tbuckley/cabot-search huggingface dataset:
A pilot study evaluating peripheral blood lymphocyte telomere length in elderly versus young patients with colorectal cancer (CRC).
Authors: Efrat Dotan, Emmanuelle Nicolas, Karthik Devarajan, Robert J Beck, Steven J. Cohen
Journal: Journal of Clinical Oncology (2012)

512 Background: Telomere length (TL) is associated with aging as well as high cancer incidence. We conducted a pilot study to assess the TL of younger versus older (≥70 years) patients with CRC and its effect on survival. Methods: QPCR was used to analyze the relationship between telomere repeat copy number and single gene copy number (T/S ratio) on peripheral blood lymphocytes DNA of 94 CRC patients, and used as a surrogate value for relative TL. The primary aim of the study was to evaluate differences in TL between different age groups. Correlation with overall survival (OS) was the secondary aim. Samples were run in triplicate, and a standard curve was used to calculate the relative T/S ratio and account for plate to plate variability. Univariate statistical analyses were performed using the Mann-Whitney test for continuous variables and the log-rank test for OS. Multivariable analyses were performed using the Classification and Regression Trees methodology. A Type I error of 5% was used to determine statistical significance. Results: The mean relative TL was 0.95 (range 0.64-1.84). The assay demonstrated high correlation of technical replicates between plates (Pearson correlation: 0.96 and 0.81, for sample and control). Comparing patient under and over 70 years of age revealed a borderline significant difference in TL between the groups (mean TL 0.981 versus 0.925 respectively; p=0.067). Assessment using 4 age groups (50-60, 60-70, 70-80, &gt;80) demonstrated a statistically significant difference in TL between the youngest and the oldest age groups (mean TL 1.022 versus 0.874 respectively; p=0.02) with evidence of shorter TL with advanced age. Marginal relationship was seen between OS and age (p-value=0.066) with older patients exhibiting slightly poorer survival (hazard ratio of 1.03, 95% confidence interval (0.998, 1.065)). No correlation was noted between relative TL and OS in univariate and multivariable analysis. Conclusions: These results validate the ability of a qPCR-based assay to differentiate between younger and older CRC patients by TL. Ongoing studies are utilizing this methodology to evaluate the relationship of TL to treatment tolerance in elderly CRC patients.
A phase I study of atrasentan in combination with liposomal doxorubicin in platinum resistant ovarian cancer
Authors: P. O. Witteveen, M. Los, G. Groenewegen, E. E. Voest
Journal: Journal of Clinical Oncology (2005)

3170 Background: Endothelin-1 (ET-1) is a peptide that upon binding to its cognate ET-A receptor triggers tumor cell growth, survival, angiogenesis and invasion. Ovarian cancer overexpresses ET-1 and in vitro studies have shown that ET-1 confers resistance to anthracycline containing chemotherapy. Atrasentan has been developed as a specific oral receptor antagonist. From phase I and II human trials a dose of 10 mg/day is considered safe and the preferred dose for further clinical studies. The combination of atrasentan with chemotherapy might be an attractive approach in the treatment of ovarian cancer. The objective of the study was to investigate the feasibility and toxicity of adding increasing doses of atrasentan (to a maximum of 10 mg/day) to second -line liposomal doxorubicin in patients with progressive ovarian cancer. Methods: Patients with platinum resistant ovarian cancer (progressing during platinum therapy or recurrence within 6 months after platinum therapy) were treated with liposomal doxorubicin 50 mg/sqm on day 1 (and repeated every 4 weeks) in combination with escalating doses of atrasentan once daily. The starting dose was 2.5 mg and escalated in cohorts of 3 patients from 5 mg up to 10 mg. Results: Ten patients (median age 63, range 49 - 73) have been treated at these 3 dose levels. Nine patients were evaluable for toxicity and eight patients were evaluable for response. One patient had a CA-125 response. No dose limiting toxicities have been observed. Adverse events related to liposomal doxorubicin include grade 2 mucositis (n=1) and grade 2 bone marrow toxicity (n=5). Atrasentan related toxicity consisted of nasal congestion grade 2 (n=1). Cardiac toxicity, intensively monitored, was not observed. Conclusions: The addition of atrasentan to standard dose liposomal doxorubicin is feasible in patients with platinum resistant ovarian cancer. A phase II study with this combination has been initiated. No significant financial relationships to disclose.
Potentiation of Apoptosis in MDS/AML by Combination of Azacitidine and the EGFR-Tyrosine Kinase Inhibitor (TKI) erlotinib
Authors: Elodie Lainey, Marie Sebert, Cyrielle Bouteloup, Carole Leroy, Sylvain Thepot, Maximilien Tailler, Lionel Ades, Claude Gardin, Guido Kroemer, Pierre Fenaux, Simone Boehrer
Journal: Blood (2011)
Detector-C 2.0: A highly accurate blood-based IVD test for early detection of colorectal cancer with sensitivity and specificity over 90%.
Authors: Andre Rosenthal, Tobias Mayr, Hartmut Koeppen, Reiner Musikowski, Johannes Berendt, Uwe Goebel, Matthias Pross, Jörg Pertschy, Peter Nartschik, Hubertus J.C. Wehnisch, Thomas Manger, Rene Mantke, Thomas Steinmueller, Karsten Ridwelski, Thomas Buthut, Bernd Hinzmann, Dieter Nuernberg, Wilfried Pommerien, Hans-Peter Adams
Journal: Journal of Clinical Oncology (2012)

