tbuckley/cabot-search huggingface dataset:
Analyzing Repeated Measurements Using Mixed Models
Authors: Michelle A. Detry, Yan Ma
Journal: JAMA (2016)

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OP19 Differential expression of microRNAs during hepatic stellate cell activation and their role in the regulation of hepatic stellate cell proliferation and apoptosis
Authors: A J Fowell, T Sanchez-Elsner, R C Benyon, W M Rosenberg, J E Collins
Journal: Gut (2010)

Introduction  Activation and proliferation of myofibroblastic hepatic stellate cells (HSC) is a pivotal event in liver fibrogenesis. MicroRNAs (miRNAs) are implicated in the regulation of a large number of important cellular functions including cell proliferation, differentiation and apoptosis.  Aim  To characterise changes in miRNA expression during HSC activation and to investigate the effect of silencing candidate miRNAs on HSC proliferation and apoptosis.  Method  Expression of all known miRNAs was determined in quiescent (day 1) and culture-activated (day 10) rat HSC by microarray. Expression of selected, differentially regulated miRNAs was verified by real-time PCR at multiple time-points during culture-activation. Putative target genes of up- and down-regulated miRNA were organised into hierarchical categories based on their gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) classification. Activated HSC were transfected with chemically modified, single stranded nucleic acid miRNA inhibitors by electroporation. HSC proliferation and apoptosis were determined by [ 3 H]-thymidine incorporation and acridine orange staining, respectively.  Results  A total of 21 and 17 miRNA were up- or down-regulated >1.5-fold during HSC culture-activation. The level of expression of eight selected miRNAs identified by microarray was confirmed by real-time PCR, with up to 170-fold change in expression observed between day 1 and day 10 (Abstract OP19 Table 1). Multiple GO terms and KEGG pathways were functionally enriched amongst the targets of up- and down-regulated miRNAs. Inhibition of mir-143 in activated myofibroblastic HSC inhibited proliferation by 33.5% (p=0.001) and increased serum-deprivation induced apoptosis by 68.3% (p=0.027).  Conclusion  Activation of rat HSC was accompanied by marked up- and down-regulation of multiple miRNAs with potential to influence many cellular functions. Inhibition of mir-143 is pro-apoptotic and anti-proliferative in HSC, suggesting an important pro-fibrotic role for this miRNA in HSC and identifying a potential novel target for anti-fibrotic therapy in the liver.
Development and validation of a robust prognostic and predictive signature for colorectal cancer (CRC) patients
Authors: A. M. Glas, P. Roepman, R. Salazar, G. Capella, V. Moreno, J. Westerga, P. J. Kuppen, I. Simon, L. J. Van ’t Veer, R. Tollenaar
Journal: Journal of Clinical Oncology (2009)

4036 Background: Between 25 and 35% of stage II CRC patients will experience a recurrence of their disease and may benefit from adjuvant chemotherapy. Official guidelines give suggestions but no clear recommendation for best risk stratification. Here we describe the development a robust signature that predicts disease relapse and can assist in treatment decisions. Methods: Fresh frozen tumor tissues from 180 patients with stage I, II and III colorectal cancer undergoing surgery were analyzed using high density Agilent 44K oligonucleotide arrays. Median FU was 70.2 months; 85% of patients did not receive adjuvant chemotherapy. Unsupervised hierarchical clustering based on full-genome gene expression measurement indicated the existence of 3 main colon molecular subclasses. Survival analysis of the 3 classes showed that subtype C (n= 27) had a poor outcome and subtype A (n= 48) good outcome. Only the intermediate group B (n=104) was used to develop a signature by using a cross validation procedure to score all genes for their association with 5-yr distant metastasis free survival (DMFS) and subsequently applied to all samples (n=180). The obtained gene signature was further validated on an independent cohort of 178 stage II + III colon samples. Results: A set of 38 prognosis related gene probes showed robust DMFS association in over 50% of all iterations in the Training Set of 180 samples. The gene signature was validated on an independent cohort of 178 samples from stage II + III colon cancer patients. The profile classified 61% of the validation samples as low-risk and 39% as high-risk. The low- and high-risk samples showed a significant difference in DMFS with a HR of 3.19 (P= 8.5e-4). Five-year DMFS rates were 89% (95%CI 83–95) for low-risk and 62% (95%CI 50–77) for high-risk samples. Moreover, the profile showed a significant performance within stage II (P=0.0058) and III (P=0.036) only samples. The performance of the profile was significant for both untreated (P=0.0082) and treated patients (P=0.016) suggesting that its power is independent of treatment benefits. Conclusions: ColoPrint is able to predict the prognosis of stage II and III colon cancer patients and facilitates the identification of patients who would benefit from adjuvant chemotherapy. [Table: see text]
Pharmacodynamics of RAD001 measured by early FDG PET in patients with recurrent NSCLC
Authors: L. Nogova, T. Zander, S. H. Gross, S. Dimitrijevic, K. Schmidt, R. K. Thomas, M. Dietlein, G. Giaccone, O. S. Hoekstra, J. Wolf
Journal: Journal of Clinical Oncology (2008)

