tbuckley/cabot-search huggingface dataset:
Additional binding mechanism of palonosetron to the 5-HT<sub>3</sub> receptor versus first generation 5-HT<sub>3</sub> receptor antagonists
Authors: C. Rojas, M. Stathis, J. Alt, E. Rubenstein, S. Cantoreggi, S. Sebastiani, B. Slusher
Journal: Journal of Clinical Oncology (2007)

19583 Background: Palonosetron has a higher binding affinity and longer plasma half-life than first generation 5-HT 3 receptor antagonists. Clinical trials have demonstrated that a single intravenous dose of palonosetron 0.25 mg provides better protection from chemotherapy-induced nausea and vomiting than other 5-HT 3 receptor antagonists throughout the 5-day post-chemotherapy period. The purpose of this work is to determine differences in the molecular interactions of the antagonists with the receptor that could help explain the clinical efficacy differences. Methods: Molecular ligand-receptor relationships for commonly used 5-HT 3 receptor antagonists were investigated. In particular, competitive vs. potential allosteric interactions between ondansetron, granisetron and palonosetron and the 5-HT 3 receptor were examined. Binding experiments were carried out using each unlabeled antagonist in competition with [ 3 H]-antagonist. Concentrations of [ 3 H]-antagonists used in these experiments included the equilibrium dissociation constant (K i ) and several-fold K i values in an effort to represent the probable concentrations of each antagonist at the receptor site in vivo. The inhibitory concentration of unlabeled antagonist needed to observe half maximal binding (IC 50 ) as a function of [ 3 H]-antagonist concentration was plotted for comparisons between ondansetron, granisetron and palonosetron. Results: A plot of the concentration of unlabeled antagonist needed to observe IC 50 as a function of [ 3 H]- antagonist concentration was linear when ondansetron and granisetron were in competition. On the other hand, when palonosetron was in competition with either granisetron or ondansetron the plot was curvilinear in each case. Conclusions: These results indicate that palonosetron exhibits both competitive and allosteric interactions with the 5-HT 3 receptor, in contrast to ondansetron and granisetron which display strictly competitive antagonism. As allosteric interactions may induce changes in the receptor conformation, we can speculate that palonosetron's dual action on the 5-HT 3 -receptor could induce amplification of its inhibitory effect at the primary receptor binding site. No significant financial relationships to disclose.
Imatinib mesylate in chronic myeloid leukemia (CML): A single institution experience of 174 patients
Authors: C. D. Deshmukh, T. Saikia, A. V. Bakshi, P. M. Parikh
Journal: Journal of Clinical Oncology (2004)

6710 Background: Imatinib mesylate is a novel tyrosine kinase inhibitor. It has been found to be effective in CML and c-kit positive tumors. Methods: We conducted a prospective non-randomized single arm study of imatinib mesylate monotherapy in CML. 174 patients (122 males, 52 females) with Philadelphia positive CML (Chronic phase- 97, Accelerated phase- 47and Blast crisis-30) from May 2001 to September 2003 received imatinib mesylate as monotherapy in recommended doses. Results: Thrombocytopenia, neutropenia and dermatitis were dose-limiting toxicities. 121 patients (69.5%) had lightening of skin color. Nine patients developed photosensitivity, 1 had phototoxicity. Imatinib may have interaction with the endocrine system. Edema, weight gain improvement are known estrogenic actions. Some patients with generalized lightening of skin had hyperpigmentation over the malar area, similar to chloasma of pregnancy. Thirty-five patients had dermatitis of which 31 were males and 4 females (88.6% Vs 11.4%, p=0.007). Conclusions: Imatinib mesylate is effective in all phases of chronic myeloid leukemia. The endocrine and dermatological aspects mandate further studies. No significant financial relationships to disclose.
