tbuckley/cabot-search huggingface dataset:
ToTem: A phase Ib trial of temisirolimus with gemcitabine and cisplatin.
Authors: Simon Pacey, Robert J. Jones, Alison Claire Young, Andrew Protheroe, Alison J. Birtle, Javier Garcia Corbacho, Mirela Hategan, Sanjeev Kumar, Margaret Knowles, Paul Loadman, Gareth Griffiths, Angela Claire Casbard, Tracie-Ann Madden, Richard Adams, John David Chester
Journal: Journal of Clinical Oncology (2016)

e16032 Background: gemcitabine (G) and cisplatin (C) is a standard-of-care, combination chemotherapy regimen for neoadjuvant treatment of muscle-invasive and palliative treatment of advanced bladder cancer (BC). More effective regimens are urgently needed, with no significant improvements on GC in more than a decade. Mammalian target of rapamycin (mTOR) is a rational target for BC therapy, as abnormalities are commonly seen in mTOR’s upstream activators/downstream effectors in the PI3K/AKT/mTOR signaling pathway. We therefore performed a Phase Ib trial, combining escalating doses of the mTOR inhibitor, temsirolimus (T) with GC. Methods: following regulatory and ethical approvals, eligible patients with advanced malignancy were treated with one or more doses of intravenous (IV) T plus fixed doses of IV GC in a 21-day (d) cycle. Previous unpublished data suggest a possible interaction between G and T. We therefore pursued a cautious escalation strategy (see table), as a precaution against excessive toxicity. Results: 14 patients (3 BC, 2 lung, 2 ovarian, 7 other cancers; 7 previous platinum exposure) were treated, at 4 dose schedules in 2 UK centers. There were no treatment-related deaths or SUSARs. Of 14 SAEs, 4 were SARs, in 10 individuals, 7 of whom had received IMP. Addition of 10mg T on d15, then d8&15 was tolerated, but DLTs were encountered when administering three 10mg doses of T, both on d1,8&15 (neutropenia; hypokalaemia) and d2,9&15 (febrile neutropenia; rash). T was omitted because of myelosuppression on d15, cycle 1 in 6/8 patients scheduled to receive 3 doses of T. Conclusions: it has not been feasible to add three, weekly doses of T to GC, even at low T doses, in the patient group tested, because of predominantly hematological toxicity. We plan to amend the schedule to include two doses of T, on d2&9, informed by data from pre-planned PK analyses of patients already treated. ToTem was developed by the UK NCRI Bladder Cancer Clinical Studies Group, sponsored by Cardiff University, funded by Cancer Research UK, and supported by supply of free drug and distribution costs from Pfizer. Clinical trial information: 31546330.Cohort Cisplatin (mg/m2) d1 Gemcitabine (mg/m2) d1&8 Temsirolimus (mg) d1 d2 d8 d9 d15 1 70 1000 10 2 70 1000 10 10 3a 70 1000 10 10 10 3b 70 1000 10 10 10
The use of esophageal stent in controlling acute refractory variceal bleeding
Authors: Gin‐Ho Lo
Journal: Hepatology (2016)