14616 Background: RAD001 (everolimus) is a novel inhibitor of mTOR currently investigated as an anticancer agent. RAD001- induced inhibition of mTOR showed a prominent impact on glucose homeostasis with the transcription factor HIF-1 as one of the primary mediators and the inhibition of FDG uptake demonstrated by FDG-PET imaging in preclinical models treated with RAD001. We postulated that the glucose metabolism measured by 18F-FDG-PET might serve as pharmacodynamic marker of RAD001 treatment in lung cancer patients. Methods: Patients with previously treated advanced non-small cell lung cancer (NSCLC) were treatedwith a 10 mg daily dose of RAD001 in an open label, multi-centre phase II study. A subgroup of 8 pts enrolled in two of the study centres was evaluated by serial 18F-FDG-PET scans. 18F-FDG-PET was performed on day 1 and day 8 of RAD001 treatment in all 8 patients. In addition, in 5 out of these 8 pts FDG-PET was performed on day 28 of treatment. Percentage change of the sum of the maximum standardized uptake values (sSUVmax) from baseline was calculated on days 8 and 28. In addition, the computed tomography (CT) scans was obtained at baseline and on day 28 as a standard assessment of response. Results: Reduction of sSUVmax on day 8 was observed in all patients ranging from −1.4% to −89.1% (median −19.3). On day 28, the reduction of sSUVmax was much less in 4 patients and we found an increase versus baseline in 1 patient (median −9.7). On day 28, according to the PET response criteria, one patient achieved a PR and two each had SD or PD. TTP ranged from 12 to 191 days. Conclusions: Although based on evaluation of a small cohort of patients, the results suggest that (I) inhibition of glucose metabolism is an early effect of RAD001 treatment in lung cancer patients and (II) this early pharmacodynamic effect can be assessed by 18F-FDG-PET. The results indicate that 18F-FDG-PET may represent a suitable tool for early pharmacodynamic evaluation of mTOR inhibitors such as RAD001 in patients with NSCLC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis Novartis
Use of tumor gene expression signatures and drug-induced changes to discriminate early response in human breast cancer
Authors: S. Lee, M. Watson, X. Xu, C. I. Wong, P. Iau, N. Sukri, S. E. Lim, B. Chuah, H. McLeod, B. C. Goh
Journal: Journal of Clinical Oncology (2007)

2524 Background: To elucidate the genomics of tumor responses to different classes of chemotherapy, we analyzed breast cancer gene expression before and after in vivo treatment with adriamycin or docetaxel. Methods: Tumor biopsies were obtained before and 3 weeks after one chemotherapy cycle and tumor RNA amplified and hybridized on the Affymetrix HG-U133+2 array containing 33,000 genes. Results: Pre- and post-treatment tumors from 46 chemonaive patients with unresectable breast cancers were studied, of which 24 and 22 respectively received adriamycin and docetaxel in the first cycle, and 14 in each group had early response sensitive tumors (=25% shrinkage after 1 cycle). Comparison of our baseline gene signatures with drug-specific panels generated in vitro (Nevins, Nat Med 2006,12:1294) revealed 12 and 2 common genes (p&lt;0.05) that predicted for adriamycin and docetaxel response respectively, with the 12 common adriamycin-response gene panel correctly predicting response in 76% of patients. Analysis of the relative change in tumor gene expression (ratio of post- and pre-treatment differential values to pre-treatment values) in our dataset revealed adriamycin to up- or down- regulate 209 transcripts (p&lt;0.005) including genes that encode for nuclear protein, cell cycle regulation, aminopeptidases, and Ankyrin repeats, while docetaxel up- or down-regulated 469 transcripts (p&lt;0.005) including genes that encode for extracellular matrix, transmembrane signaling, endocytosis, EGF-like calcium binding, tubulin and actin binding functions. Adriamycin and docetaxel concordantly up- or down-regulated 269 transcripts (p&lt;0.01) that may be common response markers, including genes involved in cell cycle proliferation, mitosis, DNA damage, and carboxypeptidase activities. Adriamycin and docetaxel differentially induced 92 transcripts (p&lt;0.01) that distinguished between the two drugs with 96% accuracy. 27 adriamycin- and 100 docetaxel-induced transcripts (p&lt;0.005) predicted response to each drug with &gt;90% accuracy. Conclusions: Drug-specific genomic changes can predict clinical response, and may yield insights to targets to overcome drug resistance. No significant financial relationships to disclose.
A novel, selective, proliferation based procedure to eliminate alloreactive T-cells induces mixed chimerism and reduces GvHD in sublethally irradiated mice receiving allogeneic bone marrow transplantation
Authors: A. Pachnio, S. Dietrich, W. Klapper, C. Schulte, M. Kneba, C. Beck
Journal: Journal of Clinical Oncology (2004)

