tbuckley/cabot-search huggingface dataset:
Meta-analysis of genome-wide association studies of single nucleotide polymorphisms in selected genes of the WNT signaling pathway
Authors: Thomas P.J. Hofer, Nicole M. Probst-Hensch, Emmanuelle Bouzigon, Medea Imboden, Marjo-Riitta Jarvelin, Adaikalavan Ramasamy, Alexessander Da Silva Couto Alves, Ivan Curjuric, Joachim Heinrich, Marie Standl, Alexandra Schneider, Regina Hampel, Valerie Siroux, Francine Kauffmann, Florence Demenais, Thierry Rochat, David Strachan, Deborah L Jarvis, Oliver Eickelberg, Melanie Königshoff, Matthias Wjst
Journal: European Respiratory Journal (2012)

Background: The WNT signaling pathway is involved in a wide range of developmental events and maintenance of homeostasis in adult tissue, including lung development and health. WNT signaling genes have also been suggested to play a role in pathogenesis of lung diseases such as chronic obstructive pulmonary disease (COPD) and asthma.

Aims and Objectives: The aim of this meta-analysis was to identify consistent disease markers for COPD, asthma, forced expiratory volume in one second (FEV1), and forced vital capacity (FVC) in nine genes of the WNT signaling cascade pathway (WNT10b, WIF1, WISP1, SFRP2, SFRP5, DKK1, Axin2, TCF7L2, and FZD3) using genome-wide association data from six European cohort studies.

Methods: The six European cohort studies included are: B58C (UK), ECRHS (multicentre), EGEA (France), GINI / LISA (Germany), NFBC1966 (Finland), and SAPALDIA (Switzerland). We identified a total of 105 single nucleotide polymorphisms (SNPs) in the nine genes (including a region 2 kb in size up- and downstream the gene). Effect estimates were analyzed using a fixed or random effect pooled testing (depending on homogeneity) for association in the overall study population.

Results and Conclusions: We identified weak genetic associations (p-values between 0.002 and 0.046) in our meta-analysis for COPD (Axin2), asthma (SFRP2, TCF7L2, WIF1, DKK1), FEV1 (SFRP2, TCF7L2, DKK1), and FVC (TCF7L2, WNT10b). Notably in TCF7L2 six different SNPs were identified (p-values between 0.002 and 0.046) in association with asthma, FEV1, and FVC. In literature, WNT signaling genes were linked to COPD (Axin2), asthma (TCF7L2, SFRP2), and decreased FEV1 and FVC (TCF7L2).
Biodegradable poly(ethylene glycol) methyl ether acrylate- b -poly( l -lysine)- b -poly( l -histidine) triblock copolypeptides for non-viral gene delivery
Authors: Renjith P. Johnson, Saji Uthaman, Johnson V. John, Hye Ri Lee, In Kyu Park, Il Kim
Journal: Journal of Controlled Release (2015)
Correlation of engraftment, mutation status, and response to chemotherapy in primary tumor xenograft models of NSCLC.
Authors: T. John, D. Kohler, N. Yanagawa, M. Pintilie, M. Li, D. Panchal, N. Pham, S. Der, F. A. Shepherd, M. S. Tsao
Journal: Journal of Clinical Oncology (2010)

