tbuckley/cabot-search huggingface dataset:
Two distinct molecular subgroups of lobular carcinoma in situ associated with invasive lobular carcinoma.
Authors: V. P. Andrade, M. Morrogh, R. Sakr, S. Muhsen, W. Paik, Q. Li-Xuan, G. Dilip, E. Brogi, M. Morrow, T. A. King
Journal: Journal of Clinical Oncology (2010)

e21077 Background: The role of lobular carcinoma in situ (LCIS) as a precursor of invasive lobular carcinoma (ILC) is unclear. In spite of morphological and immunohistochemical similarities, lobular carcinoma in situ (LCIS) has been considered as a risk marker but not a true precursor. Our aim was to investigate the transcriptome profile of LCIS associated with ILC. Methods: We prospectively collected and analyzed clinical presentation, pathological data and the transcriptome profile of 22 cases of LCIS with concurrent ILC using Affymetrix cDNA microarrays after laser capture microdissection of frozen samples. Statistical analysis was performed with R software (Bioconductor package) and results interpreted using the Ingenuity Pathway Analyses website. Alfa error was p < 0.001. Results: Unsupervised analysis of normalized gene expression data identified two stable clusters of LCIS. When analyzed by cluster assignment there were no differences in clinical parameters (family history, age of diagnosis, method of detection, tumor size, axillary status; p>0.05) or pathological findings (tumor size, multifocality, calcification, proximity LCIS-ILC, ER/PR/HER2 status; p > 0.05) between groups. 2,816 of 20,963 mapped probe sets were differentially expressed between clusters 1 (n = 12) and 2 (n = 10). 2015 probes were upregulated in Cluster 2 vs Cluster 1 representing pathways involved in G-Protein Coupled Receptor Signaling and cAMP mediated signaling. 801 probes were downregulated in cluster 2 vs Cluster 1 representing pathways involved in Protein Ubiquitination and EIF2 Signaling. Conclusions: Unsupervised analysis of gene expression data identified two stable clusters of LCIS in patients with ILC. Group assignment by gene expression could not be correlated with standard clinicopathologic variables. The relationship between the differential gene expression of the two LCIS clusters identified in this analysis and the risk of subsequent invasive cancer may provide insight into the role of LCIS as a precursor to invasive disease. No significant financial relationships to disclose.
Design and analysis methods for assessing drug synergy: Illustration using histone deacetylase (HDAC) inhibitor LBH589 combined with CDDP in mesothelioma (meso) cell lines
Authors: J. T. Symanowski, Y. Giraud, P. Dino, P. Atadja, N. Vogelzang, S. Sharma
Journal: Journal of Clinical Oncology (2007)

18108 Background: LBH589 (Novartis) is an investigational agent belonging to a cinnamic hydroxamic acid class of compounds that was shown to inhibit HDAC enzyme activity. LBH589 is in phase I clinical testing and combinations with various agents are being explored in the laboratory. Common experimental designs used for in-vitro cell viability experiments to assess drug synergy in cancer cell lines include complete factorial design (CFD) and fixed dose ratio design (FRD). While CFD provides data for the entire response surface, it can result in unfeasibly large experiments and complex synergy calculations, especially when 3 or more drugs are under evaluation. We investigated the FRD and alternative analysis methods to estimate and test synergy between two or more drugs. Methods: Experiments in meso cell lines were conducted using a colorimetric MTS assay. The FRD included 4 LBH concentrations (10 to 100 nM) and 4 CDDP concentrations (.5 to 5 μM), for each drug alone and in combination at a 50:1 CDDP:LBH ratio. Data were analyzed by applying the median effect equations (Chou, Adv Enzyme Regul, 1984) to the joint modeling approach by Straetemans, Biom. J., 2005. This method provides a straightforward estimate of the combination index (CI) and a statistical test for synergy (CI values less than 1.0 indicate synergy). Results: Results showed CI values significantly less than 1 for cell lines 2052 and MSTO for low to mid effect levels. Additive results were seen in cell line 2452. IC50’s were not greatly exceeded; therefore, CI’s for higher effect levels were not estimated. Conclusions: LBH appears to be synergistic with CDDP in some meso cell lines. The FRD is an efficient method to assess drug synergy and will be used for larger experiments to study 3 drug combinations involving LBH589. We propose a straightforward analysis method based on the median effect equations that jointly models the data, providing confidence intervals and a statistical test for synergy. [Table: see text] No significant financial relationships to disclose.