393 Background: We previously reported on the discovery and prospective validation of a blood based test (Detector C) for early detection of colorectal cancer (CRC). Detector C measures 202 RNA markers in white blood cells as a response of the host to tumor formation and growth. Detector C was validated using a prospective, multicenter case-control study with 343 patients (pts), 210 cases with confirmed CRC and 133 controls undergoing a complete screening colonoscopy. Detector C has a validated sensitivity (S + ) of 90% (95% CI 0.851-0.937) and specificity (S - ) of 88% (95% CI 0.812-0.930) (Rosental A. et al, J Clin Oncol 28:7s, 2010 (suppl; abstr 3580)). We now present the discovery of Detector C 2.0 based on 445 samples representing most of the pts previously used in the discovery and validation sets of Detector C. Methods: We used Affymetrix U133 plus 2.0 expression data of 291 CRC cases and 154 controls for discovery of Detector C 2.0. Random forest was used for feature (gene) selection and the support vector machine algorithm was employed as classifier in 600 repetitions of double-nested bootstraps to discriminate between cases and controls. Within each repetition, randomly chosen 23 controls and 160 CRC cases served as prospective validation set. The most frequent chosen genes for discrimination between cases and controls formed the consensus signature, namely Detector C 2.0. Results: Choosing a signature length of 1000 genes resulted in the following second order unbiased prospective performance estimates: S + =0.916 (95% CI 0.863-0.954) and S - = 0.948 (95% CI 0.773-0.994). S + for UICC stage I and stage II cases were 0.93 and 0.94. S + for high-grade intraepithelial neoplasia was ∼ 0.67 and S + for adenoma ≥ 10 mm was ∼ 0.45. Conclusions: Using a three times larger discovery set for Detector C 2.0 than for Detector C we improved S + (cancer detection rate) by 1.6% to 91.6%. The most important enhancement is the high S - of 94.8% of Detector C 2.0 which is six percent higher than the S- of Detector C. Detector C 2.0 is based on a much larger pts set and should be even more robust than Detector C. We will prospectively validate this test in the largest case-control study ever performed in early detection of CRC.
Prognostic significance of p53 protein overexpression in localized gastrointestinal stromal tumors of the small intestine.
Authors: Young Soo Park, Young Wha Kon, Min-Hee Ryu, Baek-Yeol Ryoo, Hye Jin Park, Jeong Hwan Yook, Byung Sik Kim, Yoon-Koo Kang
Journal: Journal of Clinical Oncology (2013)

