tbuckley/cabot-search huggingface dataset:
Phase Ib dose finding trial of intravenous panobinostat with docetaxel in patients with castration-resistant prostate cancer (CRPC)
Authors: D. E. Rathkopf, K. N. Chi, U. Vaishampayan, S. Hotte, N. Vogelzang, J. Alumkal, M. Agrawal, T. M. Nydam, A. Fandi, H. I. Scher
Journal: Journal of Clinical Oncology (2009)

5064 Background: Panobinostat (LBH589) is a potent pan-deacetylase inhibitor that has demonstrated activity in both in vivo and in vitro prostate cancer models. Methods: An open-label, multicenter, dose-finding trial of i.v. panobinostat given on Days 1 and 8 (10, 15, and 20 mg/m 2 ) with fixed-dose docetaxel on Day 1 (75 mg/m 2 ) and prednisone (5 mg bid) in a 21-day cycle is being conducted in chemotherapy-naïve patients (pts) with CRPC. All pts have adequate organ function and ECOG performance status (PS) &lt; 1. Pts with significant cardiovascular abnormalities or QTcF &gt;450 msec on screening ECG are excluded. This treatment is continued until disease progression or intolerability. The primary endpoint is determination of the maximum tolerated dose (MTD) of i.v. panobinostat in combination with docetaxel using the Bayesian logistic regression model. Dose-limiting toxicities (DLTs) are defined in first cycle. Results: Twenty-one pts (Cohort 1, n = 8; Cohort 2, n = 10; Cohort 3, n = 3) have been treated, with a median age of 66 yrs (range 50–88), median Gleason score of 9 (range 7–9), and median entry PSA of 67.1 (range 1.3–7920). DLTs include: Gr 4 bradycardia in Cohort 1 (n = 1) and Gr 4 neutropenia, resulting in Day 8 panobinostat dose omission (Cohort 2, n = 2; Cohort 3, n = 1). Gr 3/4 adverse events (AEs) include: neutropenia (n = 12), febrile neutropenia (n = 3), dizziness (n = 2), DVT (n = 1). Other Gr 1 or 2 AEs include: thrombocytopenia (n = 4), fatigue (n = 10), alopecia (n = 7), diarrhea, nausea, and rash (n = 5). Among the 599 ECGs, there was 1 QTcF increase of &gt;60 ms from baseline and no QTcF &gt;480 ms. Preliminary Cohort 1 pharmacokinetic (PK) data shows the mean panobinostat AUC 0-inf does not differ between Day 1 (239 ng*hr/mL ) and Day 8 (254 ng*hr/mL), and the mean clearance value appeared to be similar between Days 1 and 8. In Cohort 1, the median number of cycles was 6. Four of 8 pts received &gt;6 cycles. Five and four pts had &gt;30% and &gt;50% PSA reduction from baseline, respectively. In Cohort 2, 9 of 10 pts are still on treatment after 3 cycles. Conclusions: The combination of panobinostat at 10 or 15 mg/m 2 with docetaxel is feasible and to date no PK interaction is apparent. Full safety, efficacy, and PK results will be presented. Under DOD PCCTC. [Table: see text]
<i>ERINA</i> Is an Estrogen-Responsive LncRNA That Drives Breast Cancer through the E2F1/RB1 Pathway
Authors: Zihui Fang, Yue Wang, Zehua Wang, Meishu Xu, Songrong Ren, Da Yang, Mei Hong, Wen Xie
Journal: Cancer Research (2020)

