tbuckley/cabot-search huggingface dataset:
Base of tongue squamous cell carcinoma susceptibility: Novel candidate genetic polymorphisms identified in genome-wide association study.
Authors: Carmen Silvia Passos Lima, Benilton Carvalho, Renata Pellegrino, Leticia Khater, Carlos Takahiro Chone, Fernando Ferreira Costa, Gustavo Jacob Lourenco
Journal: Journal of Clinical Oncology (2012)

e16041 Background: Inherited genetic alterations, such as single nucleotide polymorphisms (SNPs), were described in association with oropharyngeal cancer risk in few reports with restrict number of SNPs analyzed. Base of tongue (BT) squamous cell carcinoma (SCC) is a common tumor of oropharynx; however, the association of SNPs and BTSCC risk is not clarified and, therefore, this was the aim of this study. Methods: DNA from 49 BTSCC patients and 49 controls was extracted using the QIamp kit (Qiagen ). Each sample was genotyped individually using DNA high-resolution microarrays containing 500.568 SNPs (SNP array 5.0, Affymetrix). Further sample processing, including digestion, adaptor ligation, amplification, fragmentation, labeling, hybridization, washing and scanning was assayed according to the standard protocol. Genotype data were acquired by genotyping calling of samples using crlmm algorithm provided by Bioconductor software. The differences between groups were analyzed by the logistic regression model. The SNPs localized in genes of interest were selected by data base analysis in DAVID and NCBI websites. The validation of selected SNPs was performed by RT-PCR, using TaqMan SNP Genotyping Assays (Applied Biosystems ) in all samples studied. Results: We observed 6.609 SNPs with distinct frequencies between BTSCC patients and controls. Fifty-two SNPs (0.8%) were located in coding sequence (CDS), 51 (0.8%) in 3’ and 5’- untranslated regions (UTR), 3.461 (52.4%) in up or downstream regions (DWS) and 3.045 (46.0%) in introns. Ten SNPs were selected and validated in study, including those localized in genes related to cell cycle (3’-UTR: ERP29, rs7114; MCC, rs7033; DWS: LEF1, rs2107028 and rs4245926; PTCH1, rs16909856 and rs16909859), transcription process (CDS: IKBKAP, rs3204145; 3’-UTR: ZNF415, rs3814), and cell adhesion (CDS: COL22A1, rs2292927; DWS: LY6K, rs1995467). Conclusions: Our preliminary results suggest that SNPs in genes involved in tumor development may predispose individuals to BTSCC. However, these results should be confirmed by functional protein studies and validated in larger epidemiological studies. Financial support: FAPESP and FINEP.
Impact of tumor size on survival in stage IB (T2N0M0) non-small cell lung cancer (NSCLC)
Authors: A. Rajan, N. Newman, N. Vajpayee, J. Husain, S. L. Graziano, A. Gajra
Journal: Journal of Clinical Oncology (2007)

