tbuckley/cabot-search huggingface dataset:
PTH-020 Transpancreatic sphincterotomy: a valuable technique for gaining cbd access
Authors: M Elzubier, S Esmaily, D Dwarakanath, B Chaudhury, D Majumdar, V Mitra, J Hancock
Journal: Endoscopy (2017)

<h3>Introduction</h3> Transpancreatic Sphincterotomy (TPS) involves wire-guided cannulation of the main pancreatic duct (MPD) followed by standard pull-type sphincterotome cutting towards the main channel. Typically MPD stent insertion follows TPS to prevent post ERCP pancreatitis (PEP). ESGE [1] recommends that in patients with a small papilla that is difficult to cannulate, TPS should be considered if unintentional wire guided MPD cannulation occurs. A previous study has suggested that TPS maybe as effective as double guide wire (DGW) in achieving biliary cannulation and has a lower PEP rate. [1] The aim of this study was to review the practice, complications and outcomes of TPS at University Hospital of North Tees. <h3>Method</h3> A retrospective review of all ERCP procedures between January 2014 and October 2016. Endoscopy reports, radiology, blood results and discharge letters were reviewed. <h3>Results</h3> 1365 ERCP procedures were performed in the study period. Overall CBD cannulation rate was 91.3%. 105/1365 (7.7%) wire guided TPS procedures were carried out. Mean age in the TPS group was 67 years (range: 20–91) - 64/105 (61%) male and 41/105 (39%) females. 3 senior consultants and a senior endoscopic fellow performed TPS. TPS was used as the initial strategy in the event of MPD cannulation and without using alternative methods such as DGW. ERCP indication in TPS group is shown in chart. CBD cannulation was achieved in 96/105 (90.5%) of cases - 81/105 (77.1%) during the first ERCP and 15/105 (14.2%) at second ERCP [where CBD cannulation was achieved at second attempt, TPS had been done at the first ERCP]. In 9/105 patients CBD cannulation was not achieved. 8/105 (7.6%) had a complication. 6/105 (5.7%) patients had PEP - 5/6 had a prophylactic MPD stent. 1/105 had a post sphincterotomy bleed which was controlled with endoscopic therapy. 1/105 had a perforation and a subsequent long hospital stay. There were no procedural related deaths. <h3>Conclusion</h3> This study demonstrates that TPS is a safe and effective way of gaining CBD access. Our data suggests that experienced operators in a DGH setting can safely carry out TPS. Our study is the second largest cohort in the literature and the largest cohort in the UK. We would suggest early adoption of TPS if wire access to the pancreatic duct is achieved, this will likely reduce complication rate as a result of less engagement with the papilla and overall reduced time at CBD cannulation. <h3>References</h3> . Papillary cannulation and sphincterotomy techniques at ERCP: ESGE Clinical Guideline. Endoscopy. 2016Jul;48(07):657–83. . Kahaleh M, et al. Prospective evaluation of pancreatic sphincterotomy as a precut technique for biliary cannulation. Clinical Gastroenterology and Hepatology. 2004Nov 30;2(11):971–7 <h3>Disclosure of Interest</h3> None Declared
Is Weekend-Only Physical Activity Enough to Compensate for a Sedentary Lifestyle?
Authors: Alejandro Santos-Lozano, Helios Pareja-Galeano, Alejandro Lucia
Journal: JAMA Internal Medicine (2017)