Resistance to therapeutic drugs is a major challenge in the treatment of cancers, including breast cancer. Long noncoding RNAs (lncRNA) are known to have diverse physiologic and pathophysiologic functions, including in cancer. In searching for lncRNA responsible for cancer drug resistance, we identified an intergenic lncRNA ERINA (estrogen inducible lncRNA) as a novel lncRNA highly expressed in multiple cancer types, especially in estrogen receptor-positive (ER+) breast cancers. Expression of ERINA was inversely correlated with survival of patients with ER+ breast cancer and sensitivity to CDK inhibitor in breast cancer cell lines. Functional characterization established ERINA as an oncogenic lncRNA, as knockdown of ERINA in breast cancer cells inhibited cell-cycle progression and tumor cell proliferation in vitro and xenograft tumor growth in vivo. In contrast, overexpression of ERINA promoted cell growth and cell-cycle progression. ERINA promoted cell-cycle progression by interacting with the E2F transcription factor 1 (E2F1), which prevents the binding of E2F1 to the tumor suppressor retinoblastoma protein 1 (RB1). ERINA also functioned as an estrogen and ER-responsive gene, and an intronic ER-binding site was identified as an enhancer that mediates the transactivation of ERINA. In summary, ERINA is an estrogen-responsive oncogenic lncRNA that may serve as a novel biomarker and potential therapeutic target in breast cancer. SIGNIFICANCE: These findings identify ERINA as an estrogen-responsive, oncogenic lncRNA, whose elevated expression may contribute to drug resistance and poor survival of patients with ER+ breast cancer.
Phase I study of Imatinib Mesylate(Gleevec) and Gemcitabine in patients with refractory solid tumor malignancy
Authors: Elizabeth A. Poplin, Mecide Gharibo, Lorna Rodriquez, Yusri Elsayed, Margaret Wojtowicz, Murugesan Gounder, Theodore Lagattuta, Eric Rubin, Merrill Egorin
Journal: Cancer Research (2004)