7557 Background: Patients with stage IB NSCLC have a relatively poor survival of ∼60% despite adequate surgical resection. The role of adjuvant chemotherapy in this disease remains controversial since the results of the IALT, JBR.10, ANITA and CALGB 9633 trials. It is important to risk stratify patients with Stage IB NSCLC and to offer adjuvant therapies to those at greatest risk for recurrence. Methods: We conducted a retrospective review of 216 consecutive, surgically treated patients with stage IB NSCLC. None of the patients received adjuvant chemotherapy. We studied the association of various clinical factors as well as tumor size and visceral pleural invasion upon tumor recurrence, disease free survival (DFS) and overall survival (OS) at 5 years. Results: Of 216 patients, 135 (62%) were male, 97 (45%) had adenocarcinoma, 115 (53%) had poorly differentiated tumors and the majority (88%) were treated with lobectomy. Visceral pleural invasion was noted in 37 (17%) patients. The 5 year OS and DFS rates were 59% and 54% respectively. Tumor size was = 4cm in 120 (56%) patients, 4.1–5 cm and &gt;5cm in 48 (22%) patients each. The 5 year DFS was 40% and 58% for tumors &gt; 5cm and = 5 cm respectively (p &lt; 0.01). The 5 year OS was 49% and 61% respectively for tumors &gt; 5cm and = 5cm. Pleural invasion was a predictor for DFS in the univariate analysis (p &lt; 0.01) but not for OS. In the multivariable analysis, tumor size = 5cm was the only independent predictor of improved DFS (HR 0.46, C.I. 0.25–.84) and OS (HR=0.43, C.I. 0.23–0.80). Age, gender, histology, differentiation and visceral pleural invasion did not impact upon survival. Conclusions: In stage IB NSCLC, tumors &gt; 5cm in diameter have a significantly worse prognosis. These findings if confirmed in other large series, make a case for subdividing Stage IB NSCLC. Tumor size appears to be the most important factor in risk stratification for patients with stage IB NSCLC. Hence patients with large tumors should be offered adjuvant therapy. No significant financial relationships to disclose.
Imatinib mesylate inhibits C-kit and PDGF mediated cell growth in vitro in ovarian cancer
Authors: C. Mundhenke, I. Meinhold-Heerlein, K. H. Stuerner, F. Roesel, C. Schem, F. Hilpert, K. Nagasaki, W. Jonat, N. Maass
Journal: Journal of Clinical Oncology (2004)

3130 Background: Enhanced and altered signaling at tyrosinkinase receptors (TKR) as abl, c-kit and PDGF-R (receptors) influences tumor growth in a number of solid malignancies. The drug Imatinib is able to reduce cell proliferation by blocking these TKR. Expression patterns of TKR and their impact on growth control in ovarian cancer are investigated. Also the potential therapeutic role of Imatinib for ovarian cancer is examined in vitro. Methods:The ovarian cancer cell lines BG-1, HEY, OVCAR 3, OVCAR 8 and SK-OV 3 are screened for abl, c-kit, PDGF-R-α and -β expression by immunohistochemistry and PCR. Cell lines are incubated 3, 5 and 7 days with rising concentrations of single Imatinib, single Paclitaxel and single Paraplatin. Also combinations of Imatinib with Paclitaxel and Imatinib with Paraplatin are used. Finally ovarian cancer cells are incubated with triple combination of Imatinib, Paclitaxel and Paraplatin. After incubation drug sensibility assays (proliferation and apoptosis) are performed. Results:Abl and PDGF-R-β are expressed in all cell lines. PDGF-R-α is deteceted in BG-1, Skov 3, OVCAR 3 and weakly in OVCAR 8. C-kit expression is only detected in Skov-3 and OVCAR 3. High dose Imatinib incubation (>15 μM for 72 h) leads to receptor independent decrease of cell numbers (IC 50) and pro-apoptotic effects in all cell lines. 72 h combinations of low dose Imatinib (≤ 2 μM) with Paraplatin (IC50), as well as triple combination of Imatinib (≤ 2 μM) with Paclitaxel (IC25) and Paraplatin (IC25) show synergistic effects. Imatinib (≤ 2 μM) in combination with Paclitaxel (IC50) has an additive effect. The chemo-sensitizing effect of low dose Imatinib appears to be mediated by multiple factors, but is enhanced in c-kit positive cell lines (OVCAR 3 and Skov-3). Conclusions: High dose Imatinib leads to unspecific growth inhibition in ovarian cancer cell lines. Additive and even synergistic anti-cancer effects of Imatinib are seen in combination with cytostatic drugs as Paraplatin and Paclitaxel. Further interactions of Imatinib with PDGF-R and c-kit need to be investigated. Additional pre-clinical and clinical studies have to be performed to confirm results in vivo. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Pharmaceutical, Germany Novartis Novartis
Phase I study of BAY 73–4506, a multikinase inhibitor, administered for 21 days on/7 days off in patients with advanced solid tumors
Authors: S. Hedbom, S. Steinbild, A. Frost, M. Büchert, C. Unger, O. Christensen, M. Kornacker, D. Voliotis, R. Heinig, K. Mross
Journal: Journal of Clinical Oncology (2007)

