tbuckley/cabot-search huggingface dataset:
Treatment of biliary strictures with fully covered self-expandable metal stents after pancreaticoduodenectomy
Authors: Hitoshi Shibuya, Kazuo Hara, Nobumasa Mizuno, Susumu Hijioka, Hiroshi Imaoka, Masahiro Tajika, Tsutomu Tanaka, Makoto Ishihara, Yutaka Hirayama, Tsukasa Yoshida, Nozomi Okuno, Nobuhiro Hieda, Patommatat Bhanthumkomol, Yasuhiro Shimizu, Yoshiki Senda, Seiji Natsume, Yasumasa Niwa, Kenji Yamao
Journal: Endoscopy (2016)

<b>Background and study aims</b> Anastomotic stricture is a late complication after biliary reconstructive surgery, but standard treatments are currently lacking. We selected patients who had undergone pancreaticoduodenectomy and Child's procedure, and aimed to evaluate the safety and efficacy of temporary placement of fully covered self-expandable metal stents (FCSEMSs) to treat postoperative anastomotic stricture. <b>Patients and methods</b> This study retrospectively analyzed 13 patients who underwent treatment with FCSEMSs for anastomotic stricture between June 2011 and March 2016. We evaluated technical and clinical success, complications, duration of patency after FCSEMS removal, and re-stenosis. <b>Results</b> All of the anastomotic strictures were improved by FCSEMS placement and luminal patency was maintained throughout the follow-up period, with no complications. After 2 months, the FCSEMSs were removed endoscopically in nine patients, and in four patients the stent had been expelled spontaneously per rectum. Median duration of follow-up was 225 days (range 30 – 935 days). No re-stenosis occurred in any of the 13 cases following stent removal. <b>Conclusion </b>Deployment of FCSEMSs for anastomotic stricture offers a safe and promising treatment that may replace percutaneous transhepatic biliary drainage and deployment of multiple plastic stents as the first-line treatment.
743. Minicircles Are Similar to Plasmids in Providing High Level, Long-Term Expression in the Lung
Authors: Deborah R. Gill, Reto P. Bazzani, Mary M. Connolly, Martin Schleef, Stephen C. Hyde, Ian A. Pringle
Journal: Molecular Therapy (2016)

Background: Many gene therapy applications require persistent transgene expression to treat chronic disease. We have previously developed CpG-free plasmids capable of robust, long-term transgene expression in the mouse lung (Hyde et al; 2008 Nat. Biotech. 26:549) and confirmed their utility in clinical trials, where monthly aerosol delivery of plasmid/liposomes to patients with Cystic Fibrosis resulted in a stabilisation of their lung function over a 12-month period (Alton et al 2015 Lancet Respir. Med. 3:684). The removal of all CpGs from a plasmid, including the selection of a CpG-free promoter, can be time-consuming, therefore we evaluated which aspects of plasmid design were crucial for long-term transgene expression in the lung, including the use of minicircles instead of conventional plasmids. Results: First, we measured luciferase (Lux) expression in the lungs of BALB/c mice from a CpG-free transgene expression cassette (hCEFI-soLux) compared with a standard CpG-rich (hCEFI-Lux) cassette. Plasmid DNA was complexed with 25 kDa branched polyethylenimine (PEI) and delivered as an aerosol to the lungs of BALB/c mice (n=6 per time-point). Lux activity from the CpG-free hCEFI-soLux cassette was greater than its CpG-rich counterpart (p < 0.005) at every time-point (up to 28 days), with no loss of activity over the course of the study. Expression from the expression cassette containing CpGs, however, was not persistent, but declined to between 30% and 2% of respective day 1 levels by day 28 (p < 0.05). Next, we performed similar studies using minicircles, where the CpG-free and CpG-rich expression cassettes were manufactured as minicircles with minimal backbone sequences (209bp with 11 CpGs). When the CpG-free cassette was used there was no significant difference between Lux activity obtained from the plasmid and minicircles; in both cases robust expression persisted beyond the duration of the study (28 days). Finally, we investigated whether the detection of CpGs by the Toll-like receptor-9 (TLR9) signalling pathway played a role in the loss of expression from the CpG-rich cassette. The experiments were repeated in TLR9-deficient mice and the results showed that Lux levels were similar to those obtained in BALB/c mice. This indicated that the effect of CpGs on the in vivo expression profile (whether in the transgene cassette or backbone) is independent of the TLR9 pathway. Conclusion: These studies indicate that a CpG-free transgene cassette is crucial to achieving high levels of persistent expression in the murine lung, when delivered as a plasmid or minicircle. Minicircles have not yet been evaluated clinically, but they have several advantages over plasmids, including their reduced overall size such that a higher effective dose is delivered. These findings could also be applicable to other organs, such as muscle and liver.
Gene Expression Signature of B-Cell Chronic Lymphocytic Leukemia with Trisomy 12.
Authors: Edit Porpaczy, Martin Bilban, Elisabeth Kroemer, Georg Heinze, Michaela Gruber, Katrina Vanura, Daniel Heintel, Martin Hilgarth, Bernadette Hilgarth, Trang Le, Rainer Hubmann, Susanne Schnabl, Andreas Chott, Ilse Schwarzinger, Alexander Hauswirth, Cathrin Scrabs, Stephan Stilgenbauer, Oswald Wagner, Christa Fonatsch, Ulrich Jaeger, Medhat Shehata, Alexander Gaiger
Journal: Blood (2007)
Clinical significance of elevation of the serum IL-6 level in patients with advanced pancreatic cancer.
Authors: S. Mitsunaga, M. Ikeda, K. Nakachi, I. Ohno, S. Shimizu, H. Takahashi, H. Okuyama, M. Inagaki, J. Furuse, A. Ochiai
Journal: Journal of Clinical Oncology (2011)

