tbuckley/cabot-search huggingface dataset:
Abstract 19629: Experience With a Novel Hybrid Cryo/rf Focused Technique in Long-Standing Persistent Atrial Fibrillation - Low Voltage Bridge Mapping
Authors: Michael C Giudici, Steven J Bailin
Journal: Circulation (2016)

Introduction:  Despite advances in catheter technologies and energy sources for atrial fibrillation (AF) ablation, patient outcomes when treating long-standing persistent AF with pulmonary vein isolation (PVI) combined with empiric roof and isthmus lines is inferior to those seen in paroxysmal AF. Recent advances in mapping systems allow very detailed substrate analysis to be performed rapidly. We previously described a method of substrate ablation (SA) by targeting low voltage bridges (LVB) based upon voltage gradient mapping (VGM). Studies have suggested that targeting “low voltage bridges” (LVB) can be successful in ablating atrial fibrillation, atrial flutter, and slow pathways. We sought to apply this technique in these difficult patients with long-standing persistent AF.   Methods:  31 pts (24M/7F) mean age 61 (42-78 yrs) with mean AF duration 2.4 (.75-4.0 yrs) underwent AF ablation between December, 2014 and May, 2016. The procedure consisted of initial PVI using a 28 mm cryoballoon (Arctic Front, Medtronic, Mpls., MN) followed by detailed mapping of the left atrium using the Navix mapping system and an HD catheter (St. Jude Medical, Mpls, MN). 2 pts. required additional right atrial mapping. Low-voltage bridges were determined and then ablated using a 4 mm tip RF catheter. Sequential mapping was performed after each “layer” of LVBs was eliminated until no LVBs could be found in the chamber.   Results:  29 of 31 procedures were successful with all of these patients remaining in sinus rhythm at most recent f/u on no (26 pts) or tapering (3 pts) antiarrhythmic drug therapy. Mean f/u duration 8.5 mos (1-18). Two patients left the hospital in AF. One failed a cardioversion after a 3-month amiodarone load and had subsequent AV nodal ablation and pacemaker placement.   Conclusions:  These early positive outcomes suggest that a more targeted approach to ablation in long-standing persistent AF targeting LVBs may be superior to empiric roof and isthmus lines. We are early in our experience, however, and will need more patients and longer follow-up to confirm these results.
Active Leprosy Neuritis Detected on FDG PET/CT
Authors: Shambo Guha Roy, Girish Kumar Parida, Sarthak Tripathy, Chandan J. Das, Rakesh Kumar
Journal: Clinical Nuclear Medicine (2017)

Abstract Uses of FDG PET/CT have been previously documented in multiple series in peripheral nerve pathologies, including neurolymphomatosis, peripheral nerve sheath tumor, and plexopathies. We present the case of a 24-year-old man with leprosy neuritis who underwent FDG PET/CT. We suggest that FDG PET/CT can be used as an adjunct tool to monitor neuritis in leprosy patients.
Safety and clinical activity of first-line durvalumab in advanced NSCLC: Updated results from a Phase 1/2 study.
Authors: Scott Joseph Antonia, Julie R. Brahmer, Ani Sarkis Balmanoukian, Dong-Wan Kim, Sang-We Kim, Myung-Ju Ahn, Rahima Jamal, Dirk Jaeger, Patrick Alexander Ott, Paolo Antonio Ascierto, Vanesa Gregorc, Jonathan Wade Goldman, Collin M. Blakely, Xiaoping Jin, Joyce Antal, Ashok Kumar Gupta, Neil Howard Segal
Journal: Journal of Clinical Oncology (2017)