measuring changes in health-related quality of life, symptoms, or function "…have suffered from methodological issues and poor data quality, limiting their use in regulatory decisions."They indicate that those methodological weaknesses justify keeping drugs on the market when there is no clear evidence of clinical benefit.However, there are numerous reliable, validated quality-of-life measures that are used in research 2 ; they have been and should be used to determine whether oncology drugs have a significant impact, or they should be revised to be more appropriate to measure such impact.Blumenthal and colleagues give several examples where cancer-related symptoms were measured to determine quality of life; these examples support our conclusions rather than challenging them.While we agree with Blumenthal and colleagues that the cost of a cancer drug "…is not within the purview of the FDA," FDA approval of oncology drugs that have no proven clinical benefit in terms of patient health or quality of life is well within the purview of the FDA.New cancer drugs are unaffordable for many patients and their families.It is appropriate for physicians and patients to expect that the FDA would require proven clinical benefits before drugs are approved, or at least rescind approval if postmarket studies do not prove that those drugs provide measurable benefits to patients, and not just to biomarkers or nonclinical end points.The statement by Blumenthal and colleagues that requiring such proof would not be practical could have a chilling effect on physicians as they make treatment decisions on behalf of their patients.
Irinotecan plus temozolomide in children with recurrent or refractory neuroblastoma: A phase II Children's Oncology Group study
Authors: R. Bagatell, L. M. Wagner, S. L. Cohn, J. M. Maris, C. P. Reynolds, C. F. Stewart, S. D. Voss, M. Gelfand, C. S. Kretschmar, W. B. London
Journal: Journal of Clinical Oncology (2009)

10011 Background: Treatment of children with relapsed or refractory neuroblastoma (NB) remains a challenge. Responses to irinotecan (IRN) + temozolomide (TEM) were seen in NB xenograft-bearing mice, and objective responses were observed in patients with NB treated on a phase I study of this combination. Methods: A phase II study of IRN (10 mg/m2/dose IV daily × 5 days times; 2 weeks) + TEM (100 mg/m2/dose PO daily × 5 days) for children with relapsed or refractory NB was conducted. A one-stage design (endpoint: best overall response) required 5 or more responders out of the first 25 evaluable patients on each of two strata: 1) patients with disease measurable by CT or MRI; and 2) patients with disease detected only by bone marrow aspirate/biopsy and/or MIBG scan. Patients with stable disease or better after 3 cycles could receive an additional 3 cycles of study therapy. International Neuroblastoma Response Criteria were used for response assessment. Radiographic responses were centrally reviewed. Results: Fifty-five eligible and evaluable patients were enrolled, 28 on stratum 1 and 27 on stratum 2. Four responses were observed in the first 25 evaluable stratum 1 patients, and five responses were observed in the first 25 evaluable stratum 2 patients. Three patients had complete responses, but the overall objective response rate (CR+PR) was 16% (9/55). Eleven (stratum 1) and 13 (stratum 2) patients had stable disease. Less than 5% of patients experienced Grade 3 or 4 diarrhea. Although 18% of patients on stratum 1 and 35% of patients on stratum 2 experienced Grade 3 or 4 neutropenia during the first 3 cycles of therapy, &lt;10% of all patients developed evidence of infection while neutropenic. Thrombocytopenia (Grade 3 or 4) was observed in only 7% of patients on stratum 1 and 12% on stratum 2. Conclusions: The combination of IRN+TEM was well tolerated in patients with recurrent or refractory NB. There were 9 objective responses, including 3 complete responses. The minimum desired response rate was attained within stratum 2, but not stratum 1. IRN+TEM may be an appropriate backbone for further study in the relapse setting in combination with novel, targeted agents. No significant financial relationships to disclose.
03.17 Impaired mitophagy in tregs is involved in breakdown of self-tolerance and development of autoimmune responses
Authors: Maria Lazari, Lydia Kalafati, Themis Alissafi, Panayotis Verginis
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Regulatory T cells (Tregs) play a major role in the maintenance of immune homeostasis and in the suppression of autoimmune responses. Breakdown of immune tolerance, a hallmark of autoimmune diseases, has been linked to both altered generation and impaired function of Tregs. However, the mechanism that leads to this defect remains elusive. Mitochondria are indispensible for proper function of the cell and clearance of damaged mitochondria through operation of mitophagy is essential for the survival of the cell. However whether this mechanism is functional in Tregs during an autoimmune response has not been demonstrated. Thus our hypothesis is that impaired mitophagy in Tregs could affect their suppressive capacity and lead to development of autoimmune disorders. <h3>Materials and methods</h3> For the purposes of this study, we utilised <i>Foxp3gfp</i>.KI transgenic mice that express the gfp protein under the promoter of the <i>foxp3</i> gene and <i>Atg5<sup>ΔCd4</sup></i> mice, which lack the autophagy pathway in CD4<sup>+</sup> T cells. Experimental Autoimmune Encephalomyelitis (EAE) was induced by immunisation with the myelin peptide (Mog<sub>35-55</sub>) emulsified in complete Freund adjuvant (CFA). <h3>Results</h3> Herein we show that Tregs isolated from draining lymph nodes of Mog<sub>35-55</sub>/CFA immunised mice exerted increased autophagosome formation and lysosomal function compared to naïve Tregs, whereas their mitophagy was impaired. In addition Tregs from immunised animals exhibited decreased mitochondrial membrane potential, enhanced production of mitochondrial ROS and increased metabolic requirements compared to naïve mice. Finally, Tregs deficient in authophagy demonstrated elevated numbers of mitochondria, increased production of mitochondrial ROS and lysosomal function. <h3>Conclusions</h3> Overall, our results indicate an impaired mitophagy in Tregs during an autoimmune response that results in accumulation of dysfunctional mitochondria that might contribute to loss of Treg suppressive function. Future experiments will be focused on understanding the molecular mechanism underlying the deregulated mitophagy in Tregs in autoimmune disorders that will orientate us in new potential therapeutic targets.
Note on the Colloid Osmotic Pressure of the Serums of Rats Bearing the Transplanted Jensen Sarcoma
Authors: Jesse P. Greenstein, J. W. Thompson
Journal: JNCI Journal of the National Cancer Institute (1943)