3593 Background: BAY 73–4506 is a multikinase inhibitor targeting both the tumor and its vasculature. BAY 73–4506 inhibits VEGFR-2 and -3, and tumor cell signaling kinases (RET, KIT, PDGFR, and Raf). This drug shows potent, oral activity in a wide variety of preclinical xenograft models. Methods: This phase I dose-escalation trial investigated the safety, pharmacokinetic (PK), and pharmacodynamic (PD) profile of BAY 73–4506 given orally in 21 days on/7 days off cycles, until discontinuation due to toxicity or tumor progression. PK was assessed on days 1 and 21 of cycle 1. PD markers included dynamic contrast-enhanced MRI (DCE-MRI) and circulating sVEGFR-2 and VEGF levels assessed at each cycle. Tumor response was evaluated per RECIST criteria. Results: 22 patients (pts) with documented progressive disease were enrolled at doses of 10 mg to 120 mg once daily. Tumor types included CRC (27%), RCC (18%) and pancreatic cancer (14%). Pts had received a median of 3 prior therapies, including anti-VEGF agents in 5 pts. BAY 73–4506 PK appeared linear with dose; the AUC target exposure level of 13 mg*h/L (from preclinical models) was reached at 30 mg. The major metabolite of BAY 73–4506 (active in vitro) reached a similar AUC(0–24) ss as the parent drug at 120 mg. Commonly reported drug-related adverse events (=10% of pts) were hoarseness (7 [32%], all CTC grade 1), hypertension (5 [23%], all CTC grade 1–2), fatigue (3 [14%], CTC grade 3 in 1 pt [5%]), hand-foot-skin reaction (HFSR) (3 [14%], CTC grade 3 in 1 pt [5%], mucositis (3 [14%], all CTC grade 1). Maximum tolerated dose was exceeded at 120 mg with dose-limiting toxicities including fever without documented infection, HFSR, fatigue, and leukopenia. 2 pts (RCC &amp; osteosarcoma) achieved RECIST partial response. 4 pts had stable disease, one of them a cervical cancer pt with extensive tumor cavitation. PD parameters (decrease in sVEGFR-2 levels, decrease in iAUC60s of Gd-DTPA by DCE-MRI) correlated with drug exposure. Conclusions: BAY 73–4506 was well tolerated at 60 mg with report of dose-limiting toxicities at 120 mg. 6 (28%) of 22 pts demonstrated antitumor activity. Optimal dose and regimen are under evaluation in preparation for phase II trials. No significant financial relationships to disclose.
Abstract 10990: Regulatory Implications of Different Definitions and Outcomes in Worsening Heart Failure
Authors: Jacob P Kelly, Robert J Mentz, Dianne Gallup, Kevin J Anstrom, Margaret M Redfield, Horng H Chen, Christopher M O'Connor, Adrian F Hernandez, G. Michael Felker
Journal: Circulation (2015)

Introduction: Despite the use of different definitions for worsening heart failure (WHF) in prior clinical trials and registries, an in-hospital WHF event has consistently been associated with worse patient outcomes. WHF is being considered as a potential endpoint to support drug approval. We combined patients from two acute HF trials conducted by the HF Network (ROSE-AHF and DOSE-AHF) to understand how different WHF definitions are associated with event rates. Methods: WHF was defined as persistent or worsening HF requiring rescue therapy including IV vasoactive agents, ultrafiltration, or mechanical support over 72 hours after randomization in ROSE and also included additional open label loop or thiazide diuretic in DOSE. We assessed the relationship between WHF and the composite endpoint (CE) of re-hospitalization, emergency room visits for HF and mortality through 60 days. We also assessed for a differential relationship of WHF from 0-24 hours, 24-48 hours and 48-72 hours post-randomization. Results: The overall incidence of WHF was 14.6% (24.1% in DOSE and 6.3% in ROSE). Patients who developed WHF had lower baseline systolic blood pressure, less peripheral edema and higher BUN. In the combined dataset, WHF was associated with an increase in the CE (hazard ratio [HR] 1.64; 95% confidence interval [CI] 1.11-2.42; p-value 0.01). However, the association between WHF and 60-day outcomes was significant in ROSE but not in DOSE (Table). The development of WHF between 48-72 hours compared with 0-24 hours or 24-48 hours was associated with improved outcomes ([HR] 0.48, 95% CI 0.27 - 0.88, p-value 0.02 and [HR] 0.45, 95% CI 0.26 - 0.78, p-value 0.004, respectively). Conclusions: A WHF definition that incorporated intensification of diuretics increased the event rate but was not associated with worse 60-day outcomes. The timing of a WHF event also had a differential association with outcomes. These data support the use of a standardized WHF definition in clinical trials.
Application of the Edmonton Functional Assessment Tool (EFAT) in patients with brain metastases (BM) treated only with palliative radiotherapy (PRT)
Authors: S. Kahl, R. A. Sala, L. Mengelle, M. Alarcón, L. E. Fein
Journal: Journal of Clinical Oncology (2004)

