tbuckley/cabot-search huggingface dataset:
Salvage combination ipilimumab and nivolumab after failure of prior checkpoint inhibitor therapy in patients with advanced melanoma.
Authors: Elizabeth Mary Gaughan, Gina R. Petroni, William W. Grosh, Craig L. Slingluff
Journal: Journal of Clinical Oncology (2017)

e21009 Background: The combination of Ipilimumab and Nivolumab is standard initial therapy in patients with advanced melanoma based on trials involving treatment-naïve patients. The benefit in those previously managed with checkpoint monotherapy is not well defined. Methods: We identified metastatic melanoma patients from our Immunotherapy database managed with combination Ipilimumab/Nivolumab after progression on prior checkpoint monotherapy. Baseline clinical factors, treatment history, combination therapy outcome by RECIST v1.1 and toxicity data were collected. Descriptive statistics were used to summarize the data. Given the small sample size and limited numbers of deaths, it is too early to look for preliminary associations between outcomes and clinicopathologic factors. Results: We identified 19 patients treated with combination Ipilimumab/Nivolumab after progression on prior checkpoint monotherapy. The cohort included 15 men and 4 women with an average age of 63 years. Thirteen patients had M1c disease, and 7 had a BRAF mutation. Patients had received up to four lines of prior immunotherapy including 9 treated with both prior anti-PD1 and anti-CTLA4 monotherapy. Seven patients completed all four doses of combination therapy with 6 proceeding onto maintenance nivolumab. Eight patients stopped treatment due to toxicity and 4 due to progressive disease. Thirteen patients had clinically significant toxicity, with rash, colitis, hepatitis, and hypophysitis reported most frequently. There were no treatment-related deaths. Overall, 2/19 patients (10.5%, 95% CI [1.3% to 33.1%]) had an objective response (CR+PR) and 9/19 patients (47.4%, 95% CI [24.5% to 71.1%]) had disease control (CR+PR+SD). Four of the patients had stable disease for over 6 months. Six of the 19 patients went on to receive subsequent treatment. Median follow-up for patients still alive was 7 months (range 1 to 20 months) and median survival was not reached. Six-month survival was 68.5% (95% CI [39.3% to 85.8%]) Conclusions: The combination of Ipilimumab and Nivolumab can result in melanoma control in patients with progression on prior checkpoint monotherapy with an expected toxicity profile.
AB0224 Simulation for choice of bdmards and tsdmards in order to success for three-year survival in rheumatoid arthritis treatment
Authors: I Yoshii
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> In rheumatoid arthritis (RA) treatment, bDMARDs and tsDMARDs (BIO) perform tremendous disease activity control, however, its effectiveness is uncertain and unstable, because their survival ratio is not good enough to tolerate. If more right choice is done in guided by some simulation. <h3>Objectives</h3> This study aims more than 80% of three-year survival ratio (SR@3Y) in simulating risk of BIO by using statistical clinical data and post marketing surveillance (PMS) data with Bayes estimation. <h3>Methods</h3> Infection risk and survival risk were harvested from Japanese PMS data, and our clinical data. All our cases were calculated with last observation carried forward method (LOCF). If BIO was continued for more than three years or discontinued by attaining clinical remission, it was evaluated as success, while other cases were evaluated as failure. Patient9s clinical data and general status were calculated for each case, and SR@3Y for success was statistically evaluated with Binary Logistic Analysis for success. Evaluation methods for parameters were divided according to general risk and drug specific possibility. If calculated general risk went above 0.2, selection of BIO was discarded. In other case which had gone below, choice of BIO is done in according to point that had been cumulated by drug specific possibility in choosing what took maximum calculated expectation value. If chosen drug have matched used BIO, it was evaluated as true, if not, it was evaluated as false, while if true case was in success, it was evaluated as true success, and if in failure, it was evaluated as true failure, while false case was in success, it was evaluated as false success, and if in failure, it was evaluated as true failure. Sensitivity in success cases and specificity in failure cases was evaluated in patients in whom BIO was administered. Statistical evaluation was done with chi-square test. <h3>Results</h3> 188 cases have had enough data for simulating. In these, 108 were success and 80 were failure. In success cases, simulated TNF inhibitor (TNF-i) counted 73, Tocilizumab (TCZ) counted 11, Abatacept (ABT) counted 12, and Tofacitinib (TOF) counted 2 while real chosen cases were TNF-i counted 65, TCZ counted 11, ABT counted 21, and TOF counted 11. Overall success ratio was 57.4%. In these cases, true choice had been done in 97 cases of 108. In failure cases, simulated TNF-i counted 44, TCZ counted 16, ABT counted 2, and TOF counted 1, while real chosen cases were TNF-i counted 49, TCZ counted 17, ABT counted 10, and TOF counted 4. True success counted 97, and false success counted 11, while false success counted 37 and true failure counted 54. Then, sensitivity was 89.8% and specificity was 67.5% (&lt;0.01). <h3>Conclusions</h3> Drug choice of BIO supported with simulation was superior to real choice. If risk management was adequately performed, SR@3Y is expected more than 85%. <h3>Disclosure of Interest</h3> None declared
Plasma sequencing to detect a multitude of secondary KIT resistance mutations in metastatic gastrointestinal stromal tumors (GIST).
