tbuckley/cabot-search huggingface dataset:
Thiazolidinedione (TZD) exposure and risk of squamous cell carcinoma of head and neck (SCCHN)
Authors: R. Govindarajan, E. R. Siegel, D. L. Simmons, N. P. Lang
Journal: Journal of Clinical Oncology (2007)

1511 Background: Peroxisome proliferator-activated receptor γ (PPARγ), a nucleic acid receptor, heterodimerizes with retinoic acid X receptor (RXR). Ligand activation of RXR leads to decreased proliferation of SCCHN cell lines. TZDs (syn: glitazones), used to treat diabetes mellitus (DM), are ligands for the RXR:PPARγ heterodimer. A retrospective study of diabetics attending the Veterans Affairs (VA) health care system was undertaken to assess the association between TZD exposure and the risk of developing SCCHN. Methods: Data were obtained from the electronic patient database VISN 16 (covering 10 VA institutions) for males aged ≥40 presenting with DM and no prior SCCHN between 10/01/96 and 12/31/03. DM and SCCHN diagnoses were identified using ICD9 codes. Subjects were followed until 12/31/05, and analyzed for SCCHN risk via Cox regression, using time-dependent covariates to model exposure to TZDs, insulin and other anti-DM agents. Results: 130,406 subjects met the study criteria. Median (quartiles) age at DM presentation was 64 (55–72).18.5% were African-American, 61.3% were Caucasian, and 20.2% were other/unknown. The table shows TZD exposure, SCCHN incidence and hazard ratios for SCCHN with exposure to TZD alone or in combination with insulin and other anti-DM agents after adjusting for age, race, BMI, and HbA1C. Conclusions: A 41%-55% reduction in the risk of SCCHN was observed in diabetic subjects treated with TZD alone, with insulin, and with other anti-DM agents. The decrease was statistically significant (P&lt;0.05) for TZD alone and TZD with other agents, but not for TZD with insulin. These findings suggest a protective effect of TZD on the development of SCCHN. The mechanism is not clearly known but possibly mediated through RXR:PPARγ pathway. [Table: see text] No significant financial relationships to disclose.
Noninvasive ventilation(NIV) as a prevention of cognitive dysfunctions in early postoperative period in children
Authors: Antonina Lobodiuk, Dmytro Dmytriiev
Journal: European Respiratory Journal (2014)

BACKGROUND: Noninvasive ventilation(NIV) is effective method for management and

prevention of respiratory failure . Side effects of traditional mechanical ventilation can cause acute respiratory disorders and hypoxia. Cognitive dysfunctions are relatively common in postoperative and critically ill patients. The aim of present study was to assess the effects of NIV on cognitive status.

METHODS: The research was performed in 46 children in age from 8 to 18 years (10,5 ± 2,4) , after different operations , which were used mechanical (invasive) ventilation during the operations . All patients were divided into two groups. The patients of the first group (24) were conducted mechanical (invasive) ventilation in the early postoperative period. Patients of the second group (22) have got NIV. The cognitive status were assessed by scale Mini-Mental State Examination(MMSE) , Frontal Assessment Battery(FAB) The level of analgesia was controlled by the level of cortisol in blood plasma and faces scale. For a statistical analysis the Student's criterion was used.

RESULTS: The level of cortisol in blood plasma in first group(186,2±3,7nM/L) is no significantly difference the level of cortisol in patients second group (194,2±3,8nM/L). Average point of assess cognitive functions ( MMSE 24,4±2.2; FAB 19,2±2.6) in first group were higher than average points of assess cognitive functions(MMSE 28,4±1.8; FAB 24,2±2,6) in patients of the second group (p<0,05). :

CONCLUSION: The children of the second group have a lower rate of cognitive dysfunctions as patients of the first group . The obtained data reveal that noninvasive ventilation(NIV) is useful for prevention cognitive dysfunctions.
Circulating tumour cells (CTC) in breast cancer patients enumerated after filtration enrichment: Evaluation of prognostic significance
Authors: N. S. Wong, H. J. Kahn, L. Y. Zhang, S. Oldfield, L. Y. Yang, A. Marks, M. Trudeau
Journal: Journal of Clinical Oncology (2005)