10517 Background: Recapitulating the complexity of tumor growth in preclinical models is important for mechanistic and functional studies of cancer biology. Primary tumor xenografts may represent the histological complexity of NSCLC better than cell lines. However, not all tumors engraft when implanted into immunodefficient mice. We assessed whether histological and mutational profiles affected tumor engraftability and response to chemotherapy. Methods: Tumor fragments from patients undergoing curative surgery were placed subcutaneously into NOD-scid mice. Patient characteristics for tumors that engrafted (XG) and did not engraft (No-XG) were compared. Patient tumor DNA was analyzed using the Sequenom OncoCarta Panel. XGs were treated with intraperitoneal cisplatin, vinorelbine, pemetrexed or saline (10 replicates/group). A tissue microarray containing all primary and XG tumors was developed for immunohistochemical studies (IHC). Results: Of 63/157 (40%) NSCLCs that engrafted, histology was maintained in 97%. Mutations in primary tumors were also detected in XGs. Histological factors significantly associated with engraftment included squamous histology, poor tumor differentiation and larger primary tumor size. Amongst adenocarcinomas, significantly fewer EGFR mutated tumors engrafted (p = 0.03); conversely, more KRAS mutated tumors engrafted (p = 0.05). In multivariate analysis including age, sex, stage, histology and mutation status, patients whose tumors formed XG had significantly shorter DFS (HR 6.1 95%CI 2.6-14.6; p = 0.00004). Chemotherapy response was seen in 5/21 (23%) cisplatin, 8/18 (44%) vinorelbine and 1/12 pemetrexed treated XGs. EGFR mutations and increased expression of phospho-S6-RP, a marker in the mTOR/AKT pathway, appeared predictive for response to cisplatin. Other markers including KRAS mutational status, P53 and EGFR IHC were not predictive. Conclusions: XGs closely mirror primary tumors histologically and mutationally. Response rates to chemotherapy were similar to that observed clinically. Tumors that engraft are biologically more aggressive. These factors should be considered when interpreting results from preclinical studies. No significant financial relationships to disclose.
Paclitaxel, carboplatin and etoposid (TCE) in the treatment of advanced neuroendocrine tumours
Authors: T. Kegel, W. Grothe, K. Jordan, M. Graubner, D. Arnold, H. J. Schmoll
Journal: Journal of Clinical Oncology (2005)

4263 Background: Combination chemotherapy with paclitaxel, carboplatin and etoposide has been evaluated by Hainsworth et al. (1997) in the treatment of carcinoma of unknown primary. In this study 6 patients (pts.) with undifferentiated neuroendocrine tumors were included with a favorable response and safety profile in comparison to cisplatin/etoposide based regimen which represents the standard treatment for undifferentiated neuroendocrine tumors. Methods: We performed a retrospective analysis of 13 pts. (f/m 7/6 - median age 56 (range 35–75)) with moderate or poorly differentiated neuroendocrine tumors, which have been treated at our center from 1999 to 2003 with paclitaxel 200 mg/m2 d1, carboplatin AUC 6 d1 plus etoposide 50 mg alternated with 100 mg orally d1–10, qd 22. 13 pts. were evaluable for toxicity and 10 for response (3 patients were lost to follow up). Results: A total of 57 cycles were administered (median 4, range 1 - 14). NCI-CTC grade III/IV toxicity was anemia 1/0 pt., thrombocytopenia 4/1 pts., leucopenia 2/1 pts., sensory neuropathy 2/0 pts. In 8 pts. a dose adjustment due to toxicity was necessary. Efficacy: 3/10 pts. showed a CR, 2/10 pts. a PR and 5/10 pts. a SD. The 2 pts. with a CR were under observation for 18 and 17 mts. with no signs of relapse. Median progression-free survival was 18+ month (range 9 - 47+). Conclusion: The combination of paclitaxel, carboplatin and etoposide is very active in neuroendocrine tumors and is well tollerated in an outpatient setting. The main toxicity was grade 3 thrombocytopenia. These promising results justify further evaluation of this combination. No significant financial relationships to disclose.
Simultaneous Denoising, Deconvolution, and Demixing of Calcium Imaging Data
Authors: Eftychios A. Pnevmatikakis, Daniel Soudry, Yuanjun Gao, Timothy A. Machado, Josh Merel, David Pfau, Thomas Reardon, Yu Mu, Clay Lacefield, Weijian Yang, Misha Ahrens, Randy Bruno, Thomas M. Jessell, Darcy S. Peterka, Rafael Yuste, Liam Paninski
Journal: Neuron (2016)
Octreotide for the treatment of symptoms of bowel obstruction in advanced cancer
Authors: S. Imamura, S. Maehara
Journal: Journal of Clinical Oncology (2007)