A phase II trial of pemetrexed (P) in patients (pts) with performance status (PS) 2 and 3 as first- and second-line treatment for advanced non-small cell lung cancer (NSCLC)
Authors: R. Zinner, F. V. Fossella, M. S. Kies, R. S. Herbst, C. Lu, F. M. Johnson, S. V. Bhat, J. S. Price, C. Cleeland, X. Wang
Journal: Journal of Clinical Oncology (2007)

18149 P (Alimta) is approved as second-line therapy in pts with advanced NSCLC. In a phase III trial comparing P with docetaxel (D), median survival was 8.3 mos (P) vs 7.9 mos (D); P had a more favorable safety profile than D (Hanna, 2004). There are few data on pts with PS 3, and ASCO 2003 guidelines recommend that chemotherapy be reserved for pts with PS 0, 1 and possibly 2. Since P is well tolerated, PS3 pts may tolerate and benefit from it. In this trial, we treated 20 pts with stage IIIb/IV NSCLC and PS 2–3 who were chemo-naive or had received 1 prior regimen. Pts received P 500 mg/m 2 IV D1 Q 3 wks. All pts received folic acid, vitamin B12 and dexamethasone prophylaxis. Serial blood samples were obtained to monitor inflammatory cytokines, and symptoms were monitored using the validated MDASI instrument. All pts were assessable for toxicity-symptoms, and 17 pts were evaluable for response (assessed after first cycle). Pt characteristics: 8 pts were PS 3 (4/8 first line) and 12 pts were PS 2 (6/12 first line). Median age was 69 for PS3 and 68 for PS2. 5/8 PS3 pts and 6/12 PS2 pts were men. 2/8 PS3 pts and 4/12 PS2 pts had stage IIIb. 4/8 PS3 pts and 6/12 PS2 pts were chemo-naive. Grade 3–4 toxicities for PS3/PS2 cohorts were: neutropenia 0/1 pt, anemia 1/2, fatigue 2/0, pneumonia 1/1, hypotension 1/1, neutropenic fever 0/1, atrial fibrillation 1/1. Response rates (RR) in PS3 pts were minor response (MR) 1/8, stable disease (SD) 5/8, progressive disease (PD) 2/8; RR in PS2 pts were partial response (PR) 1/12, MR 2/12, SD 3/12, PD 3/12, inevaluable 3/12. RR by line of therapy: first-line 6/10 SD, 2/10 PD, 2/10 inevaluable, and second-line, 1/10 PR, 2/10 MR, 3/10 SD, 3/10 PD, and 1/10 inevaluable. Reasons for PS3 pts coming off study were progression (4/8), constitutional toxicity (3/8), fatal pulmonary emboli (1/8); PS2 pts came off study due to progression (5/12), constitutional toxicity (2/12), and pneumonia (1/12). 4/12 PS2 pts are still on study. These preliminary data suggest that single-agent P is well-tolerated and has a promising RR in poor PS pts. Total planned accrual is 30 PS3 and 45 PS2 pts. Survival, symptom, cytokine data will be presented. [Table: see text]
MicroRNAs as powerful diagnostic tools for the differential diagnosis of lung tumors
Authors: E. Meiri, Y. Spector, L. Cohen, S. Rosenwald, Z. Bentwich, M. Perelman, R. Aharonov, I. Barshack
Journal: Journal of Clinical Oncology (2008)

11112 Background: Lung cancer is a heterogeneous disease with many histological subtypes, further complicated by the frequent occurrence of lung metastases from various tumor origins. Therefore, determining the correct diagnosis of any lung tumor often poses a difficult diagnostic challenge that may have very significant therapeutic implications. MicroRNAs are short non-coding RNAs that regulate gene expression, and are strongly associated with cancer and development. In the present study we have used microRNAs for differentiating between different primary lung tumors and metastases to the lung. Methods: We used our protocols for extracting RNA from formalin-fixed, paraffin-embedded (FFPE) and fresh/frozen samples, and profiled the RNA on proprietary microRNA microarray. We profiled hundreds of samples from different histological subtypes of lung cancer including small cell carcinoma, different neuroendocrine lung cancers, subtypes of non small cell lung cancer (NSCLC), and metastases to the lung. Expression levels of more than 700 microRNAs were measured and compared between the sample groups. Emerging differences in expression are validated by specific microRNA-based assays using a highly specific qRT-PCR platform we developed. Results: We found that a surprisingly small number of microRNAs can be used as biomarkers for differential diagnosis of various types of lung tumors: 1) a panel of four microRNAs can distinguish between primary lung tumors and metastases to the lung. 2) One microRNA is able to distinguish between squamous cell carcinoma and other NSCLC. 3) A combination of two microRNAs is sufficient to distinguish between carcinoid and other neuroendocrine tumors. 4) A set of two microRNAs distinguishes between neuroendocrine tumors and small cell lung cancer. Conclusions: Combinations of small numbers of microRNAs can successfully answer specific differential diagnosis in lung tumors, and provide a basis for the development of simple and reliable assays in clinical oncology. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Rosetta Genomics Rosetta Genomics
Assessment of HER2 status from an epidemiology study in tumor tissue samples of gastric and gastro-esophageal junction cancer: Results from the french cohort of the HER-EAGLE study.