2561 Background: Allogeneic bone marrow transplantation is an established procedure for a variety of diseases of the hematopoetic system, including leukemia, but the major complication, graft-versus-host-disease, has a profound impact on quality of life and survival. GvHD is induced by alloreactive T-cells and different strategies to reduce GvHD by manipulating the graft are under investigation. We describe here a novel approach to eliminate alloreactive T-cells by selecting for non-proliferating T-cells after in vitro stimulation with recipient stimulator cells. Methods: Murine splenic T-cells stimulated in vitro are separated from resting cells by using CFSE-dye dilution method and FACS-sorting. Proliferating, non-proliferating or unseparated T-cells were transplanted with T-cell depleted bone-marrow in a fully allogeneic transplantation model. Results: Mice receiving proliferating T-cells rapidly develop GvHD, while those receiving resting T-cells show significantly reduced signs of GvHD. FACS analysis on day 7 reveals complete lymphatic chimerism in the spleens after receiving alloreactive cells. Mice receiving resting cells show reconstitution of donor and recipient lymphopoiesis in spleen and bone-marrow. Histology of livers reveal leucocyte infiltration in mice developing GvHD while no infiltrates are seen in those mice receiving resting cells. Conclusion: After allogeneic in vitro stimulation, resting T-cells have the potential to repopulate sublethally irradiated hosts and are tolerant towards host lymphopoiesis. Therefore, separation of alloreactive T-cells might be an efficient method to reduce the severity and outcome of GvHD after allogeneic mismatch-transplantation and may allow the development of tolerance towards the host. This work is supported by the German José Carreras Leukemia fund (DJCLS), Munich No significant financial relationships to disclose.
Improved Overall Survival with Gemtuzumab Ozogamicin (GO) Compared with Best Supportive Care (BSC) in Elderly Patients with Untreated Acute Myeloid Leukemia (AML) Not Considered Fit for Intensive Chemotherapy: Final Results from the Randomized Phase III Study (AML-19) of the EORTC and Gimema Leukemia Groups
Authors: Sergio Amadori, Stefan Suciu, Dominik Selleslag, Elena Rossetti, Gianluca Gaidano, Maurizio Musso, Luciana Annino, Adriano Venditti, Domenico Magro, Paolo de Fabritiis, Petra Muus, Giuliana Alimena, Marco Mancini, Anne Hagemeijer, Francesca Cotugno, Marco Vignetti, Paola Fazi, Liv Meert, Safaa M Ramadan, Roelof Willemze, Theo de Witte, Frederic Baron
Journal: Blood (2014)
Inhibition of Spleen Cell Cytotoxic Capacity Toward Tumor by Elevated Prostaglandin E&lt;sub&gt;2&lt;/sub&gt; Levels in Mice Bearing Lewis Lung Carcinoma&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: M R Young, C S Hoover
Journal: JNCI Journal of the National Cancer Institute (1986)