8054 Background: The EFAT is a validated tool to asses the functional status of cancer patients in palliative care, like Karnofsky index (KPS) and neurological function class (NFC) scales. BM are a frequent complication of cancer. Despite PRT plus corticoids mean overall survival does not exceed 6 months. At present, the evaluation of PRT impact in terms other than survival are scarce. To evaluate the impact of PRT in patients with BM, we applied EFAT and their results were compared with KPS and NFC (all performed before and after treatment). Methods: Between January 1997 and December 2002, 71 (of 122) patients with BM were treated only with PRT and corticoids. Wilcoxon, t-Student, χ2 or Fisher tests were used as needed; P<0.01 was considered of statistical significance. Results: 37 women and 34 men (60.3 ± 1.3 years ± SE). Mean survival was 6.5 ± 0.6 months. KPS did not showed significant changes after PRT; however, NFC did (P=0.001). Mean EFAT score had a statistically significant improvement with PRT in patients with BM only (group 1), (P< 0.0001); but in patients with metastases in and outside CNS (group 2) (Table I) the score did not showed significance. Conclusions: Both EFAT and NFC showed statistical significance as a measure of positive impact of PRT in group 1. Moreover, EFAT best identified specific areas of benefit in both groups of patients probably allowing further treatment strategies. If proper symptom control could improve statistical significance in group 2 remains to be established. Table I. EFAT score of patients with BM and out of SNC metastases. No significant financial relationships to disclose.
Evaluation of humoral response to trivalent influenza vaccination in patients with non-Hodgkin lymphoma (NHL) previously treated or untreated with chemotherapy
Authors: K. Warzocha, P. Centkowski, L. B. Brydak, M. Machała, E. Kalinka, M. Błasińska-Morawiec, J. Wȩgrzyn, J. Sawczuk-Chabin, I. Federowicz, J. Walewski
Journal: Journal of Clinical Oncology (2005)

