tbuckley/cabot-search huggingface dataset:
Genetic variations in A20 DUB domain provide a genetic link to citrullination and neutrophil extracellular traps in systemic lupus erythematosus
Authors: Lina Odqvist, Zala Jevnikar, Rebecca Riise, Lisa Öberg, Magdalena Rhedin, Dag Leonard, Linda Yrlid, Sonya Jackson, Johan Mattsson, Sambit Nanda, Philip Cohen, Axel Knebel, Simon Arthur, Kristofer Thörn, Elisabet Svenungsson, Andreas Jönsen, Iva Gunnarsson, Karolina Tandre, Andrei Alexsson, Alf Kastbom, Solbritt Rantapää-Dahlqvist, Maija-Leena Eloranta, Ann-Christine Syvänen, Anders Bengtsson, Patrik Johansson, Johanna K Sandling, Christopher Sjöwall, Lars Rönnblom, Barry Collins, Outi Vaarala
Journal: Annals of the Rheumatic Diseases (2019)

Objectives Genetic variations in TNFAIP3 (A20) de-ubiquitinase (DUB) domain increase the risk of systemic lupus erythematosus (SLE) and rheumatoid arthritis. A20 is a negative regulator of NF-κB but the role of its DUB domain and related genetic variants remain unclear. We aimed to study the functional effects of A20 DUB-domain alterations in immune cells and understand its link to SLE pathogenesis. Methods CRISPR/Cas9 was used to generate human U937 monocytes with A20 DUB-inactivating C103A knock-in (KI) mutation. Whole genome RNA-sequencing was used to identify differentially expressed genes between WT and C103A KI cells. Functional studies were performed in A20 C103A U937 cells and in immune cells from A20 C103A mice and genotyped healthy individuals with A20 DUB polymorphism rs2230926. Neutrophil extracellular trap (NET) formation was addressed ex vivo in neutrophils from A20 C103A mice and SLE-patients with rs2230926. Results Genetic disruption of A20 DUB domain in human and murine myeloid cells did not give rise to enhanced NF-κB signalling. Instead, cells with C103A mutation or rs2230926 polymorphism presented an upregulated expression of PADI4 , an enzyme regulating protein citrullination and NET formation, two key mechanisms in autoimmune pathology. A20 C103A cells exhibited enhanced protein citrullination and extracellular trap formation, which could be suppressed by selective PAD4 inhibition. Moreover, SLE-patients with rs2230926 showed increased NETs and increased frequency of autoantibodies to citrullinated epitopes. Conclusions We propose that genetic alterations disrupting the A20 DUB domain mediate increased susceptibility to SLE through the upregulation of PADI4 with resultant protein citrullination and extracellular trap formation.
Chemotherapy associated myelosuppression and disease-free and overall survival: A systematic review and evidence summary.
Authors: Marek S. Poniewierski, Adane Wogu, Eva Culakova, Alexander Rosen, Nicole Maria Kuderer, Jeffrey Crawford, David C. Dale, Gary H. Lyman
Journal: Journal of Clinical Oncology (2012)

6129 Background: Myelosuppression remains the major dose-limiting toxicity of cancer chemotherapy. The risk of myelotoxicity is associated with the specific drugs, doses and schedule utilized along with patient differences in drug metabolism and tolerance. Several retrospective studies have suggested that patients surviving early myelosuppression may experience improved disease-free and overall survival. Methods: A literature search was conducted of studies published between 1980 - 2011 reporting a relationship between chemotherapy-associated myelosuppression and cancer recurrence and/or mortality. Eligibility was restricted to adult cancer patients receiving chemotherapy and reporting disease recurrence or mortality in relationship to myelosuppression. Dual blinded study identification and data extraction were employed. Hazard ratio (HR) estimates for clinical outcomes were based on random effects models. Results: A total of 1,896 studies were identified in the initial search. A total of 25 studies analyzing results in 14,029 (range 23 – 4,626) patients were deemed to be eligible. Studies included cancers of the breast (7), lung (8), ovary (3), gastrointestinal (5), and Hodgkin lymphoma (2). Overall, neutropenia was observed in 7,577 (54%) patients. Overall survival was reported in 17 studies, recurrence or progression free survival in 11, and both in 5. Outcomes were based on HRs in 16, median survival in 14 and neither in 2. The HRs for survival and progression/recurrence free survival with and without myelosuppression were 0.66 [95%CI: 0.56-0.78; P&lt;.001] and 0.72 [95%CI: 0.60-0.87; P&lt;.001], respectively. There was no difference in estimated HRs in studies employing landmark analysis. Conclusions: Myelosuppression appears to be associated with lower risk of recurrence and death across cancer types and settings. These data do not distinguish between the effects of chemotherapy dose intensity versus patient variation drug metabolism resulting in greater efficacy and toxicity in some patients. Nevertheless, these results suggest that reducing chemotherapy dose intensity to avoid myelosuppression may not be a prudent strategy even in patients with advanced disease.
Role of investigational monoclonal antibodies in the treatment of multiple myeloma: A systematic review.
Authors: Hamza Hassan, Ahmad Iftikhar, Nimra Iftikhar, Adeela Mushtaq, Abdul Rafae, Faryal Razzaq, Jason Neil Valent, Abraham Sebastian Kanate, Rajshekhar Chakraborty, Faiz Anwer
Journal: Journal of Clinical Oncology (2019)