Authors: Genevieve Monges, Benoit Terris, Marie-Pierre Chenard, Frederique Penault-Llorca, Sophie Beauclair, Frederic Bibeau, Jean-François Emile, Alain Volant, Laurent Doucet
Journal: Journal of Clinical Oncology (2013)

26 Background: HER2 is an important prognostic and also a predictive biomarker for trastuzumab response in gastric cancer. Therefore, HER2 status should be tested in all gastro-esophageal junction (GEJ) and gastric cancer (GC) patients. ToGA phase III study showed a benefit in overall survival of trastuzumab added to standard chemotherapy in patients with HER2-positive advanced GEJ/GC. The objective of the HER-EAGLE study was to assess the incidence of HER2 positivity in GEJ/GC cancer. Methods: HER-EAGLE was an international epidemiological, non-interventional study assessing HER2 status by IHC/ISH in tumor samples from any stage in patients with GEJ/GC. Samples were obtained by excision or core biopsy and routinely analyzed via validated Ventana or Dako methods and scoring criteria used in ToGA: HER2-positive if IHC 3+ or IHC 2+ (FISH/SISH confirmed; HER2/CEP17 ratio ≥ 2.0); HER2-negative if IHC 0 or IHC 1+ or IHC 2+ if FISH/SISH negative ratio &lt; 2.0. Overall and subgroup estimates calculated with 95% CI. Data from the French cohort are presented. Results: The HER-EAGLE French cohort included 267 patients (68.6% males) from 7 centers (May 2007 to March 2012), with 150 biopsies (56.2%) and 117 excisions (43.8%). Tumor locations were 65.9% stomach and 34.1% GEJ, and adenocarcinoma types were according to Lauren classification: 170 intestinal (63.7%), 72 diffused (27%), 22 mixed (8.2%) and 3 not available (1.1%). HER2 status was: 36 cases IHC 3+ (13.5%), 51 IHC 2+ (19.1%) whereof 18 ISH positive (35.3%), 35 IHC 1+ (13.1%) and 145 IHC 0 (54.3%). Overall HER2 positivity (IHC 3+ or IHC 2+/ISH+) was 20.2%. Heterogeneity for HER2 staining was observed in 81 samples (30.3%). No statistical difference was found according to cancer stage. HER2 positivity was higher in GEJ (31.9%) than in GC (14.2%), p&lt;0,001, and higher in intestinal (28.2%) compared to diffused adenocarcinomas (5.6%), p&lt;0,001. Conclusions: HER-EAGLE French cohort results confirmed the feasibility of HER2 testing in GEJ/GC in routine practice. The incidence of HER2 overexpression was similar to the literature review, and it was higher in GEJ and intestinal adenocarcinomas type.