181 Background: IL-6, one of the pro-inflammatory cytokines, is a recognized mediator of cachexia and cancer cell invasion. It has been reported that elevation of the serum IL-6 level may be associated with deterioration of the clinical condition and tumor progression in advanced pancreatic cancer (PC) patients. The aim of this study was to clarify the clinical features of increased serum IL-6 levels in patients with advanced PC receiving chemotherapy. Methods: Patients with treatment-naïve unresectable PC and no obvious infectious conditions were eligible for this study. Serum levels of IL-6 were measured by an electrochemiluminescence assay. Symptoms were rated numerically from 0 to 10 using the Japanese version of the M. D. Anderson Symptom Inventory. Tumor volume was calculated as the sum of the long diameters of the tumors. The measurements were performed before chemotherapy and at one month after the start of chemotherapy. Results: A total of 87 patients (male/female: 41/46; ECOG performance status: 0/1/2: 59/26/1; media age: 66 years) were enrolled; all patients were administered systemic chemotherapy (gemcitabine [GEM]/GEM+S-1/GEM+other/S-1: 52/11/9/15). The median serum level of IL-6 was 1.3 pg/mL before chemotherapy (at baseline) and 1.8 pg/mL at one-month after the start of chemotherapy. The median change of IL-6 from the baseline was +0.18 pg/mL. Patients with increase of the serum IL-6 level by more than 0.18 pg/mL were assigned to the elevated IL-6 group (n=42; median change in IL-6: +1.66 pg/mL). The elevated IL-6 group showed more sadness (p=0.019), numbness (p=0.008), and gain of body weight (p=0.016) at the baseline as compared to the non-IL-6-elevated group (n=42; median change in IL-6: -0.27 pg/mL). Comparison of the elevated and non-IL-6-elevated groups revealed a greater degree of increase in the tumor volume (p=0.015), deterioration of nausea (p=0.046) and vomiting (p=0.028), neutrophilia (p=0.004), and elevation of the serum C-reactive protein (p=0.011) in the elevated IL-6 group than in the non-IL-6-elevated group. Conclusions: Elevation of the serum IL-6 level may be associated withsymptom deterioration, increase of the tumor mass, and inflammatory reaction in patients with advanced PC. No significant financial relationships to disclose.
Equatorial Guinea, a multidrug-resistant tuberculosis hotspot in Central Africa
Authors: Santiago Izco, Juan Eyene, Laura Pérez-Lago, Marta Herranz, Lucía Biyé, Jürgen Noeske, Felipe Pérez-García, Deograciana Omoha, María-Jesús Ruiz-Serrano, Marcial Ondó, Teodora Mbang, Juan-Carlos Momo, Maxima Angue, Teresa-Sabina Ebee, Darío García-de-Viedma, Emilio Bouza
Journal: European Respiratory Journal (2016)