617 Background: We previously found a higher incidence of CTC in women with metastatic breast cancer (MBC) compared to early breast cancer (EBC). We present follow-up data to explore the prognostic significance of these findings. Methods: CTC was quantified by immunostaining and direct visualization after centrifugation and filtration enrichment of peripheral blood from 131 patients. Time to progression (TTP) and overall survival (OS) were defined as interval from first blood sampling to first documented disease progression, or death respectively. Median and peak CTC levels were determined if patients had >1 sample. Survival analysis was by the Kaplan-Meier method, with comparison using the log-rank test. Hazard ratios for progression free and overall survival were determined using a Cox proportional hazard model. Results: Data is available for 126 patients. Characteristics of EBC patients (n=80) were: median age 51 (range 25 to 73); 45 (56.3%) node negative; 34 (43.6%) tumour grade 3; 54 (69.2%) with lymphovascular invasion (LVI); 23 (28.8%) hormone receptor negative; 70 (87.5%) sampled during chemotherapy and 9 (11.3%) preoperatively; 49 (61.3%) had >1 sample. Characteristics of MBC patients (n=46)were: median age 53 (range 35 to 91); 13 (31.0%) receptor negative;16 (34.8%) 3rd line therapy; 23 (50.0%) ≥3 metastatic sites; 40 (87.0%) sampled on chemotherapy; 4(8.7%) on tamoxifen; 23 (50.0%) were sampled repeatedly and the remainder,once. In EBC, median CTC ≥4 best distinguished patients with shorter time to relapse (p = 0.05,log-rank test) but not OS. On univariate analysis, T stage, grade, LVI and receptor status predicted for disease relapse but not first, peak or median CTC level. In MBC, median CTC ≥ 13 optimally identified patients with shorter TTP (p= 0.01) but not OS. In univariate analysis, median CTC level≥13 and prior lines of chemotherapy predicted for TTP while on multivariate analysis, median CTC level ≥13 was the only significant prognostic factor (p=0.02). No relationship between CTC level and OS was found. Conclusions: Median CTC level determined in the course of treatment predicts for TTP in MBC. A trend towards significance was also noted for median CTC ≥4 in EBC. No significant financial relationships to disclose.
PD-1 blockade upregulate TIM-3 expression as a compensatory regulation of immune check point receptors in HNSCC TIL
Authors: Gulidanna Shayan, Robert L Ferris
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Programmed Death 1 (PD-1) and T cell Ig and mucin domain-3 protein (Tim-3) are immune check point receptors that are upregulated on tumor infiltrating lymphocytes (TIL) in tumor-bearing mice and humans. As anti-PD-1 single agent response rates are still relatively low (20%) in HNC
A Randomized Phase III Trial of Melphalan and Dexamethasone (MDex) Versus Bortezomib, Melphalan and Dexamethasone (BMDex) for Untreated Patients with AL Amyloidosis
Authors: Efstathios Kastritis, Xavier Leleu, Bertrand Arnulf, Elena Zamagni, María Teresa Cibeira, Fiona Kwok, Peter Mollee, Roman Hajek, Philippe Moreau, Arnaud Jaccard, Stefan Schönland, Robin Filshie, Emmanuelle Nicolas-Virelizier, Bradley Augustson, Maria-Victoria Mateos, Ashutosh Wechalekar, Eric Hachulla, Paolo Milani, Meletios A Dimopoulos, Jean-Paul Fermand, Andrea Foli, Maria Gavriatopoulou, Antonio Palumbo, Pieter Sonneveld, Hans Erik Johnsen, Giampaolo Merlini, Giovanni Palladini
Journal: Blood (2016)
A phase I study of oral metronomic vinorelbine plus capecitabine in patients with metastatic breast cancer
Authors: A. Kalykaki, S. Agelaki, A. Kotsakis, L. Vamvakas, V. Bozionelou, K. Kalbakis, N. Androulakis, V. Georgoulias, D. Mavroudis
Journal: Journal of Clinical Oncology (2009)

