tbuckley/cabot-search huggingface dataset:
Phase II evaluation of vinorelbine in recurrent pediatric malignancies
Authors: J. F. Kuttesch, M. D. Krailo, W. A. Bleyer, G. H. Reaman
Journal: Journal of Clinical Oncology (2005)

8521 Background: Vinca alkaloids have broad activity against pediatric malignancies. Vinorelbine is a unique semi synthetic vinca alkaloid that has less potential of neurotoxicity. These observations were the basis for evaluation of vinorelbine in pediatric patients. Methods: Fifty patients with recurrent malignancy were enrolled among 3 strata (sarcoma, neuroblastoma, brain tumor). All patients had received ≤ 2 chemotherapy regimens. Vinorelbine was given weekly for 6 weeks with a 2 week rest period prior to repeating this schedule. Endpoints were response rate and toxicity analysis. Statistical analysis utilized a two stage design to define activity as a response rate (complete response (CR) + partial response (PR)) of 30% with probability 0.88. Stable disease (SD) was defined as < 25% change in tumor size for an interval of ≥ 16 weeks. Results: Median age of the patients was 10 years, ranging 1- 25 years. Other characteristics included: Gender (female 26: male 24); Ethnicity (Caucasian 64%, Hispanic 20%, and African American 12%); Prior therapy (radiation therapy in 92%, stem cell transplant in 28%); Disease extent (5% with bone marrow involvement). Among 49 evaluable patients, three responses (1CR, 2PR) occurred. All responses occurred in the sarcoma strata (n=20). Within the sarcoma strata, 1CR, 2PR and 6SD occurred among patients with rhabdomyosarcoma (RMS) (n=10). Four SD occurred among non-RMS. (n=10) Overall response rates as CR, PR, SD, and PD were 2%, 4%, 35%, and 59%, respectively. Excess neutropenia was noted among 35 patients receiving vinorelbine at 35 mg/m2 resulting in dose reduction to 30 mg/m2 in the last 15 patients. The major grade 3/4 toxicities were neutropenia (68%), anemia (20%) and neurological (10%). Conclusions: Vinorelbine at dose of 30 mg/m2 can be safely administered as a single agent to children with recurrent malignancies. The target of 30% response was not achieved in any of the strata. Further study of vinorelbine is warranted to define activity against rhabdomyosarcoma. Incorporation of vinorelbine into combination therapy in pediatric malignancies may be limited by drug-associated neutropenia. No significant financial relationships to disclose.
Assessment of nutrition in cancer patients and its effect on treatment outcome—A study from a developing country
Authors: S. Mukhopadhyay, C. Paul, K. Thander, J. Gorai, M. Purakayet, S. Biswas, R. Choudhury, R. Ahmed, P. Gupta, A. Mukhopadhyay
Journal: Journal of Clinical Oncology (2006)

6125 Background: In developing countries one-third of the people suffer from mal-nutrition. It has been shown that a good nutritional status can reduce complications of treatment, strengthen the immune system and contribute to the patient’s general well being throughout treatment. A good nutritional status is therefore essential for optimal treatment of a cancer patient. The aim of our study was to see the nutritional status of cancer patients on diagnosis and effect of nutrition on outcome of therapy. Methods: In this study we prospectively analyzed the nutritional status of 500 cancer patients in Netaji Subhash Chandra Bose Cancer Research Institute, a tertiary cancer center of eastern India during period from January 2004 to December 2005. The age range of the patients was 19 years to 74 years (median age 46 years). The parameter analyzed were weight for age, total protein, serum albumin and mid arm circumference. The weight for age and mid arm circumference were taken as normal if they were between 3rd and 97th percentile curve of the growth chart recommended by the Indian Council of Medical Research. The albumin level and the total protein were considered normal if the value is equal to or more than 3gm% and 5.8gm%. Result: It was seen that total 120 patients (24%) were low weight for age and 100 patients (20%) had low mid arm circumference. Total 90 patients (18%) had low serum albumin while 130 patients (26%) were low serum protein. Low weight for age, low serum albumin and low mid arm circumference were significant factors in disease free survival and toxicity of chemotherapy (p value &lt; .001) Conclusion: We conclude that mal-nutrition is a major finding in cancer patients in developing country like ours. The patient with mal-nutrition had less disease free survival and more toxicities during therapy as compared to well-nourished patients. No significant financial relationships to disclose.
Combined treatment of colorectal cancer cell lines with aspirin and bortezomib
Authors: I. Voutsadakis, A. Patrikidou, K. Tsapakidis, N. E. Stathakis, C. N. Papandreou
Journal: Journal of Clinical Oncology (2007)