I read with interest the article by Escorsell et al. regarding the comparison between esophageal balloon tamponade and esophageal stent in controlling acute refractory variceal bleeding.1 The authors demonstrated that esophageal stent was superior to balloon tamponade in controlling acute refractory variceal bleeding, with fewer severe adverse events and similar survival. However, several points need further clarification. Firstly, the current trial enrolled only 28 patients, and 16 of them were actually good candidates for receiving early transjugular intrahepatic portosystemic shunt (TIPS).2 The options to use balloon tamponade or esophageal stent in hospitals with available expertise for TIPS appear to be against medical ethics. Secondly, 11 patients in this trial were enrolled for massive variceal bleeding. Balloon tamponade was instituted for 24 hours, and esophageal stent was placed for 7 days. In clinical practice, the use of either balloon tamponade or esophageal stent serves as a bridge to definitive therapies such as endoscopic therapy or TIPS. Thus, the duration of either balloon tamponade or esophageal stent placement should be as short as possible to reduce potential complications such as aspiration pneumonia. Thirdly, absence of bleeding at 15 days was significantly better in the stent group than the tamponade group. Prior to assessment for the absence of bleeding at 15 days, there was a significantly higher incidence of patients in the stent group receiving combined banding ligation plus nonselective beta-blockers and a higher incidence of patients in the tamponade group treated with TIPS. This may imply that stent insertion followed by combined banding ligation plus nonselective beta-blockers was superior to the use of tamponade followed by TIPS. Six of 15 patients (40%) in the tamponade group died of hypovolemic shock. This incidence was higher than in previous reports on the treatment for high-risk variceal bleeding.3, 4 Apart from 10 patients who received TIPS, it appeared that another 5 patients did not receive definitive therapy after removal of balloon tamponade. Fourthly, 1 patient allocated to the esophageal stent group failed to be deployed and then received balloon tamponade. This may prove that it is technically easier to deploy balloon tamponade than esophageal stent. Though esophageal stent is proven to be more effective and safer than balloon tamponade in the therapy of acute refractory esophageal variceal hemorrhage, cautious use of balloon tamponade is still a viable modality in most medical centers. Gin-Ho Lo, M.D. Department of Medical Research Digestive Center, E-DA Hospital School of Medicine for International Students I-Shou University Kaohsiung, Taiwan
Abstract LB-002: Methylation of the EGF receptor regulates signaling and therapeutic response
Authors: Hsin-Wei Liao, Jung-Mao Hsu, Weiya Xia, Mien-Chie Hung
Journal: Cancer Research (2016)

Abstract Epidermal growth factor receptor (EGFR)-targeted monoclonal antibody, cetuximab, is one of the most effective ways of controlling colorectal cancer progression. However, resistance to cetuximab has been observed in clinical setting. Here, we report a mechanism contributing to cetuximab resistance in which protein arginine methyltransferase 1 (PRMT1) methylates the extracellular domain of EGFR at R198 and R200, leading to an increase in the binding affinity between EGF and methylated EGFR, and subsequently receptor dimerization, downstream signaling activation, and cell proliferation in vitro. R/K mutation of the EGFR methylation sites reduces tumor growth in mouse orthotopic xenograft model. Increased EGFR methylation retains its signaling activation and cell proliferation in the presence of cetuximab. Importantly, EGFR methylation level is correlated with higher recurrence rate after cetuximab treatment and poor overall survival, suggesting that the methylation status of EGFR has the potential to predict resistance to cetuximab treatment in colorectal cancer and head and neck cancer patients. Citation Format: Hsin-Wei Liao, Jung-Mao Hsu, Weiya Xia, Mien-Chie Hung. Methylation of the EGF receptor regulates signaling and therapeutic response. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-002.
An Electrocardiogram-Based Risk Equation for Incident Cardiovascular Disease From the National Health and Nutrition Examination Survey
Authors: Amit J. Shah, Viola Vaccarino, A. Cecile J. W. Janssens, W. Dana Flanders, Suman Kundu, Emir Veledar, Peter W. F. Wilson, Elsayed Z. Soliman
Journal: JAMA Cardiology (2016)

Electrocardiography (ECG) may detect subclinical cardiovascular disease (CVD) in asymptomatic individuals, but its role in assessing adverse events beyond traditional risk factors is not clear. Interval and vector data that are commonly available on modern ECGs may offer independent prognostic information that improves risk classification.
Abstract 730: The roles of FGF-2-NCAM/FGFR1 interplay in esophageal squamous cell carcinomas and its microenvironment including tumor-associated macrophages
Authors: NOBUHISA TAKASE, Yuichiro Koma, Noriaki Arai, Himiko Kodaira, Masayoshi Hosono, Yumi Ichihara, Mari Nishio, Manabu Shigeoka, Hiroshi Yokozaki
Journal: Cancer Research (2016)