1127 Background: The combination of capecitabine plus intravenous vinorelbine has shown substantial activity in anthracycline and/or taxane pretreated patients with metastatic breast cancer (MBC). The metronomic administration may be associated with reduced toxicity and enhanced efficacy. We conducted a phase I study to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of capecitabine plus oral vinorelbine administered metronomically in patients with MBC. Methods: Patients were treated with vinorelbine (30–60 mg total dose) p.o three times per week continuously and capecitabine (800–1250 mg/m2 twice a day) from day 1 to 14 in three week cycles. DLT was defined during the first cycle as grade (G) 4 neutropenia or thrombocytopenia, febrile neutropenia, any ≥ G 3 non-hematological toxicity, and any delay of treatment due to toxicity. Results: To date 27 patients have been enrolled on 7 different dose levels. Treatment was first line for 16 and second line for 11 patients. DLTs included G3 febrile neutropenia and treatment delay due to G2 neutropenia occurring in 1 patient each, at dose level 4 and G3 diarrhea and treatment delay due to G2 neutropenia in 1 patient each, at dose level 7. The MTD has not yet been reached. Hematologic and nonhematological toxicities were generally mild to moderate. Most common were myelosuppression, asthenia, nausea, and diarrhea. Nine objective responses were observed with 2 complete and 7 partial. Conclusions: Vinorelbine 60 mg three times a week in combination with capecitabine 1250mg/m2 twice a day, has been well tolerated. Enrollment is ongoing. Updated data will be presented at the meeting. No significant financial relationships to disclose.
Utility of 18-fluorodeoxyglucose positron emission tomography (FDG-PET) in the staging, radiotherapy planning and prognostication of anal cancer
Authors: E. de Winton, A. Heriot, M. Ng, R. Hicks, A. Hogg, A. Milner, T. Leong, M. Fay, J. MacKay, S. Ngan
Journal: Journal of Clinical Oncology (2007)

4559 Background: Accurate inguinal and pelvic nodal staging in anal cancer is important for prognosis and planning of (chemo)radiation fields. There is strong evidence for the impact of FDG-PET in staging and management of cancer, with early reports of an increasing role in outcome prognostication for a number of tumours. We aimed to determine the impact of FDG-PET on the nodal staging, radiotherapy planning and prognostication of patients with primary anal cancer. Methods: Sixty-two consecutive patients with anal cancer referred to a single tertiary oncology centre between August 1997 and November 2005 were staged with conventional imaging (CIm), computed tomography, magnetic resonance imaging and chest x-ray and by FDG-PET. The stage determined by CIm and the proposed management plan was prospectively recorded and changes in stage and management as a result of FDG-PET assessed. Patients were treated using uniform radiotherapy technique and dose. The accuracy of changes and prognostication of FDG-PET was validated by subsequent clinical follow-up. Kaplan-Meier survival analysis was used to assess survival for the cohort and by FDG-PET and CIm stage. Results: The TNM stage group was changed in 23% (14/62) as a result of FDG-PET (15% up-staged, 8% down-staged). Fourteen percent of T1 patients (3/22), 42% of T2 patients (10/24) and 38% of T3–4 patients (6/16), assessed using CIm, had a change in their N or M stage following FDG-PET. Sensitivity for nodal disease by FDG-PET and CIm was 92% and 72% respectively. The staging FDG-PET scan altered management intent in 3% (2/62), and altered radiotherapy fields in 13% (8/62). Estimated 5 year overall survival and progression free survival (PFS) for the cohort was 77.3% (95% CI 55.3%-90.4%) and 72.2% (95% CI 51.5%-86.4%) respectively. Estimated 5 year PFS for FDG-PET and CIm staged N2–3 disease was 70% (95% CI 42.8%-87.9%) and 55.3% (95% CI 23.3%-83.4%) respectively. Conclusions: FDG-PET shows increased sensitivity over CIm for staging nodal disease in anal cancer and changes treatment intent or radiotherapy fields in a significant proportion of patients. Improved 5 year PFS for FDG-PET staged N2–3 disease could be consistent with more accurate nodal staging and radiotherapy targeting. No significant financial relationships to disclose.
Differential survival following trastuzumab treatment based on quantitative HER2 expression and HER2:HER2 dimerization in a clinic-based cohort of patients with metastatic breast cancer
Authors: M. Toi, J. Sperinde, W. Huang, S. Saji, S. Ohno, S. Nakamura, H. Iwata, N. Masuda, K. Aogi, M. Bates
Journal: Journal of Clinical Oncology (2007)