e20504 Background: Single-agent durvalumab demonstrated manageable safety and encouraging clinical activity in advanced squamous and non-squamous NSCLC in preliminary analyses from the Phase 1/2 1108 study (NCT01693562). Here we present updated safety data and clinical activity in NSCLC pts with no prior treatment for advanced disease. Methods: In this Phase 1/2 dose-escalation and expansion study, pts with Stage IIIB/IV NSCLC, ECOG PS 0–1, and availability of a fresh tumor biopsy and/or archival tumor tissue for PD-L1 testing received durvalumab 10 mg/kg every 2 weeks for up to 12 months, with retreatment permitted for those progressing after 12 months of therapy. Tumor PD-L1 expression was assessed using the Ventana PD-L1 (SP263) Assay (PD-L1 high: ≥25% of tumor cells with membrane staining). Results: As of 24 October 2016, 59 pts (63% ECOG PS 1, 49% squamous) received first-line durvalumab. Median duration of follow-up was 17.3 (1.0–36.8) mos. Safety profile was consistent with the overall (N = 304, ≥0 prior lines of therapy) NSCLC cohort. All-grade treatment-related adverse events (AEs) were reported in 56%; the most common were fatigue (15%), diarrhea (13%), and decreased appetite (10%). 7% had a treatment-related AE leading to discontinuation of durvalumab, including diarrhea in 2 pts. Grade ≥3 treatment-related AEs (all n = 1) occurred in 10%; 1 pt died due to drug-related pneumonia. 49 pts had high PD-L1 expression and 9 pts had low/negative PD-L1 expression; data are not summarized for the latter group due to the small number of pts. For the PD-L1 high subpopulation, confirmed ORR (investigator-assessed RECIST v1.1) was 28.6% (95% CI 16.6–43.3) and disease control rate (stable disease ≥24 weeks) was 42.9% (95% CI 28.8–57.8); median PFS was 4.0 months (95% CI 2.3–9.1), median OS was 21.0 months (95% CI 14.5–not estimable), and 12-month OS rate was 72% (95% CI 56–83). Response rates were similar and durable regardless of histology. Conclusions: Consistent with prior data, durvalumab had a tolerable safety profile in advanced treatment-naïve NSCLC. Clinical activity was seen in PD-L1 high pts, with encouraging OS. Clinical trial information: NCT01693562.
Are Value Frameworks Missing the Mark When Considering Long-term Benefits From Immuno-oncology Drugs?
Authors: Lowell E. Schnipper, Richard L. Schilsky
Journal: JAMA Oncology (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Pathophysiology of Chronic Graft-versus-Host Disease and Therapeutic Targets
Authors: Robert Zeiser, Bruce R. Blazar
Journal: New England Journal of Medicine (2017)

Chronic GVHD, an autoimmune disease that follows allogeneic hematopoietic-cell transplantation, is characterized by infections and debilitating tissue injury leading to irreversible fibrosis. Insights into the pathophysiology of the disease are providing new therapeutic targets.
FLT3 inhibitors in acute myeloid leukemia: Choosing the best when the optimal does not exist
Authors: Rita Assi, Farhad Ravandi
Journal: American Journal of Hematology (2017)

Abstract Despite significant advances in deciphering the molecular and cytogenetic pathways governing acute myeloid leukemia, improvements in treatment strategies and clinical outcomes have been limited. The discovery of FLT3 pathway and its potential role in leukemogenesis has generated excitement in the field and has provided a potential target for drug development. Despite setbacks encountered with first‐generation inhibitors, we are witnessing an outbreak of novel agents with potent activity and improved pharmacodynamics which continue to generate promising results. The disease, however, remains a challenge to both patients and physicians with rapid emergence of resistance and subsequent treatment failure. Multiple unanswered questions remain as to which are the optimal FLT3‐inhibitors and which strategies and combinations are likely to overcome resistance. This review revisits the development of FLT3‐inhibitors, the pathways incriminated in their failure and summarizes available molecularly‐designed strategies to design better clinical trials.
Botanicals as immunological adjuvants
Authors: Philip Livingston, Chandra Hood, Simon Yeung, Nai-Kong Cheung, Barrie Cassileth, Gary Deng, Govind Ragupathi
Journal: Cancer Research (2007)

