tbuckley/cabot-search huggingface dataset:
WHO dementia guidelines highlight a lack of evidence for lifestyle interventions
Authors: Elisabeth Mahase
Journal: BMJ (2019)

People can reduce their risk of dementia by adapting their lifestyle—such as getting regular exercise, not smoking, and maintaining healthy blood pressure, cholesterol, and blood sugar levels—according to World Health Organisation guidelines.1

Researchers have criticised the guidance, however, saying there is a lack of evidence for the effectiveness of many of the recommendations on how to prevent cognitive decline and an absence of cost or benefit calculations.

The guidance, which brings together decades of research, outlines a number of recommendations and indicates the quality of evidence behind them.

It is targeted at healthcare providers and aims …
PREDICTIVE FACTORS OF LACK OF RESPONSE TO ENDOSCOPIC TREATMENT FOR POST-OPERATIVE BILIARY LEAKS: A PROSPECTIVE STUDY
Authors: R Ballester-Clau, M Albuquerque Miranda, G Torres Vicente, A Luz Vargas, I Miguel Salas, N Zaragoza Velasco, M Figa Francesch, JM Miñana Calafat, JM Reñé Espinet, F Gonzalez-Huix Lladó
Journal: Endoscopy (2019)

To determine the predictive factors of lack of resolution of post-operative biliary leaks after endoscopic treatment.
End-to-end lung cancer screening with three-dimensional deep learning on low-dose chest computed tomography
Authors: Diego Ardila, Atilla P. Kiraly, Sujeeth Bharadwaj, Bokyung Choi, Joshua J. Reicher, Lily Peng, Daniel Tse, Mozziyar Etemadi, Wenxing Ye, Greg Corrado, David P. Naidich, Shravya Shetty
Journal: Nature Medicine (2019)
CLIPS + RUBBER BAND COUNTERTRACTION: A NEW SIMPLE METHOD TO ALLOW INTRADIVERTICULAR PAPILLA CANNULATION
Authors: M Schaefer, A Belle, B Dirrenberger, M Morin, A Lamoureux, J Jacques, JB Chevaux
Journal: Endoscopy (2019)

We report the case of a patient with main bile duct stones, confirmed after EUS examination. The endoscopic view of the duodenal tract showed an intradiverticular papilla. In order to facilitate the exposure of the papilla, we proceed to a counter traction by clip and rubber band. A first Boston Resolution 360 clip, on which was hung a dental rubber band (Ormco Ostrich 19.1 mm) was set up in para-papillary position by the operating channel of the duodenoscope (Olympus). A second clip was introduced into the operator channel to tract the elastic on the outer edge of the duodenum. The papillary exposure was improved and cannulation of the main bile duct was achieved in 3 minutes and 10 seconds with a Boston Jagwire guide wire and a Boston sphincterotome 4.4. After performing a sphincterotomy, the stones were extracted with an balloon and hemostatic compression was performed due to post-sphincterotomy bleeding. The haemostasis was completed by the placement of a covered SEMS Cook Evolution 40 × 10 mm, then by the injection of saline and adrenaline 1/1000.
EnanDIM - a novel family of L-nucleotide-protected TLR9 agonists for cancer immunotherapy
Authors: Kerstin Kapp, Barbara Volz, Michael A. Curran, Detlef Oswald, Burghardt Wittig, Manuel Schmidt
Journal: Journal for ImmunoTherapy of Cancer (2019)