Journal Article Note on the Colloid Osmotic Pressure of the Serums of Rats Bearing the Transplanted Jensen Sarcoma Get access Jesse P. Greenstein, Jesse P. Greenstein senior biochemist Search for other works by this author on: Oxford Academic PubMed Google Scholar J. W. Thompson J. W. Thompson pharmacologist National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 4, Issue 1, August 1943, Pages 63–64, https://doi.org/10.1093/jnci/4.1.63 Published: 01 August 1943
A phase I study of DSTP3086S, an antibody-drug conjugate (ADC) targeting STEAP-1, in patients (pts) with metastatic castration-resistant prostate cancer (CRPC).
Authors: Daniel Costin Danila, Russell Zelig Szmulewitz, Ari David Baron, Celestia S. Higano, Howard I. Scher, Michael J. Morris, Houston Gilbert, Flavia Brunstein, Vanessa Lemahieu, Omar Kabbarah, Bernard M. Fine, Daniel J. Maslyar, Ulka N. Vaishampayan
Journal: Journal of Clinical Oncology (2014)

5024 Background: Six-transmembrane epithelial antigen of the prostate-1 (STEAP1) protein is a cell-surface protein frequently overexpressed in prostate cancer. The ADC DSTP3086S contains the humanized IgG1 anti-STEAP1 monoclonal antibody linked to the potent anti-mitotic agent MMAE. Methods: This study evaluated safety and activity of DSTP3086S (0.3-2.8 mg/kg IV) given every 3 weeks (q3w) to pts with CRPC. A traditional 3+3 design was used to determine maximum-tolerated dose, followed by cohort expansion at the recommended Phase II dose (RP2D). Clinical activity was evaluated per PCWG2 criteria. Results: As of 18 Dec 2013, 59 pts were enrolled with a median age of 68 (43-87), all ECOG PS 0-1, and with a median of 6 prior systemic regimens (71% received prior taxanes). Pts received a median of 3 doses (range 1-14) of DSTP3086S, with 14 pts (24%) still ongoing. Two patients in dose escalation (1 at 2.25 mg/kg and 1 at 2.8 mg/kg) had dose limiting G3 transaminitis. Cohort expansion started at 2.8 mg/kg (n=10). Frequent dose reductions at 2.8mg/kg led to testing 2.4 mg/kg (n=22) which had increased tolerability. The most common related AEs (>10%) across all doses were fatigue, nausea, constipation, peripheral neuropathy, anorexia, vomiting, diarrhea, and abdominal pain. There were 9 treatment-related serious AEs in 6 pts, including DVT (G3) at 1.5 mg/kg, sepsis (G5) and GI hemorrhage (G3) at 2.25 mg/kg, bacteremia (G4), neutropenia (G3 and G4), presyncope (G2), and constipation (G2) at 2.4 mg/kg; and abdominal pain (G3) at 2.8 mg/kg. Approximately 60% of archival tumor tissues from Ph1 dose escalation patients were STEAP1 IHC high (2+/3+), while STEAP1 IHC high was required in the expansion cohort. PSA declines by >50% were obtained in 1/7 at 2.25 mg/kg, 3/21 at 2.4 mg/kg, and 5/16 at 2.8 mg/kg; 2 pts at 2.8 mg/kg also had RECIST responses. CTC conversions from unfavorable to favorable (<5) occurred in 1/5 at 2.25 mg/kg, 3/5 at 2.4 mg/kg, and 7/10 at 2.8 mg/kg. Conclusions: DSTP3086S at dose levels between 2.25 and 2.8 mg/kg demonstrated anti-tumor activity and the RP2D is 2.4 mg/kg q3w. Clinical trial information: NCT01283373.
Abstract 18912: Platelet Derived Growth Factor Promotes Myofibroblastic Differentiation of Cardiac Resident Mesenchymal Stem Cells and Exacerbates Post-Infarction Left Ventricular Remodeling
Authors: Tariq Hamid, Yuanyuan Xu, Mohamed A Ismahil, Shyam S Bansal, Sumanth D Prabhu
Journal: Circulation (2016)