19626 Background: Symptom of bowel obstruction are common and serious complications in terminal advanced cancer patients. Mechanisms of bowel obstructions include intraabdominal carcinomatosis, drug-induced intestinal immobility and intraluminal obstruction. Octreotide inhibits the release of the several gastrointestinal hormones thereby reducing GI tract secretion, and increase the GI tract absorption by slowing down intestinal mobility and decreasing the splanchnic blood flow. Methods: Objectives of this study evaluated efficacy of octreotide in terminal cancer patients with bowel obstruction. We treated all patients with recurrent or advanced cancer admitted to our palliative unit in last 2 years, who had continuous nausea and vomiting related to no surgically bowel obstruction. Octreotide started at a dose of 150 mcg/day in subcutaneous infusion or continuous intravenous infusion, and increase to a dose of 300 mcg/day depending on the symptom. Results: 52 patients with terminal cancer were included in this study. Primary tumor were 13 colon-rectum 13, gastric 8, pancreas 8, biliary tract 4, esophagus 2, gynecological 3 and others 12. The mean age of patients is 71 years of age. All patient have died from tumor progression. The mean dose is 232 mcg/day and the mean duration of treatment is 24 days. 23 patients (45%) were remarkably improved and can take a meal. 15 patients (29%) were improved and diminished vomiting. But 13 patients (25%) remained continuous vomiting. The patient with markedly efficacy lived 2 times longer than other groups. No serious side effects were present. Conclusions: Octreotide shows good efficacy in the management of symptom of malignant obstruction and can be used safely in this population. No significant financial relationships to disclose.
Pathology Data in the Central Databases of Multicenter Randomized Trials Need to Be Based on Pathology Reports and Controlled by Trained Quality Managers
Authors: I.D. Nagtegaal, E. Klein Kranenbarg, J. Hermans, C.J. H. van de Velde, J.H. J. M. van Krieken
Journal: Journal of Clinical Oncology (2000)

PURPOSE: Randomized multicenter trials form the basis of health care development. Regarding cancer research, pathology data are crucial. To maintain the quality of these trials, the auditing of subsequent processes is necessary. The aim of the present study was to examine the completeness and accuracy of data obtained from a special-purpose standardized pathology form compared with the data available through traditional hospital pathology reports. PATIENTS AND METHODS: A retrospective comparison of pathology data case record forms with hospital pathology reports was performed using the data from 300 patients with primary rectal cancer. All of these patients had been included in a large multicenter trial in the Netherlands. Three independent audits were carried out. Special attention was given to the accuracy of parameters, which are important for prognosis and treatment decisions. Furthermore, various factors that possibly influence the occurrence of errors were investigated. RESULTS: Quality control of the pathology data revealed a high accuracy of 86.5% of all data items. However, only one third of the forms were complete and correct. Missing values were most prominent in the number of lymph nodes examined, whereas most errors were made in relation to the circumferential margin. Trained review pathologists made fewer major errors. Discrepancies were detected in all control rounds. CONCLUSION: Successive rounds of quality control are required for accuracy and completeness of pathology data in multicenter trials. In addition to the special-purpose pathology forms, original pathology reports have to be collected, and the data should also be controlled by a trained pathology quality manager.
A first-in-human phase I study to evaluate the fully human monoclonal antibody MNRP1685A (anti-NRP1) administered intravenously every three weeks in patients with advanced solid tumors.
Authors: C. D. Weekes, P. Hegde, Y. Xin, R. Yu, H. Xiang, M. Beeram, L. Gore, R. K. Brachmann, A. Patnaik
Journal: Journal of Clinical Oncology (2010)

