of-concept, study is ongoing. As additive and synergistic effects have been observed in various cell lines and primary cells from patients, the design of the phase II study will most probably involve combination treatment with APR-246 and conventional chemotherapy. This will allow for lower doses of chemotherapy resulting in less severe side effects. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Apera AB, Aprea AB Aprea AB Aprea AB Aprea AB
Number needed to treat (NNT) to compare benefits of letrozole (LET) with adjuvant chemotherapy (CT) in patients (pts) with node-positive (N+) breast cancer (BC)
Authors: N. Dhillon, S. Kaura, G. Dranitsaris, H. Rugo
Journal: Journal of Clinical Oncology (2009)

581 Background: Adjuvant CT is an accepted treatment for N+ BC. The addition of taxanes to anthracycline based adjuvant CT has been demonstrated to improve overall survival (OS) in all but one study as in table below. BIG 1–98 has reported a survival gain with the aromatase inhibitor LET compared to tamoxifen (TAM). NNT (the reciprocal of absolute benefit) is the number of pts that need to be treated with a new intervention to avoid 1 additional event over the benefit provided by standard therapy. For multiple numerical outcomes from randomized trials, NNT is an effective method to express results in a clinically meaningful way. To evaluate the degree of benefit of LET over TAM in women with early stage N+ BC in BIG 1–98, we compared the NNT for survival benefit from LET to that needed to see benefit from the addition of a taxane to anthracycline based CT based on clinical trial data in BC pts with N+ disease. Methods: 5-yr survival data were taken from the pivotal randomized controlled trial (RCT) for LET (N+ pts from BIG 1–98, TAM arm censored for crossover to LET) and from 4 RCTs of adjuvant CT trials, AC-T, FEC-D, and DAC. NNT was calculated with respect to OS at 5 yrs; outcome is presented as the NNT to save a life (see Table). Results: The NNT to save a life for adjuvant LET vs TAM is comparable to the NNT for the addition of a taxane to anthracycline based CT in women with N+ BC. Conclusions: The magnitude of survival benefit of LET over TAM in terms of NNT is comparable to that needed to see a survival benefit from paradigm- changing modern adjuvant CT regimens. F= fluorouracil, E = epirubicin, C = cyclophosphamide, D = docetaxel, T = paclitaxel, A = doxorubicin [Table: see text] [Table: see text]
Association of papillary subtype of lung adenocarcinoma with response to gefitinib
Authors: Y. H. Kim, K. Goto, G. Ishii, R. Kakinuma, K. Kubota, H. Ohmatsu, S. Niho, K. Nagai, Y. Nishiwaki, A. Ochiai
Journal: Journal of Clinical Oncology (2004)

7092 Background: Recently bronchiolo-alveolar carcinoma ( BAC ) is considered as an ideal target of gefitinib, and the association of expression of EGFR with the response to gefitinib is still controversial. However, prior studies used only biopsy specimens, and no studies analyzed histopathological features in detail using surgically resected specimens so far. The aim of this study was to identify favorable histopathological and immunohistochemical features to the treatment with this newly developed agent in patients with lung adenocarcinoma. Methods: From June 2002 to October 2003, 36 patients with lung adenocarcinoma, who relapsed after surgical resection, were treated with gefitinib in our hospital. The association of their histopathological features, and immunohistochemical expression of EGFR, phosphorylated EGFR ( p-EGFR ), and c-erbB-2, with response to gefitinib, was investigated. The tumors were classified into the following four distinctive histological types according to the revised WHO histological classification: BAC, acinar, papillary, and solid adenocarcinoma with mucin. The dominant histologic subtype in maximum cut surface of each case was documented. Results: There were 7 cases in BAC, 5 in acinar subtype, 17 in papillary subtype, and 7 in solid adenocarcinoma with mucin. The significant association between papillary subtype and response to gefitinib was observed ( p=0.0021 ), and the survival time was also significantly prolonged in patients with papillary subtype than non-papillary subtypes ( p=0.03 ). The expression of EGFR, p-EGFR, and c-erbB-2, were not associated with the response to gefitinib. Conclusions: Not BAC, but papillary subtype of lung adenocarcinoma is a significant predictor to the response to gefitinib. This type of lung adenocarcinoma might be a possible target of post-operative adjuvant treatment with this agent. No significant financial relationships to disclose.
Requirement of Caspase-8 Versus Caspase-9 during Apoptosis in Multiple Myeloma Cells Induced by Bortezomib- or a Novel Proteasome Inhibitor NPI-0052.
Authors: Dharminder Chauhan, Laurence Catley, Mugdha Velankar, Anthony Letai, Teru Hideshima, Klaus Podar, Hiroshi Yasui, Nicholas Mitsiades, Constantine Mitsiades, Yu-Tzu Tai, Noopur Raje, Nikhil Munshi, Michael A. Palladino, Kenneth C. Anderson
Journal: Blood (2005)