1890  Background: Saponins and beta glucans are widely distributed in the plant kingdom and when injected as purified extracts mixed with antigen, are two of the most potent immunological adjuvants. Many widely consumed botanicals are advertised as immune enhancers, but clear evidence is lacking. Globo H is a cell surface hexasaccharide expressed on many epithelial cancers. When conjugated to keyhole limpet hemocyanin (KLH) and mixed with an immunological adjuvant, the magnitude of the antibody responses against globo H and KLH depend largely on the potency of the adjuvant. We previously described the adjuvant activity of three botanicals (AACR Proceedings 2006: 47: 5559) and now report results with four additional botanicals.  Methods: Using the globo H-KLH conjugate, groups of 5 mice were immunized subcutaneously (SC) or orally by gavage 3 times at 1 week intervals. Antibody responses were measured 1 and 2 weeks after the 3rd immunization. Botanicals were mixed with the conjugate either alone or with a sub-optimal dose of the semisynthetic saponin GPI-0100. The following seven botanicals were tested: (1) H-48 (Honso USA Co.), (2) Coriolus vesicolor raw water extract, purified polysaccharide-K (PSK) or purified polysaccharide-peptide (PSP) (Institute of Chinese Medicine (ICM)), (3) Maitake MD fraction (Yukiguni Maitake Co Ltd. and Tradeworks Group), (4) Echinacea lipophilic, neutral or acidic extracts (Gaia Herbs), (5) Astragalus water, 50% or 95% ethanol extracts (ICM), (6) Tumeric supercritical or hydro-ethanolic extracts ( New Chapter) or 60% ethanol extract (ICM) and (7) yeast s glucan (Biotec Pharmacon). Mixed saponins (Sigma) and semi-synthetic saponin GPI-0100 (Advanced BioTherapies Inc.) were also used as positive controls. Botanicals were tested over a dose range between 50 and 500 mcg in SC vaccines and 1-2 mg in oral vaccines. Sera were analyzed by ELISA against synthetic globo H ceramide and KLH.  Results: 10 separate experiments were performed. Adjuvant activity was clearest in the anti-KLH responses. Representative median serologic titers against KLH after SC vaccinations are: Conjugate alone 1/800, PSK 1/51,200*. Astragalus water extract 1/800, Astragalus 50% EtOH extract 1/3200, Astragalus 95% EtOH extract 1/25,600*, Yeast β-glucan 1/819,200* and GPI-0100 (suboptimal dose) 1/409,600* (*P  Conclusions: Among a series of botanical extracts used as adjuvantin vaccines containing globo H-KLH conjugates, significant adjuvant activity was observed after SC vaccination with PSK, astragalus (both 50% and 95% ethanol extracts), yeast β-glucan, and the semi-synthetic saponin GPI-0100. When administered orally, only the saponin mix and β-glucan significantly raised the serologic titer. PSK and astragalus are being further fractionated to identify the most active components. Support by Botanical Research Center Grant P50 AT002779 from the NIH.
A phase I study to assess the safety, pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activities of daily oral BAL101553, a novel tumor checkpoint controller (TCC) in adult patients with progressive or recurrent glioblastoma (GBM) or high-grade glioma.
Authors: Alvaro Henrique Ingles Garces, Elizabeth R. Plummer, Juanita Suzanne Lopez, Rebecca Sophie Kristeleit, Julie MacDonald, Lorna Sweeting, Michael-John Devlin, Yvette Drew, Alison L. Hannah, Nicola Aceto, Stephanie Anderson, Heidi A Lane, Patrice Larger, Martina Maurer, Phil McKernan, Marc Frederick Engelhardt, Alastair Greystoke, Niamh Coleman, T.R. Jeffry Evans, Paul James Mulholland
Journal: Journal of Clinical Oncology (2017)