14562 Background: The ubiquitin-Proteasome system (UPS) has emerged as an important proteolytic system for the regulation of a wide range of cellular functions. Key determinants of carcinogenesis, are regulated in multiple levels by UPS. Proteasome inhibition by the boronic containing molecule bortezomib is already in use for the treatment of multiple myeloma and is in various phases of investigation for other malignancies. Cox inhibitors such as NSAIDs have been shown to inhibit the growth of colorectal cancer cells in vitro and polyp formation in vivo. Methods: HT-29 and HCT116 colorectal cancer cell lines were treated with aspirin (ASA), bortezomib and their combination. MTT assay was used to evaluate the effect of treatment on cell proliferation compared to controls. Cox activity and proteasome activity were measured with colorimetric methods. The effect of drug treatments on specific proteins expression was assayed by western blotting. Results: Both cell lines are inhibited by ASA and bortezomib and their proliferation is further inhibited by the combination of the two drugs. In HT-29 cells both ASA and bortezomib inhibit proteasome and their combination has additive effect in this inhibition. In contrast in HCT116 cells ASA-mediated inhibition is accompanied by increased proteasome activity while bortezomib-mediated growth inhibition is accompanied as expected by proteasome inhibition. ASA-mediated inhibition is not Cox-mediated since no Cox activity was detected in either cell line. Cell cycle inhibitor p27 expression is induced in HCT116 cells by bortezomib while ASA fails to do so. In HT29 cells p27 is expressed at baseline and does not change significantly by treatments. Conclusion: The combination of ASA and bortezomib inhibited the proliferation of both cell lines more than either drug alone in a Cox-independent way. ASA had opposite effects on proteasome activity in the two lines. p27 induction may mediate at least partially the anti-proliferative effect of bortezomib in HCT116 cells. Further studies are in progress to determine other molecular components of the cellular processes taking place during treatment by the combination of these drugs in order to better understand their mechanism of action and thus explore their potential therapeutic use. No significant financial relationships to disclose.
Dexamethasone as an <i>in vivo</i> probe for CYP3A metabolism: application to docetaxel and vinorelbine
Authors: F. Dalenc, F. Puisset, T. Cresteil, I. Lochon, T. Laffont, I. Hennebelle, C. Chevreau, H. Roché, E. Chatelut
Journal: Journal of Clinical Oncology (2005)

2036 Background: Since none endogenous marker is able to predict accurately clearance of metabolised drugs, two separate studies were conducted in order to assess the possibility to use dexamethasone as an in vivo probe for predicting docetaxel and/or vinorelbine clearance. Indeed, dexamethasone, vinorelbine and docetaxel are all mainly metabolised by cytochrome P450 3A4/5 and all are substrate of the ABCB1 transporter. Methods: Patients were receiving docetaxel (21 pts) or vinorelbine (20 pts) as part of established protocols. Dexamethasone (20 mg, iv) was given the day before chemotherapy. Plasma and urinary concentrations of both unchanged dexamethasone and its main metabolite, 6-beta-hydroxydexamethasone, were determined by HPLC Method: Genotyping of both CYP3A5 and ABCB1 have been also performed. The correlation between docetaxel or vinorelbine clearance and dexamethasone pharmacokinetic parameters was assessed using a population pharmacokinetic approach and NONMEM program. Results: A significant correlation between dexamethasone pharmacokinetic parameters and both docetaxel and vinorelbine clearance was found. Covariate models were obtained by considering dexamethasone plasma clearance (DPC) together with other covariates. For docetaxel, best covariate model was: CL (L/hr) = 356. fu. (1 - 0.17 . HPMT) . (1 + 0.126 . DPC) with fu for the unbound plasma fraction of docetaxel estimated from serum alpha 1 acid glycoprotein level, HPMT =1 or =0 if presence of hepatic metastasis or not, and DPC in L/hr. Interindividual variability in CL decreased from 38% (no covariate) to 15% by considering these three covariates. Mean total docetaxel AUC was not significantly larger in patients who experienced severe neutropenia, then the difference was significant (p=0.02) for AUCu (unbound docetaxel plasma exposure) between patients with or without severe toxicity. For vinorelbine, the best covariate model was: CL (L/hr) = 39.8. (DPC/13.2)0.524. (ALP/137)−0.198 with ALP for alkaline phosphatase level (IU). Interindividual variability in CL decreased from 29.7% (no covariate) to 14.7% by considering DPC and ALP. Conclusions: Dexamethasone may be used as a probe for individual dosing of docetaxel and vinorelbine. No significant financial relationships to disclose.
Different expression of progesterone receptor between uterine serous carcinoma and ovarian serous carcinoma
Authors: K. Matsuo, M. L. Eno, A. M. Abouzied, D. D. Im, N. B. Rosenshein
Journal: Journal of Clinical Oncology (2009)