Outcome after liver transplantation compared with chemotherapy in colorectal cancer patients with nonresectable liver-only disease.
Authors: Svein Dueland, Tormod Kyrre Guren, Morten Hagness, Bengt Glimelius, Pål-Dag Line, Per Pfeiffer, Aksel Foss, Kjell Magne Tveit
Journal: Journal of Clinical Oncology (2014)

531 Background: Surgical treatment of colorectal liver metastases (CLM) is the only treatment option with curative potential; however, only about 10-20% of the patients are candidates for surgical resection. The majority of CLM patients has non-resectable disease, and receives palliative chemotherapy. These patients have poor prognosis with median OS of about 20-24 months after starting first-line chemotherapy and only about 10% survive five years. Methods: Individual data from patients with non-resectable liver only disease who had received liver transplantation (Ltx) (SECA-study, Hagness et al., Ann Surg. 2013) were compared to a similar group of patients with non-resectable liver only metastases included in the NORDIC VII study (first-line Flox chemotherapy ± Cetuximab, Tveit et al., J Clin Oncol. 2012). Twenty one patient included in the Ltx study were compared to 47 patients with liver only metastases included in the NORDIC VII study. All patients in the NORDIC VII study started first-line chemotherapy, whereas 57% of patients in the Ltx study had received second- or third-line chemotherapy at time of Ltx. Results: Median age of the Ltx group was 56 years (range 45-65 years) and 57 years (range 34-65 years) in the Nordic VII study. Median tumor size was 4.5cm (range 2.8-13.0cm) and 5.0cm (range 1.4-16.0cm) in the Ltx and Nordic VII groups, respectively. 5 year OS in the Ltx group was 60% compared to a 5 year OS of 9% in the NORDIC VII group. The 5 year OS of the 21 patients in the NORDIC VII data set with the longest OS was 19%. The patients in the Ltx study who had received only first-line chemotherapy at time of Ltx had a 5 year OS of 80%. Patients in the NORDIC VII study had an OS from end of second-line chemotherapy of 6-7 months. In comparison, patients with progressive disease on second-line/third-line chemotherapy at time of Ltx, had a median OS of 39 months and a 5 year OS of 30%. Conclusions: Patients with non-resectable CLMonly, has a dramatic improved OS after Ltx compared to chemotherapy. The difference could not be explained by patient selection. Selected patients with CRC obtain OS similar to Ltx patients transplanted for primary liver malignancies. Selected CRC patients should therefore be considered for Ltx. Clinical trial information: NCT01311453.
Trends in the use of implantable partial breast radiation therapy for early-stage breast cancer in the United States.
