tbuckley/cabot-search huggingface dataset:
PTU-009 Giant laterally spreading tumours of the papilla: endoscopic features, resection technique and outcome
Authors: A D Hopper, M J Bourke, S J Williams, M P Swan
Journal: Gut (2010)

<h3>Introduction</h3> Successful endoscopic papillectomy of conventional ampullary adenomas is well described. However, many authors recommend surgical ampullectomy for larger lesions with extra-papillary extension. Our objective was to describe the classification, technique and outcome for the endoscopic resection of giant laterally spreading tumours of the papilla (LST-P). <h3>Methods</h3> Over a 24-month period to May 2009, patients referred for endoscopic treatment of ampullary adenomas were enrolled prospectively. LST-P lesions were identified as adenomatous tumours arising from the major duodenal papilla, &gt;30 mm, extending beyond the papilla onto the duodenal wall, and involving up to 2/3 of the duodenal circumference. LST-P lesions were classified as per the Paris classification. All patients underwent pre-resection staging. Resection technique: The key aspect was en-bloc excision of the papilla. LST-P lesions with predominant vertical extra papillary extension (Paris 0-Is+IIa) were treated by initial maximal papillectomy. Following papillectomy, EMR of residual adenomatous tissue was performed. LST-P lesions with predominant lateral spreading morphology (Paris 0-IIa+Is) underwent EMR and submucosal injection at one edge to isolate the papilla, this allowed subsequent en-bloc papillectomy. In all these predominant lateral spreading adenomas injection directly placed into the papillary region before adjacent adenoma was removed was avoided as this could cause a sunken papillary region. Argon plasma coagulation was avoided. The aim was to remove all neoplastic tissue with snare resection. For ampullary adenomas &lt;30 mm complete en-bloc resection was performed without submucosal injection. A 5Fr pancreatic stent was attempted after papillectomy in all cases. Follow-up was performed at 3, 6 and 12-month intervals. <h3>Results</h3> 25 patients with ampullary adenomas were referred. In 10 patients identified with LST-P (mean age 70.2 years; size 30–80 mm) combination EMR and papillectomy was performed in a single session. Median admission duration was 1.0 night (range 0–35). Complications included bleeding (30%) and cholecystitis (10%), with no cases of pancreatitis or perforation. Adenoma recurrence at 3 months was found in one patient (10%). 15 patients were noted to have conventional ampullary adenomas &lt;30 mm (mean age 65). Comparing the bleeding and recurrence rates between the smaller and larger resection groups showed no significant statistical difference between bleeding (30% vs 7.7%: p=0.28) or recurrence (10% vs 23%: p=0.6). <h3>Conclusion</h3> Endoscopic resection of carefully staged LST-P is a viable therapeutic alternative to surgery. In experienced hands the outcomes are comparable to those for conventional ampullary adenomas.
Thalidomide-Dexamethasone vs Interferon-α-Dexamethasone as Maintenance Treatment after ThaDD Induction for Multiple Myeloma (MM): Final Analysis of a Prospective, Randomized Study.