Authors: Sebastian Bauer, Thomas Herold, Thomas Mühlenberg, Anna-Carina Reis, Johanna Falkenhorst, Miriam Backs, Julia Ketzer, Frank Breitenbuecher, Martin H. Schuler, Susanne Grunewald
Journal: Journal of Clinical Oncology (2015)

10518 Background: Resistance to kinase inhibitors is associated with a marked genomic heterogeneity of secondary mutations of KIT in metastatic GIST which is poorly represented in single tumor biopsies. We sought to evaluate plasma sequencing (plasma seq) as a novel approach to detect or monitor the spectrum of resistance mutations in GIST. Methods: We prospectively collected 30 plasma samples from 22 patients with metastatic GIST (incl. corresponding tumor from same time point: n = 13; median pretreatment: n = 2). Circulating free DNA (cf DNA) and tumor DNA were sequenced on an Illumina MiSeq platform using a custom designed targeted sequencing panel. Mutations with a percentage < 0.5% of total reads were excluded. Results: We detected 87 non-synonymous KIT mutations in plasma samples with various percentages of total reads (0.5-20% of cf-DNA). Primary mutations were found in 41% (all matching the tumor analysis), resistance mutations were seen in 86% of pts including patients responding to imatinib. Mutations in exon 17 were the most common resistance mutations. Resistance mutations detected in tumor samples were infrequently matched by plasma DNA. Notably, p53 mutations were detected in 77%, mutations of RAS or RAF in 59% of patients albeit at low levels. A comparator group of 19 plasma samples from pts with NSCLC harboured 6 low level KIT mutations at levels of 0.9% fc-DNA (median). Extended storage time, high storage temperature and mechanical stress negatively impacted the purity of cf-DNA. Conclusions: Plasma seq in pts with metastatic GIST detects a multitude of resistance mutations of KIT and other genes. Future validations should incorporate comprehensive sequencing of corresponding tumor tissue. Handling of plasma samples should be standardized in order to maximize the yield of mutant DNA. The clinical value of plasma seq should be tested in randomized trials.