405  Gemcitabine(Gem) is widely active and the standard of care in pancreatic cancer. Imatinib mesylate(IM) is a tyrosine kinase inhibitor with demonstrable activity in chronic myelogenous leukemia and gastrointestinal stromal tumors, due to its inhibition of bcr-abl and c-kit, respectively. IM also binds and inhibits platelet-derived growth factor receptor, which is upregulated in pancreatic cancer. The combination of IM and gem demonstrated activity in an orthotopic nude mouse pancreatic cancer model, (R. Hwang et al). The primary objective of this phase I study is the determination of MTDs for both gem and IM when administered in combination. The study also includes assessment of gem pharmacokinetics(PK) on both days 1 (in the absence of IM) and 8 (in the presence of IM), to determine whether the PK of gem are altered by co-administration of IM. IM PK are also being assessed. Patients (pts) with refractory malignancy; intact intestinal absorption, measurable or evaluable disease, adequate hepatic, renal and hematologic function; ECOG PS 0-2 and survival time estimated > 3 months and signed informed consent were eligible. Gem was administered by fixed dose rate infusion, 10 mg/m2/min,weekly. The initial two pts, with pancreatic cancer, received gem 600 mg/m2, days 1, 8, and 15 q28 days and IM 300 mg daily, starting day 2. Worst drug-related toxicities included gr 3 ALT in one pt and gr 3 dysesthesia in the second, necessitating dose reduction. Both pts had initial reductions in CA19-9. One pt was removed for toxicity, the other at time of progression. Three additional pts were treated with gem 500 mg/m2 and IM 300 mg daily. Worst toxicities were gr 3 neutropenia (1 pt), gr 3 nausea/vomiting(1 pt). One pt was removed from study for toxicity; one, for disease progression; one pt with adrenal cancer remains on treatment 6+ months. Because of the capricious nature of toxicity, possibly consistent with IM-facilitated uptake of Gem, treatment was modified. The first 21-day cycle consisted of gem 450 mg/m2 on days 3 and 10 and IM 300 mg on days 8-12. Subsequent cycles, starting on day 22, consisted of gem 450 mg/m2 days 3 and 10 and IM given days 1-5 and 8-12 q21 days. Three pts received this schedule of treatment with tolerable drug-related toxicity. A partial response was noted in one pt with laryngeal cancer. Two additional pts have been entered at a dose of gem 500 mg/m2. Further escalation is planned. Pharmacokinetic assessment shows that the concentrations of gem and IM are within expected ranges for both agents. More complete PK data will be available at completion of the study. Correlative MR spectroscopy is planned. Gem-IM is a novel and potentially interesting combination that appears to require careful scheduling and dosing to avoid toxicity. (Supported by Novartis).
AB0025 ATYPICAL, ACTIVATED MEMORY B CELLS ARE EXPANDED IN THE SYNOVIAL FLUID OF PATIENTS WITH OLIGOARTHRITIS COMPARED TO PERIPHERAL B CELLS
Authors: Nina de Gruijter, Elizabeth Rosser, Chrysothemis Brown, Lucy Wedderburn
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Juvenile idiopathic arthritis (JIA) is an umbrella term used to describe a group of chronic arthritides of unknown cause in children and adolescents. It is the most common rheumatic disease in children and young people under the age of 16, and if left untreated can cause significant morbidity. Oligoarthritis is the most common of the seven different JIA subtypes and is characterized by autoantibody production and the differentiation of autoreactive T cells. B lymphocytes are known to contribute to the pathophysiology of oligoarthritis by producing autoantibodies, but recent developments suggest that they may further contribute to disease by presenting auto-antigens to (autoreactive) T cells, or secreting by cytokines that influence the function of other inflammatory cell types. <h3>Objectives:</h3> To carry out in-depth immunophenotyping of B cells in the peripheral blood (PB) and synovial fluid (SF) of patients with oligoarthritis. Greater understanding into the phenotype and function of B lymphocytes in oligoarthritis may help clinicians identify novel treatment targets for patients that fail first-line methotrexate therapy. <h3>Methods:</h3> Patients with oligoarthritis (n=28, age 0-15), adult healthy controls (n=4, age&gt;21) and child healthy controls (n=3, age 7-15) were included in this study. All patients and controls were recruited in the United Kingdom with fully informed and age-appropriate consent as approved by the London-Bloomsbury Research Ethics Committee (ref: 95RU04) in accordance with the Declaration of Helsinki. PB and SF mononuclear cells were prepared by density centrifugation and immunophenotyped by flow cytometry. <h3>Results:</h3> CD19+CD24loCD38lo (atypical) and CD19+CD2hiCD38lo (memory) B cells were enriched in synovial fluid compared to peripheral blood, whereas CD19+CD24hiCD38hi (immature) and CD19+CD24intCD38int (mature) B cells were depleted. The B cell activation markers CD27 and CD86 were also found to be upregulated on SF B cells compared to PB B cells. Further analysis using extracellular markers identified by single cell sequencing analysis revealed that SF B cells also express higher levels of complement receptor 4 (CD11c/CD18) and the oxysterol receptor GPR183 than PB B cells. <h3>Conclusion:</h3> Flow cytometry analysis demonstrated that B cells in the synovial fluid have a distinct phenotype compared to B cells in the peripheral blood. Future work will investigate the functional implications of these results. <h3>Acknowledgement:</h3> This research was funded by Versus Arthritis, Great Ormond Street Children's Charity, UCL Partners, the National Institute for Health Research (NIHR) UCL Hospitals Biomedical Research Centre, and NIHR- Great Ormond Street Biomedical Research Centre. <h3>Disclosure of Interests:</h3> None declared
AB0233 Productivity costs in as. comparison among 3 european countries
Authors: AH Boonen, D Van der Heijde, M Rutten, F Guillemin, M Dougados, K De Vlam, H Mielants, A Spoorenberg, H Van der Tempel, S Van der Linden
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> To compare productivity costs due to inability to perform paid work for ankylosing spondylitis (AS) in three European countries: the Netherlands (NL), France (F) and Belgium (B). <h3>Methods</h3> 216 consecutive prevalent out-patients with AS started a 2 year cost-of-illness cohort study. Questionnaires assessed AS-related health resource utilisation every 2 months. Productivity costs were calculated from societal perspective by friction costs (FC) method (costs of first 3 months of sick-leave) and human capital (HC) approach (costs of sick-leave and work-disability). In addition, loss of income for the patients was assessed. Differences in social security systems among countries were taken into account. Means and 95% CI after bootstrapping are presented. T-tests were performed on the results of the bootstraps to compare countries. <h3>Results</h3> 209 patients completed follow-up. In NL, F and B respectively, 70, 69 and 74% were male, mean age 46 (SD:12), 38 (SD:12) and 42 (SD:14) yr, mean disease duration 24 (SD:12), 14 (SD:9) and 13 (SD:10) yr and 24, 13 and 24% had a manual profession. <h3>Conclusion</h3> Productivity costs due to AS are substantial for society and patients and differ among countries. FC underestimate the economic impact of disease. These findings have implications for generalizability of economic studies.
FDA may fine clinical trial sponsors that don’t report data
Authors: Janice Hopkins Tanne
Journal: BMJ (2020)

The US Food and Drug Administration has said it will penalise sponsors of clinical trials that do not report data to the ClinicalTrials.gov database, but it has not indicated whether it will go after all offenders.