3014 Background: Anti-NRP1 specifically targets neuropilin-1 (NRP1), a multi-domain receptor known to bind a variety of ligands, including VEGF family members. NRP1 is expressed by endothelial cells, pericytes and other stromal elements, but also a subset of tumor cells. Genetic and pharmacologic modulation of NRP1 shows that it is necessary for blood vessel maturation. Anti-NRP1 prevents vascular maturation keeping blood vessels in an immature, highly VEGF-dependent state. In preclinical studies, anti-NRP1 shows substantial antitumor activity in combination with anti- VEGF. Methods: A phase I dose escalation study (3+3 design) was initiated in patients with solid tumors. Anti-NRP1 was administered intravenously on day 1 of 3-week cycles to study safety, pharmacokinetics (PK), and pharmacodynamics (PD), and to determine the maximum tolerated dose. Results: Twenty-seven patients have been enrolled in 6 dose-escalation cohorts at doses of 2, 5, 10, 15, 20 and 30 mg/kg. The most frequently reported drug-related adverse events were grade 1 and 2 acute infusion reactions manifested mainly by rigors, pyrexia, headaches, and pruritus. Institution of dexamethasone premedication (days 1 and −1) resulted in well-tolerated anti-NRP1 infusions. One dose-limiting toxicity of grade 3 upper gastrointestinal bleeding (20 mg/kg cohort) was observed. Consistent with wide expression of its target, anti-NRP1 demonstrated nonlinear PK with more-than-dose proportional increases in exposure. At higher doses, clearance was faster than a typical IgG1 monoclonal antibody but target exposure, based on preclinical studies, was achieved with every 3-week dosing. One patient (10 mg/kg) with rectal cancer has been on study for 10 cycles with stable disease. Six other patients had stable disease for at least 4 cycles. Sustained elevation of PD biomarker Placental Growth Factor (PlGF) was observed starting at 10 mg/kg. Conclusions: Anti-NRP1 is generally well tolerated. Estimated target exposure can be achieved with every 3-week dosing. Anti-NRP1 led to increased levels of PD biomarker PlGF. The final cohort (40 mg/kg) is currently enrolling. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech Genentech Genentech
EGFR mutations: Comparison of Sanger- and pyrosequencing.
Authors: V. Schildgen, J. Lusebrink, C. Schulz, R. L. Tillmann, W. Engel-Riedel, E. Stoelben, O. Schildgen, M. Brockmann
Journal: Journal of Clinical Oncology (2011)

e21019 Background: In 1980 an increased EGFR (epidermal growth factor receptor) expression was discovered in non-small cell lung cancer (NSCLC) patients coupled to poor survival prognosis. It was observed that sensitivity to gefitinib and erlotinib is correlated to activating mutations in the kinase domain of EGFR present in a subset of NSCLC patients whereas at least the mutation T790M leads to resistance to tyrosine kinase inhibitors. To analyse the tumour DNA mutation profile of 20 NSCLC lung biopsies in exons 18, 19, 20, and 21 we made use of pyrosequencing and compared this method with Sanger-sequencing and results of an external supplier. Methods: All analyses were performed on formalin-fixed paraffin-embedded lung biopsies from randomly selected patients suffering from NSCLC with previous EGFR-mutation analyses by an external supplier. Sanger-sequencing was performed by Eurofins MWG Operon (Munich, Germany) with primers published by Yunxia et al. (2010). Pyrosequencing was performed with the Qiagen Therascreen EGFR Pyro Kit (Hilden, Germany) according to the manufacturer’s instructions. Sensitivity and specifity were determined in comparison with the results of the external supplier for all relevant mutations in exons 18, 19, 20, and 21. Results: Our analyses revealed that pyrosequencing is faster and more sensitive for the common mutations compared with Sanger-sequencing and the results of the external supplier. Beyond we found additional mutations by Sanger-sequencing in exon 18 in 50% of the patients leading to a frame shift. Conclusions: Divergences regarding the detection of the common mutations could be traced back to inhomogeneous or insufficient tumour material. Surprisingly, none of the newly identified mutations have been described although they occurred in 50% of randomly selected cases. Maybe these mutations are results of artefacts, induced by the fixation process, the sequencing reaction, or a combination of both. Further investigations would be informative to exclude the possibility that other mutations rely on such artefacts. All in all pyrosequencing seems to be preferable as it is faster, more precisely, and more sensitive compared to Sanger-sequencing.
Pattern of invasion of advanced gingivobuccal complex cancer.
Authors: N. P. Trivedi, V. Kekatpure, M. A. Kuriakose, A. Gangoli
Journal: Journal of Clinical Oncology (2011)