5578 Background: Clinical presentation and progression of uterine serous carcinoma (USC) often mimicks that of ovarian serous carcinoma (OSC), making the diagnosis difficult. The aim of this study is to compare characteristics of biomarker expression of USC to OSC. Methods: We evaluated all patients with FIGO stage III-IV USC and OSC, who underwent initial cytoreductive surgery between January 1, 1995, and March 31, 2008. Cases that received neoadjuvant chemotherapy were excluded. Patient demographics and clinico-pathologic data were abstracted from the medical records. Biomarker expression results were evaluated for mutation of p53 (m-p53), DNA profiling, multi-drug resistance gene-1 (MDR-1), estrogen receptor, and progesterone receptor. In-vitro drug resistance assay results were compared among platinum, taxane, cyclophosphamide, doxil, etoposide, gemcitabin, and topotecan (EDR Assay, Oncotech, Inc.). Results: There were 19 cases of USC and 185 cases of OSC identified. USC and OSC showed similar biomarker expressions except for the DNA index and expression of progesterone receptor. Biomarker expressions were: m-p53, 83.3% vs 68.7%, p = 0.28; DNA aneuploidity, 88.8% vs 80.8%, p = 0.53; DNA index, 1.7 (1.0–2.7) vs 1.5 (0.8–3.2), p = 0.044; S-phase fraction, 8.1% (3.1–19) vs 8.6% (0.3–19.2), p = 0.5; MDR-1, 33.3% vs 19.1%, p = 0.21; and estrogen receptor, 82.3% vs 82.9%, p = 1.0. Increased progesterone receptor expression was seen in USC compared to OSC (29.4% vs 9.2%, odds ratio 4.1, 95%CI 1.25–13.7, p = 0.028). In the in-vitro drug resistance assay, proportions of extreme drug resistance were similar in all tested drugs, including: cisplatin, 7.7% vs 7.2%, p = 0.5; carboplatin, 11.1% vs 9.5%, p = 0.3; paclitaxel 26.7% vs 23.5%, p = 1.0; doxil, 44.4% vs 33.9%, p = 0.69; and topotecan, 15.4% vs 18.5%, p = 1.0. Conclusions: Advanced uterine serous carcinoma was associated with increased expression of progesterone receptor compared to advanced ovarian serous carcinoma. The different expression potentially could be used to differentiate the two conditions and as a target in treatment therapies for uterine serous carcinoma. No significant financial relationships to disclose.
Abstract 13593: Spironolactone Suppresses the Inflammasome in Aldosterone Induced Renal Dysfunction via Blood Pressure Independent Pathway
Authors: Hiroyuki Kadoya, Minoru Satoh, Tamaki Sasaki, Naoki Kashihara
Journal: Circulation (2012)

Background: The inflammasome is a cytoplasmic multiprotein complex that activates caspase-1, leading to the processing and secretion of the pro-inflammatory cytokines, such as IL-1β,IL-18, and IL-3...
Clinical activity of the ALK inhibitor LDK378 in advanced, ALK-positive NSCLC.
Authors: Alice Tsang Shaw, Ranee Mehra, Dong-Wan Kim, Enriqueta Felip, Laura Quan Man Chow, D. Ross Camidge, Daniel Shao-Weng Tan, Johan F. Vansteenkiste, Sunil Sharma, Tommaso De Pas, Juergen Wolf, Ryohei Katayama, Yi-Yang Yvonne Lau, Meredith Goldwasser, Anthony Boral, Jeffrey A. Engelman
Journal: Journal of Clinical Oncology (2013)