The national tuberculosis programme (NTP) of Cameroon has recently reported that an alarming number of tuberculosis (TB) patients are border-crossing from neighboring Equatorial Guinea to seek multi-drug-resistant tuberculosis (MDR-TB) treatment [1, 2]. The World Health Organization (WHO) African Region is reported to bear a low MDR-TB proportion of new tuberculosis cases (2.1%) compared with other WHO regions [3]. Nonetheless, there are big differences between African countries, and data on MDR-TB burden are still lacking from almost half of them. Some could hide true MDR-TB hotspots, brought about by weak diagnostic and control capacities and fueled by health and social factors of vulnerability [4, 5]. A survey of rifampicin-resistant tuberculosis in Equatorial Guinea unveiled a hot spot of MDR-TB in central Africa <http://ow.ly/YeOl304cqxT> We are grateful to Lluís Tartera for his help with the figures and to CRCE project (funded by AECID) for helping S. Izco with accommodation and some logistical aspects in Equatorial Guinea.
Transmucosal fentanyl (TF) and breakthrough pain (BP): Systematic review of literature and meta-analysis of randomized clinical trials (RCTs).
Authors: E. Tamburini, D. Tassinari, L. Gianni, C. Pittureri, M. Maltoni, M. Papi, F. Drudi, G. Pasini, M. Fantini, E. Amaducci, A. Ravaioli
Journal: Journal of Clinical Oncology (2011)

e19672 Background: Historically the use of immediate-release morphine was the standard of care in the treatment of BP. The aim of our review was to analyze the use of TF in the control of BP, exploring the possibility of detecting some applications in clinical practice. Methods: A systematic review of MEDLINE, EMBASE and Cochrane Systematic reviews databases from January 1966 to January 2011 was performed independently by two Authors (ET and DT). A systematic review of the main oncologic and palliative congress reports of the period 2000-2010 was performed by the same Authors. All randomized phase III trials comparing TF with placebo or other approaches in treatment of BP were considered eligible and included in the selection. Primary end point was pain intensity difference at 15 minuts (PID15). Secondary endpoint were pain intensity difference at 30 minuts (PID 30). Heterogeneity between the trials was assessed using the Mantel-Haenszel test. An alpha error <5% was assumed as index of statistical significance. Results: 835 patients in 10 trials were randomized to placebo or TF in the treatment of BP. 468 patients in 6 trials were randomized to TF or other approaches. A significant improve in PID 15 (p<0.0001, difference in means 0.6) and PID 30 (P<0.0001, difference in means 1.033) were observed in patients treated with TF when compared with placebo. Conclusions: TF significantly improve PID 15 and PID 30 when compared with placebo. Howewer literature data appears inconclusive on the role of immediate-release morphine compared with TF and on the effectiveness of different formulations of TF. Further trials, comparing different formulations of fentanyl and comparing fentanyl and oral morphine are probably still needed to better define the role of TF in the treatment of BP.
Abstract 1877: Age at introduction to solids is associated with the odds ratio of pediatric acute lymphoblastic leukemia
Authors: Jeremy M. Schraw, Michael Scheurer, Michele R. Forman
Journal: Cancer Research (2015)

Abstract Introduction: Breastfeeding for &amp;gt; 6 months is associated with protection from acute lymphoblastic leukemia (ALL) (OR 0.81 95% CI 0.72-0.91), the most common pediatric cancer in the United States. These data are based on any breastfeeding. There is little research concerning infant formula or solid food consumption patterns and risk of pediatric ALL. We previously identified greater duration of milk formula feeding and later age at introduction to solid foods as risk factors for ALL. The purpose of this study was to determine whether the increased OR of ALL was confined to children who began receiving solids after 4 or 6 months of age. Methods: 172 incident cases of ALL aged 0-14 years were recruited at Texas Children's Cancer Center (TCCC) and matched on sex, age at diagnosis/interview and ethnicity to 344 healthy population-based controls from Houston, San Antonio and Austin, Texas. Data were collected on sociodemographics, infant feeding patterns and known or hypothesized risk factors for ALL. Logistic regression was used to model the OR of ALL according to quartile of age at introduction of solids with the first/earliest quartile as the reference group. Results: In adjusted models, the OR of ALL among children in quartile 3 (7-9 months) was 3.43, 95% CI 1.66 - 7.09; for children in quartile 4 (≥ 10 months) the OR was 4.19, 95% CI 2.00 - 8.75. Each additional month of milk formula feeding was associated with a 7% increase in the OR of ALL (95% CI 1.02 - 1.12). The OR of ALL among non-Hispanic compared to Hispanic children was 1.76 (95% CI 1.10 - 2.84). Discussion: These results support our published findings that later introduction to solids is positively associated with ALL. Our finding of lower risk among Hispanic children contrasts with previous research indicating this group is at greater risk than non-Hispanics. Citation Format: Jeremy M. Schraw, Michael Scheurer, Michele R. Forman. Age at introduction to solids is associated with the odds ratio of pediatric acute lymphoblastic leukemia. [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 1877. doi:10.1158/1538-7445.AM2015-1877
719. Stability Could Be a Weak Point for Gene Therapy Sponsors
Authors: Dominique Kissick
Journal: Molecular Therapy (2016)