1025 Background: Women with metastatic breast cancer (MBC) that overexpress HER2 experience improved overall survival (OS) when treated with trastuzumab. Immunohistochemistry (IHC) for HER2 protein expression and fluorescence in situ hybridization (FISH) for HER2 gene amplification are the preferred methods of determining HER2 positivity. However, not all HER2 positive patients respond equally well to trastuzumab. We describe the identification of subgroups of HER2+ patients with distinct clinical outcomes based on their quantitative levels of HER2 expression and HER2:HER2 dimerization. Methods: 75 patients with MBC drawn from six oncology clinics in Japan were assayed for HER2 expression and HER2:HER2 dimerization using FFPE specimens by the eTag assay, a proximity-based assay designed to detect and quantify protein-protein dimers. All patients had MBC, were treated with at least one chemotherapy (CT) regimen prior to receiving trastuzumab, and had FFPE specimens available for testing. 33% had at least 3 metastatic sites. 88% were selected for treatment based on IHC and 12% based on FISH. 16% were treated with trastuzumab alone and 84% with trastuzumab plus CT. Median clinical follow-up was 26 months. Cox proportional hazards and Kaplan-Meier (KM) analyses were performed. Results: The most significant variables associated with OS were the presence of brain metastases and the total number of metastases. In the overall population, correcting for the confounding influence of number of metastases, KM analyses demonstrated that patients with higher HER2 expression survived significantly longer than patients with lower HER2 expression (HR for death = 0.36, p = 0.0036). This relationship was even more significant for HER2:HER2 dimers (HR = 0.29, p = 0.0003). Conclusions: In a clinic-based population of Japanese women with MBC treated with heterogeneous prior and concomitant (with trastuzumab) CT regimens, the quantitative levels of HER2 expression and HER2:HER2 dimerization identified subsets of patients within a population of pre-selected HER2+ patients with different probabilities of long-term survival following trastuzumab treatment. No significant financial relationships to disclose.
Characterization of pseudoprogression in patients with glioblastoma: Is histology the gold standard?
Authors: I. Melguizo, J. Bruner, N. Guha-Thakurta, K. R. Hess, V. K. Puduvalli
Journal: Journal of Clinical Oncology (2010)