The capacity to generate cytotoxic cells toward Lewis lung carcinoma (LLC) in mixed cultures of stimulator LLC and responder spleen cells of LLC-bearing C57BL/6 mice was monitored during the course of tumor growth. The cytotoxic response of mice bearing tumors that were not yet palpable was enhanced. However, as palpable tumors developed and tumor growth progressed, their cytotoxic capacity became suppressed. Concurrent with this decline in cytotoxic capacity, there was an increase in systemic immunoreactive prostaglandin E2 (PGE2) concentrations in tumor-bearing mice. Administration of indomethacin, a prostaglandin synthesis inhibitor, to LLC-bearing mice prevented the rise in PGE2 concentrations and the suppression in cytotoxic capacity toward LLC. A relationship between the elevated immunoreactive PGE2 levels, suppression in cytotoxic capacity, and progressive tumor growth was indicated when administration of indomethacin to tumor-bearing mice also reduced the rate of tumor development.
Radioimmunoscintigraphy for post-prostatectomy radiotherapy: Analysis of toxicity and biochemical control
Authors: A. B. Jani, M. J. Blend, R. Hamilton, C. Brendler, C. Pelizzari, L. Krauz, B. Sapra, S. Vijayakumar, A. Awan, R. R. Weichselbaum
Journal: Journal of Clinical Oncology (2004)

4660 Background: To evaluate the role of radioimmunoscintigraphy (RIS) directed against prostate specific membrane antigen (PSMA) [ProstaScint] in influencing post-radical retropubic prostatectomy (RRP) radiotherapy (RT) toxicity and biochemical failure-free survival (BFFS). Methods: The records of 107 consecutive post-RRP patients who underwent RT were reviewed. The group for whom no RIS scan was obtained (Group A, n=54, mean follow-up (FU) 26.7 months) was identified, as was the group for whom RIS was obtained (Group B, n=53, mean FU 21.3 months). Group B was comprised of those who had a RIS/computed tomography (CT) correlation to aid in treatment planning (Subgroup B1, n=40) and those who did not (Subgroup B2, n=13). The acute and late gastrointestinal (GI) and genitourinary (GU) toxicity were reviewed. BFFS curves were constructed, using two successive PSA rises after a nadir to a value > 0.2 ng/mL as the definition of failure. Results: No significant differences in late toxicity were observed between any Group/Subgroup. However, acute GI toxicity was higher for Group B vs A (p=0.026), and acute GU toxicity was higher in Subgroup B2 vs B1 (p=0.050). Most toxicity was Grade 1 or Grade 2; only 1 case of Grade 3 toxicity and no cases of Grade 4 or Grade 5 toxicity were seen. 3-year BFFS was higher for Group B vs A (80.7 vs 75.5%) and for Subgroup B1 vs Subgroup B2 (84.5 vs 71.6%). On multivariate analysis of patient (age, race), surgical (stage, grade, margin status, extracapsular extension, seminal vesicle invasion, post-RRP PSA nadir, post-RRP PSA max, and RRP to RT interval), and treatment (hormone therapy, RT dose, RT technique, RIS scan, and RIS/CT correlation) factors on BFFS, only RIS/CT correlation (p=0.042) reached significance. Conclusions: A BFFS advantage was observed in patients for whom RIS was obtained; however, this advantage only reached significance for the population in which RIS/CT correlation was used to guide RT target definition. The improved PSA control using RIS was achieved with a small increase in acute toxicity, but with no observed change in late toxicity. These findings can serve as the basis for prospective studies in this area. No significant financial relationships to disclose.
High specificity and sensitivity of NRAS Q61R immunohistochemistry (IHC) in melanomas
Authors: Pierre-Alexandre Just, Christelle Pouliquen, Anne Audebourg, Sara Laurent-Roussel, Agnès Carlotti, Nicolas Dupin, Marie-Cécile Vacher-Lavenu, Michel Vidaud, Benoît Terris, Eric Pasmant
Journal: Journal of the American Academy of Dermatology (2016)
Improved outcomes in patients with lymph node-only stage IV disease in clear cell sarcoma: Results from a large single-institution experience and SEER database analysis
Authors: D. G. Blazer III, A. J. Lazar, Y. Xing, R. L. Askew, D. C. Lev, B. W. Feig, P. W. Pisters, R. E. Pollock, K. K. Hunt, J. N. Cormier
Journal: Journal of Clinical Oncology (2008)