Toll-like receptor 9 agonists are potent activators of the immune system. Their clinical potential in immunotherapy against metastatic cancers is being evaluated across a number of clinical trials. TLR9 agonists are DNA-based molecules that contain several non-methylated CG-motifs for TLR9 recognition. Chemical modifications of DNA backbones are usually employed to prevent degradation by nucleases. These, however, can promote undesirable off-target effects and therapeutic restrictions.Within the EnanDIM® family members of TLR9 agonists described here, D-deoxyribose nucleotides at the nuclease-accessible 3'-ends are replaced by nuclease-resistant L-deoxyribose nucleotides. EnanDIM® molecules with varying sequences were screened for their activation of human peripheral blood mononuclear cells based on secretion of IFN-alpha and IP-10 as well as activation of immune cells. Selected molecules were evaluated in mice in a maximum feasible dose study and for analysis of immune activation. The ability to modulate the tumor-microenvironment and anti-tumor responses after EnanDIM® administration was analyzed in syngeneic murine tumor models.The presence of L-deoxyribose containing nucleotides at their 3'-ends is sufficient to prevent EnanDIM® molecules from nucleolytic degradation. EnanDIM® molecules show broad immune activation targeting specific components of both the innate and adaptive immune systems. Activation was strictly dependent on the presence of CG-motifs, known to be recognized by TLR9. The absence of off-target effects may enable a wide therapeutic window. This advantageous anti-tumoral immune profile also promotes increased T cell infiltration into CT26 colon carcinoma tumors, which translates into reduced tumor growth. EnanDIM® molecules also drove regression of multiple other murine syngeneic tumors including MC38 colon carcinoma, B16 melanoma, A20 lymphoma, and EMT-6 breast cancer. In A20 and EMT-6, EnanDIM® immunotherapy cured a majority of mice and established persistent anti-tumor immune memory as evidenced by the complete immunity of these mice to subsequent tumor re-challenge.In summary, EnanDIM® comprise a novel family of TLR9 agonists that facilitate an efficacious activation of both innate and adaptive immunity. Their proven potential in onco-immunotherapy, as shown by cytotoxic activity, beneficial modulation of the tumor microenvironment, inhibition of tumor growth, and induction of long-lasting, tumor-specific memory, supports EnanDIM® molecules for further preclinical and clinical development.
Lung Computational Models and the Role of the Small Airways in Asthma
Authors: Brody H. Foy, Marcia Soares, Rafel Bordas, Matthew Richardson, Alex Bell, Amisha Singapuri, Beverley Hargadon, Christopher Brightling, Kelly Burrowes, David Kay, John Owers-Bradley, Salman Siddiqui
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Rationale: Asthma is characterized by disease within the small airways. Several studies have suggested that forced oscillation technique–derived resistance at 5 Hz (R5) − resistance at 20 Hz (R20) is a measure of small airway disease; however, there has been limited validation of this measurement to date.Objectives: To validate the use of forced oscillation R5 − R20 as a measure of small airway narrowing in asthma, and to investigate the role that small airway narrowing plays in asthma.Methods: Patient-based complete conducting airway models were generated from computed tomography scans to simulate the impact of different degrees of airway narrowing at different levels of the airway tree on forced oscillation R5 − R20 (n = 31). The computational models were coupled with regression models in an asthmatic cohort (n = 177) to simulate the impact of small airway narrowing on asthma control and quality of life. The computational models were used to predict the impact on small airway narrowing of type-2 targeting biologics using pooled data from two similarly design randomized, placebo-controlled biologic trials (n = 137).Measurements and Main Results: Simulations demonstrated that narrowing of the small airways had a greater impact on R5 − R20 than narrowing of the larger airways and was associated (above a threshold of approximately 40% narrowing) with marked deterioration in both asthma control and asthma quality of life, above the minimal clinical important difference. The observed treatment effect on R5 − R20 in the pooled trials equated to a predicted small airway narrowing reversal of approximately 40%.Conclusions: We have demonstrated, using computational modeling, that forced oscillation R5 − R20 is a direct measure of anatomical narrowing in the small airways and that small airway narrowing has a marked impact on both asthma control and quality of life and may be modified by biologics.
ENDOSCOPIC ULTRASOUND-THROUGH-THE-NEEDLE MICROFORCEPS BIOPSY IN PANCREATIC CYSTIC LESIONS: A SYSTEMATIC REVIEW
Authors: IM Cazacu, D Vasile Balaban, L Pinte, M Jinga, MS Bhutani, A Saftoiu
Journal: Endoscopy (2019)

The Moray microforceps biopsy device (MFB) is a disposable tissue acquisition device that can be passed through a 19-gauge needle and it has been recently introduced to facilitate the EUS-guided biopsy of pancreatic cystic lesions (PCL). Our aim was to perform a systematic review of studies evaluating the technical aspects, safety and efficacy of the EUS-guided microforceps biopsy for PCLs.
Trastuzumab related cardiotoxicity in nonmetastatic breast cancer: A real-world scenario
Authors: S. Shrivastva, S.K. Prasad, R. Chennamaneni, B. Stalin, M.L. Konatam, S. Gundeti
Journal: Annals of Oncology (2019)