Authors: Massimo Offidani, Claudia Polloni, Laura Corvatta, Maria-Novella Piersantelli, Piero Galieni, Giuseppe Visani, Francesco Alesiani, Massimo Catarini, Marino Brunori, Maurizio Burattini, Riccardo Centurioni, Mario Ferranti, Luciano Giuliodori, Marco Candela, Anna Mele, Monica Marconi, Pietro Leoni
Journal: Blood (2007)
Patterns of response and relapse in primary CNS lymphomas after first-line chemotherapy: imaging analysis of the ANOCEF-GOELAMS prospective randomized trial
Authors: E. Tabouret, C. Houillier, N. Martin-Duverneuil, M. Blonski, C Soussain, H. Ghesquières, R. Houot, D. Larrieu, P. Soubeyran, R. Gressin, E. Gyan, O. Chinot, L. Taillandier, S. Choquet, A. Alentorn, D. Leclercq, A. Omuro, M.L. Tanguy, K. Hoang-Xuan
Journal: Neuro-Oncology (2016)

Our aim was to review MRI characteristics of patients with primary CNS lymphoma (PCNSL) enrolled in a randomized phase II trial and to evaluate their potential prognostic value and patterns of relapse, including T2 fluid attenuated inversion recovery (FLAIR) MRI abnormalities.Neuroimaging findings in 85 patients with PCNSL enrolled in a prospective trial were reviewed blinded to outcomes. MRI characteristics and responses according to International PCNSL Collaborative Group (IPCG) criteria were correlated with progression-free survival (PFS) and overall survival (OS).Multivariate analysis showed that objective response at 2 months (P < .001) and at end of treatment (P = .015) were predictors of prolonged OS. Infratentorial location (P = .008) and large (>11.4 cm3) enhancing tumor volume (P = .006) were associated with poor OS and PFS, respectively. Ratio of change in product of largest diameters at early MRI evaluation but not timing of complete response achievement (early vs delayed) was prognostic for OS. Sixty-nine patients relapsed. Relapse in the brain (n = 52) involved an initial enhancing site, a different site, or both in 46%, 40%, and 14% of patients, respectively. At baseline, non-enhancing T2-FLAIR hypersignal lesions distant from the enhancing tumor site were detected in 18 patients. These lesions markedly decreased (>50%) in 16 patients after chemotherapy, supporting their neoplastic nature. Of these patients, 10/18 relapsed, half (n = 5) in the initially non-enhancing T2-FLAIR lesions.Baseline tumor size and infratentorial localization are of prognostic value in PCNSL. Our findings provide evidence that non-enhancing FLAIR abnormalities may add to overall tumor burden, suggesting that response criteria should be refined to incorporate evaluation of T2-weighted/FLAIR sequences.
Abstract 1745: NPY1 receptor specific peptide-drug-conjugates as novel treatment for metastatic breast cancer
Authors: Lutz Weber, Robert Rennert
Journal: Cancer Research (2015)

Abstract The NPY1 receptor is a known marker for breast cancer that was characterized first at the university hospital Bern by the group of Reubi. In healthy breast tissue the NPY2 receptor (NPY2R) can be found, expression of which is switched to the NPY1R in tumor tissues (Reubi et al., Cancer Res. 2001, 61, 4636-4641). Particularly high NPY1R densities were also found in tumor biopsies of patients suffering from Ewing's sarcoma, which is a rare, difficult to treat juvenile bone cancer (Körner et al., Clin. Cancer Res. 2008, 14, 5043-5049.). Our own results verify these literature reports, shown on a panel of patient biopsies where nearly 50% of the tumors strongly overexpress the NPY1R, whereas NPY2R could not be detected. OntoChem has developed peptide-drug-conjugates (“CytoPep”) that are selective agonists of the NPY1 receptor. As drugs we have used tubulin binding cytolysins and maytansines. CytoPep shall be developed as novel approach to treat Ewing's sarcoma and NPY1R expressing breast