Chronic heart failure (HF) is characterized by inflammation, macrophage infiltration, and progressive fibrosis. Along with fibroblasts, mesenchymal stem cells (MSCs) can differentiate into pro-fibr...
Case 24-2017
Authors: Uzma Shah, Allan M. Goldstein, Michael S. Gee, Vikram Deshpande
Journal: New England Journal of Medicine (2017)

An 8-month-old girl presented with a 6-day history of fever and decreased oral intake. The abdomen was distended and nontender; a multicystic mass in the midabdomen was seen on imaging. Diagnostic procedures were performed.
Estimated life years saved with trastuzumab in first-line HER2+ metastatic breast cancer from 1999 to 2013.
Authors: Mark Danese, Deepa Lalla, Melissa Brammer, Eduardo Santos, Abraham Lee, Anthony Masaquel
Journal: Journal of Clinical Oncology (2013)

625 Background: Trastuzumab was approved in the United States (US) in September 1998 for the treatment of HER2+ metastatic breast cancer (MBC). This model estimates the total number of life years saved (LYS) in US women treated with trastuzumab over a 15-year period (1999-2013). Methods: Using US population estimates and cancer registry-based incidence data, we estimated the number of women with recurrent stage I-III or de novo stage IV HER2+ MBC by year, age, hormone receptor, and nodal status. Trastuzumab utilization was based on published studies of HER2 testing rates, true positive rates in the community, and treatment initiation rates. Survival was estimated by extrapolating survival data pooled across 5 trials and 2 observational studies separately for women treated with trastuzumab and with chemotherapy alone. Few studies reported survival in women with HER2+ MBC without trastuzumab (N=3). Sensitivity analyses were conducted by estimating overall survival from the initial phase 3 trial (67% of placebo patients crossed over to trastuzumab after progression; HR=0.80), and assuming a higher risk reduction to account for crossover effects in clinical trials (HR=0.60). Results: In the base case, approximately 83,462 women with HER2+ MBC were estimated to receive 1 st line trastuzumab over a 15-year period. The pooled median overall survival across studies without and with trastuzumab was 21.2 and 35.5 months, respectively. Patients were projected to live a total of 216,290 life years if trastuzumab had not been available and if they received chemotherapy only. These same patients were estimated to live a total of 294,877 life years with first-line trastuzumab, for an incremental benefit of 78,587 LYS. In sensitivity analysis, total LYS ranged from 48,334-96,360. Conclusions: Real-world evidence supports a median overall survival of approximately 36 months in women with HER2+ MBC receiving 1 st line trastuzumab. Using a population-based, conservative model, we found that trastuzumab use has resulted in &gt; 75,000 life years over 15 years in women with HER2+ MBC. Future research is warranted to examine the characteristics, experiences, and outcomes among women living longer with HER2+ MBC.
Formulation design of granules prepared by wet granulation method using a multi-functional single-punch tablet press to avoid tableting failures
Authors: Takashi Osamura, Yoshiko Takeuchi, Risako Onodera, Masahiro Kitamura, Yoshiteru Takahashi, Kohei Tahara, Hirofumi Takeuchi
Journal: Asian Journal of Pharmaceutical Sciences (2017)