6612 Background: Influenza virus infection can lead to severe complications in patients with immunodeficiency. Vaccination has been proved as beneficial in high risk groups. Methods: In autumn 2003, 47 patients with non-Hodgkin lymphoma (NHL) and 45 healthy individuals (group C) (age 12–76 y, median 41 y; 13 M and 32 F) were vaccinated with subunit trivalent influenza vaccine. Patients (age 36–82, median 60 y; 24 M and 23 F) consisted of two groups, previously treated with chemotherapy (group A, n=32) or untreated (group B, n=15). Antibody titers to influenza hemagglutinin (HI) and neuraminidase (NI) were determined in sera collected before vaccination and 1 month after using HI and NI inhibition tests. Statistical analysis was performed using the Mann-Whitney unpaired and Wilcoxon paired tests. Results: Geometric mean antibody titers (GMTs) of anty-HI antibodies significantly increased (p<0.05) after vaccination and mean fold increases (MFIs) from 10.3 to 26.7 in group A, 5.9 to 48.9 in group B and from 9.1 to 24.4 in group C. Pre-vaccination protection rate, i.e. the number of subjects with the protective HI antibody titers >1:40, ranged from 0% to 9.4% in group A, 0% to 13.3% in group B and from 2.2% to 20% in group C. After vaccination protection rates increased and ranged from 78.1% to 87.5%, 73.3% to 93.3% and 66.7% to 82.2%, respectively. Response rates, i.e. the number of subjects with at least 4-fold increase of HI antibody titers after vaccination, ranged from 59.4% to 84.4%, 73.3% to 86.7% and from 51.1% to 66.7%, respectively. In both study groups and in the control, post-vaccination NI antibody titers were higher (p<0.05) than pre-vaccination titers. MFIs of NI antibody levels ranged from 9.8 to 17.3 in group A, 6.5 to 10.9 in group B and 4.8 to 10.3 in the controls. After vaccination, only hemagglutinin H1 antibody titers were higher in the control than in the groups A and B (p<0.05). In the other cases, there were no differences between groups or there were higher values in patients with NHL than in the control group. Conclusions: Influenza vaccine is immunogenic in pts with NHL and stimulates production of HI and NI antibodies in the titers comparable to healthy subjects. No significant financial relationships to disclose.
The microrna Mir-16 is a novel Tumour suppressor gene in malignant pleural mesothelioma
Authors: G. Reid, M. Pel, M. Kirschner, M. Williams, C. Wright, Y. Y. Cheng, B. McCaughan, J. Edelman, M. Vallely, R. Bowman, S. Klebe, N. van Zandwijk
Journal: Journal of Thoracic Oncology (2012)
Impact of prognostic factors on outcome in a phase III study comparing alemtuzumab to chlorambucil as first-line therapy for B-cell chronic lymphocytic leukemia (BCLL)
Authors: J. Mayer, T. Robak, A. Skotnicki, B. Jaksic, A. Dmoszynska, C. Sirard, P. Hillmen
Journal: Journal of Clinical Oncology (2007)

7035 Background: CAM307 is a phase III, open-label, randomized controlled trial comparing alemtuzumab (CAM) with chlorambucil (CHLO) for previously untreated B-CLL. Methods: The trial enrolled 297 previously untreated patients requiring therapy according to NCI-WG criteria. Patients were randomized 1:1 to CAM (n=149) vs CHLO (n=148) using standard dosing regimens. Diagnosis, Rai stage, response and disease progression were confirmed by an independent response review panel. In the overall study population, CAM demonstrated significantly higher overall response rates (ORR) than CHLO (83 % vs 55%) and a significant improvement in PFS (p= 0.0001) with manageable toxicities 1 . Outcomes according to Rai stage and cytogenetics have been previously reported. 1,2 A pre-specified subgroup analysis of response rates (RR) and progression-free survival (PFS) by prognostic factors was performed. Results: Additional analyses revealed statistically significant PFS advantage in favor for CAM vs. CHLO for patients with β-2 microglobulin =3 mg/L (p&lt;0.0001) or marrow infiltration =90% (p=0.0001). Conclusions: CAM is significantly superior to CHLO relative to overall and complete RR and PFS in the overall study population of previously untreated patients with CLL, and in patients &lt; 65 years of age, &lt; 70 years of age, maximum lymph node size &lt; 5cm, and, performance status &lt;2. Campath deserves further study in patients with age = 70, patients with massive lymphadenopathy, and in those with poor performance status. 1. Hillmen, P et al, Blood 108(11), abstract 301 2. Robak, T et al, Blood 108(11), abstract 2092 No significant financial relationships to disclose. [Table: see text]
Abstract 11260: Leukemia Inhibitory Factor Activates JAK-STAT Pathway in Side Population Cells and Enhances Stem Cell-Derived Cardiomyocyte Renewal after Myocardial Infarction
Authors: Masato Kanda, Toshio Nagai, Toshinao Takahashi, Mei Lan Liu, Naomichi Kondou, Atsuhiko T Naito, Hiroshi Akazawa, Yoshio Kobahashi, Issei Komuro
Journal: Circulation (2012)