cancer. We will present data on in vitro and in vivo pharmacology of these PDCs. IN particular efficacy is directly correlated with NPY1R expression levels in cells. We will also demonstrate internalization studies, showing a fast and selective internalization into NPY1R expressing cells. These in vitro data will be compared with corresponding data from ADCs such as for example trastuzumab emtansine, that show a considerably slower internalization and efficacy. Citation Format: Lutz Weber, Robert Rennert. NPY1 receptor specific peptide-drug-conjugates as novel treatment for metastatic breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1745. doi:10.1158/1538-7445.AM2015-1745
Novel Complement Modulators for Paroxysmal Nocturnal Hemoglobinuria: Peptide and Protein Inhibitors of C3 Convertase Prevent Both Surface C3 Deposition and Subsequent Hemolysis of Affected Erythrocytes in Vitro
Authors: Antonio M. Risitano, Patrizia Ricci, Caterina Pascariello, Maddalena Raia, Christoph Q Schmidt, Yingxue Li, Edimara S Reis, Michela Sica, Rosario Notaro, Luigi Del Vecchio, Fabrizio Pane, Daniel Ricklin, John D Lambris
Journal: Blood (2012)
Similar Overall Survival and Toxicity After CB Transplanation with Co-Infusion of CD34+ Cells From a Third Party Donor Compared to Myeloablative MUD Stem Cell Transplantation In High Risk Patients
Authors: Mi Kwon, Maria Infante, Pascual Balsalobre, Cristina Muñoz, Ismael Buno, Jorge Gayoso, David Serrano, Jose L. Diez-Martin
Journal: Blood (2010)
Prospective studies on the routine use of a novel multivariant enzyme-linked immunosorbent assay for the diagnosis of autoimmune bullous diseases
Authors: Nina van Beek, Cornelia Dähnrich, Nora Johannsen, Susanne Lemcke, Stephanie Goletz, Franziska Hübner, Giovanni Di Zenzo, Marian Dmochowski, Kossara Drenovska, Shamir Geller, Michael Horn, Cezary Kowalewski, Ljiljana Medenica, Dedee F. Murrell, Aikaterini Patsatsi, Soner Uzun, Snejina Vassileva, Detlef Zillikens, Wolfgang Schlumberger, Enno Schmidt
Journal: Journal of the American Academy of Dermatology (2016)
Non-Selective Beta-Blockers (NSBB) for Prevention of Growth of Small Esophageal Varices in Patients With Cirrhosis: A Meta-analysis
Authors: Ashish Kumar, Praveen Sharma, Anil Arora
Journal: Clinical Gastroenterology and Hepatology (2016)

Non-selective beta-blockers (NSBBs) are recommended for prophylaxis of first variceal bleeding in patients of cirrhosis with large esophageal varices. However, the data is conflicting whether NSBBs can also prevent growth of small esophageal varices to large size. The aim of this study is to perform a meta-analysis of the randomised clinical trials comparing NSBBs with placebo for prevention of development of large esophageal varices in patients of cirrhosis with small esophageal varices. The PubMed, EMBASE, Science Direct, and Cochrane library databases were searched for relevant papers. A meta-analysis was performed using ORs with 95% CI as the effect sizes. Overall, 314 trials were initially retrieved from the database searches, of which three randomized controlled trials were included in the meta-analysis. The incidences of development of large varices (OR = 0.91, 95% CI: 0.29-2.86; P = 0.87), first variceal bleeding (OR = 0.82, 95% CI: 0.14-4.89; P = 0.83), and death (OR = 0.74, 95% CI: 0.44-1.24; P = 0.26) were similar between NSBB and placebo groups. However, the incidence of adverse events was significantly higher in the NSBB group compared with the placebo group (OR = 5.73, 95% CI: 2.16-15.23; P = 0.0005). The results of this meta-analysis indicate that NSBBs are not effective in preventing growth of small varices and may lead to significant adverse effects. Hence, NSBBs should not be recommended for cirrhotic patients with small varices.