Abstract Tumor-associated macrophages (TAMs) have important roles in the angiogenesis, tumor immunosuppression and tumor infiltration of various cancers. Previously, we reported that a large number of infiltrated tumor promoting CD204+ TAMs within esophageal squamous cell carcinomas (ESCCs) contributed to the significant association of clinicopathological malignancy and poor disease free survival. However, the relevant malignant progression mechanisms have not been studied explicitly yet. To elucidate roles of TAMs in ESCCs, we established an in vitro macrophage model using human peripheral blood acquired by healthy volunteer donors. Peripheral blood monocytes were treated with 25 ng/mL recombinant human M-CSF for 6 days to induce macrophage-like differentiation (macrophage-like cells), then exposed to the conditioned media of TE series ESCC cell lines (TECM) for 2 days to induce TAM-like cells. From the cDNA microarray data between macrophages-like cells treated with and without TECM, we interested in upregulated genes. Among highly expressed genes in TAM-like cells, we focused on neural cell adhesion molecule (NCAM) which was a possibility to act on the regulation between tumor and its surrounding stroma. Gene knockdown of NCAM by siRNA in TAM-like cells revealed significant suppression of cell survival and migration via decrease of PI3K/Akt signaling and downregulation of fibroblast growth factor receptor 1 (FGFR1) expression. Interestingly, fibroblast growth factor-2 (FGF-2) derived from ESCCs promotes FGF2/FGFR1 autocrine loop, and activates FGFR1 signaling in TAM-like cells. Furthermore, we analyzed 70 ESCC tissue samples by immunohistochemistry whether the expression levels of FGF-2 were associated with clinicopathological background factors of ESCC patients. Relationships of the expression levels of FGF-2 in human ESCC stromal cells including macrophages had a correlation with the depth of invasion, blood vessel invasion, TNM classification UICC cancer staging and high number of infiltrating CD163 positive and CD204 positive macrophages as a marker for the M2 macrophage phenotype. These findings may indicate novel roles of FGF-2-NCAM/FGFR1 interplay in ESCCs and its microenvironment including TAMs. Citation Format: NOBUHISA TAKASE, Yuichiro Koma, Noriaki Arai, Himiko Kodaira, Masayoshi Hosono, Yumi Ichihara, Mari Nishio, Manabu Shigeoka, Hiroshi Yokozaki. The roles of FGF-2-NCAM/FGFR1 interplay in esophageal squamous cell carcinomas and its microenvironment including tumor-associated macrophages. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 730.
Infectious Disease Expert Sees Threat From Colistin-Resistant Superbug
Authors: Jennifer Abbasi
Journal: JAMA (2016)

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Abstract 3818: Therapeutic potential of blocking CCR5 by maraviroc in breast cancer bone metastasis
Authors: Asim Pervaiz, Michael Zepp, Doaa M. Ali, Martin R. Berger, Hassan Adwan
Journal: Cancer Research (2016)

Abstract Introduction: Bone metastasis is a highly unfavorable condition observed in up to 70% of the patients with breast cancer. Treatment options for this condition are not curative, but palliative, only, which highlights the need for exploring new therapeutic options. In this study, we propose that targeting a chemokine receptor (CCR5), often upregulated in primary and secondary breast cancers, can contribute to a more successful treatment of breast cancer bone metastasis. Methodology: Following the blockage of CCR5 by maraviroc, cytotoxic effects were measured by MTT assay, while the migratory effects were determined by migration and scratch healing assays. Apoptosis related activities were investigated by nuclear staining and western blot analysis. Maraviroc mediated cytostatic changes were analyzed by a ready-made Human Cell Cycle Regulation Panel (Roche, Germany). In vivo experiments were performed by implanting MDA-MB-231 cells via the saphenous artery to the left hind limb of male nude rats (RNU strain) for inducing bone metastasis. Treatment with maraviroc was started from 2nd and 7th day of transplantation in two groups of rats (n = 6/group) designated as A and B, respectively, and was compared with an untreated control group (n = 8 rats). Results: CCR5 blockage by maraviroc (concentration &amp;gt; 100μM) induced concentration dependent cytotoxicity in MDA-MB-231 and MCF-7 cells. Maraviroc exposure also showed significant inhibition of migration of the cells, while nuclear staining indicated the condensation/fragmentation of nuclear content. Maraviroc exposure induced significant expression of cleaved caspase 7 and PARP, while real time RT-PCR showed pronounced inhibition of multiple genes (≥2fold) including cyclins, CDKs and their down-stream targets. Treatment of tumor bearing animals, with intra-peritoneal injections of maraviroc (25mg/kg, 3-4 weeks daily), reduced the tumor burden significantly (p &amp;lt; 0.05) in group A (50-75%), while the effects were minimal in group B (&amp;lt;25%). Concomitantly, no signs of toxicity were observed in rats of the two groups. Conclusion: CCR5 blockage by maraviroc induces significant anti-neoplastic effects in breast cancer cells. At mechanistic level, these effects included induction of apoptosis and alterations in cell cycle. Considerable inhibition in group A, but minimal inhibition of tumor burden in group B indicates that targeting CCR5 by maraviroc during early stages of breast cancer bone metastasis is a promising treatment option which should be further explored. Citation Format: Asim Pervaiz, Michael Zepp, Doaa M. Ali, Martin R. Berger, Hassan Adwan. Therapeutic potential of blocking CCR5 by maraviroc in breast cancer bone metastasis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3818.
간암과 감별이 필요한 양성 병변: 혈관성 병변
Authors: 탁원영
Journal: Clinical and Molecular Hepatology (2012)