e19533 Background: Immunotherapy for multiple myeloma (MM) has been of focus in recent years due to its myeloma-specific immune responses. We reviewed literature on non-FDA approved monoclonal antibodies (MoAbs) to highlight future perspectives. Methods: We searched PubMed, EMBASE, Web of Science, Cochrane and Clinicaltrilas.gov to include phase I/II clinical trials. Results: 40 studies (1917 patients) were included. Isatuximab (anti-CD38) and F50067 (anti-CXCR4) were the only MoAbs which produced encouraging results as monotherapy with ORR of 66.7% and 32% respectively. Isatuximab use in combination with Len-Dex produced CBR of 83%, and in combination with pomalidomide and dexamethasone CBR of 73%. Indatuximab Ravtansine, an antibody-drug conjugate, produced ORR 78% and 79% in combination with Len-Dex and pomalidomide + dexamethasone respectively. Conclusions: CD38 remains an important target for further clinical trials in combination therapy. Trials using indatuximab, pembrolizumab, lorvotuzumab, siltuximab, and dacetuzumab in combination therapy produced better outcomes as compared to monotherapies. [Table: see text]
Allergic Reaction to Exenatide and Lixisenatide but Not to Liraglutide: Unveiling Anaphylaxis to Glucagon-Like Peptide 1 Receptor Agonists
Authors: Oded Shamriz, Adeeb NaserEddin, Ofri Mosenzon, Sigal Sviri, Yuval Tal
Journal: Diabetes Care (2019)

A 61-year-old man was admitted to our center following anaphylactic shock. His history includes type 2 diabetes, hypertension, and dyslipidemia. He was treated with extended-release (ER) exenatide (2 mg/week), which was later replaced with liraglutide (18 mg/day), and well tolerated both glucagon-like peptide 1 receptor agonists (GLP-1RA). After 2 years of liraglutide treatment he was prescribed a fixed-ratio combination (FRC) of insulin glargine and lixisenatide (300 units and 100 μg, respectively).

The morning of his admission, he was vaccinated for influenza and afterward received his first glargine/lixisenatide injection. Minutes later, he developed generalized urticaria, itching, dyspnea, and hoarseness. His systolic blood pressure was 70 mmHg. He was intubated, treated with adrenaline, and transferred to the emergency room. Upon arrival, his blood pressure was 103/57 mmHg. Adrenaline, antihistamines, and corticosteroids were commenced and the patient was transferred to the intensive care unit. The following day he was extubated, and he was discharged on the fifth day of admission.

Three months following admission, his blood count demonstrated no eosinophilia (absolute eosinophil count, 0.3; normal range, 0–1.3 cells × 109/L). Total immunoglobulin (Ig)E and tryptase levels were within normal ranges (values [normal ranges] 40.9 [0–87] IU/mL and 7.22 [0–11] μg/L, respectively).