Authors: A. M. Abbott, E. B. Habermann, T. M. Tuttle
Journal: Journal of Clinical Oncology (2010)

631 Background: In 2002 the U.S. Food and Drug Administration approved an implantable balloon catheter device that delivers partial breast radiation directly to the tumor bed and surrounding area. Our aim was to determine the use of implantable partial breast radiation therapy (IPBRT) in the United States and to identify the patient and tumor factors associated with IPBRT use. Methods: Using the Surveillance, Epidemiology, and End Results database, we conducted a retrospective cohort analysis of patients that received external beam radiation therapy (EBRT) or IPBRT after breast conserving surgery for ductal carcinoma in situ, stage I or stage II breast cancer from 2000 through 2006. Patients were excluded if they had a previous history of cancer. We determined EBRT and IPBRT rates across time and various demographic and tumor factors using chi-square tests and Cochran-Armitage tests for trend for our unadjusted analyses. We used logistic regression for our multivariate analysis, allowing for adjustment for potential confounders. Results: We identified 109,512 patients who met inclusion criteria. Over the period of our study, the proportion of patients receiving IPBRT increased by > 1,000% (2000: 0.4%; 2006: 4.8%; p < 0.001). This trend remained significant when using logistic regression and adjusting for potential confounders (OR = 14.1, 95% CI 10.8 to 18.5). The increase in IPBRT use was statistically significant across all stage and age categories over 40 years (p < 0.001). The use of IPBRT was most notable in older women with a > 1,500% increase in IPBRT use in ages 70-79 during the study period (2000: 0.4%; 2006: 7.2%; p < 0.001). Women age 80 and older were much more likely to have IPBRT than women under 40 (OR = 6.7; 95% CI 4.2 to 10.9). We found significant variation in IPBRT use by region (OR for Atlanta vs Hawaii = 7.3; 95% CI 4.1 to 13.1) and by race (OR for Whites vs. African Americans = 1.3; 95% CI 1.1 to 1.5). Conclusions: IPBRT use has markedly increased since 2000, particularly in the elderly population. The rapid and widespread adoption of IPBRT is concerning, because multicenter randomized controlled trials have not yet demonstrated effectiveness of IPBRT as compared to EBRT. No significant financial relationships to disclose.
Reduced Intensity Allogeneic Tranplants Are Well Tolerated In Patients Over the Age of 60: Identification of Factors Predicting Overall Survival
Authors: Emmanouil Nikolousis, Sandeep Nagra, Janice Ward, Fiona L Dignan, Bronwen E. Shaw, Simon Littlewood, Jenny Byrne, Maria Helena Gilleece, Eleni Tholouli, Fiona Clark, Mark Cook, Premini Mahendra, Gordon Cook, John Yin, Nigel H. Russell, Charles Craddock
Journal: Blood (2010)
International randomized, double-blind, placebo-controlled, phase 3 study of linsitinib (OSI-906, L) in patients (pts) with locally advanced or metastatic adrenocortical carcinoma (ACC).
Authors: David I. Quinn, Eric Baudin, Michael J. Demeure, Martin Fassnacht, Gary D Hammer, Srinivasu Poondru, Tanya Fleege, Ramona Rorig, Alfredo Berruti
Journal: Journal of Clinical Oncology (2014)

4507 Background: ACC is an uncommon but frequently fatal cancer. For pts with metastatic or recurrent nonoperable ACC, there are very limited treatment options. Insulin-like growth factor 2 (IGF2) overexpression occurs in >90% of ACC, hence the IGF pathway is a potential therapeutic target. We assessed the activity of a potent IGF-1 receptor TKIlinsitinib in ACC. Methods: In a double-blind phase III trial accruing over 21 months, pts with measurable locally advanced or recurrent ACC following 1st- or 2nd-line treatment were randomly assigned to linsitinib 150mg BID orally or best supportive care & placebo (P), in a 2:1 ratio, respectively. The primary endpoint was overall survival (OS; power 80% for ñOS from 9 to 15.6 months); secondary endpoints: PFS, disease-control & objective response rate (blinded central review by RECIST 1.1), QoL & safety/toxicity (CTCAEv4.02). Results: 139 pts (median age 50yrs, 67% female, ECOG 0/1: 44.6, 51.1%) were enrolled with 90 assigned to linsitinib & 49 to P. Prior therapies included surgery: 90.6%; radiotherapy: 30.9%; mitotane: 100% & cytotoxic chemotherapy: 73.4%. The median time from diagnosis to trial initiation was 26.5 months. There was no difference between linsitinib and placebo in overall survival (median 323 days (10.8 months) vs 356d (11.8); p=0.77, HR 0.94); PFS (44 vs 46d; p=0.3, HR 0.83) & DCR (32.2 vs 34.7%). However, 3 pts on linsitinib experienced PR and 8 had prolonged PFS >100d (4 on drug >400d), whereas these events did not occur with placebo. Dose modification: L: 43.3, P 29.2%. Treatment-emerged adverse events (TEAEs) occurred in 97.8 vs 93.8%, grade 5: 5.6 vs 10.4%, gr 4: 10.1 vs 2.1%, gr 3: 45.6 vs 31.3% for L vs P respectively. Common TEAEs: fatigue (33.3 vs 22.9%), nausea (26.7 vs 31.3%), vomiting (20.0 vs 20.8%), abdominal pain (20.0 vs 20.8%), QTc prolonged (20 vs 6.3%) for L vs P. Conclusions: Targeting the IGF pathway with linsitinib did not improve overall or progression-free survival in adrenocortical cancer patients, although a small subgroup of patients seemed to benefit from this drug. Timely and efficient accrual to phase III trials in rare cancers is internationally feasible. Clinical trial information: NCT00924989.