e16000 Background: Squamous cell carcinoma of the gingivobuccal complex (GBC) is the most common oral cancer in India (Pathak et al. Head Neck 2005;27:597-602). Majority of patients with GBC are detected at an advanced stage (Pathak et al. Head Neck 2005;27:597-602). Locoregional recurrence remains the major problem after curative intent treatment (Pathak et al. Head Neck 2005;27:597-602). Advanced GBC tumors involve multiple structures and there is no study in literature that has systemically evaluated GBC tumors for pattern of invasion into various structures and extent of their involvement. Methods: All the patients underwent a standard surgical resection (compartmental resection). Surgically resected specimen was systemically evaluated for all the structures involved, their extent of involvement and their margin status. Detailed clinical history, findings of computed tomography scanning (CT scanning) and findings of pathologic evaluation were compared and results were evaluated. Results: Twenty-six patients with advanced GBC tumors (stage T4) were included in this study. Skin and mandible were involved in 12 cases while pterygoid muscles in 20 cases and masseter muscle in 21 cases. Lymphnodes were involved in ten cases and in six instances only one lymphnode was positive. Imaging missed the diagnosis of Infratemporal fossa (ITF) involvement in 7 cases and recent onset trismus was a better marker to predict ITF involvement. Margins were positive in two cases. Conclusions: Advanced GBC tumors have significant soft tissue extension and involve multiple structures. They are locally aggressive cancers with low lymphnode involvement. Structure Clinical Radiology Pathology Skin 16 13 12 Mandible 18 12 12 Maxilla 8 7 8 Infratemporal fossa 24 13 20 Node 6 6 10
Role of PET/CT scanning in detecting asymptomatic brain metastases in non-small cell lung cancer
Authors: S. Virani, M. Almubarak, G. Marano, J. S. Rogers
Journal: Journal of Clinical Oncology (2009)

e19038 Background: Up to one-third of non-small cell lung cancer (NSCLC) patients are diagnosed with brain metastasis. Our study aims to evaluate the role of whole body and brain FDG-PET/CT in detecting asymptomatic brain metastasis in this population. Methods: We performed a retrospective chart review of 282 consecutive non-small cell lung cancer patients between February of 2005 and June of 2008. 60 patients with brain metastasis were identified. Information regarding tumor histology and presence of neurological symptoms at the time of discovery of brain metastasis was collected. In addition, data was acquired from brain MRI and PET/CT (with IV contrast) reports including: study date, findings and any change in staging secondary to the study. Results: The median age was 63 years (47 % women). 39 (65%) of the patients had neurological symptoms at the time of discovery of brain metastasis. PET/CT scan with IV contrast was performed in 53 patients with brain metastasis. For patients who had a PET/CT scan, the histological types were: adenocarcinoma (58.4%), unclassified (22.6%), squamous (13.2%), large cell (3.8%) and other (1.8%). PET/CT scan had a sensitivity of 97.8% in detecting CNS metastasis seen on brain MRI. 19/53 patients were found to have asymptomatic brain metastasis on PET/CT scan (2 stage I, 1 stage II, 2 stage III and 13 stage IV). Overall, PET/CT scan resulted in upstaging of 5 asymptomatic and 6 symptomatic patients or 11/53 (20.7%). Conclusions: PET/CT scan with IV contrast has a high sensitivity in detecting brain metastasis in patients with NSCLC when compared to brain MRI. It is effective in detecting asymptomatic brain metastasis in this population. Those patients, who initially were thought to have non-metastatic disease, are spared inappropriate aggressive surgery or radiation. No significant financial relationships to disclose.
Abstract 12522: Preceding Starvation Prevents Acute Doxorubicin Cardiotoxicity via Autophagy Activation
Authors: Tomonori Kawaguchi, Genzou Takemura, Hiromitsu Kanamori, Akiko Tsujimoto, Kazuko Goto, Atushi Ogino, Takeyama Toshiaki, Takatomo Watanabe, Morishita Kentaro, Hisayoshi Fujiwara, Takako Fujiwara, Shinya Minatoguchi
Journal: Circulation (2011)