212 Background: Mutation of c-kit is a relatively early event in the tumorigenesis of gastrointestinal stromal tumors (GISTs). p53 alteration has been suggested as an additional genetic change that affects patient outcome in some studies. However there has been few studies in GISTs of the small intestine. The aim of this study was to determine the prognostic significance of p53 alterations in localized GISTs of the small intestine. Methods: We retrospectively reviewed 113 patients with completely resected localized GISTs in the small intestine who were not treated with adjuvant imatinib between 1994 and 2008. Immunohistochemical staining of CD117, CD34, S-100, SMA and p53 were performed in all patients and mutational analyses of c-kit exons 9, 11, 13 and 17 were conducted in 81 (56.6%) patients. Results: The median follow-up after diagnosis was 84 months (range, 40-146 months). Overexpression of p53 were observed in 38 patients (33.6%). p53 overexpression was strongly correlated with high mitotic index (p = 0.01) and higher risk groups based on the National Institutes of Health’s (NIH) risk category (p = 0.019). On univariate analysis, patients with p53 overexpression showed worse recurrence-free survival (RFS, p = 0.003). c-kit mutation status was not a prognostic factor (p = 0.411). Multivariate analysis indicated that p53 overexpression remained as independent poor prognostic factors for RFS (hazard ratio = 2.66, p = 0.026) as well as tumor size and mitosis. The p53 overexpression was marginally associated with poor RFS in the low or intermediate risk groups according to NIH's risk category (p = 0.081). Conclusions: Our results suggest that the p53 overexpression is an independent prognostic factor for RFS in localized GISTs of the small intestine. Additionally, p53 overexpression could be a helpful marker for selecting patients for further treatment in low or intermediate risk group patients.
Immunological and anti-tumor activity of a novel a chemo-immunotherapy regimen with gemcitabine, oxaliplatin, levo-folinic acid, and 5-fluorouracil followed by GM-CSF and Interleukin-2 in patients with metastatic colorectal cancer
Authors: P. Correale, M. G. Cusi, K. Y. Tsang, M. T. Del Vecchio, S. Marsili, C. Intrivici, M. La Placa, A. Aquino, E. Bonmassar, G. Francini
Journal: Journal of Clinical Oncology (2005)

2538 Background: Gemcitabine + FOLFOX-4 (GOLF) regimen is a powerful multi-drug regimen which is able to determine molecular changes in colon cancer cells that make them a powerful means to induce an antigen specific CTL response in human PBMCs in vitroif taken up and processed by dendritic cells (DCs). We also showed that cancer patients’ activated DCs and CTL response may be induced with the subcutaneous (sc.) administration of GM-CSF and low dose IL-2 (IG-1 regimen). All together these results offered the rationale to design an original chemo immunotherapy protocol in colon cancer patients. Methods: We designed a phase II trial aimed to evaluate in metastatic colorectal carcinoma patients, the toxicity, the anti-tumor and the immunological activity of GOLF regimen [intravenous (iv.) GEM (1g/m2) - day 1 and 15; iv. levo-folinic acid (LF, 100 mg/m2) + iv. bolus (400 mg/m2) and 24 hour-infusional (800 mg/m2) 5-FU - day 1,2, 15,16-; and iv. 6–8 hour infusional oxaliplatin (85 mg/m2) - day 2 and 16, before LF/5-FU administration] combined with IG-1 immunotherapy [sc.GM-CSF (100 μg/day -days 3→7) and sc.IL-2 (0.5 MIU twice a day, days 8→14 and 17→30]. Twenty nine patients, 16 males and 13 females, with an average age of 69 years and an ECOG ≤ 2 were enrolled; among these, 21 had received a previous line of treatment, and 19 had liver involvement. Results: The treatment was well tolerated and induced a very high rate of objective responses (68.9%%) and disease control (96.5%), with a median time to progression of 12.5 months. An immunological study demonstrated the treatment ability to enhance a cell mediated immune response to colon carcinoma antigens and reduce the expression of regulatory T lymphocytes Conclusions: These results show that the GOLFIG regimen determines a strong immunological and anti-tumor activity in colorectal cancer patients and deserves to be investigated in future comparative phase III trials. No significant financial relationships to disclose.
Changes in serum proteomic profile of non-small cell lung cancer (NSCLC) patients during therapy with epidermal growth factor receptor tirosine kinase inhibitors (EGFR-TKIs): Preliminary report
Authors: A. Spreafico, J. Grigorieva, A. Cattaneo, C. Belli, M. Tsypin, H. Roder, M. Giovannini, M. Alessio, V. Gregorc, A. Bachi
Journal: Journal of Clinical Oncology (2008)