10571 Background: Clear cell sarcoma, or malignant melanoma of soft parts, is a rare soft tissue tumor unusual among mesenchymal malignancies for its propensity to metastasize to regional lymph node basins. Current AJCC staging for soft tissue sarcoma classifies nodal disease (N1) as stage IV disease. We sought to determine whether patients with lymph node-only disease (N1M0) had better outcomes than patients with distant metastases (M1) by looking at outcomes from both a single institution and population-based data. Methods: Clinical and pathologic factors were retrospectively examined utilizing a prospectively maintained database on patients treated at the University of Texas M.D. Anderson Cancer Center (MDACC) between 1980 and 2007. Histology on all patients was independently reviewed by a single MDACC pathologist with molecular confirmation of the characteristic EWSR1-ATF1 fusion transcript or EWSR1 rearrangement when possible. We also performed a SEER database analysis on patients diagnosed with clear cell sarcoma (1988–2007). Overall and stage-specific disease-specific survival (DSS) were estimated using the methods of Kaplan and Meier. Results: Fifty-three patients with clear cell sarcoma were identified from the MDACC database. Median age at diagnosis was 41 years and 60% were female. Our SEER analysis yielded 130 patients with a median age of diagnosis of 40 years and 54% female. Median follow-up for the MDACC cohort was 7.4 years and median follow-up for SEER was 6 years. MDACC 5-year DSS was 67.9% and, in the SEER analysis, 5-year DSS was 61.9%. The 5 year DSS of N1 patients from MDACC was 74%, while M1 was 14% (p=0.0142). The 5-year DSS of N1 patients from SEER was 52%, while M1 was 0% (p=0.0142). Conclusions: Overall DSS in both our single-institution cohort and in SEER is higher than in previously published series. There is a significant difference in DSS between N1M0 and M1 patients for both MDACC and SEER cohorts. These data underscore the importance of lymph node assessment in these patients and suggest that future staging of clear cell sarcoma should differentiate these groups. No significant financial relationships to disclose.
Activity and tolerability of cisplatin (CDDP) and fotemustine (FTM) in non-small cell lung cancer (NSCLC) patients (PTS) with brain metastases (BM): A multicentric phase II study of the Gruppo Oncologico dell’Italia Meridionale (GOIM)
Authors: D. Galetta, V. Gebbia, F. Ferraù, F. Carrozza, S. Cigolari, P. Russo, F. Calista, V. Adamo, G. Colucci
Journal: Journal of Clinical Oncology (2009)

e19085 Background: More than 50% of BM occurs in advanced NSCLC. In most cases BM are multiple and their standard therapy is whole-brain radiation therapy (WBRT) since the role of systemic therapies for is still a matter for investigation due to concerns on the drugs ability cross the blood brain barrier (BBB). FTM is a nitrosourea able to cross BBB and CDDP remains the backbone for medical treatment of NSCLC. Methods: Pts with advanced NSCLC, ECOG PS 0–1 and multiple BM were treated with 2 cycles of FTM 80 mg/m 2 d1,8 and CDDP 80 mg/m 2 d1 q3 wks followed by WBRT 30 Gy/3 Gy daily; radiological response using Recist Criteria were analysed before WBRT to assess the role of FTM/CDDP both for cranial and extracranial disease. Pts with disease control (DC) received further CT up to 6 cycles. Barthel ADL Index was administered every 2 cycles. The trial has a two step design according to Simon: 29 pts were required to verify if FTM/CDDP was able to achieve a &gt;25% response rate both for cranial and extracranial disease (step 1), and if this was true further pts had to be enrolled up to 81 pts (step 2). Results: At first evaluation 4/29 pts were excluded from the study (2 not treated/ 1 never included/1 not eligible). Therefore patient's demographics were: median age 61 (range 48–73), M/F 16/9, adeno 11, squamous 5, large cell 2, nos 7; PS 0/1: 1/14, Barthel Index median value at the starting point 20 (13–20). Overall 3/25 (12%) partial responses were observed with 9 (36%) stable diseases and 13 (52%) progressions of disease. These data did not satisfy the pre-planned hypothesis and the study was stopped at the first step. Before WBRT after the first 2 CT cycles 13/25 pts (48%) had a systemic DC in contrast with 15/25 pts (60%) with brain tumour DC. WBRT seemed not useful to further modify the results of CT. CT was relatively well tolerated with asthenia as the most relevant specific toxicity while the hematological toxicity was mild. Conclusions: CDDP and FTM combined with WBRT could represent a therapeutic option for patients with NSCLC even if the global therapeutic index was not satisfactory. Further studies evaluating the combination of systemic treatments with WBRT are warranted. No significant financial relationships to disclose.