Focal lesions of the liver are commonly found in middle aged and older patients because of increasing usage and improved sensitivity of imaging modalities. Focal lesions of the liver often have various imaging characteristics which may be interpreted as either benign or malignant. Benign lesions include cystic lesions, vascular lesions, benign tumors, pseudo lesions, and various infectious lesions. Hepatic hemangioma is known as the most common benign hepatic tumor and other vascular lesions are not common. Clinical significance of these vascular lesions is differentiation from other tumors. Understanding the underlying pathophysiology of these lesions may lead to characteristic imaging manifestations, which direct the radiologist to the diagnosis. We reviewed the characteristic imaging features, clinical symptoms, treatment and prognosis of the several hepatic vascular lesions based on the recent literatures.
Predicting the in vivo accumulation of nanoparticles in tumor based on in vitro macrophage uptake and circulation in zebrafish
Authors: Hyeyoun Chang, Ji Young Yhee, Gun Hyuk Jang, Dong Gil You, Ju Hee Ryu, Yongwhan Choi, Jin Hee Na, Jae Hyung Park, Kwan Hyi Lee, Kuiwon Choi, Kwangmeyung Kim, Ick Chan Kwon
Journal: Journal of Controlled Release (2016)
Abstract 5155: Integrated genomic analysis of colorectal cancer progression reveals activation of EGFR through demethylation of the EREG promoter
Authors: Xueping Qu, Thomas Sandmann, Henry Frierson, Ling Fu, Eloisa Fuentes, Kimberly Walter, Kwame Okrah, Craig Rumpel, Christopher Moskaluk, Shan Lu, Yulei Wang, Richard Bourgon, Elicia Penuel, Andrea Pirzkall, Lukas Amler, Mark Lackner, Josep Tabenero, Garret Hampton, Omar Kabbarah
Journal: Cancer Research (2016)