So far, no gene therapy product has been approved by the Food and Drug Administration (FDA). One gene therapy for an extremely rare disease was approved in Europe in 2012, but questions about its effectiveness remain. Gene therapy refers to products that introduce genetic material into a person's DNA to replace faulty or missing genetic material, thus treating a disease or abnormal medical condition. There have been hundreds of trials of gene therapy in humans since 1990, and few gene therapies have reached advanced stages of development and have been submitted for authorization. Therefore, regulators have not yet worked out how best to assess gene therapy. While the same requirements as other medicinal products generally apply to the clinical development of gene therapies, regulators recognize that there might be cases where the principles might not apply and have issued guidance specific to gene therapy in order to facilitate product development and marketing approval. The shelf lives of gene therapy products may vary widely, depending on the nature of the product and its storage conditions. The design of stability testing should be based on a comprehensive understanding of the final product and its intended use. Testing should be based on real-time, real-temperature studies and should include a measure of product integrity, sterility, identity, purity, quality and other applicable assays. Additionally, potency assays should measure a relevant biological functionality either in vitro or in vivo. Interaction with the FDA however indicates that, beyond what is provided in the current guidelines, the regulators will likely scrutinize the results from the stability program for gene therapy during submission for marketing approval. Therefore, establishing shelf life and storage conditions of gene therapy products would most likely be a weak point for gene therapy sponsors. Even if the stability protocols follow the current guidelines, because the gene therapy territory is new and innovative, it is difficult to gauge whether an unexpected impact on product quality can occur years after stability has been completed. Based on this feedback, the recommendation is that the stability protocol should be established conservatively, maximizing time points, lot testing and with a careful evaluation of quality parameters and critical product attribute. In conclusion, the regulatory environment for gene therapy is still being established and commonly accepted principles guiding current product development should be thoroughly evaluated and most likely reassessed. Because of the biological complexities of these products, a conservative approach should be followed with regards to the stability program.
Abstract A68: Oncogenic Kras prevents myeloid cell-mediated pancreatic tissue repair
Authors: Yaqing Zhang, Wei Yan, Esha Mathew, Kevin T. Kane, Marina Pasca di Magliano
Journal: Cancer Research (2016)

Abstract The iKras* mouse model of pancreatic cancer allows inducible and reversible expression of oncogenic Kras, and is thus perfectly suited to determine the role of Kras at different stages of carcinogenesis. KRAS has emerged as a targeted interest for study by the NCI; elucidating Kras-dependent signaling pathways and understanding the role of epithelial cells harboring oncogenic Kras in modulating essential components of the tumor microenvironment will provide new opportunities to attack KRAS driven cancers. Using this model, we have demonstrated that, in addition to epithelial changes, the accumulation of a fibro-inflammatory stroma is continuously dependent on oncogenic Kras. Pancreatic Intraepithelial Neoplasia (PanIN), the precursor lesion to pancreatic cancer, is characterized by the accumulation of a fibro-inflammatory stroma rich in myeloid cell infiltrates. Here, we generated p48Cre; TetO-KrasG12D; Rosa26rtTa-IRES-EGFP; CD11b-diphtheria toxin (DT) receptor (iKras*;CD11b-DTR) mice that allow us to deplete myeloid cells during the onset and progression of PanINs. We show that myelois infiltration and polarization is dependent on oncogenic Kras both during the initiation and the progression of PanINs. Furthermore, signals derived from oncogenic Kras–expressing cells regulate the polarization of myeloid cells, maintaining them in a pro-tumor status. We show that myeloid cells are required for the initiation and progression of pancreatic cancer precursor lesions by regulating the inflammatory microenvironment and the extracellular matrix (ECM) deposition in pancreatic neoplasia. Inactivation of oncogenic Kras leads to a change in polarization of myeloid cells, which take on a pro-repair phenotype. Finally, by ablating myeloid cells upon inactivation of oncogenic Kras we show that pro-repair myeloid cells are required for pancreas remodeling and repair by regulating ECM degradation and epithelial cell survival involving activation of multiple signaling pathways in both stromal and epithelial compartments. Thus, the interplay between epithelial cells expressing oncogenic Kras and myeloid cells determines the balance between carcinogenesis and tissue remodeling, a finding that could be exploited to favor repair at the expense of tumor progression. Citation Format: Yaqing Zhang, Wei Yan, Esha Mathew, Kevin T. Kane, Marina Pasca di Magliano.{Authors}. Oncogenic Kras prevents myeloid cell-mediated pancreatic tissue repair. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A68.
The protective effect of zoledronic acid on bone loss in postmenopausal women with early breast cancer treated with sequential tamoxifen and letrozole: 36-month follow-up.
Authors: J. Greenberg, S. M. Stemmer, R. Bernstein-Molho, S. Pelles-Avraham, I. Stephansky, M. J. Inbar, D. B. Geffen, T. Safra
Journal: Journal of Clinical Oncology (2011)