We previously determined "Tableting properties" by using a multi-functional single-punch tablet press (GTP-1). We plotted "Compactability" on the x-axis against "Manufacturability" on the y-axis to allow visual evaluation of "Tableting properties". Here, we examined whether this evaluation method can be used in the formulation design of tablets prepared by wet granulation. We used the GTP-1 to measure "Tableting properties" with different amounts of binder, disintegrant, and lubricant, and compared the results with those of tableting on a commercial rotary tableting machine. Tableting failures (capping and binding in particular) occurred when samples that had been evaluated as having poor "Compactability" or "Manufacturability" on the GTP-1 were compressed on the rotary tableting machine. Thus, our evaluation method predicted tableting failure at the commercial scale. The method will prove useful for scaling up production.
Implant and Midterm Outcomes of the Subcutaneous Implantable Cardioverter-Defibrillator Registry
Authors: Lucas Boersma, Craig Barr, Reinoud Knops, Dominic Theuns, Lars Eckardt, Petr Neuzil, Marcoen Scholten, Margaret Hood, Juergen Kuschyk, Paul Jones, Elizabeth Duffy, Michael Husby, Kenneth Stein, Pier D. Lambiase
Journal: Journal of the American College of Cardiology (2017)

The subcutaneous implantable cardioverter-defibrillator (S-ICD) was developed to defibrillate ventricular arrhythmias, avoiding drawbacks of transvenous leads. The global EFFORTLESS S-ICD (Evaluation oF FactORs ImpacTing CLinical Outcome and Cost EffectiveneSS of the S-ICD) registry is collecting outcomes in 985 patients during a 5-year follow-up. The primary goal of the EFFORTLESS registry is to determine the safety of the S-ICD by evaluating complications and inappropriate shock rate. This is the first report on the full patient cohort and study endpoints with follow-up ≥1 year. The predefined endpoints are 30- and 360-day complications, and shocks for atrial fibrillation or supraventricular tachycardia. Patients were followed for 3.1 ± 1.5 years and 82 completed the study protocol 5-year visit. Average age was 48 years, 28% were women, ejection fraction was 43 ± 18%, and 65% had a primary prevention indication. The S-ICD system and procedure complication rate was 4.1% at 30 days and 8.4% at 360 days. The 1-year complication rate trended toward improvement from the first to last quartile of enrollment (11.3% [quartile 1]) to 7.8% [quartile 2], 6.6% [quartile 3], and 7.4% [quartile 4]; quartile 1 vs. quartiles 2 to 4; p = 0.06). Few device extractions occurred due to need for antitachycardia (n = 5), or biventricular (n = 4) or bradycardia pacing (n = 1). Inappropriate shocks occurred in 8.1% at 1 year and 11.7% after 3.1 years. At implant, 99.5% of patients had a successful conversion of induced ventricular tachycardia or ventricular fibrillation. The 1- and 5-year rates of appropriate shock were 5.8% and 13.5%, respectively. Conversion success for discrete spontaneous episodes was 97.4% overall. This registry demonstrates that the S-ICD fulfills predefined endpoints for safety and efficacy. Midterm performance rates on complications, inappropriate shocks, and conversion efficacy were comparable to rates observed in transvenous implantable cardioverter-defibrillator studies. (Evaluation oF Factors ImpacTing CLinical Outcome and Cost EffectiveneSS of the S-ICD [The EFFORTLESS S-ICD Registry]; NCT01085435)
ATM Deficiency Generating Genomic Instability Sensitizes Pancreatic Ductal Adenocarcinoma Cells to Therapy-Induced DNA Damage
Authors: Lukas Perkhofer, Anna Schmitt, Maria Carolina Romero Carrasco, Michaela Ihle, Stephanie Hampp, Dietrich Alexander Ruess, Elisabeth Hessmann, Ronan Russell, André Lechel, Ninel Azoitei, Qiong Lin, Stefan Liebau, Meike Hohwieler, Hanibal Bohnenberger, Marina Lesina, Hana Algül, Laura Gieldon, Evelin Schröck, Jochen Gaedcke, Martin Wagner, Lisa Wiesmüller, Bence Sipos, Thomas Seufferlein, Hans Christian Reinhardt, Pierre-Olivier Frappart, Alexander Kleger
Journal: Cancer Research (2017)