Abstract 1410: Evaluation of the immunogenicity of ALDHhigh human head and neck squamous cell carcinoma cancer stem cells <i>in vitro</i>
Authors: Mark E.P. Prince, Li Zhou, Yang Xia, Huimin Tao, Jeffrey S. Moyer, Lin Lu, John Owen, Alfred E. Chang, Jianchuan Xia, Gregory Wolf, Max S. Wicha, Xiubao Ren, Yangyi Bao, Shiang Huang, Qiao Li
Journal: Cancer Research (2015)

Abstract Using mouse models we reported that dendritic cells (DC) pulsed with cancer stem cells (CSC) enriched by virtue of their expression of the CSC marker aldehyde dehydrogenase (ALDH) significantly reduced development of pulmonary metastases and prolonged survival. In this recent study, we established the concept that the antigenicity/immunogenicity of ALDHhigh human head and neck squamous cell carcinoma (HNSCC) cancer stem cells is distinct from that of ALDHlow non-CSCs. To this end, we generated CSC-loaded DCs to sensitize autologous peripheral blood lymphocytes to react with CSCs using human HNSCC samples in vitro. From peripheral blood and paired tumor tissues collected from 9 patients with HNSCC, we obtained PBMCs and established 4 HNSCC tumor cell lines. DCs generated from the PBMC and pulsed with the lysate of ALDHhigh cells isolated from cultured HNSCC cells (CSC-DC) could sensitize autologous T, B lymphocytes in vitro, which was evident by cytokine production, CTL activity, and antibody secretion of these primed T, B cells in response to ALDHhigh CSCs. In contrast, DCs pulsed with lysate of ALDHlow cells from the same HNSCC patient (ALDHlow-DC) resulted in limited sensitization/priming of autologous T, B lymphocytes to produce IFNγ, lyse CSCs, and secrete IgM and IgG in response to ALDHhigh CSCs. These results demonstrated significant differences in the antigenicity/immunogenicity between ALDHhigh CSCs vs. ALDHlow cells isolated from the tumor specimen of patients with HNSCC, which indicates the existence of unique CSC antigens in the ALDHhigh population. In addition, this study demonstrates that it is feasible to generate DCs from the PBMCs and isolate ALDHhigh CSCs from cultured tumor cells of the patients with HNSCC to prepare CSC-DC vaccines for clinical application. Citation Format: Mark E.P. Prince, Li Zhou, Yang Xia, Huimin Tao, Jeffrey S. Moyer, Lin Lu, John Owen, Alfred E. Chang, Jianchuan Xia, Gregory Wolf, Max S. Wicha, Xiubao Ren, Yangyi Bao, Shiang Huang, Qiao Li. Evaluation of the immunogenicity of ALDHhigh human head and neck squamous cell carcinoma cancer stem cells in vitro. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1410. doi:10.1158/1538-7445.AM2015-1410
EBI2 overexpression in mice leads to B1 B-cell expansion and chronic lymphocytic leukemia–like B-cell malignancies
Authors: Kristine Niss Arfelt, Line Barington, Tau Benned-Jensen, Valentina Kubale, Alexander L. Kovalchuk, Viktorija Daugvilaite, Jan Pravsgaard Christensen, Allan Randrup Thomsen, Kristoffer L. Egerod, Maria R. Bassi, Katja Spiess, Thue W. Schwartz, Hongsheng Wang, Herbert C. Morse, Peter J. Holst, Mette M. Rosenkilde
Journal: Blood (2016)
153. Efficient Expression of mRNA PEG-Peptide Polyplexes in Mouse Liver
Authors: Samuel T. Crowley, Jacob A. Poliskey, Kevin G. Rice
Journal: Molecular Therapy (2015)

The delivery of mRNA has garnered much attention in recent years as genome editing techniques such as CRISPR/Cas9, Zinc Finger endonucleases, and TALEN endonucleases have been developed. The short-term protein expression offered by mRNA is attractive in these situations, where long-term expression could cause unwanted side-effects. mRNA also has the chief advantage of not needing to enter the nucleus to produce protein, a major barrier to successful nonviral DNA delivery. However, mRNA is highly susceptible to degradation by nucleases, and methods must be developed to stabilize it in the bloodstream before it can used effectively in vivo. PEGylated polyacridine peptides1 have been shown to protect plasmid DNA in the bloodstream for up 12 hours through a combination of nuclease protection and scavenger receptor inhibition2, and the protected DNA was shown to remain transfection competent by the delayed hydrodynamic dosing of normal saline. In this study, PEGylated polyacridine peptides were used to form stabilized luciferase mRNA polyplexes. In vitro transcription of a codon optimized mRNA construct containing both a 5' and 3' β-globin untranslated regions (UTRs). This mRNA was found to be 2000-fold more efficient at expressing luciferase in mouse liver when delivering a 1 mg dose hydrodynamically compared to mRNA lacking UTRs. The gene transfer efficiency in mouse liver increased an additional 15-fold when HD-dosing 1 mg of UTR-mRNA polyplex. The combined use of UTR-mRNA and PEGylated polyacridine peptide increased the expression efficiency in liver 3500-fold over the only prior report of hydrodynamically delivered mRNA in liver3. PEGylated polyacridine peptide, but not a simple polylysine PEG-peptide lacking acridine groups, was able to protect UTR-mRNA polyplexes from direct serum digestion for up to 30 minutes, demonstrating that a PEGylated polyacridine peptide binds to and stabilizes double stranded regions in native mRNA.