An allergic …
Neoadjuvant chemotherapy in high-risk soft tissue sarcomas: Final results of a randomized clinical trial from the Italian Sarcoma Group, the Spanish Sarcoma Group (GEIS), the French Sarcoma Group (FSG), and the Polish Sarcoma Group (PSG).
Authors: Alessandro Gronchi, Emanuela Palmerini, Vittorio Quagliuolo, Javier Martin Broto, Antonio Lopez Pousa, Giovanni Grignani, Antonella Brunello, Jean-Yves Blay, Robert Diaz Beveridge, Virginia Ferraresi, Iwona Lugowska, Franco Domenico Merlo, Valeria Fontana, Elena Palassini, Carlo Morosi, Silvia Stacchiotti, Angelo Paolo Dei Tos, Piero Picci, Paolo Bruzzi, Paolo Giovanni Casali
Journal: Journal of Clinical Oncology (2019)

11000 Background: A ISG randomized trial on 5 cycles of adjuvant epirubicin+ifosfamide (EI) versus no chemotherapy suggested an OS benefit in localized high-risk STS (JCO 2001;19:1238). A subsequent trial showed no difference between 3 vs 5 cycles of the same neoadjuvant regimen (JCO 2012;30:850). The aim of this trial was to compare 3 cycles of EI versus a histology-tailored (HT) neoadjuvant regimen in selected localized high-risk STS. Methods: This is a multicenter European randomized trial comparing EI versus a HT regimen: gemcitabine+docetaxel in undifferentiated pleomorphic sarcoma (UPS); trabectedin in high-grade myxoid liposarcoma; high-dose prolonged-infusion ifosfamide in synovial sarcoma (SS); etoposide+ifosfamide in malignant peripheral nerve sheath tumors (MPNST); gemcitabine+dacarbazine in leiomyosarcoma (LMS). Patients had localized high-risk (grade = 3; size ≥5 cm) STS of extremities or trunk wall. Primary end-point was Disease Free Survival (DFS). The final analysis was planned after the observation of 130 events. This allows an 80% power to detect a significant difference at the 5% 2-sided level, if the true HR is 0.6 in favor of EI, as shown by the interim analysis (Lancet Oncol 2017;18:812-822). Results: From May 2011 to May 2016, 287 patients were randomized (97 = UPS; 65 = myxoid liposarcoma; 70 = SS; 27 = MPNST; 28 = LMS). The median follow-up was 51.75 months for the alive patients (IQ 28.03) The DFS and OS probability at 60 months were 0.48 and 0.55 (HR:1.232; 95%CI: 0.875-1.733; log rank p=0.323) and 0.66 and 0.76 (HR:1.766; 95%CI:1.101-2.831; log rank p=0.018), in the HT and EI arm, respectively. Conclusions: The final analysis shows a non-statistically significant DFS difference in favor of EI over HT chemotherapy with a larger and statistically significant OS difference. The outcome of patients on EI overlapped previous ISG trials. EI should remain the regimen of choice when neoadjuvant chemotherapy is used in high-risk localized STS. However this trial cannot be used as a formal proof of efficacy of (neo)adjuvant chemotherapy per se. EUDRACT 2010 – 023484 – 17. Funding source: Eurosarc FP7 278472. Clinical trial information: NCT01710176.
Abstract 10725: Fractional Flow Reserve Correlates to Oxygen-sensitive T2-prepared Magnetic Resonance Imaging in Coronary Heart Disease
Authors: Thomas Walcher, Vinzenz Hombach, Wolfgang Rottbauer, Jochen Wöhrle, Peter Bernhardt
Journal: Circulation (2012)

Background: Oxygen-sensitive T2-prepared steady-state free-precession (T2prep SSFP) cardiac magnetic resonance imaging (CMR) has the potential to evaluate myocardial ischemia due to different T2 an...
Magnetic Resonance Imaging of Lesions in the Sacroiliac Joints for Differentiation of Patients With Axial Spondyloarthritis From Control Subjects With or Without Pelvic or Buttock Pain: A Prospective, Cross‐Sectional Study of 204 Participants
Authors: Sengül Seven, Mikkel Østergaard, Lone Morsel‐Carlsen, Inge Juul Sørensen, Birthe Bonde, Gorm Thamsborg, Jens Jørgen Lykkegaard, Oliver Hendricks, Niklas Rye Jørgensen, Susanne Juhl Pedersen
Journal: Arthritis & Rheumatology (2019)