Background: Trastuzumab, a humanized monoclonal antibody significantly improves outcomes in Her2 neu positive breast cancer. The incidence of cardiotoxicity with trastuzumab is approximately 8-10%. The present study was designed to analyze the incidence and risk factors associated with trastuzmab related cardiotoxicity. Methods: The present study was a single institutional retrospective analysis of the incidence of trastuzumab induced cardiotoxicity in nonmetastatic invasive breast cancer from January 2011 to December 2018. Trastuzumab induced cardiotoxicity (TIC) was defined as symptomatic heart failure or asymptomatic decline in left ventricular ejection fraction (LVEF) by > 10% or LVEF < 50%. Risk factors analysed were BMI (≥30 vs < 30), history of diabetes, hypertension, coronary artery disease (CAD) (yes or no), left sided radiotherapy (RT) and prior anthracycline (yes or no). Results: Data of 246 patients with Her2 neu positive breast cancer was collected. Of these, 117(47.5%) received trastuzumab. The median age at presentation was 51 years (range,28-72). Of 117 patients who received adjuvant trastuzumab TIC was seen in 16(13.6%) patients, asymptomatic LV dysfunction in 9.4% and symptomatic LV dysfunction in 4.2% patients. The median baseline ejection fraction of 65% (range, 56 - 72). The median time to development of TIC was 18.5 (range, 3-52) weeks and median trastuzumab cycle for TIC was 6 (range, 2-16). Presence of ≥ 2 risk factors (20%) had significant impact on incidence of TIC compared to < 2 risk factors (p = 0.04). 10 (62.5%) patients were rechallenged with trastuzumab and 6(37.5%) discontinued trastuzumab. Following rechallenge 1 patient developed asymptomatic decline in EF and 1 developed symptomatic heart failure and were stopped completely. No cardiacrelated mortality was seen.Table214P Risk factors in relation to TICRisk factorTIC PresentTIC absentp ValueBMI ≥ 30 < 302 1414 780.54History of diabetes Yes No3 1321 800.88History of hypertension Yes No8 831 700.2CAD Yes No1 152 990.8Left side RT Yes No9 723 780.012Prior anthracycline Yes No13 365 360.29 Open table in a new tab Conclusions: Approximately 14% developed TIC which was higher in real-world population compared to that seen in clinical trials. Left sided RT to chest and presence of 2 or more risk factors had significant impact on development of TIC. Stringent monitoring of cardiac function to avoid cardiotoxicity and prompt resumption of trastuzumab following recovery may further improve outcomes in nonmetastatic breast cancer. Legal entity responsible for the study: Department of Medical Oncology, NIMS, Punjagutta, Hyderabad, India. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
ENDOSCOPIC SLEEVE PLICATION (ESP) FOR TREATMENT OF OBESITY I-II. PRELIMINARY RESULTS OF 2 SITES WITH THE NEW PATTERN FOR GASTRIC EMPTYING DELAY
Authors: R Turró Arau, B Abu Dayeh, G Lopez Nava, M Rosinach Ribera, J Michelena Escudero, H Ikuo Uchima Koecklin, A Mata Bilbao, J Turró Homedes, JC Espinos Perez
Journal: Endoscopy (2019)

Obesity is major disease in our society. Intragastric balloon is the endoscopic gold standard on short time weight loss. Endoscopic plicature can offer us better middle long term results than balloon for its durability.
DIFFICULT BILIARY CANNULATION IN PATIENTS WITH DISTAL MALIGNANT BILIARY OBSTRUCTION: AN UNDERESTIMATED PROBLEM?
Authors: A Anderloni, F D'Amico, A Fugazza, E Troncone, G Donato, P Occhipinti, A Amato, F Radaelli, G Mogavero, I Tarantino, M Amata, D Ligresti, M Spadaccini, V Craviotto, L Lamonaca, PJ Belletrutti, A Repici
Journal: Endoscopy (2019)

To date, there are no available data on rates of difficult biliary cannulation (DBC) in the specific setting of patients (pts) with distal biliary malignant obstruction (DBMO). Aim of the study was to investigate the incidence and outcome of DBC in patients undergoing ERCP for DBMO.
Effect of Dietary and Supplemental Omega‐3 Polyunsaturated Fatty Acids on Risk of Recurrent Gout Flares
Authors: MaryAnn Zhang, Yuqing Zhang, Robert Terkeltaub, Clara Chen, Tuhina Neogi
Journal: Arthritis & Rheumatology (2019)