19034 Background: serum proteomics has been demonstrated to predict outcome in patients (pts) treated with EGFR-TKIs. VeriStrat is a classification test that separates pts into two groups: VeriStrat+ (good) and VeriStrat-(poor). These profiles have been found specific for EGFR-TKIs and not for chemotherapy treatments. It has been shown repeatedly in blinded tests on pts treated with EGFR-TKIs that progression free survival as well as overall survival is considerably greater in VeriStrat+ than in VeriStrat- pts. Aim of this study is to evaluate if the proteomic profile is pts specific or if it may change during therapy with gefitinib. Methods: sera of advanced NSCLC pts treated with gefitinib have been analyzed using the Matrix Assisted Laser-Desorption Ionization Time of Flight Mass Spectrometry (MALDI ToF MS). Pts characteristics are those already reported in JNCI paper 2007;99:838–47. Mass spectra have been acquired in linear mode using a Voyager DE-STR mass spectrometer. Seventy-five spectra have been collected from seven positions within each MALDI spot in order to generate an average of 500 spectra for each serum specimen. Spectra have been externally calibrated using a mixture of proteins standards [Insulin (bovine), thioredoxin (E. coli), and Apomyoglobin (equine)]. Results: serumsamples of 29 pts were analyzed in triplicate at baseline and at treatment withdrawal (progression, toxicity, discontinuation for any case). Twenty-two samples were classified as VeriStrat+ and seven were classified VeriStrat- at the moment of the beginning of gefitinib. Eleven out of 22 (50%) pts shift from VeriStrat+ to Veristrat- profile at the moment of treatment withdrawal due to disease progression. Longitudinal analysis on 157 enrolled patients and 585 samples is ongoing and will be presented. Conclusions: serum profile classified as good at baseline by MALDI ToF MS during EGFR-TKIs therapy changed to bad profile at progression in some patients; definitive analysis will answer if changes in serum profile correlate with appearance of acquired resistance. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Biodesix Steamboat Springs, Co, USA
Incidence and predictors of delayed congestive heart failure (CHF) after hematologic malignancies treated with autologous hematopoietic cell transplantation (aHCT).
Authors: S. Armenian, C. Sun, T. Shannon, M. Shangguan, G. MIlls, L. Francisco, F. L. Wong, S. J. Forman, S. Bhatia
Journal: Journal of Clinical Oncology (2011)

9042 Background: aHCT survivors are at risk for CHF due to exposure to cardiotoxic agents (pre-aHCT anthracyclines, chest radiation, aHCT conditioning). The magnitude of risk of CHF and risk factors are not defined, nor is the modifying effect of preventable causes, such as cardiovascular risk factors (CV RF). Methods: A retrospective cohort design was used to describe the cumulative incidence (CI) of CHF and examine the role of aHCT conditioning and sociodemographic factors. Next, a nested case-control approach was used to evaluate the role of pre-aHCT exposures and post-aHCT CV RF. Results: Eighty-one cases of CHF were observed in a cohort of 1,010 aHCT survivors transplanted at City of Hope between 1988 and 2002, followed for a median of 6.7 yrs (1-21). Median age at aHCT was 44.4 yrs (17-69); median time to CHF: 3.0 yrs (0.02-18.6); 40% were females; 71% non-Hispanic white; 68% underwent aHCT for lymphoma. CI of CHF was 7.8% at 10 yrs and 10.4% at 15 yrs post-aHCT. Female gender (Hazard Ratio [HR] 2.5, p<0.01), diagnosis of Hodgkin lymphoma (HR 2.9, p=0.02), and older age at aHCT (35-44 yrs: HR 2.2, p=0.03; 45-54 yrs: HR 2.9, p<0.01; ≥55 yrs: HR 4.5, p<0.01; referent group <35 yrs) were independent predictors of CHF. Risk was highest for female lymphoma survivors: CI of 17.5% at 15 yrs. Conditioning-related exposures were not associated with CHF risk. A clear interaction between cumulative anthracycline exposure ≥250 mg/m2 and post-aHCT CV RF (hypertension and diabetes) were identified (Table). Overall survival was 28% at 5 yrs after diagnosis of CHF. Conclusions: Cumulative incidence of CHF exceeds 10% at 15 years after aHCT. Female lymphoma survivors constitute a vulnerable population. Post-aHCT diabetes and hypertension interact with high-dose anthracycline exposure to significantly increase risk. These data form the basis for targeted surveillance and aggressive management of comorbidities. Hypertension Diabetes Dyslipidemia OR P OR P OR P No CV RF, no HD anthracycline 1.0 1.0 1.0 CV RF, no HD anthracycline 2.9 0.14 4.1 0.13 3.2 0.16 No CV RF, HD anthracycline 3.7 <0.01 3.8 <0.01 4.7 <0.01 CV RF + HD anthracycline 27.4 <0.01 21.5 <0.01 4.0 0.03 Abbreviation: HD, high dose.
Risk of renal cell cancer in people immunodepressed after solid organ transplant: Results from an Italian multicenter cohort study.
Authors: Pierluca Piselli, Ghil Busnach, Franco Citterio, Patrizia Burra, Giuseppe Maria Ettorre, Giuseppe Paolo Segoloni, Piergiorgio Messa, Silvio Sandrini, Paolo Rigotti, Maria Piera Scolari, Gian Benedetto Piredda, Donato Donati, Maria Cristina Maresca, Giuseppe Tisone, Vito Sparacino, Giovanni Battista Vizzini, Claudia Cimaglia, Lucia Fratino, Diego Serraino, Giuseppe Grandaliano
Journal: Journal of Clinical Oncology (2014)