TPS2601 Background: BAL101553 (prodrug of BAL27862) is a novel TCC that promotes tumor cell death by modulating the spindle assembly checkpoint. BAL27862 is a lipophilic, small molecule (MW 387) shown in rats to penetrate the brain (1:1 plasma ratio) and has shown promising antitumor activity in orthotopic preclinical models of GBM as monotherapy or in combination with radiotherapy (RT) with/without chemotherapy. In a completed Phase 1 study with 2-h IV infusions (Days 1, 8, 15, q28d, NCT01397929 , CDI-CS-001, Lopez et al. J Clin Oncol 34, 2016 suppl; 2525), dose-limiting vascular effects were observed and appeared C max related. Preclinical data suggest that antiproliferative effects of BAL101553/27862 are driven by exposure (AUC); thus vascular toxicity and antitumor activity are mediated by different PK drivers. In this ongoing study (NCT02490800, CDI-CS-002), daily oral BAL101553 was initially examined in solid-tumor patients; no vascular toxicities were observed at doses up to the MAD of 30 mg QD. Given this absence, the study was amended to enroll separate cohorts of patients with progressive or recurrent GBM or high-grade glioma. Methods: This is an ongoing multicenter, open-label, Phase 1 dose-escalation study using a 3+3 design to determine the MTD, characterize dose-limiting toxicities and assess the PK, PD and antitumor activities of daily oral administration of BAL101553 in consecutive 28-day cycles at a starting dose of 8 mg QD. Patients with histologically-confirmed GBM or high-grade glioma, with progressive or recurrent disease after prior RT with/without chemotherapy, are eligible for enrollment. This includes patients with histologically-confirmed low-grade glioma with unequivocal evidence by imaging of transformation to high-grade glioma. Adverse events are assessed using CTCAEv4; tumor response by RANO (every 2 cycles). The dose escalation allows for doubling of dose levels depending on observed toxicities. PD assessments include circulating tumor cells. PK profiles are assessed throughout the first two treatment cycles. Clinical trial information: NCT02490800.
Неінвазивна діагностика фіброзу печінки у хворих із неалкогольною жировою хворобою печінки
Authors: Yu.M. Stepanov, N.V. Nedzvetskaya, V.B. Yagmur, I.A. Klenina, N.Yu. Oshmyanskaya
Journal: GASTROENTEROLOGY (2017)

Актуальність. Неалкогольна жирова хвороба печінки (НАЖХП) — хронічна дифузна патологія печінки, що пов’язана з інсулінорезистентністю та метаболічними порушеннями, серед яких ожиріння, цукровий діабет 2 типу та дисліпідемія. НАЖХП охоплює простий стеатоз, який має доброякісний перебіг, неалкогольний стеатогепатит, що може прогресувати до цирозу та гепатоцелюлярної карциноми. Морфологічне дослідження печінки залишається золотим стандартом для оцінки ступеня стеатозу, печінкового запалення і фіброзу, однак все більший інтерес останнім часом викликають неінвазивні методи, серед яких оцінка різних індексів, заснованих на сироваткових маркерах. Мета. Оцінка показників діагностичної точності сироваткових маркерів та неінвазивних лабораторних індексів у визначенні морфологічних змін печінки у хворих на НАЖХП. Матеріали та методи. У дослідження включені 60 пацієнтів із НАЖХП, які проходили обстеження й лікування у відділенні захворювань печінки та підшлункової залози ДУ «Інститут гастроентерології НАМН України». Серед досліджених 26 (42,3 %) чоловіків та 34 (56,7 %) жінки, середнім віком (37,1 ± 12,4) та (44,3 ± 7,3) року відповідно. Усім пацієнтам була проведена черезшкірна пункційна трепан-біопсія печінки з подальшим морфологічним дослідженням пунктату; виконано визначення вмісту гіалуронової кислоти, a2-макроглобуліну, аполіпопротеїну А1, фібронектину, гаптоглобіну в сироватці крові, був проведений розрахунок неінвазивних маркерів фіброзу печінки: AAR, APRI, FIB-4. Результати. У хворих на НАЖХП встановлено високу діагностичну точність сироваткових маркерів фіброзу як при розмежуванні різних стадій фіброзу, так і при виключенні саме наявності фіброзу. Висновки. Визначення сироваткових маркерів має значення для вирішення питання про необхідність медикаментозного лікування та його тактику, а відповідність неінвазивних маркерів золотому стандарту — морфологічному дослідженню дозволяє уникати біопсії печінки як методу з потенційно можливими ускладненнями внаслідок своєї інвазивності.
A phase II study of TR105 in patients with hepatocellular carcinoma (HCC) who have progressed on sorafenib.
Authors: Austin G. Duffy, Osama E. Rahma, Susanna Varkey Ulahannan, Suzanne Fioravanti, Aradhana Venkatesan, Ismail B. Turkbey, Peter L. Choyke, Jane B. Trepel, William Douglas Figg, Tim F. Greten
Journal: Journal of Clinical Oncology (2013)