8010 Background: Lung cancers harboring anaplastic lymphoma kinase (ALK) gene rearrangements are sensitive to the tyrosine kinase inhibitor (TKI) crizotinib (CRZ), but invariably develop resistance. LDK378 is a novel, more potent ALK TKI than CRZ, with significant antitumor activity in preclinical models. Methods: In this multicenter phase I study, 131 patients (pts) with advanced malignancies harboring a genetic alteration in ALK, including 123 with ALK-rearranged (ALK+) NSCLC (as determined by FISH), were enrolled. LDK378 was administered orally at doses of 50–750 mg once daily. All pts were assessed for PK, response to therapy, and adverse events (AEs). In &gt;20 pts with CRZ-resistant disease, tumor biopsy was performed before LDK378 treatment to identify CRZ resistance mutations. Results: As of November 8, 2012, 131 pts had been enrolled (38% male, median age 53 years), including 59 pts in the dose escalation phase, during which the MTD of 750 mg once daily was established, and 72 pts in an expanded cohort at the MTD. Among 88 evaluable NSCLC pts who received LDK378 at 400–750 mg daily, the overall response rate (ORR) was 70%, with 40 confirmed and 22 unconfirmed responses. In the subset of 64 CRZ-resistant pts, the ORR was 73%, with 31 confirmed and 16 unconfirmed responses. As of November 8, 2012 50% of pts with unconfirmed responses were ongoing. Responses were observed in pts with different CRZ resistance mutations as well as in pts without detectable mutation. Responses were also seen in pts with untreated CNS metastases. Among NSCLC pts with confirmed response, median duration of response (DOR) was 7.4 months (95% CI, 6.7 – NR), and 78% had a DOR of ≥6 months. In all 123 NSCLC pts, median PFS was 8.6 months (95% CI, 4.3 – 19.3). The most common AEs were nausea (72%), diarrhea (69%), vomiting (50%), and fatigue (31%). The most common Grade 3/4 AEs were ALT elevation (12%), diarrhea (7%), and AST elevation (6%). Conclusions: LDK378 induces durable responses in the majority of pts with advanced, ALK+ NSCLC, including CRZ-resistant pts with and without CRZ resistance mutations. These results suggest that more potent ALK inhibition by LDK378 represents a highly efficacious treatment strategy for ALK+ pts, particularly those who relapse on CRZ. Clinical trial information: NCT01283516.
Differential diagnosis of mesothelioma using a microRNA assay
Authors: H. Benjamin, D. Lebanony, L. Cohen, E. Elyakim, N. Rosenfeld, A. Chajut, D. Cohen
Journal: Journal of Clinical Oncology (2008)

22000 Background: MicroRNAs are a novel class of short non-coding RNAs that regulate gene expression at the translational level. MicroRNAs play a central role in developmental processes and are differentially expressed in various cancers. Malignant mesothelioma is an aggressive pleural neoplasm primarily induced by asbestos exposure. Mesothelioma in the lung pleura is difficult to differentiate from other tumors in the lung pleura, such as primary lung adenocarcinoma protruding into the pleural space and metastatic adenocarcinoma from other tissues. We investigated the microRNA expression profiles of lung mesothelioma and adenocarcinoma, and the potential of microRNAs as clinical biomarkers that distinguish between mesothelioma and adenocarcinoma. Methods: We profiled 7 mesothelioma formalin- fixed paraffin-embedded (FFPE) samples and 85 adenocarcinoma FFPE samples from multiple origins, including breast, colon, pancreas and others using the Rosetta Genomics microRNA microarray. Expression levels of over 700 microRNAs were measured on the microarray and compared between the two sample groups. Differentially expressed microRNAs were identified based on their expression on the microarray. We further developed a microRNA-based assay using qRT-PCR and tested it on 22 mesothelioma samples and 44 adenocarcinoma samples from the following origins: lung, colon, pancreas, bladder, kidney, ovary and breast. Results: Three microRNAs were significantly differentially expressed between mesothelioma and adenocarcinoma. One microRNA was over-expressed and two microRNAs were under- expressed in mesothelioma relative to adenocarcinoma. We were able to separate mesothelioma primary tumors from lung adenocarcinoma tumors with sensitivity and specificity exceeding 95%. Mesothelioma could be separated from the full set of adenocarcinoma samples with sensitivity and specificity above 90%. Conclusions: A small number of microRNAs is sufficient to discriminate mesothelioma from adenocarcinoma from multiple origins. Based on these results, we developed an assay for diagnosing mesothelioma, an important factor in treatment management. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Rosetta Genomics Rosetta Genomics
Effect of age on survival benefit of adjuvant chemotherapy in elderly stage III colon cancer patients: a population-based analysis
Authors: I. H. Zuckerman, A. J. Davidoff, E. Onukwugha, N. Pandya, J. F. Gardner, B. Seal, N. Obeidat, T. Rapp, C. D. Mullins, M. A. Choti
Journal: Journal of Clinical Oncology (2008)