Pancreatic ductal adenocarcinomas (PDAC) harbor recurrent functional mutations of the master DNA damage response kinase ATM, which has been shown to accelerate tumorigenesis and epithelial-mesenchymal transition. To study how ATM deficiency affects genome integrity in this setting, we evaluated the molecular and functional effects of conditional Atm deletion in a mouse model of PDAC. ATM deficiency was associated with increased mitotic defects, recurrent genomic rearrangements, and deregulated DNA integrity checkpoints, reminiscent of human PDAC. We hypothesized that altered genome integrity might allow synthetic lethality-based options for targeted therapeutic intervention. Supporting this possibility, we found that the PARP inhibitor olaparib or ATR inhibitors reduced the viability of PDAC cells in vitro and in vivo associated with a genotype-selective increase in apoptosis. Overall, our results offered a preclinical mechanistic rationale for the use of PARP and ATR inhibitors to improve treatment of ATM-mutant PDAC. Cancer Res; 77(20); 5576-90. ©2017 AACR.
Abstract #5446: Mechanisms of myocyte cytotoxicity induced by the anticancer serine/threonine multikinase inhibitor sorafenib
Authors: Brian Hasinoff, Daywin Patel
Journal: Cancer Research (2009)

The anticancer serine/threonine multikinase inhibitor sorafenib has recently been shown to be cardiotoxic. Using a neonatal rat myocyte model we investigated various mechanisms that might be responsible for its cardiotoxicity. It had been hypothesized that inhibition of RAF1 and BRAF kinases may be responsible for sorafenib-induced cardiotoxicity. As measured by lactate dehydrogenase release sorafenib treatment of myocytes caused dose-dependent damage at therapeutically relevant concentrations. Heart tissue with its high energy needs might be particularly sensitive to inhibition of critical kinases. At longer times (15 hr) sorafenib treatment of myocytes also reduced cellular ATP levels at pharmacological concentrations. Likewise, at longer times sorafenib treatment induced caspase 3/7 activity which was suggestive of induction of apoptosis. Dexrazoxane, which is a clinically approved doxorubicin cardioprotective agent did not protect myocytes from damage, which suggests that sorafenib did not damage myocytes through induction of oxidative damage. In a published profiling study of sorafenib binding to 317 kinases at therapeutic concentrations, sorafenib was found to strongly bind to 18% of the kinases tested. In conclusion, given the extreme lack of kinase selectivity that sorafenib exhibits it is likely that inhibition of other kinases or combinations of kinases also contribute to the cardiotoxic effects of sorafenib.  Support: CIHR and a Canada Research Chair in Drug Development to BBH.    Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5446.