Abstract The molecular drivers that underlie transformation of colonic epithelium into colorectal adenocarcinoma (CRC) have been well described. However, the mechanisms through which some of the clinically targeted pathways are activated during CRC progression have yet to be elucidated. Here, we employed an integrative genomics approach to examine CRC progression. Transcriptional profiling of laser capture microdissected colonic crypt cells, differentiated surface epithelium, adenomas, carcinomas, and metastases, showed distinctive patterns in the activation of developmental and oncogenic pathways, including the clinically important EGFR axis. We observed a dramatic up-regulation of the EGFR ligand EREG in primary and metastatic cancer cells as compared to normal and adenomatous tissues that was indicative of autocrine tumor production, and confirmed this pattern of gene expression by in situ hybridization. Global methylation analysis indicated that up-regulation of EREG during the adenoma-carcinoma transition was associated with de-methylation of two key sites within the EREG promoter and this was accompanied by an increase in the levels of EGFR phosphorylation, as assessed by reverse phase protein analysis. In a clinical trial setting, we observed that low levels of EREG methylation in patients who received cetuximab as part of a Phase II study were associated with high expression of the ligand and a favorable response to therapy. Conversely, high levels of promoter methylation and low levels of EREG expression were observed in tumors that progressed after treatment. We also noted an inverse correlation between EREG methylation and expression levels in several other cancers from the TCGA datasets, including those of the head and neck, lung, and bladder. We propose that up-regulation of EREG expression through promoter de-methylation might be an important means of activating the EGFR pathway during the genesis of CRC and, potentially, other types of cancer. Citation Format: Xueping Qu, Thomas Sandmann, Henry Frierson, Ling Fu, Eloisa Fuentes, Kimberly Walter, Kwame Okrah, Craig Rumpel, Christopher Moskaluk, Shan Lu, Yulei Wang, Richard Bourgon, Elicia Penuel, Andrea Pirzkall, Lukas Amler, Mark Lackner, Josep Tabenero, Garret Hampton, Omar Kabbarah. Integrated genomic analysis of colorectal cancer progression reveals activation of EGFR through demethylation of the EREG promoter. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5155.
Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease
Authors: Saurav Singh, Alexander Grabner, Christopher Yanucil, Karla Schramm, Brian Czaya, Stefanie Krick, Mark J. Czaja, Rene Bartz, Reimar Abraham, Giovana S. Di Marco, Marcus Brand, Myles Wolf, Christian Faul
Journal: Kidney International (2016)
MicroArrays comparative genomic hybridisation (aCGH) and response to neoadjuvant chemotherapy (CT) in breast cancer (BC)
Authors: J. Y. Pierga, S. J. Cleator, J. S. Reis-Filho, T. Dexter, A. Mackay, P. Simpson, A. Ashworth, I. E. Smith, T. Powles, M. Dowsett
Journal: Journal of Clinical Oncology (2005)

607 Background: To develop comprehensive molecular predictors of response to neoadjuvant CT in breast cancer, we combined aCGH with expression profiling (cDNA arrays). Methods: Microdissected frozen breast core biopsies from 43 patients (pts) with operable BC were obtained before a neoadjuvant combination of doxorubicin-cyclophosphamide. In 17 pts, samples were also obtained 3 weeks after the first course of CT. aCGH was performed in 41 pts using ‘in-house’ microarrays containing ∼5.8K BAC clones, which comprise the whole genome in intervals of 1Mb. Data were analysed using CGH Analyser and an aCGH package built on S-Plus platform. We compared the aCGH results with expression profiling data of the same cases performed on an ‘in-house’ cDNA array with 4.6K clones. Results: 18/41 (44%) pts had a poor response to CT. aCGH results were validated by means of repeated independent biological replicates, chromosomal CGH and in situ hybridisation for HER2/neu (with a concordance of 97.5%). The most frequent genomic changes comprised gains of 1q (39%), 5p (34%), 8q (34%), 20q (24%), with the minimal regions of amplifications on 1q21.1, 1q32.1–32.2, 5p15.1, 8q22.1-q24.22, 20q13.12 and 20q13.13.q13.2, respectively. Losses were observed on 9p (24%), 5p (22%) and 16q (19%), with the minimal regions of deletion on 9p13.1-p12, 5p15.1, 16q22.1, 16q22.3 and 16q23.1-q23.3. Hierarchical clustering analysis based upon genetic alterations on all chromosomes showed that all but 1 pair of pre and post biopsies clustered together (correlation coefficients: 0.94–0.47) with a higher correlation in poor compared to good responders (p=0.013, Kolmogorov-Smirnov test). Gains on 8q23.3 and losses on 13q34 were the most significantly associated with poor response (p=0.01, Fisher exact Test). We detected correlations between amplifications and overexpressed genes in our predictive set for response. Conclusions: Specific chemotherapy-driven genomic changes were not detected following 3 weeks of treatment aCGH is a powerful method for the genome-wide detection of chromosomal imbalances and may be used in conjunction with expression profile data to build more biologically meaningful classifiers No significant financial relationships to disclose.