Melanoma brain metastases treated with stereotactic radiosurgery and concurrent pembrolizumab display marked regression; efficacy and safety of combined treatment
Authors: Erik S. Anderson, Michael A. Postow, Jedd D. Wolchok, Robert J. Young, Åse Ballangrud, Timothy A. Chan, Yoshiya Yamada, Kathryn Beal
Journal: Journal for ImmunoTherapy of Cancer (2017)

Brain metastases are common in patients with metastatic melanoma. With increasing numbers of melanoma patients on anti-PD-1 therapy, we sought to evaluate the safety and initial response of brain metastases treated with concurrent pembrolizumab and radiation therapy.From an institutional database, we retrospectively identified patients with melanoma brain metastases treated with radiation therapy (RT) who received concurrent pembrolizumab. Concurrent treatment was defined as RT during pembrolizumab administration period and up to 4 months after most recent pembrolizumab treatment. Response was categorized by change in maximum diameter on first scheduled follow-up MRI. Lesion and patient specific outcomes including response, lesion control, brain control and overall survival were recorded and descriptively compared to contemporary treatments with RT and concurrent ipilimumab or RT without immunotherapy.From January 2014 through December 2015, we identified 21 patients who received concurrent radiation therapy and pembrolizumab for brain metastases or resection cavities that had at least one scheduled follow-up MRI. Eleven underwent stereotactic radiosurgery (SRS), 7 received hypofractionated radiation and 3 had whole brain treatment (WBRT). All treatments were well tolerated with no observed Grade 4 or 5 toxicities; Grade 3 edema and confusion occurred in 1 patient treated with WBRT after prior SRS. For metastases treated with SRS, at first scheduled follow-up MRI (median 57 days post SRS), 70% (16/23) exhibited complete (CR, n = 8) or partial response (PR, n = 8). The intracranial response rates (CR/PR) for patients treated with SRS and concurrent ipilimumab and SRS without concurrent immunotherapy was 32% and 22%, respectively.Concurrent pembrolizumab with brain RT appears safe in patients with metastatic melanoma, and SRS in particular is effective in markedly reducing the size of brain metastases at the time of first follow-up MRI. These results compare favorably to SRS in combination with ipilimumab and SRS without concurrent immunotherapy.
AB1067 Suitability of cadaver models in ultrasound diagnostics and interventions in rheumatology: foot and ankle
Authors: V Halász, Ά Nemeskéri, D Bong, P Mandl, I Möller, E Naredo, PV Bálint
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Employment of cadaver specimens in ultrasonography provides a useful and safe model for education, enhances the anatomical knowledge of sonographers and may help determine the accuracy of ultrasound-guided interventions. <h3>Objectives</h3> In this systemic literature review (SLR) we assessed the role and use of cadaver specimens in sonographic studies of the foot and ankle in the field of rheumatology. <h3>Methods</h3> For our literature review we utilized the MEDLINE database, which were supplemented by searches in Google Scholar and Science Direct when the articles were not available through PubMed. Original studies in English language were included in the full paper review with an exception of three German language studies with English abstracts were also included. In the full paper review studies were selected for inclusion featured the sonographic study of cadaver specimens of the foot and ankle. Data were extracted on study characteristics and interventions. <h3>Results</h3> The search yielded 1241 articles, of which 130 were selected for detailed review. In the end, 23 full papers met inclusion criteria. The studies could be grouped as follows: description of detailed ultrasound anatomy (9), testing of accuracy of ultrasound guided interventional procedures (8), examination of artificial tears and lesions (4), foreign bodies (1) and joint effusions (1). The results that were obtained in the studies of the fully reviewed papers utilized a total of 294 cadaveric specimens, with an average of 12.78 (range: 1–48) cadaveric specimens included in each study. <h3>Conclusions</h3> The use of cadaver specimens of the foot and ankle may facilitate the validation of new sonographic methods which assess these joint regions, however the major disadvantage of these studies was the low number of cadaveric specimens. <h3>Disclosure of Interest</h3> None declared
AB0885 Prevalence of ultrasonographic gout specific signs of foot joints