422 Background: The etiology of renal cell cancer (RCC) is poorly understood, and data from immunosuppressed population may help to highlights risk factors unknown in the immune competent population. To assess incidence and risk factors for renal cell cancer (RCC) after kidney and liver transplant (KT and LT, respectively), we carried out a cohort investigation in 24 Italian transplant centers. Methods: This study is part of an ongoing cohort investigation conducted in 24 transplant centers in all of Italy. Two cohorts have been implemented, including 7,217 KT recipients (64.2% men) and 2,770 LT recipients (74.7% men) transplanted between 1997 and 2009—and followed-up until 2010. Person years (PY) at risk of cancer were computed from 30 days after transplant to cancer diagnosis, death, return to dialysis (for KT) or to study closure. The number of observed cancers was compared to that expected in the general population through standardized incidence ratios (SIR) and 95% confidence intervals (CI). To identify risk factors, incidence rate ratios (IRR) were computed through Poisson regression. Results: Overall, 581 cancers were diagnosed during 61,817 PYs of follow-up, with Kaposi’s sarcoma, non-Hodgkin lymphoma, lung, RCC, and prostate as the most common types. Thirty-eight cases of RCC were diagnosed (36 in KT and 2 in LT). As compared to the general population, the risk of RCC was 4.9-fold significantly higher in KT recipients than expected (95% CI: 3.4-6.8). The increased risk was restricted to the native kidney (31 native kidney OR=4.2, 95% CI:2.9-6.0), and no risk elevation was found in LT recipients (SIR=0.5 95% CI: 0.1-1.9). Use of mTOR inhibitors seemed to exert a 40% reduced risk (IRR=0.6, 95% CI: 0.2–1.4) of RCC, but the difference was not statistically significant. Conclusions: Our study findings confirmed, in Italy, the increased risks for RCC following KT, and they also suggested a possible protective effect of mTORi. The magnitude of the excess risk documented in this cohort study was higher than reported for potential risk factors described in immune competent people—or in people under dialysis—thus suggesting a role for the immune system in the etiology of RCC.
TACE plus sorafenib for the treatment of hepatocellular carcinoma: Final results of the multicenter SOCRATES trial.
Authors: A. Erhardt, F. T. Kolligs, M. M. Dollinger, E. Schott, H. Wege, M. Bitzer, C. Gog, J. Raedle, M. Schuchmann, C. Walter, D. Blondin, C. Ohmann, D. Haeussinger
Journal: Journal of Clinical Oncology (2011)

4107 Background: HCC is considered to be a hypervascular tumor. Therefore, transarterial chemoembolization (TACE) and inhibition of angiogenesis appear rational treatment strategies. The present multicenter phase II study investigated for the first time the combination of TACE and sorafenib, a multikinase inhibitor with anti-angiogenic activities approved for the treatment of HCC. Methods: Eligibility criteria included histologically confirmed, unresectable hepatocellular carcinoma beyond Milan criteria, no extrahepatic spread, Child Pugh score ≤8, ECOG PS 0-2, platelets >100K/µl, and bilirubin <4.5 mg/dl. Patients were naïve to treatment with respect to HCC. Sorafenib was given at a dose 400mg/bid continuously (interrupted only around TACE). TACE with lipiodol and 50 mg doxorubicin was repeated at six week intervals if indicated. Tumor assessment was performed q6w according to RECIST and EASL criteria by a central radiology. Primary endpoint was time to progression (TTP). Results: Between December 2007 and December 2009 45 patients were enrolled. Patients received a mean of 2.0±2.1 TACE interventions (range 1-10). There was no CR (complete remission), one PR (partial remission) and 34 SD (stable diseases) according to RECIST criteria, compared to 3 CR, 17 PR and 14 SD according to EASL criteria. TTP was 526 days (Fig.1.) and median overall survival (OS) was 562 days. Grade 3 and 4 toxicities were noted in 18% and 7% of patients, there were four SAE related deaths (CTC 5). Eight patients discontinued treatment due to adverse events. Conclusions: The combination of TACE with sorafenib is tolerable for most patients and associated with a promising rate of radiographic response, TTP and OS.