Should we treat 'mild' hypertension?
Authors: N. H. McAlister
Journal: JAMA (1983)

MILD, essential hypertension has been defined as the "gray zone" between normal BP and essential hypertension that clearly warrants treatment.<sup>1</sup>While many agree that in adults diastolic BP (DBP) below 90 mm Hg is "normal," this upper limit is artificial. The Framingham study has been interpreted as showing a linear relationship between the subsequent development of cardiovascular disease and baseline DBP over 60 mm Hg<sup>2</sup>(although this interpretation has been disputed).<sup>3</sup>Normal DBP depends on age, sex, and race; but the use of 90 mm Hg as the universal upper limit of normotension seems safe and utilitarian. Defining the lower limit of DBP that clearly demands treatment is even more difficult. The Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure recommends that all patients with a DBP of 105 mm Hg or greater be treated.<sup>4</sup>The clinical effectiveness of treating such patients was shown
485. ZFN-Mediated Liver-Targeting Gene Therapy Corrects Systemic and Neurological Disease of Mucopolysaccharidosis Type I
Authors: Li Ou, Russell DeKelver, Susan Tom, Robert Radeke, Michelle Rohde, Amy Manning-Bog, Scott Sproul, Michael J. Przybilla, Brenda L. Komar, Kelly Podetz-Pedersen, Kanut Laoharawee, Renee D. Cooksley, Michael C. Holmes, Thomas Wechsler, R. Scott McIvor, Chester B. Whitley
Journal: Molecular Therapy (2016)

Mucopolysaccharidosis type I (MPS I) is characterized by progressive neurodegeneration, and premature death (<10 years). Caused by α-L-iduronidase (IDUA) deficiency and systemic accumulation of glycosaminoglycans (GAG), current therapies include stem cell transplant (with significant risk of morbidity and mortality), and enzyme replacement therapy (requiring costly and frequent long therapeutic infusion sessions). A promising alternative is genome editing by integration of a therapeutic hIDUA transgene using zinc finger nucleases (ZFN). We have previously demonstrated AAV-mediated in vivo targeting of the albumin locus as a "safe harbor" for coagulation factors, correcting clotting defects in hemophilic mice. Targeted insertion of a transgene into the genome offers multiple advantages. We can exploit the highly active albumin enhancer/promoter, such that stably modified hepatocytes demonstrate long-term transgene expression. Also, utilization of an endogenous promoter allows efficient packaging of the transgene donor into AAV. MPS I mice (n=8 per gender, 4-9 weeks old) were injected with a single dose of AAV2/8 encoding albumin-targeted ZFN and a donor encoding a partial hIDUA cDNA. MiSeq analysis showed that treated mice displayed significant levels of insertions/deletions (indels) (up to 56%) at the target locus, demonstrating efficient delivery and expression of the albumin ZFNs. Significant plasma IDUA activity was also observed in the ZFN+hIDUA donor treated mice, up to 10-fold of wild type levels, throughout the 120-day study. Urine GAG levels serving as a biomarker for hIDUA activity were reduced significantly (up to 90%). IDUA levels in these animals increased significantly in liver (up to 14 fold), heart, lung, muscle and spleen. Tissue GAG levels were significantly reduced in liver (by 91%), heart (85%), lung (86%), muscle (68%) and spleen (84%). Barnes maze tests at the end of the study showed that ZFN+hIDUA donor treated MPS I mice achieved significant neurological benefits compared with untreated MPS I mice. ZFN-mediated genome editing of hepatocytes in vivo thus resulted in high and stable levels of hIDUA expression in treated animals. This enzyme was secreted into plasma and then taken up by secondary tissues, leading to significant GAG reduction. The correction of the observable neurological impairment in MPS I mice suggests that a small but sufficient amount of hIDUA protein crossed the blood-brain barrier in these animals. The study provides a general "proof-of-concept" for treatment of lysosomal diseases.