Authors: MA Mahdi, H Rkain, M Erraoui, R Watfeh, S Aktaou, L Tahiri, R Bahiri, F Allali, N Hajjaj-Hassouni
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Objectives</h3> To evaluate the prevalence of ultrasonographic gout specific signs of foot joints. <h3>Methods</h3> This is a cross-sectional study which includes 15 patients with chronic gout, defined according to the American College of Rheumatology criteria (ACR 1977). Ultrasound (US) examination was performed using a high-frequency linear probe (Toshiba Xario®, frequency (8–14 MHz)) in B mode. 330 articular sites were studied at their dorsal surface. The ultrasound has objectified the presence of two signs: hyperechoic band over the superficial margin of the articular cartilage described as a double contour (DC) and tophaceous deposits at the joint cavity. <h3>Results</h3> The mean age at onset was 54.7±12,6 years, and the median diagnosis duration was 0 (0.3) years). The results of the US examination are summarized in Table 1. <h3>Conclusions</h3> This study showed a predilection for the gout specific ultrasound signs (DC and tophaceous deposits) in the tarsometatarsal and metatarsophalangeal joints, especially in the first MTP. The contribution of musculoskeletal ultrasound seems to be very interesting to objectify the presence of gout specific signs of the foot joints. <h3>Disclosure of Interest</h3> None declared
OP0179 Brafv600e promotes myeloid skewing in multisystemic langerhans cell histiocytosis humanized mouse model
Authors: R Biavasco, M Norelli, B Camisa, D Cesana, P Gallina, B Gentner, M Ponzoni, L Dagna, A Bondanza, E Montini
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Multisystemic Langerhans cell histiocytosis (mLCH) is an aggressive disease characterized by the accumulation of mononuclear phagocytes with immunohistochemical features of dendritic cell (histiocytes)<sup>1</sup>. Histiocytes infiltrate mostly the skin, bone marrow (BM), lung and spleen, and produce high levels of proinflammatory cyto/chemokines, leading to organ dysfunction<sup>2,3</sup>. In patients, around 10% of cells in lesions carries an oncogenic mutation in the MAPK pathway, mostly BRAF<sup>V600E</sup> (70% of cases). BRAF<sup>V600E</sup> can be detected also in monocytes and BM progenitors (HSPC) from these patients, whereas only a fraction of them carries a mutation in B cells and none in T cells<sup>4</sup>. <h3>Objectives</h3> To study the role of BRAF<sup>V600E</sup> in the pathogenesis of mLCH, we set up a humanized mouse model of mLCH based on the transplantation into immunodeficient mice (NSG) of human HSPC expressing BRAF<sup>V600E</sup>. <h3>Methods</h3> We isolated HSPC from human cord blood and transduced them at two different levels (50% and 20%) with lentiviral vectors that ubiquitously express BRAF<sup>V600E</sup>, BRAF<sup>WT</sup> or GFP. <h3>Results</h3> All BRAF<sup>V600E</sup> mice manifested severe weight loss within 7 weeks with a median of 3 and 5 weeks for 50% and 20% transduction groups, respectively. Mice showed dysplastic bone marrow (BM) with infiltration of histiocytes; lesions were present also in lungs, kidneys, CNS, spleen and liver. Immunophenotype of infiltrating histiocytes closely resembles mLCH, staining positive for CD14, CD68, S-100 and langerin. None of the control mice lost weight nor displayed organ alteration. Flow cytometry analyses of BM showed 5- to 7-fold reduction in engraftment of human cells in BRAF<sup>V600E</sup> vs GFP groups (p&lt;0,001). Percentage of myeloid cells increased by 3- to 4-fold in BRAF<sup>V600E</sup> vs GFP groups (p&lt;0,001). On the contrary, percentage of B cells was reduced by 3- to 6,5-fold in BRAF<sup>V600E</sup> vs GFP groups (p&lt;0,001). Moreover, there was no difference in the percentage of GFP-positive cells between myeloid cells, whole BM and <i>in vitro</i> sample, suggesting a non-cell autonomous mechanism underlying this myeloid phenotype. <h3>Conclusions</h3> In summary, we generated for the first time a human xenogeneic transplantation mouse model of mLCH, showing that BRAF<sup>V600E</sup> in human HSPC promotes myeloid skewing rather than proliferation. <h3>References</h3> Wilejto et al. Curr Opin Rheumatol 2012. DOI: 10.1097/BOR.0b013e32834db53e. Donadieu et al. Histiocytic Disorders of Children and Adults 2005. Kannourakis et al. Br J Cancer 1994, Sep;23:S37–40. Berres et al. J Exp Med 2014, DOI: 10.1084/jem.20130977. <h3>Disclosure of Interest</h3> None declared
Malignant Neoplasms in Patients With Rheumatoid Arthritis Treated With Tumor Necrosis Factor Inhibitors, Tocilizumab, Abatacept, or Rituximab in Clinical Practice
Authors: Hjalmar Wadström, Thomas Frisell, Johan Askling