e15177 Background: CD105, also known as endoglin, is an endothelial cell membrane receptor that is highly expressed on tumor vasculature, including HCC. CD105 is essential for angiogenesis and its expression is upregulated by hypoxia and VEGF inhibition. TRC105 is a chimeric IgG1 anti-CD105 monoclonal antibody that inhibits angiogenesis and tumor growth by endothelial cell growth inhibition, ADCC and apoptosis. Methods: Patients with HCC and compensated liver function (Childs Pugh A/B7), ECOG 0/1, were enrolled to a single arm phase II study of TRC105 15mg/kg IV every 2 weeks. Patients must have progressed on or been intolerant of prior sorafenib. A Simon optimal 2-stage design was employed with a 50% 4-month PFS target for progression to the second stage. Correlative biomarkers evaluated included: DCE-MRI; FDG-PET; color Doppler ultrasonography; circulating endothelial progenitor cells, plasma levels of angiogenic factors; soluble CD105 and tumor IHC for CD105. Immunogenicity studies were also performed. Results: 8 pts have been treated so far; M:F 6:2; Median age = 58 (range 24-67); 7 pts had progressed following sorafenib (N=1 intolerant). N=1 pt had fibrolammellar HCC. There were no grade 3/4 treatment-related toxicities. Most frequent toxicities were headache (G2; N=3) and epistaxis (G1; N=4). One patient with a history of ischemic heart disease developed acute cardiac syndrome during the first infusion and was replaced. No patient was progression free at 4 months by RECIST criteria. Median time on study was 8 weeks (range 4-16 weeks). Median no. of doses administered was 4 (range 2-7). Preliminary evidence of biologic response was seen on DCE-MRI in 1pt (of 3 evaluable) with a reduction in kTrans and kep and 3pts (of 3 evaluable) who demonstrated reduction in intra-tumoral color flow on color Doppler. Conclusions: TRC105 is well tolerated in this HCC population post-sorafenib. Although there was biological evidence of antiangiogenic activity it is unlikely that the study will proceed to the second stage. Full clinical and correlative data for the first stage of the study will be presented. Future role of TRC105 in HCC will most likely be as combination therapy with sorafenib or other anti-VEGF therapy. Clinical trial information: NCT01375569.
Increased expression of GATA zinc finger domain containing 1 through gene amplification promotes liver cancer by directly inducing phosphatase of regenerating liver 3
Authors: Wei Sun, Yanquan Zhang, Ka Chun Wong, Ken Liu, Yidong Yang, Bin Wu, Joanna H.M. Tong, Anthony W.H. Chan, Henry L.Y. Chan, Jun Yu
Journal: Hepatology (2017)