Objective To determine the relationship between omega‐3 polyunsaturated fatty acid (n‐3 PUFA ) consumption (dietary or supplemental) and risk of gout flares. Methods We used data from the Boston University Online Gout Study, an internet‐based case‐crossover study conducted from February 2003 to January 2012. At the times of gout flares (hazard period) and during gout flare–free periods (control periods), participants completed questionnaires regarding exposures, including supplements and diet, during the preceding 48 hours. We examined the relationship of self‐reported n‐3 PUFA –rich supplements and fish intake with the risk of recurrent gout flares using conditional logistic regression, adjusting for total purine intake, diuretic use, and other urate‐lowering or flare prophylactic medications (allopurinol, nonsteroidal antiinflammatory drugs, or colchicine). Results Of the 724 participants, 85% met the 1977 American College of Rheumatology preliminary criteria for the classification of the acute arthritis of primary gout. Twenty‐two percent of the participants reported some form of n‐3 PUFA consumption (supplements, 4.6%; dietary fatty fish, 19%) in the 48 hours preceding a gout flare or flare‐free period. The adjusted odds ratios were 1.01 (95% confidence interval [95% CI ] 0.63–1.60; P = 0.98) for all 3 supplements combined and 0.74 (95% CI 0.54–0.99; P = 0.04) for consumption of ≥2 n‐3 PUFA –rich fish servings. Conclusion Dietary n‐3 PUFA –rich fish consumption, when adjusted for total purine intake, was associated with lower risk of recurrent gout flares, whereas n‐3 PUFA supplementation alone, as taken in a self‐directed manner, was not. Consumption of specific sources and adequate doses of n‐3 PUFA for gout flare prevention warrants further study in an adequately powered clinical trial.
OAKLAND SCORE IS NOT BETTER THAN HAEMOGLOBIN FOR PREDICTING OUTCOMES IN LOWER GASTROINTESTINAL BLEEDING
Authors: A Lira, S Machlab, P García-Iglesias, E Martínez-Bauer, C Mármol, M Gallach, L Hernández, E Brunet, L Melcarne, J Da Costa, G Llibre, V Puig-Diví, F Junquera, R Campo, X Calvet, E Brullet
Journal: Endoscopy (2019)

The aim of this study was to compare the accuracy of Oakland score (OakS) with haemoglobin alone (Hb) for predicting outcomes after lower gastrointestinal bleeding (LGB).
Adjuvant radiotherapy induces secondary tumor events in breast cancer patients with Li-Fraumeni syndrome
Authors: K. Rounis, T. Koukaki, C. Christodoulou, C. Papadimitriou, D. Tryfonopoulos, D. Mavroudis, S. Aggelaki, F. Fostira, E. Saloustros
Journal: Annals of Oncology (2019)

Background: Breast cancer (BrCa) patients with Li-Fraumeni Syndrome (LFS) require customized clinical care, mainly due to elevated lifetime cancer risks that these patients face, as well as the diagnosis of secondary, radio-induced neoplasms. Preclinical data have shown that TP53 deficient cells are at increased risk of malignant transformation in the setting of ionizing radiation. TP53 pathogenic variants are strongly associated with very early onset, frequently HER2-amplified BrCa diagnosis. Methods: In total, thirteen patients fulling clinical criteria for LFS and previously referred to the Molecular Diagnostics Laboratory of NSCR 'Demokritos' from 2005 to 2016, carried a pathogenic TP53 variant. Of these, twelve and one had been diagnosed with BrCa as the first and second tumor event, respectively. Eight of these were treated with total mastectomy without postoperative radiotherapy, while five were treated with lumpectomy plus postoperative radiotherapy. A loco-regional relapse was defined as an ipsilateral relapse in either the breast or lymph node bearing areas (axillary, internal mammary, supra-clavicular) or both occurring since the date of the diagnosis. Distant disease was defined as BrCa recurrences that were not in the contralateral breast nor in loco-regional areas. Radio-induced malignancies were defined as malignancies occurring in the radiation area. Results: Of the five patients who received postoperative radiation, four had a secondary, non-metastatic cancer diagnosis, summarizing a total of six events and more specifically, three were contralateral BrCa, one was a local relapse and two malignancies in other sites, of which one was a radio-induced lung cancer, developed at the site of the radiation area. On the contrary, a single event occurred among patients initially treated with total mastectomy without receiving postoperative radiation. Conclusions: These data highlight the necessity of TP53 genetic testing, especially in young women diagnosed with BrCa, prior to treatment decision and are in accordance with published clinical observations and favor the avoidance of postoperative radiotherapy in breast cancer patients with LFS. Legal entity responsible for the study: Hellenic Academy for Oncology. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Bone health in childhood cancer: review of the literature and recommendations for the management of bone health in childhood cancer survivors
Authors: G. Marcucci, G. Beltrami, A. Tamburini, J.J. Body, C.B. Confavreux, P. Hadji, G. Holzer, D. Kendler, N. Napoli, D.D. Pierroz, R. Rizzoli, M.L. Brandi
Journal: Annals of Oncology (2019)