The move came after the US Department of Health and Human Services, the FDA, and the National Institutes of Health were sued for failure to require reporting of clinical trial results and to make the results public.1 They lost the case earlier this year, after a federal court ruled that clinical trial sponsors …
Pharmacotherapy for pulmonary arterial hypertension
Authors: Talha Khan Burki
Journal: The Lancet Respiratory Medicine (2020)

A new study has concluded that adding selexipag to macitentan and tadalafil does not improve pulmonary vascular resistance in patients with pulmonary arterial hypertension (PAH). The results were presented at this year's American Thoracic Society International Conference, which was held online because of the COVID-19 pandemic.
Abstract 224: 20-hydroxyeicosatetraenoic Acid Mediated Amp Activated Protein Kinase Suppression Induces Endothelial Nitric Oxide Synthase Uncoupling
Authors: Natalie Ward, Kai Chen, Kevin Croft, John Keaney
Journal: Circulation (2008)

20-Hydroxyeicosatetraenoic acid (20-HETE), a cytochrome P450 product of arachidonic acid metabolism, is a potent vasoconstrictor thought to be involved in vascular dysfunction and the regulation of blood pressure. 20-HETE has been demonstrated to play an inhibitory role in eNOS activity and both animal and human studies have revealed strong associations between 20-HETE and endothelial dysfunction. However, the signalling mechanisms are largely unknown. Previous studies have shown that AMPK activity is involved in the Hsp90-eNOS association. Therefore we sought to investigate the effect of 20-HETE on eNOS and Hsp90 association, and whether this was mediated by AMPK. Treatment of human umbilical vein endothelial cells (HUVECs) with 10μM 20-HETE for 24h induces an increase in eNOS phosphorylation, which is not observed following acute treatment (30mins). This was accompanied by transient changes in Akt phosphorylation. Conversely, upstream AMPK activity increased rapidly following 20-HETE treatment (&lt;1min) before decreasing by 30mins. Treatment with 20-HETE also resulted in an acute increase in the production of reactive oxygen species (ROS), which returned to control levels at &gt;2hr post-20-HETE treatment. Immunoprecipitation of eNOS in cells treated with 20-HETE revealed a decrease in basal, VEGF and A23187 stimulated Hsp90 association with eNOS, indicating an uncoupling mechanism. Pre-treatment of the cells with AICAR (a chronic activator of AMPK) prevented the loss of Hsp90 association with eNOS following 20-HETE treatment. To further investigate the functional effect of Hsp90 dissociation, we utilised an endothelial-smooth muscle cell system to measure cGMP production. Chronic 20-HETE treatment appeared to reduce both basal and VEGF stimulated cGMP levels. Pre-treatment of the cells with AICAR protected against the 20-HETE induced decrease in cGMP levels, both basally and following VEGF stimulation. In conclusion, 20-HETE suppression of AMPK activity impairs eNOS-Hsp90 association, providing a mechanism for reduced NO bioactivity and endothelial dysfunction in diseases with elevated 20-HETE levels, such as hypertension.
Rationalizing the pathway to personalized neoadjuvant immunotherapy: the Lombard Street Approach
Authors: Judith M Versluis, Daniela S Thommen, Christian U Blank
Journal: Journal for ImmunoTherapy of Cancer (2020)

Neoadjuvant chemo(radio)therapy is part of the established standard of care in cancer treatment; neoadjuvant application of immunotherapy, however, is only performed within recent trials. Combination of programmed cell death protein 1 and cytotoxic T lymphocyte antigen 4 blockade shows promising results with high pathologic response rates in the neoadjuvant setting and a very low relapse rate in the responding patients. In addition, neoadjuvant administration allows direct determination of treatment efficacy within the individual patient, and offers easy access to paired tumor material, both pretherapy and post-therapy, thus facilitates the rational development of new combinations driven by preclinical analyses. Patient-derived human tumor explant systems such as a recently developed human patient-derived tumor fragment platform can provide an additional tool to further rationalize the development of new treatment combinations. We will discuss neoadjuvant immunotherapy as a unique opportunity for rational trial design, the development of immune signatures for non-responding patients to steer clinical trial development, and the use of patient-derived ex vivo models to identify new personalized immunotherapy combinations. In this context, we propose the ‘Lombard Street Approach’, a back and forth approach of characterizing non-responders on neoadjuvant immunotherapy combinations, identifying promising new combinations for this group in the tumor fragment platform, and performing subsequently signature-driven small proof-of-concept combination trials. Repeating this approach with smaller and smaller groups of non-responders will step by step increase the percentage of patients benefiting from neoadjuvant immunotherapy in a rational and fast manner.
PTU-050 Patients with interval colorectal cancers(crc) ‘missed’ on the national faecal occult blood (fob) screening programme have a worse outcome in the short-term compared to patients who declined to join the programme – results from a multicentre study
Authors: AT George, S Aggarwal, S Dharmavaram, A Menon, M Dube, M Vogler, A Field
Journal: Gut (2017)