Osteonecrosis of the jaw associated with intravenous bisphosphonate therapy—A single institution experience
Authors: E. M. Wallace, K. I. Quintyne, B. M. Cantwell, P. M. Calvert, G. D. Leonard
Journal: Journal of Clinical Oncology (2006)

18553 Background: Osteonecrosis of the jaw (ONJ) is a debilitating disease that has been associated with cancer therapy. Recently a link between ONJ and chronic intravenous (IV) bisphosphonates has been suggested. We assessed the incidence of ONJ and its risk factors in patients treated with IV bishosphonates at our institution. Methods: All patients with a cancer diagnosis treated at our institution with at least four cycles of either IV Zoledronic Acid, Pamidronate, or a combination of both, from 2000–2005 were evaluated using outpatient records. Patients with ONJ were identified and their characteristics were compared to all patients receiving bisphosphonate therapy. Results: One hundred and twenty-one patients were evaluated, 36 Male and 85 Female. Median age- 62 (Range 34–85). Seventy-six had metastatic Breast cancer, 25 Prostate, 7 Lung, 3 Colorectal, 3 Renal, 2 unknown primary, 1 each of Penile, Bladder, Seminoma, Lymphoma and Melanoma. Forty patients received Pamidronate infusions alone, 51 Zoledronic Acid alone and 30 a combination of the two. The median number of Pamidronate infusions was 8 (Range 4–10), Zoledronic infusions 10.7 (Range 4–32), and a combination of pamidronate and zoledronic acid was 12 (Range 5–66). Three patients developed ONJ. All 3 patients were female, had a median age of 62 (range 52–74) and had metastatic breast cancer. The median number of bisphosphonate infusions prior to the development of ONJ was 35 (Range 18–47). All patients had chest wall radiotherapy and 1 had chemotherapy and steroids. No patients had dental procedures or prolonged antibacterial therapy. Conclusions: ONJ is a complication associated with IV Bisphosphonate therapy. Our study suggests that female sex, zoledronic acid, and prolonged administration of bisphosphonates, may confer an increased risk for the development of ONJ. Further prospective studies with adequate power are needed to clarify what patients are most at risk for developing ONJ and what measures are needed to prevent its occurrence. No significant financial relationships to disclose.
High-dose chemotherapy and autologous hematopoietic stem cell transplant for women with breast cancer and 10 or more involved axillary lymph nodes: Long-term follow-up
Authors: A. Espinoza, L. E. Damon, J. L. Wolf, H. S. Rugo, E. O. Gold, C. A. Ries, C. A. Linker
Journal: Journal of Clinical Oncology (2008)

11519 Background: High-dose chemotherapy (HDCT) and autologous hematopoietic stem cell transplant (ASCT) has been a controversial treatment strategy for patients with high-risk primary breast cancer. Despite multiple prospective phase II and III trials, long-term outcomes are lacking. Methods: We used a mitoxantrone-based HDCT regimen designed to minimize the pulmonary toxicity seen with carmustine-based regimens. One hundred forty-one women with stage II/IIIA breast cancer and 10 or more involved axillary lymph nodes were treated with CTM (cyclophosphamide (6g/m2), thiotepa (600 mg/m2), and mitoxantrone (24–60 mg/m2)), followed by ASCT. Patients then received 45–50 Gy radiation to the chest wall, axillary lymph nodes, and supraclavicular lymph nodes. Patients with hormone-receptor positive tumors were treated with tamoxifen for a planned five-year course. Results: The median follow-up of survivors is 9.2 years. The median overall