4014 Background: Although sociodemographic disparities in colon cancer (CC) treatment (tx) have been documented, less attention has focused on age disparities. We estimated the modifying effect of age on the relationship between receipt of adjuvant chemotherapy (CH) and mortality among older patients with stage III CC. Methods: Medicare beneficiaries aged >66 years with stage III CC from 1997 to 2002 were identified in the Surveillance, Epidemiology and End Results cancer registries (SEER). Tx-related data were abstracted from linked Medicare claims. CH was defined as the receipt of 5-fluorouracil plus leucovorin, the recommended therapy during the study period, within 6 months of diagnosis. We used a continuous-time, interval-censored survival analysis with an interaction term to determine whether the effect of CH on hazard of CC-related death depends on age, controlling for sociodemographic and clinical factors, including proxy measures for performance status (PS). Results: 3,200 of the 6,711 stage III CC patients (48%) received CH. Increasing age was associated with a lower probability of receiving CH (78% of patients age 66–69 years versus 24% of patients age >80 years, p<0.01). Age significantly modified the survival benefit of CH (likelihood ratio test p<0.01). Compared to patients who did not receive CH, mortality was lower among patients who received CH across all ages, but the survival benefit of CH significantly decreased with increasing age [adjusted hazard ratios 0.37 (age 70 years) to 0.58 (90 years)]. Adjustment for sociodemographics, clinical factors and PS proxy measures attenuated but did not completely explain the effect modification of age on the relationship of tx and survival. Conclusion: Survival benefit of CH for CC was evident across all ages, however, most pronounced among ‘younger’ elderly. The modifying effect of age was not explained by sociodemographic or clinical factors. These findings have important clinical and policy implications for treatments among older cancer patients. Further study with newer, combination therapies and improved PS measures from claims will clarify the relationship between adjuvant treatment, age, and survival. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration sanofi-aventis sanofi-aventis Genentech™ BioOncology, sanofi-aventis sanofi-aventis
Nava Enhances Ventilatory Variability and Diaphragmatic Activity/tidal Volume Coupling
Authors: K. Moorhead, L. Piquilloud, Thomas Desaive, J. Roeseler, J. G. Chase, L. Vignaux, E. Bialais, D. Tassaux, P. Jolliet, Bernard Lambermont
Journal: Intensive Care Medicine (2010)
Novel methodology of response assessment in hepatocellular carcinoma (HCC) -Assessing response by change in tumor enhancement in distinction from conventional means
Authors: L. Wang, G. K. Abou-Alfa, F. Liu, L. B. Saltz, J. Kalaigian, B. Zhao, J. Colville, J. Nyoro, B. Schwartz, L. Schwartz
Journal: Journal of Clinical Oncology (2004)

3107 Background: The use of anti-angiogenesis agents in HCC may impact on tumor morphology in a manner that is different from what is seen with standard cytotoxic therapies. Tumor necrosis (TN), as evidenced by a decrease in Hounsfeld unit values on IV contrast-enhanced CT scans (IVCT), may better reflect response to therapy than conventional methods, such as undimensional and bidimensional measurements. We developed a semi-automated computerized technique for quantifying TN on IVCT. We then compared this method with standard determinations of response. Methods: Of the16 pts with HCC enrolled at MSKCC in a multicenter phase II trial of the signal transduction inhibitor BAY 43–9006, 11 were assessable for response and are included in this retrospective study. A dominant hepatic mass or masses were selected at baseline and followed serially every two cycles. Response assessment was calculated with both uni and bi dimensional tumor measurements. The degree of TN was calculated at each time point. All assessments were made by a radiologist blinded to the clinical data. Results: At baseline, mean TN was 9.8% (range 0.4 –33.5%), tumor diameter was 6.4 cm (2.5 –14.2) and cross-product was 28.9 cm2 (5.3 –91.3). At follow up mean TN was 27% (0.7 –75%), tumor diameter was 7.2 cm (1.7 –16.0) and cross-product was 36.9 cm2 (2.1 –162.5). There was poor correlation between TN, change in TN and the conventional uni and bi dimensional methods of response assessment. In particular, cases of tumors that increased in size by diameter and cross product, actually demonstrated apparent increase in TN. Conclusions: These results indicate that the conventional methods of response assessment may not accurately reflect the effect of antiangiogenic agents in HCC. Some patients were removed from study, possibly prematurely, based on the conventional criteria of response assessment, potentially undermining the antitumoral effects of BAY 43–9006. Necrosis may be estimated on IVCT and may serve as a marker of response. Larger scale trials are needed to evaluate the potential correlation between TN and oncologic outcome. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer Pharmaceuticals Bayer Pharmaceuticals Bayer