Abstract LB-172: Novel candidate oncogenic drivers in pineoblastoma
Authors: Matija Snuderl, Kasthuri Kannan, Olga Aminova, Igor Dolgalev, Adriana Heguy, Arline Faustin, David Zagzag, Sharon L. Gardner, Jeffrey C. Allen, Jeffrey H. Wisoff, David Capper, Volker Hovestadt, Sama Ahsan, Charles Eberhart, Stefan M. Pfister, David T. w. Jones, Matthias A. Karajannis
Journal: Cancer Research (2015)

Abstract INTRODUCTION: Pineoblastoma (PB) is one of the rarest and most aggressive brain tumors of childhood. PB is considered a “primitive neuroectodermal tumor” (PNET) based on histology, and commonly treated using treatment protocols developed for medulloblastoma; however the survival remains poor. A subset of PBs may occur in the setting of germline mutations involving DICER1 or RB1, but no next-generation sequencing studies have been published on PB to date, and the genetic drivers of sporadic PB remain unknown. METHODS: 21 tumor samples with a histological diagnosis of PB (including recurrent/metastatic samples) from 15 patients were included in this study. Matching germline DNA was available from 2 patients. We performed genome-wide methylation array profiling (Illumina Infinium 450k) on all samples, as well as whole-genome (for samples with matching germline DNA) or whole-exome sequence analysis. Fluorescence in situ hybridization (FISH) and digital droplet PCR (ddPCR) was performed to confirm select focal somatic gains. RESULTS: 14/18 samples from 9/13 patients analyzed by 450k profiling had a methylation signature similar to previously profiled PBs from a reference cohort. Samples from 4 patients were found to be more consistent with a diagnosis of embryonal tumor with multilayered rosettes (ETMR) - like tumor (non 19q amplified), papillary tumor of the pineal region, or pineal parenchymal tumor of intermediate differentiation, respectively. No mutations in DICER1 or RB1 were found. Homozygous deletions in DROSHA were found in tumors from 3 PB patients. In addition, we identified novel recurrent somatic gains involving chromosomal region 1q21 that were confirmed by FISH and ddPCR in 4/5 PB patients. CONCLUSION: Our studies revealed multiple candidate drivers of oncogenesis in PB. We identified novel homozygous deletions in DROSHA, a nuclease involved in microRNA processing. We also identified novel, highly recurrent somatic focal gains involving chromosomal region 1q21, which has been linked to brain growth, autism and schizophrenia, but not previously associated with cancer. Citation Format: Matija Snuderl, Kasthuri Kannan, Olga Aminova, Igor Dolgalev, Adriana Heguy, Arline Faustin, David Zagzag, Sharon L. Gardner, Jeffrey C. Allen, Jeffrey H. Wisoff, David Capper, Volker Hovestadt, Sama Ahsan, Charles Eberhart, Stefan M. Pfister, David T. w. Jones, Matthias A. Karajannis. Novel candidate oncogenic drivers in pineoblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-172. doi:10.1158/1538-7445.AM2015-LB-172