P0859 : Genotype 1 and 4 cirrhotics: What is the SVR rate in community clinics using simeprevir and sofosbuvir?
Authors: A.M. Hefner, I. Suliman, R. Hassanein, C. Hill, R. Pozza, T.A. Couturier, P.A. Reshamwala, T.I. Hassanein
Journal: Journal of Hepatology (2015)
Molecular mechanisms of underlying synergistic effect of combinations of histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) with docetaxel and trastuzumab against human breast cancer cells
Authors: K. N. Bhalla, P. Bali, M. Pranpat, W. Fiskus, F. Guo, C. Sigua, R. Swaby
Journal: Journal of Clinical Oncology (2005)

560 Background: Suberoylanilide hydroxamic acid (SAHA) is a histone deacetylase (HDAC) inhibitor (HDI), which inhibits class I and II HDACs, induces hyperacetylation of the core nucleosomal histones, increases p21WAF1, and induces growth arrest and apoptosis of human breast cancer cells. In the present studies, we determined the effects of SAHA on Her-2, AKT and c-Raf (all hsp90 client proteins) levels, as well as on the cytotoxic effects of docetaxel and trastuzumab on human breast cancer BT-474 and SKBR-3 cells containing Her-2 amplification. Methods: The cells were treated with SAHA (1.0 to 5.0 μM) and/or trastuzumab (10 to 20 μg/ml) or docetaxel (5 to 20 nM) for 24 to 48 hours. Following this, % of apoptotic cells was determined or Western blot analyses of p21, p27, acetylated histones H3 and H4, AKT, c-Raf, and Her-2, as well as of Bcl-2, Bcl-xL, Bak, Bax, Bim, XIAP and survivin were performed. Attenuation of HDAC6 levels was achieved by siRNA to HDAC6 and estimated by immunoblot analysis. Synergistic interaction between drugs was evaluated by median dose-effect and isobologram analysis. Results: Treatment with SAHA upregulated p21 and p27 levels, increased the % of cells in G2M phase of the cell cycle, as well as induced apoptosis of the cells. This was associated with upregulation of pro-death Bak and Bim, as well as attenuation of the levels of pro-survival XIAP, survivin, Bcl-2, Bcl-xL and Her-2 proteins. SAHA treatment induced acetylation of hsp90. Attenuation of HDAC6 levels by siRNA to HDAC6 also caused acetylation of hsp90, indicating the mechanistic role of HDAC6 in SAHA-mediated acetylation of hsp90. This reduced the chaperone association of Her-2 with hsp90, which promoted the degradation of Her-2 by the proteasome. Co-treatment with SAHA and docetaxel or trastuzumab exerted synergistic apoptotic effects. Co-treatment with SAHA and trastuzumab caused greater attenuation of Her-2, p-AKT, as well as greater induction of p27 and Bim. Conclusions: These pre-clinical findings support the development of SAHA in combination with docetaxel and/or trastuzumab against Her-2 amplified breast cancer. No significant financial relationships to disclose.