2079 Background: Pseudoprogression (psPD) refers to the increase in size or new areas of contrast enhancement on MRI immediately after radiotherapy that improves independent of treatment which has been a confounding factor in clinical management. With current standard of chemoradiation (chemoRT) with temozolomide for newly diagnosed glioblastoma (GBM) patients, the reported incidence of psPD is approximately 40%-50%. In order to better characterize these changes, we examined whether histological criteria could serve as a gold standard for determining the incidence of PsPD. Methods: We reviewed data from adults with GBM who had surgical resection due to MRI changes suggesting progression within 3 months of chemoRT. MRI and histological data was independently re-reviewed by a neuropathologist and neuroradiologist. Progression-free survival (PFS) and overall survival (OS) were calculated by the Kaplan Meier method and log rank analysis. Results: In the 34 pts who had resection based on MRI changes, the median PFS was 23 wks (8-80 wks) and median OS was 80 wks (21-164 wks). Upon independent histologic review, 10 pts (29.4%) had tumor progression, 11 (32.3%) had psPD and the remainder (38.2%), mixed (tumor and psPD). In comparison, the initial histologic review reported tumor progression in 10/34 patients, PsPD in 6/34 patients and mixed findings in 18/34 patients. The three groups (progression, psPD, mixed) showed no significant difference in PFS or OS. Conclusions: This single institution series of histologically determined psPD, the largest of its kind, showed an incidence of ∼32% PsPD in GBM patients after chemoRT. Unlike tumor progression, PsPD was reported less frequently at initial review. The large proportion of “mixed” category specimens which can include psPD can potentially confound clinical management despite histologic review. Ongoing assessment will determine the potential of proliferation markers (phosphohistone-H3 and the MIB-1 index) to identify active tumor to resolve this issue. No significant differences in clinical outcome were seen based on histologic findings. Reassessment of the histological criteria is required to effectively plan prospective studies to address the issue of psPD. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration IMEDEX Celgene, Lilly, MGI Pharma, Pfizer
Usefulness of peripheral regulatory T-cells induced by Notch signaling pathway-driven indoleamine 2, 3-dioxygenase positive dendritic cell as a biomarker for the decision for IPMN surgical indications.
Authors: Tetsuya Ikemoto, Mitsuo Shimada, Toru Utsunomiya, Yuji Morine, Satoru Imura, Hiroki Mori, Yusuke Arakawa, Mami Kanamoto, Shu-ichi Iwahashi, Shinichiro Yamada, Michihito Asanoma
Journal: Journal of Clinical Oncology (2013)

181 Background: This study was performed to elucidate the expression of the Notch signaling pathway regulated by dendetric cell (DC) and their correlations to clinicopathological factors of intraductal papillary mucinous neoplasms (IPMNs) as a new biomarker for surgical indications. We already reported that regulatory T cells (Tregs) play an important role in tumor immunity (Pancreas 2006, ASCO-GI 2009), however, the whole mechanism of control of peripheral Tregs remains unclear. It is reported that Indoleamine 2, 3-dioxygenase (IDO) induces active Treg from naïve CD4+Tcells through dendritic cells. Otherwise, we also reported that the Notch signaling pathway is involved in tumor growth and DC function (JI 2010). Thus we focused that Indoleamine 2,3-deoxygenase(IDO)-Treg axis driven by Notch signaling in IPMNs. Methods: Peripheral blood samples and resected specimens from 20 patients with IPMN were evaluated. All patients were pathologically diagnosed with IPMN. Resected specimens were immunohistochemically evaluated (anti-Notch1, anti-Notch2, anti-Notch2-intracellular domain and anti-IDO antibody staining) and compared to clinicopathological factors. Peripheral Treg populations were analyzed with an automated flow cytometer. Results: Disease-free survival was significantly worse in the Notch1 high-expression group (P&lt;0.05). Notch2 family expressions were higher in intraductal papillary mucinous carcinoma (IPMC) than in intraductal papillary mucinous adenoma (IPMA) (Notch2, P&lt; 0.05; Notch2-intracellular domain, P &lt; 0.05). Jagged1 and IDO expressions were significantly higher in IPMC than in IPMA (P &lt; 0.05) and was significantly related to recurrence. The Treg population in peripheral blood was higher in patients with IPMC than in those with IPMA (P &lt; 0.01). Conclusions: Notch signaling, especially Jagged1 expression, regulated by IDO+DC reflects IPMN aggressiveness. Our data strongly suggest that peripheral Treg induced by Notch signaling pathway driven IDO+DC may be a nobel biomarker for the decision for IPMN surgical indications.
Phase I dose-escalation study of continuously administered regorafenib (BAY 73-4506), an inhibitor of oncogenic and angiogenic kinases, in patients with advanced solid tumors.
Authors: T. Shimizu, A. W. Tolcher, A. Patnaik, K. Papadopoulos, O. Christensen, T. Lin, G. R. Blumenschein
Journal: Journal of Clinical Oncology (2010)