Journal: JAMA Internal Medicine (2017)

<h3>Importance</h3> Considering the widespread and increasing use of biological immunomodulators (biological disease-modifying antirheumatic drugs [bDMARDs]) to treat chronic inflammatory conditions, and the concern that immunomodulation may alter cancer risk and progression, the limited available data on use of these therapies as used in clinical practice and cancer risks are a concern. <h3>Objective</h3> To assess the risk of incident malignant neoplasms in patients with rheumatoid arthritis (RA) treated with bDMARDs. <h3>Design, Setting, and Participants</h3> This was a national register–based prospective cohort study of the public health care system in Sweden from 2006 to 2015. Cohorts of patients with RA initiating treatment with tocilizumab (n = 1798), abatacept (n = 2021), and rituximab (n = 3586), a tumor necrosis factor inhibitor (TNFi) as first-ever (n = 10 782) or second-ever (n = 4347) bDMARD, a biologics-naive cohort treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) (n = 46 610), and a general population comparator cohort (n = 107 491). <h3>Exposures</h3> Treatment with tocilizumab, abatacept, rituximab, or TNFi. <h3>Main Outcomes and Measures</h3> Outcomes included a first invasive solid or hematologic malignant neoplasm, or skin cancer. Hazard ratios were calculated using Cox-regression, adjusted for age, sex, disease and treatment characteristics, and educational level. <h3>Results</h3> We identified a total of 15 129 initiations of TNFi as the first or second bDMARD, 7405 initiations of other bDMARDs, and 46 610 csDMARD users. The mean age varied from 58 to 64 years, and the proportion of female patients varied from 71% to 80%, across the 7 cohorts under study. The observed numbers of events (crude incidence per 100 000 person-years) for a first invasive solid or hematologic malignant neoplasm were 50 (959) for tocilizumab, 61 (1026) for abatacept, 141 (1074) for rituximab, 478 (978) for initiators of TNFi as first bDMARD, and 169 (917) for TNFi as second bDMARD. There were no statistically significant differences between initiators of a first or second TNFi, or other bDMARDs, and bDMARD-naive RA for any of a total of 25 drug- and outcome-specific comparisons, with 1 exception (abatacept and increased risk of squamous cell skin cancer). <h3>Conclusions and Relevance</h3> The overall risk of cancer among patients with RA initiating TNFi as first or second bDMARD, tocilizumab, abatacept, or rituximab does not differ substantially from that of biologic drug–naive, csDMARD-treated patients with RA, although altered risks for specific cancer types, or those with longer latency, cannot be excluded.
Natural genetic variation of the cardiac transcriptome in non-diseased donors and patients with dilated cardiomyopathy
Authors: Matthias Heinig, Michiel E. Adriaens, Sebastian Schafer, Hanneke W. M. van Deutekom, Elisabeth M. Lodder, James S. Ware, Valentin Schneider, Leanne E. Felkin, Esther E. Creemers, Benjamin Meder, Hugo A. Katus, Frank Rühle, Monika Stoll, François Cambien, Eric Villard, Philippe Charron, Andras Varro, Nanette H. Bishopric, Alfred L. George, Cristobal dos Remedios, Aida Moreno-Moral, Francesco Pesce, Anja Bauerfeind, Franz Rüschendorf, Carola Rintisch, Enrico Petretto, Paul J. Barton, Stuart A. Cook, Yigal M. Pinto, Connie R. Bezzina, Norbert Hubner
Journal: Genome biology (2017)

Genetic variation is an important determinant of RNA transcription and splicing, which in turn contributes to variation in human traits, including cardiovascular diseases.Here we report the first in-depth survey of heart transcriptome variation using RNA-sequencing in 97 patients with dilated cardiomyopathy and 108 non-diseased controls. We reveal extensive differences of gene expression and splicing between dilated cardiomyopathy patients and controls, affecting known as well as novel dilated cardiomyopathy genes. Moreover, we show a widespread effect of genetic variation on the regulation of transcription, isoform usage, and allele-specific expression. Systematic annotation of genome-wide association SNPs identifies 60 functional candidate genes for heart phenotypes, representing 20% of all published heart genome-wide association loci. Focusing on the dilated cardiomyopathy phenotype we found that eQTL variants are also enriched for dilated cardiomyopathy genome-wide association signals in two independent cohorts.RNA transcription, splicing, and allele-specific expression are each important determinants of the dilated cardiomyopathy phenotype and are controlled by genetic factors. Our results represent a powerful resource for the field of cardiovascular genetics.