Introduction  To compare outcomes of the two groups  Method  National Bowel Cancer Audit Programme data from three centres,for all colorectal cancers(CRC)in the screening age group(60–74 years)over a 2 year period(August 2011–2013)were linked for their Faecal Occult Blood Testing(FOBT)screening status(BCSP database/Eastern Hub).Patient/tumour demographics and survival for Interval cancers(IC-screening patients developing cancers within 2 years of a negative FOB test)and cancers in those who declined the screening programme were analysed.All three centres were in incident rounds of screening.Tumours at and beyond splenic flexure were considered left-sided. 1 year mortality was looked at as all patients had a minimum of 1 year follow-up.  Results  Of the 521 CRC identified, 127 (25%)were IC and 228 (44%)were cancers in the declined screening group.The mean age at cancer diagnosis(66.8 years vrs 67.5 years;p=0.014,X2=0.33);male:female ratio(83:44vrs 130:98;p=0.024,X2=2.36)and ethnic demographics(white british:others;123:5vrs211:20; p=0.090,X2=2.87)between the IC and declined screening groups were comparable.Between the IC and Declined Screening groups,the tumour location(right-sided:left-sided;48:79vrs 66:162;p=0.024,X2=2.36)and polyp:non-polyp cancers(2:125vrs 1:227;p=0.262,X2=1.25)were comparable.  The IC had a higher proportion of advanced cancers at presentation(Dukes C/D;89 (70%)vs122(53%);p=0.002,X2=9.28)compared to the declined screening group.  Mortality-data  1 year mortality was 20 (16%)and 25 (11%)for the IC and declined screening groups respectively.There was no gender,age or ethnic differences between the two groups.The mortality of right-sided cancers in the IC group was significantly higher than that for the declined screening group(10 (21%)vrs 4 (6%);p=0.037,X2=4.32).  Conclusion  Our findings highlight that patients on the national FOBT screening programme who develop IC (specially right-sided)fared worse in the short-term, compared to CRC in patients who had declined FOBT screening-due to a higher tumour stage and a higher 1 year mortality.  Disclosure of Interest  None Declared
Special Consideration for Patients With Morgellons Disease, Even Among Psychodermatology Patients?
Authors: Nicholas D. Brownstone, John Koo
Journal: JAMA Dermatology (2020)

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 Dermatology 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 Dermatology journal
Lymphocyte predominant cells of nodular lymphocyte predominant Hodgkin lymphoma interact with rosetting T cells in an immunological synapse
Authors: Julia Bein, Lorenz Thurner, Martin‐Leo Hansmann, Sylvia Hartmann
Journal: American Journal of Hematology (2020)

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a subtype of Hodgkin lymphoma with a preserved B-cell phenotype and follicular T helper (TFH ) cells rosetting around the tumor cells, the lymphocyte-predominant (LP) cells. As we recently described reactivity of the B-cell receptors of LP cells of some NLPHL cases with Moraxella spp. proteins, we hypothesized that LP cells could present peptides to rosetting T cells in a major histocompatibility complex class II (MHCII)-bound manner. Rosetting PD1+ T cells were present in the majority of NLPHL cases, both in typical (17/20) and variant patterns (16/19). In most cases, T-cell rosettes were CD69+ (typical NLPHL, 17/20; NLPHL variant, 14/19). Furthermore, both MHCII alpha and beta chains were expressed in the LP cells in 23/39 NLPHL. Proximity ligation assay and confocal laser imaging demonstrated interaction of the MHCII beta chain expressed by the LP cells and the T-cell receptor alpha chain expressed by rosetting T cells. We thus conclude that rosetting T cells in NLPHL express markers that are encountered after antigenic exposure, that MHCII is expressed by the LP cells, and that LP cells interact with rosetting T cells in an immunological synapse in a subset of cases. As they likely receive growth stimulatory signals in this way, blockade of this interaction, for example, by PD1-directed checkpoint inhibitors, could be a treatment option in a subset of cases in the future.