AIO KRK0306, FIRE3 trial: CEA and CA19-9 influence outcome of patients with KRAS exon wild-type metastatic colorectal cancer (mCRC) receiving first-line therapy with FOLFIRI plus cetuximab or bevacizumab.
Authors: Marlies Michl, Ludwig Fischer von Weikersthal, Alexander Crispin, Thomas Decker, Alexander Kiani, Ursula Vehling-Kaiser, Salah-Eddin Al-Batran, Tobias Heintges, Christian A. Lerchenmuller, Christoph Kahl, Gernot Seipelt, Frank Kullmann, Martina Stauch, Werner Scheithauer, Joerg Hielscher, Michael Scholz, Sebastian Mueller, Dominik Paul Modest, Sebastian Stintzing, Volker Heinemann
Journal: Journal of Clinical Oncology (2014)

3592^ Background: To examine the impact of tumor marker response of carcinoembryonic antigen (CEA) and carbohydrate-antigen 19-9 (CA19-9) on overall survival (OS) and progression free survival (PFS) in patients with KRAS wild-type mCRC receiving first line chemotherapy in the FIRE3-trial comparing FOLFIRI + cetuximab (cet) vs. FOLFIRI + bevacizumab (bev). Methods: Baseline tumor marker levels, the time to nadir (in days; d) and the percentage of tumor marker decrease observed at the nadir compared with baseline were analyzed. The percentage was 0 for no change and negative if the tumor marker increased. Comparisons relied on Mann-Whitney U tests for independent groups and Wilcoxon signed-rank tests for dependent ones. ROC analysis resulted in a cut-off value using the maximum of sensitivity and specificity for best response. Results: For analysis of CEA, 472/592 pts (cet arm: 230 pts; bev arm: 242 pts) were eligible and for CA19-9, 439/592 pts (cet arm: 209 pts; bev arm: 230 pts). Baseline CEA (log) and CA19-9 (log) levels both significantly correlated with OS (p=0.008 and p<0.0001, respectively), but not with PFS (p=0.26 and p=0.15, respectively). For CEA and CA19-9 median time to nadir was comparable for both study arms, however in all patients CA19-9 nadir occurred earlier than CEA nadir (p<0.0001). Extent of CEA nadir significantly differed between treatment arms (cet arm: median: 83.0%; IQR: 40.9%-94.7%; bev arm: median: 72.3%; IQR: 26.3%-91.0%; p=0.003). A similiar trend was observed for CA19-9 nadir (cet arm: median: 64.3%; IQR: 13.4%-90.7%; bev arm: 47.0%; IQR: 1.7%-86.4%; p=0.085). In univariate analysis, a CEA decrease of more than 75% correlated with longer OS (33.2 vs. 22.9 mo; p<0.0001; HR 0.63; 95%Cl: 0.50–0.80) and PFS (11.7 vs. 9.0 mo; p=0.007; HR 0.67; 95%Cl: 0.62–0.93). Conclusions: In this analysis, we demonstrate that a greater decrease of CEA during therapy correlates with longer survival and the depth of CEA decrease is significantly greater in the cetuximab-arm compared to the bevacizumab-arm. Clinical trial information: NCT00433927.
Pilot trial of a patient-specific cutaneous electrostimulation device (MC5-A Calmare) for chemotherapy-induced peripheral neuropathy.