e11111 Background: Adjuvant treatment with aromatase inhibitors (AIs) in postmenopausal women (PMW) with early breast cancer (EBC) can be associated with bone loss. Update of BIG-98 suggests that sequential TAM and Letrozole (LET) have similar efficacy to 5 years of LET. This study evaluates whether addition of zoledronic acid (ZOL) to LET, switched from TAM, can prevent bone loss. Methods: This is an open-label, randomized phase II study of PMW with hormone receptor positive EBC previously treated with TAM for 2.5 years, with bone mineral density (BMD) T-score ≥ -2.5. Patients were randomly assigned to receive 2.5mg/day LET +/- ZOL. Patients on treatment arm receive 5 intravenous administrations of 4 mg ZOL every 6 months. All patients are evaluated with blood chemistry and BMD test every 6 months in the first 3 years and yearly in the next 2 years. All patients receive vitamin D and calcium supplements. A comparison between groups and between time points was performed by one-way ANOVA with repeated measures using the Mixed model. Results: Eighty nine patients have been randomized. Median age was 58.9 years (46.5-83.6). Eighty six patients were evaluable (3 screening failure); 39 were randomized to receive ZOL and 47 to the control group. Median follow-up was 41.4 months (range 3.4-60). Change over time in lumbar spine T-score was significantly different between the ZOL and control groups, (P=0.0013). In the control group a significant decline in lumbar BMD was noticed (P=0.0031), whereas in the ZOL group there was no significant change in BMD over time (P= 0.10). No significant differences between groups and time points were found. With regards to other parameters, no interaction between groups and time trends were observed. The most common adverse event with ZOL was a mild, transient flu-like syndrome within 2 days of administration. No serious renal adverse events or osteonecrosis of jaw (ONJ) were reported. Conclusions: Sequential TAM and AIs in the adjuvant setting of EBC in PMW can be associated with decreased BMD. In our study, LET-induced bone loss increases with time, though a significant benefit in BMD was seen when ZOL was added to LET.
Abstract A42: The stem cell signal Musashi is required for pancreatic cancer progression and therapy resistance
Authors: Nikki K. Lytle, Raymond G. Fox, Dawn V. Jaquish, Nhat-Long Pham, Park D. Frederick, Andrew M. Lowy, Tannishtha Reya
Journal: Cancer Research (2016)

Abstract Pancreatic cancer is the 4th leading cause of cancer-related deaths in the United States due to advanced stage at diagnosis and poor response to current therapies. There is an urgent need to identify factors that contribute to tumor progression and drug resistance in order to develop novel, more effective therapeutic strategies. Here we show that the RNA binding protein Musashi2 (Msi2) is critically important for pancreatic tumorigenesis: genetic deletion of Msi2 slowed progression of premalignant lesions to adenocarcinoma in the KPf/fC mouse model of pancreatic cancer and led to a profound increase in overall survival. To better understand how Msi2 contributes to tumor progression, we developed a Msi2 reporter mouse and crossed it into the KPf/fC model. We found that Msi2-reporter positive tumor cells are preferentially able to propagate adenocarcinoma growth, and are highly enriched among circulating tumor cells. Importantly, our studies reveal that tumor cells expressing Msi2 are exceptionally resistant to chemotherapy and radiation. Collectively, these studies identify Msi2 as a central regulator of pancreatic cancer and raise the possibility that targeting Msi could be a new approach for the treatment of pancreatic cancer. Citation Format: Nikki K. Lytle, Raymond G. Fox, Dawn V. Jaquish, Nhat-Long Pham, Park D. Frederick, Andrew M. Lowy, Tannishtha Reya.{Authors}. The stem cell signal Musashi is required for pancreatic cancer progression and therapy resistance. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A42.