survival was 7.6 years, and the median event-free survival was 6.9 years. The average number of involved lymph nodes was 15.7 (range 10–40). Treatment related mortality was 1%. Three patients (2%) developed secondary malignancies (cervical carcinoma, peritoneal carcinomatosis, and acute myeloid leukemia). The rate of pulmonary toxicity was low, with two patients (1%) developing diffuse alveolar hemorrhage. There were no episodes of late pulmonary toxicity. Severe cardiac toxicity was seen in 1% of patients, and moderate cardiac toxicity (defined as a decrease in left ventricle ejection fraction by 15% or more) occurred in 9% of patients. Other grade three or four extramedullary toxicities were uncommon: 3% hepatic, 2% renal, 9% stomatitis. Conclusions: In women with stage II/IIIA breast cancer and 10 or more involved axillary lymph nodes, CTM with ASCT results in a median survival approaching 8 years. The treatment-related mortality, rate of development of secondary malignancies, and incidence of pulmonary toxicity is low. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Amgen
Use of two-year disease-free survival (DFS) as a primary endpoint in stage III adjuvant colon cancer trials with fluoropyrimidines with or without oxaliplatin or irinotecan: New data from 12,676 patients from MOSAIC, X-ACT, PETACC-3, NSAPB C-06 and C-07, and C89803
Authors: D. J. Sargent, G. Yothers, E. Van Cutsem, J. Cassidy, L. Saltz, N. Wolmark, Q. Shi, M. Buyse, A. de Gramont
Journal: Journal of Clinical Oncology (2009)

4011 Background: The ACCENT group previously validated DFS with 3 years (yr) median follow-up (f-up) based on 20,898 pts from trials testing 5-FU based regimens (rx) (3yr DFS) as an endpoint to predict overall survival with 5 yr median f-up (5yr OS) (Sargent, JCO 2005). ACCENT further proposed (1) 2yr DFS predicts 5yr OS, (2) a stronger relationship between DFS and OS in stage III pts (Sargent JCO 2007) and (3) 6 or 7 yrs are necessary to demonstrate DFS and OS association in future trials due to extended survival following recurrence (de Gramont ASCO 2008). The relationship between endpoints in more recent trials with oral fluoropyrimidines, oxaliplatin, and irinotecan is unknown. Methods: Concordance between 2 and 3yr DFS, and 5 and 6yr OS was examined in 6 randomized phase III trials from 1997–2002. Individual data for 12,676 pts was analyzed; 2 trials tested oxaliplatin, 2 irinotecan, and 2 oral rx vs 5-FU/LV control. Association between DFS and OS hazard ratios (HRs) via weighted least squares (WLS), and concordance between predicted and actual within-trial HRs, were calculated overall and for stage III pts. Results: Overall association between 3 yr DFS and 5 yr OS HRs was reduced compared to the prior ACCENT analysis (Table). In stage III pts, the association between DFS and OS HRs remained strong. Observed 5 and 6yr OS HRs were predicted accurately by 2yr DFS overall and in stage III pts (within 95% prediction limits in all trials). In all pts, DFS HRs were more highly associated with 6 vs 5yr OS HRs. Conclusions: In recent trials in stage III pts, DFS HRs based on 2yr median f-up are highly predictive of 5 and 6yr OS HRs. In all pts the association between DFS and OS HRs is stronger for 6yr OS, but 7yr follow-up may be required. These data support 3yr DFS as a primary endpoint for modern stage III trials, and indicate that 2yr DFS would also be an appropriate primary endpoint. [Table: see text] [Table: see text]
Phase II results of tasisulam-sodium in previously treated patients with metastatic breast cancer.