Authors: T. J. Smith, P. J. Coyne, P. Dodson, G. L. Parker, V. Ramakrishnan
Journal: Journal of Clinical Oncology (2010)

9029 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting and persistent consequence of numerous classes of antineoplastic agents affecting up to 30-40% of patients (pts). To date, there is no highly effective prevention or therapy. An evolving hypothesis for reducing CIPN pain involves direct nerve stimulation to reduce the pain impulse. Methods: We evaluated the effect of the MC5-A Calmare therapy device on CIPN. The device is designed to generate a patient-specific cutaneous electrostimulation to reduce the abnormal pain intensity. Gel electrodes like EKG pads are applied below and above the dermatomes of pain. Pts with stable CIPN of > 5 pain, off chemotherapy, from one center received 1-hour interventions daily over 10 working days. NCT00952848. Results: The 16 pts had a mean age of 58.6 years; 4 men, 14 women; duration of CIPN all > 3 months up to 8 years. The most common drugs related to their neuropathy were taxanes, platinums, and bortezimib. The primary goal of a 20% in numeric pain scores after day 10 was achieved in 15 of 16. The primary endpoint of CIPN pain score fell by 59% from day 1 to day 10. Adjusting for the correlations and the variability between patients and daily scores with a repeated measures analysis, there was an overall 64% reduction in pain. A daily treatment benefit was seen with a significant difference between the pre and post daily scores. Four patients had their CIPN reduced to 0. No toxicity was seen. Some responses have been durable without maintenance, and some patients had return of normal sensation and motor function. Conclusions: Patient-specific cutaneous electrostimulationwith theMC5-A Calmare device appears to dramatically reduce pain in refractory CIPN patients with no toxicity. Further studies are underway to define the mechanisms of action, duration of benefit, and optimal schedule. Before After P value Reduction in pain by 20% 0 15 of 16 (94%) <0.0001, Fischer's exact test CIPN pain score 5.81 ± 1.11 2.38 ± 1.82-59% <0.0001, paired t test Adjusted pain scores 4.9 ± 0.4 1.8 ± 0.4-64% < 0.0001, repeated measures analysis Daily reduction in pain scores 3.74 ± 0.38 2.72 ± 0.38-1.02, -27% < 0.001, repeated measures analysis No significant financial relationships to disclose.
Observation study on Asian patients taking imatinib mesylate in comparison to published data focusing on dosage and adverse events
Authors: K. W. Leong, S. A. Goh
Journal: Journal of Clinical Oncology (2005)

6727 Background: Studies done mainly in Western communities have clearly described the dose, response and side effects of imatinib mesylate. There is little published data on Asian/Oriental patients. We have observed differences in our patients. Thus, a retrospective study was done. Methods: Retrospectively data on all patients treated between January 2002 to November 2004 were analysed for treatment response, dosage and side effects. Results: Forty-one patients had chronic myeloid leukaemia. 12 patients were in chronic phase. 19 patients were in accelerated phase. 10 patients were in blast crisis. 3 patients had GIST. Thirty patients are ethnic Chinese, 13 Malays and 1 Indian. 6 of 10 assessable patients in chronic phase achieved a complete haematological response. 3 had a pancytopenic response. Of 4 patients tested for cytogenetic remission, there were 1 complete and 2 partial cytogenetic response. The mean dose was 415 mg daily. Of 19 patients with accelerated phase, 13 had complete and 5 pancytopenic response. Three patients had a complete cytogenetic response, 5 patients a partial response and 4 patients did not have any cytogenetic response out of 12 patients tested. Of note 1 patient who weight 39 kg is still having a severe pancytopenic response 20 months on imatinib 100 mg daily. All 10 patients with blast crisis did not achieve any significant response. Skin depigmentation was seen in 25 of 27 assessable patients. No patient developed vertiligo. Weight gain was seen in 20 patients, averaging 3 kilogram. Fluid retention was noted in 5 patients. Conclusions: The Asian/Oriental patients in chronic phase are able to tolerate over 400 mg of imatinib. Similar haematological and cytogenetic responses have been obtained as compared to published data. We describe generalised skin depigmentation in 24 of 26 patients assessed, in contrast to published series. The skin change is gradual and is generally noted after 2–3 months of imatinib and the fairness stablise about 6 to 12 months and the depigmentation/ fairness does not progress further. No patient has vertiligo. The weight increase only in the first 3–6 months and then stablises. No significant financial relationships to disclose.