In the past decades, new cancer treatment approaches for children and adolescents have led to a decrease in recurrence rates and an increase in long-term survival. Recent studies have focused on the evaluation of the late effects on bone of pediatric cancer-related treatments, such as chemotherapy, radiation and surgery. Treatment of childhood cancer can impair the attainment of peak bone mass, predisposing to premature onset of low bone mineral density, or causing other bone side-effects, such as bone quality impairment or avascular necrosis of bone. Lower bone mineral density and microarchitectural deterioration can persist during adulthood, thereby increasing fracture risk. Overall, long-term follow-up of childhood cancer survivors is essential to define specific groups at higher risk of long-term bone complications, identify unrecognized long-term adverse effects, and improve patient care. Children and adolescents with a cancer history should be carefully monitored, and patients should be informed of possible late complications of their previous medical treatment. The International Osteoporosis Foundation convened a working group to review the bone complications of pediatric cancer survivors, outlining recommendations for the management of bone health, in order to prevent and treat these complications.
MSX-122, an orally available small molecule CXCR4 antagonist, promotes leukocytosis in monkeys at doses that were well tolerated in a 28 day toxicology study
Authors: Michael Natchus, Richard Arrendale, Lindsay Donald
Journal: Cancer Research (2008)

1189  Background: Chemokines and their receptors regulate a variety of immune responses to infection, inflammation, and tissue repair. CXCR4 is a chemokine receptor that has one known natural ligand, CXCL12 also known as stromal derived factor-1(SDF-1). Binding of CXCR4 and CXCL12 activates a variety of intracellular signal transduction pathways and effectors that regulate cell survival, proliferation, chemotaxis, migration, adhesion, angiogenesis, homing, and stem cell mobilization. CXCR4 is expressed on both hematopoietic and non hematopoietic tumor cells and its expression plays a prominent role in a number of malignancies. Accordingly, it is a therapeutic target of interest for both primary and metastatic disease. Furthermore, CXCR4 antagonism has been used clinically to enhance stem cell mobilization in autologous transplant procedures. MSX-122 is an orally available, specific small molecule antagonist of CXCR4/CXCL12 currently being tested in preclinical cancer models.  Methods: Male cynomolgus monkeys were dosed by oral gavage with 15, 150 and 500 mg/kg of MSX-122 after which plasma concentrations and total white cell counts were monitored for 12 hours. In a second experiment, female cynomolgus monkeys were dosed by oral gavage with 1, 5, and 10 mg/kg of MSX-122 after which plasma concentrations and white cell counts were again monitored for 18 hours. Differential counts of B-cell and T-cell counts were also monitored at the 10 mg/kg dose. GLP, 28-day toxicology studies were conducted in cynomolgus monkeys at doses of 20 mg/kg/day, 80 mg/kg/day and 600 mg/kg/day.  Results: At all dose levels tested, leukocytosis was observed beginning at 4 - 6 hours with a peak total white cell count at 12 - 18 hrs that was 1.5 - 2 fold higher than baseline. Differential B-cell and T-cell counts for the 10 mg/kg dose also peaked at 12 - 18 hours with cell counts that were 2 - 3 fold higher than starting counts. The observed leukocytosis is an expected pharmacodynamic response from CXCR4 inhibition and has been reported for other CXCR4 antagonists. Subsequent 28-day toxicology studies in monkeys revealed no adverse drug related clinical findings, after electrocardiographic examinations, CBC/chemistry measurements and both gross and microscopic pathology. Plasma exposures in the toxicology study well exceeded those necessary to produce leukocytosis.  Conclusion: In monkeys, MSX-122 demonstrated the expected biologic effect of leukocytosis consistent with a CXCR4 antagonist effect in vivo at doses that were well tolerated in the same species. Initial clinical evaluation in advanced solid tumor patients is underway.
INTERVAL COLORECTAL CANCERS AFTER NEGATIVE FECAL IMMUNOCHEMICAL TEST IN A 13-YEAR SCREENING PROGRAM
Authors: M Zorzi, C Hassan, C Senore, G Capodaglio, A Turrin, E Narne, A Mussato, M Rugge
Journal: Endoscopy (2019)

Interval cancers (IC) were considered in order to judge the round-specific sensitivity of fecal immunochemical tests (FIT) within a colorectal cancer screening program in Italy.