3035 Background: Regorafenib is a novel diphenylurea oral multikinase inhibitor of angiogenic (VEGFR1-3, TIE2), stromal (PDGFR- β, FGFR), and oncogenic kinases (KIT, RET, RAF). In in vivo models, regorafenib has demonstrated a broad spectrum of antitumor activity. Regorafenib administration (21 days (d) on/7 d off dosing) resulted in a 31% partial response (PR) rate in a phase II study in patients (pts) with metastatic renal cell cancer. Methods: This phase I dose-escalation study assessed the safety, pharmacokinetics (PK), and efficacy of regorafenib, given orally, once daily in continuous cycles of 21 d, until discontinuation due to toxicity or tumor progression. PK was assessed on d 1 of cycles 1 and 2. Tumor response was evaluated by RECIST. Results: Thirty-eight pts with solid tumors and progressive disease were enrolled and treated with doses of 20-140 mg. Frequent tumor types included colorectal (16%), thyroid (13%), adenoid cystic carcinoma (13%), and head and neck cancer (13%). The median treatment duration was 73 d. Drug-related adverse events (all grades, >20% of pts) were rash/desquamation (50%; CTC 3, 3%), hand-foot skin reaction (32%; CTC 3, 11%), fatigue (32%, CTC 1-2 only), extremity pain (29%; CTC 3, 5%), mucositis (24%; CTC 1-2 only), and diarrhea (21%; CTC 3, 3%). DLTs in cycles 1-2 occurred in 2/11 pts at 100 mg (skin toxicity n=1; anemia/thrombocytopenia n=1), 3/6 pts at 120 mg (skin toxicity n=2; thrombocytopenia n=1), and 4/10 pts at 140 mg (skin toxicity n=2; diarrhea n=1; hyperbilirubinemia/AST increase n=1). Steady state exposure of regorafenib increased from 20-140 mg, while exposure of the active metabolites M2 and M5 increased more than dose- proportionally. Two out of 36 evaluable pts achieved a PR (6%; neuroendocrine pancreas carcinoma and squamous-cell carcinoma periorbital) and 22 pts (61%) had stable disease (SD) ≥6 wk, including one pt with hepatocellular carcinoma and SD of 90 wk. Conclusions: Regorafenib was well tolerated and the MTD when administered as once-daily continuous dosing is 100 mg. Clinical activity (PR+SD) was demonstrated in 67% of evaluable pts and an extension cohort at 100 mg is ongoing. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer Bayer Chemotherapy Foundation Bayer
Irinotecan hydrochloride (CPT-11) and mitomycin C in docetaxel-carbopoatin (DJ) refractory ovarian cancer
Authors: Y. Aoki, T. Amikura, N. Nishikawa, M. Sekine, T. Yahata, K. Fujita, K. Tanaka
Journal: Journal of Clinical Oncology (2005)

5143 Objective: The purpose of this study was to examine the level of activity of CPT-11 and MMC combination chemotherapy (CPT-M) in a patient population with docetaxel-carbopoatin (DJ) refractory ovarian cancer. Patients and Methods: Between 2000 and 2003, 28 patients with DJ refractory ovarian cancer were received CPT-11 (140 mg/m2) in combination with MMC (7 mg/m2) on days 1, 15, 29 until disease progression, unacceptable toxicity developed, or they elected to discontinue treatment. Results: Median age was 58 year-old (range, 34–73). Overall, 146 cycles of CPT-M chemotherapy were delivered to 28 patients. The major toxicity with this regimen was neutropenia, which was brief and reversible. The incidence of grade 3 and 4 neutropenia were 39% (11/28) and 21% (6/28), respectively. The non-hematological toxicities were generally mild and well tolerated. Of the 28 patients, nine (32.1%) experienced an objective response (2 CR, 7 PRs). Among responders, the median duration of response was 33 weeks (range, 17 to 57 weeks). The median time to progression for the patients who received treatment on this trial was 17 weeks (range, 5 to 57 weeks), with a median survival of 39.5 weeks (range, 8 to 83+ weeks). Conclusions: This preliminary study shows that the combination of CPT-M appears to be an active regimen in patients with DJ refractory ovarian cancer. No significant financial relationships to disclose.