Authors: Lee Steven Schwartzberg, Hatem Hussein Soliman, Alison Katherine Conlin, Christopher O. Ruud, Haluk Tezcan, Jane Bromund, Kevin Hogeterp, Christopher Kaiser, Jian Chen, Kay Chow, Robert L. Ilaria, Kathy Miller
Journal: Journal of Clinical Oncology (2012)

114 Background: Tasisulam, a novel acylsulfonamide antineoplastic agent, promotes apoptosis, exhibits antiangiogenic activities, and demontrates antiproliferative activity against human breast cancer cell lines. In humans, tasisulam is highly albumin bound, with a median half-life of approximately 11 days. Previous phase II studies of tasisulam indicated that an albumin-corrected exposure (AUC alb ) range of 1200 to 6400 h*mcg/mL provided the optimal balance of efficacy and safety. This study investigates the drug’s activity in previously treated patients (pts) with metastatic breast cancer (mBC). Methods: Pts with at least 2 prior therapies for mBC andserum albumin level ≥3.0 g/dL received tasisulam by 2-hour infusion every 28 days, dosed by a lean body weight-based dosing algorithm targeting an AUC alb range of 1200 to 6400 h*mcg/mL. Primary objective was to show at least a 10% response rate (RR) using RECIST 1.0. Secondary objectives included progression-free survival (PFS), overall survival (OS), pharmacokinetics (PK), and safety. Results: Thirty-three pts received at least 1 dose of tasisulam. All were women, with a mean age of 55.4 (±9.7) years. Pts received a median of 2 cycles (ranges 1-8). The majority of pts achieved the target AUC alb range of 1200 to 6400 h*mcg/mL or higher in cycles 1 and 2 (63% and 69%, respectively). The most common tasisulam-related hematologic toxicities were grade 3 anemia (3.0%) and grade 4 neutropenia (6.1%). Common nonhematological adverse events possibly related to tasisulam were fatigue (39.4%), diarrhea (24.2%), and nausea (18.2%). No deaths were considered related to the study drug. The RR (1 CR, 1 PR) was 6.1% (90% CI: 1.1, 17.9), stable disease rate was 24% (n=8; 90% CI: 12.7, 39.5), with a median PFS of 1.81 months (90% CI: 1.64, 2.17) and a median OS of 6.77 months (90% CI: 4.37, 11.63). Conclusions: Tasisulam was reasonably well tolerated, but did not meet its primary objective of overall RR of 10% in this heavily pretreated mBC patient population. PK analysis of the albumin-tailored dosing regimen indicated that the majority of the patients achieved the target AUC alb or higher, suggesting that the modest activity observed was not due to suboptimal dosing.
Prediction of clinical outcome in patients with primary laryngeal carcinoma using gene expression profiling.
Authors: E. Fountzilas, N. Angouridakis, I. Karasmanis, R. M. Wirtz, A. G. Eleftheraki, E. Veltrup, K. Markou, A. Nikolaou, P. Konstantinopoulos, V. Kotoula, D. Spentzos, G. Fountzilas
Journal: Journal of Clinical Oncology (2011)

5505 Background: Local recurrence is the major manifestation of treatment failure in patients with operable laryngeal carcinoma. Established clinicopathological factors cannot sufficiently predict patients that are likely to recur after treatment. Additional tools are therefore required to accurately identify patients at high risk for recurrence. Methods: Using Affymetrix U133A Genechips, we profiled fresh-frozen tumor tissues from 66 patients with operable laryngeal cancer. All patients were treated locally with surgery, with or without radiation therapy. We performed Cox regression proportional hazards modeling to identify multigene predictors of recurrence. The end-point of our analysis was disease-free survival (DFS). Gene models were directly validated in a separate, similarly treated cohort of 54 patients using Affymetrix chips. In an attempt to further validate our results, we profiled 12 selected genes of our model in formalin-fixed tumor tissues from an independent cohort of 75 patients, using quantitative real time-polymerase chain reaction (qRT-PCR). Results: We focused on genes univariately associated with DFS (p<0.05) in the training set. Among several gene models comprising different numbers of genes, a 30-gene model demonstrated optimal performance (log-rank, p<0.001). We directly applied these gene models to the validation set, after adjusting for non-biological experimental variability, and observed similar results. Specifically, median DFS, as predicted by the 30-gene model, was 34 and 80 months for high- and low-risk patients, respectively (p=0.01). Hazard Ratio (HR) for recurrence for the high-risk group was 3.87 (95% CI 1.28-11.73, p=0.017). Furthermore, unsupervised hierarchical clustering of the 75 patients, based on the qRT-PCR 12-gene profile, yielded two groups, which differed significantly in DFS (HR=2.26, 95% CI 1.08-4.76, p=0.031). Conclusions: We have established and validated gene models that can successfully stratify patients with laryngeal cancer, based on their risk for recurrence. Thus, patients with unfavorable prognosis, when accurately identified, could be ideal candidates for the application of more aggressive treatment modalities.