We identified that GATA zinc finger domain containing 1 (GATAD1), a transcriptional factor, was significantly up‐regulated in hepatocellular carcinoma (HCC) through gene amplification. We demonstrated the critical role, molecular mechanisms, and clinical implications of GATAD1 as a novel oncogenic factor in HCC. We found that GATAD1 protein was expressed in 76.6% of primary HCCs (85/111) but silenced in normal liver tissues. Gene amplification of GATAD1 was positively correlated with its overexpression in primary HCCs ( R = 0.629, P &lt; 0.0001). GATAD1 significantly increased cell proliferation, G 1 –S cell cycle transition, and migration/invasion but suppressed apoptosis in liver cell lines and promoted tumor growth and lung metastasis in both xenograft and orthotopic mouse models. Mechanistically, GATAD1 induced the transcriptional expression of phosphatase of regenerating liver 3 (PRL3) by binding to its promoter identified by RNA sequencing and chromatin immunoprecipitation‐PCR analyses. PRL3 played an oncogenic role in HCC. Knockdown of PRL3 blunted the tumorigenic effect of GATAD1. In addition, GATAD1 activated Akt signaling, evidenced by increased phosphorylation levels of total Akt, Akt1, Akt2, and Akt target glycogen synthase kinase 3β, while knockdown of PRL3 abolished this effect of GATAD1. We further unveiled that PRL3 activated Akt signaling by dephosphorylating phosphatase and tensin homolog at tyrosine residue, thus reducing phosphatase and tensin homolog protein. The PRL3 inhibitor 5‐[[5‐bromo‐2‐[(2‐bromophenyl)methoxy]phenyl]methylene]‐2‐thioxo‐4‐thiazolidinone significantly suppressed HCC growth by inhibiting Akt activation. Moreover, high GATAD1 nuclear protein expression was associated with poor survival of HCC patients as an independent prognostic factor. Conclusion: GATAD1 plays a pivotal oncogenic role in HCC by directly inducing PRL3 transcription to activate the Akt signaling pathway. GATAD1 may serve as an independent poor prognostic factor for HCC patients. (H epatology 2018;67:2302‐2319).
Review: The Tumor‐Like Phenotype of Rheumatoid Synovium: Molecular Profiling and Prospects for Precision Medicine
Authors: Sungyong You, Jung Hee Koh, Lin Leng, Wan‐Uk Kim, Richard Bucala
Journal: Arthritis & Rheumatology (2017)

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by destructive hyperplasia of the synovium. Fibroblast-like synoviocytes (FLS) are a major component of synovial pannus and actively participate in the pathologic progression of RA. How rheumatoid FLS acquire and sustain such a uniquely aggressive phenotype remains poorly understood. We describe the current state of knowledge of the molecular alterations in rheumatoid FLS at the genomic, epigenomic, transcriptomic, proteomic, and metabolomic levels, which offers a means to reconstruct the pathways leading to rheumatoid pannus. Such data provide new pathologic insight and suggest means to more sensitively assess disease activity and response to therapy, as well as support new avenues for therapeutic development.
Mammography screening reduces breast cancer deaths in Ireland, study finds
Authors: Susan Mayor
Journal: BMJ (2017)

Deaths from breast cancer were 9% lower in women living in a region of Ireland with a mammography screening programme compared with women of the same age living in a part of the country that introduced screening eight years later, a study comparing national data over this time period has found.1

“In order to weight the benefits against the potential harmful effects such as overdiagnosis, those who fund organised mammography screening programmes need to know how many future breast cancer deaths will be averted by them,” said the study authors, including James Hanley, from McGill University, Montreal, Canada, and Katie …
Targeting death receptors for drug-resistant cancer therapy: Codelivery of pTRAIL and monensin using dual-targeting and stimuli-responsive self-assembling nanocomposites
Authors: Fan Xu, Huihai Zhong, Ya Chang, Dongdong Li, Hongyue Jin, Meng Zhang, Huiyuan Wang, Chen Jiang, Youqing Shen, Yongzhuo Huang
Journal: Biomaterials (2017)