Doxorubicin is a highly effective antineoplastic drug, but its clinical use is limited by the adverse effects on the heart. Active autophagy has recently been reported in doxorubicin cardiotoxicity...
O051 : SOX9 is a novel cancer stem cell marker surrogated by osteopontin in human hepatocellular carcinoma
Authors: T. Kawai, K. Yasuchika, T. Ishii, H. Katayama, E.Y. Yoshitoshi, S. Ogiso, S. Kita, K. Yasuda, K. Fukumitsu, M. Mizumoto, E. Hatano, Y. Kawaguchi, S. Uemoto
Journal: Journal of Hepatology (2015)
A phase I trial of concurrent chemoradiotherapy (cCRT) with the conventional administration of docetaxel (D) and cisplatin (P) for dry-stage III non-small cell lung cancer (NSCLC) (JCOG9901DI)
Authors: N. Hida, S. Tsujimura, T. Fujii, K. Naoki, H. Kunikane, H. Okamoto, T. Shimizu, K. Watanabe
Journal: Journal of Clinical Oncology (2009)

7549 Background: In cCRT for locally advanced NSCLC, full dose chemotherapy with a new agent plus a platinum doublet is considered to have unacceptable toxicities. Consequently, weekly or split chemotherapy doses are often used. However, cCRT plus conventional regimens are expected to enhance systemic effects. This phase I trial aimed to establish the MTD of cCRT plus conventional administration of DP (conv-DP). Methods: Unresectable stage III NSCLC patients (pts) (&lt;70 years) with ECOG performance status 0–1 and adequate organ function were eligible. Pts received 60 Gy in 30 fractions by once daily radiotherapy. Concurrent P (day1; 60 mg/m 2 at levels 1–3, 80 mg/m 2 at level 4) and D (day1; 30 mg/m 2 at level 1, 40 mg/m 2 at level 2, 50 mg/m 2 at levels 3–4) were given every 4 weeks for at least 2, and up to 4 courses. DLT was defined as either Gr3/4 febrile neutropenia, Gr4 neutropenia lasting ≥ 4 days, Gr4 thrombocytopenia, Gr2 pneumonitis or any Gr3 non-hematological toxicities except for nausea, vomiting and alopecia. Results: Eighteen pts were enrolled from 06/1999 to 05/2006: 6 pts at levels 2 and 4, 3 pts at levels 1 and 4; 13 males; median age 60 years (range 43–70); stage IIIA/IIIB 5/13; histology Ad/Sq/Large 9/7/2. DLTs were observed for 3 pts at level 2 (D40/P60): Gr4 pneumonitis at level 3(D50/P60), Gr3 cerebral infarction and Gr3 atrial fibrillation. Although 3 cases were added at these levels, tolerability for each level was cleared, as DLTs occurred for ≤ 2 pts among 6. MTD was not detected, even at the highest dose (D50/P80). However, dose escalation was stopped, as D60/P80 was the recommended dose for chemotherapy alone in Japan. Radiotherapy (60 Gy) was completed for 15 pts. Seventeen pts received more than 2 courses of chemotherapy. No Gr3/4 esophagitis or severe hematologic toxicities were observed. Objective response rate was 89% and 1-yr survival rate was 55%. Conclusions: The recommended dose in this regimen was D50/P80, which was near the full dose for conv-DP. Based on these promising results, we are planning a phase II trial to evaluate the efficacy and toxicity of this cCRT with conv-DP therapy. No significant financial relationships to disclose.