Cardiac stem cells or precursor cells have the potential to regenerate cardiomyocytes, but their role in the efficacy of cardioprotective drugs remains controversial. Therefore, using a genetic fat...
NCCTG phase I/II trial (N9943) of gemcitabine and pemetrexed in patients with biliary tract or gallbladder carcinoma: Phase II results
Authors: R. R. McWilliams, N. R. Foster, F. J. Quevedo, R. F. Marschke, J. W. Kugler, E. L. Friedman, A. J. Jaslowski, J. R. Sande, S. R. Alberts
Journal: Journal of Clinical Oncology (2007)

4578 Background: Gemcitabine is commonly used in patients with cholangiocarcinoma with a response rate of 20–30% and median overall survival of 6–10 months. Pemetrexed’s mechanism of action and tolerability in patients with hepatic dysfunction makes it a potential agent for cholangiocarcinoma. Methods: Patients with unresectable, previously untreated biliary tract cancers were eligible for participation. Patients received pemetrexed 500 mg/m 2 IV over 10 minutes and gemcitabine 800 mg/m 2 IV at 10 mg/m 2 /minute on days 1 and 15 of an every 4 week schedule with vitamin B12 and folate supplementation. The primary end-point is 6-month survival with a planned accrual of 59 patients. Results: 58 eligible patients are included in this analysis. 93% had metastatic disease. Median age was 61 (range: 40 - 81). Median follow-up was 6.5 months (range: 3.3 - 23.2). Median of 3 cycles of treatment was given (range: 1 - 10). Reasons for stopping treatment included disease progression (57%), adverse events (20%), refusal (17%), death on- study (4%), and other medical problems (2%). 6-month survival was 52% (95% CI: 40 - 68%). Median survival was 6.3 months (95% CI: 5.4 - 8.0 months) and median time-to-progression was 3.8 months (2.4 - 5.0). 46 of 58 patients (79%) experienced at least one grade 3+ AE (at least possible attribution), and 26 patients (45%) experienced at least one grade 4 AE (at least possible attribution), most of which were due to grade 4 neutropenia. Conclusions: This study shows similar results to what would be expected with gemcitabine alone. The addition of pemetrexed, as with other agents, has not significantly enhanced the activity of gemcitabine. Supported by NIH Grant CA25224- 18. [Table: see text] No significant financial relationships to disclose.
Bone mineral density in patients with COPD depending on pulmonary function parameters
Authors: Olga Kharevich, Irina Lapteva, Artem Tomashevsky, Natalia Porahonko, Natalia Vasilieva, Volha Vadzianava
Journal: European Respiratory Journal (2011)

Introduction:  Osteoporosis is one of the most serious systemic effects of chronic obstructive pulmonary disease (COPD), which has serious consequences and significant impact on mortality, social and economic burden.   Aims and objectives:  The aim of the study was to investigate the relations between pulmonary function parameters and bone mineral density (BMD) in patients with COPD.   Methods:  In the recent research we have studied data of pulmonary function tests (by spirometry, bodyplethysmography, diffusing lung capacity) and BMD measurements by dual-energy X-ray absorptiometry in 24 patients with COPD. To compare BMD values in patients with FEV 1  1 >50%, we used the Mann-Whitney test. Correlations were estimated by Spearman coefficient. Data are presented as median (interquartile range).   Results:  There were significant differences between BMD values (T-score) in patients with FEV 1  1 >50% (n=10, females-3, males-7, median age 56,0 [54; 58]) in lumbar spine (-1,7 [-2,4; 0,3] versus -0,3 [-0,6; 1,0], p=0,04) and in femoral neck (-1,7 [-2,6; -0,4] versus -0,5 [-0,7; -0,3], p=0,043). Correlation analysis revealed relations between BMD values and residual lung volume (Neck: r = -0,808, p = 0,005; Upper Neck: r = -0,697, p = 0,025; Total: r = -0,683, p = 0,029), ratio of residual lung volume to total lung capacity (Neck: r = -0,722, p = 0,018), diffusing lung capacity (Neck: r = 0,597, p = 0,039).   Conclusion:  The results of the study confirm the role of lung function reduction in bone loss and osteoporosis development in patients with COPD.