To evaluate whether different types of sacroiliac (SI) joint lesions identified by magnetic resonance imaging (MRI) could differentiate axial spondyloarthritis (SpA) from conditions with buttock or pelvic pain attributable to other reasons, including postpartum women and healthy subjects.The study was designed as a prospective, cross-sectional study involving 204 participants, comprising patients with axial SpA (n = 41) and control groups of subjects with or without SI joint pain, including patients with lumbar disc herniation (n = 25), women with (n = 46) or without (n = 14) postpartum buttock/pelvic pain (having given birth within the preceding 4-16 months), hospital cleaning staff (n = 26), long-distance runners (n = 23), and healthy men (n = 29). Participants underwent clinical examination and MRI, and MRIs were evaluated in a blinded manner by 2 readers according to the Spondyloarthritis Research Consortium of Canada (SPARCC) SI joint inflammation and structural lesion scores. SPARCC score cutoff levels were defined as scores above a certain threshold. Primary analyses were based on reader agreement with regard to the presence of SI joint pathologic features on MRI ("concordant reads"). Sensitivity, specificity, and positive and negative predictive values were calculated.SI joint ankylosis and backfill were detected by MRI only in patients with axial SpA (32% and 37%, respectively), while bone marrow edema (BME) and fat lesions were seen in all non-axial SpA control groups (3-39% with BME and 4-14% with fat lesions). SI joint erosion was present only in patients with axial SpA and in women with postpartum buttock/pelvic pain (at erosion score cutoffs of >1 and >4, 61% and 34%, respectively, in patients with axial SpA, and 9% and 2%, respectively, in women with postpartum buttock/pelvic pain). A SPARCC BME score of ≥5 was present only in patients with axial SpA (56%) and in women with postpartum buttock/pelvic pain (24%), while fat lesions were present, albeit rarely, at high SPARCC cutoff scores in nearly all groups. Of the 38 women from the non-postpartum control groups who had given birth (mean time since birth 9.7 years), 2 (5%) had BME, whereas none had SI joint erosion or fat lesions, and none had a BME score of ≥4.BME and fat lesions were most pronounced in patients with axial SpA, but also occurred in other groups, particularly women with postpartum buttock/pelvic pain. Erosion above a certain SPARCC score threshold as well as backfill and ankylosis were highly specific for axial SpA.
Prognosis of young patients with monoclonal gammopathy of undetermined significance.
Authors: Li Pang, Shaji Kumar, Arjun Lakshman, Robert A. Kyle, S. Vincent Rajkumar
Journal: Journal of Clinical Oncology (2019)

8049 Background: Monoclonal gammopathy of undetermined significance (MGUS) is rare in young patients (pts; age &lt;40 years at diagnosis), with a prevalence of &lt; 0.3%, representing approximately 2% of all patients with MGUS. We hypothesized that MGUS detected in pts &lt;40 years of age may be associated with a higher risk of progression. Methods: We identified 249 pts with MGUS &lt;40 yrs old, evaluated at Mayo Clinic, Rochester from 1997 to 2016. The endpoint was time to progression assessed by Kaplan-Meier method. Results: 119 were male, 130 were female. Most (n= 179, 72%) were diagnosed between the ages of 30-39. The type of MGUS was IgG 69%, IgA 10%, IgM 15%, and other 5%. 135 pts (54%) had concurrent immune-related conditions, including autoimmune, inflammatory, and infectious disorders at the time of diagnosis of MGUS. Pts without immune-related conditions tend to have higher M protein compared to pts with immune-related conditions (mean, 0.36 gm/dl VS 0.20 gm/dl, p =0.057). During follow up, the M protein resolved in 36 patients. The M protein was more likely to resolve in pts with immune-related conditions compared with pts without immune-related conditions (RR 1.91, 95% CI 1.02-3.59). Progression was seen in 16 pts: 9 smoldering multiple myeloma (SMM), 4 multiple myeloma (MM), 1 macroglobulinemia, 2 non-Hodgkin’s lymphoma. The rate of progression to SMM, MM, or related disorder at 5 and 10 years was 6.0% and 13.8%, respectively. The size of M protein was a significant risk factor for progression (HR 4.23, 95% CI 2.17-7.91) The risk of progression at 5 and 10 years for pts with immune-related conditions concurrently present when MGUS was first diagnosed was 1.5% and 10.1% respectively; corresponding rate in pts without immune-related conditions at the time of diagnosis was higher at 12.3% and 18.9%, respectively (p =0.016), (HR 2.36, 95% CI 0.85-6.52). Similar results were seen when patients in whom the M protein resolved were excluded. Conclusions: Young patients with MGUS may have a higher risk of progression, 1.4% per year; approximately 50% are diagnosed in the setting of immune-related disorders. When occurring in the setting of immune related disorders, the M protein is smaller, more likely to resolve, and may have a lower risk of progression than in pts in whom MGUS is detected without concurrent immune-related disorder.
A severe case of refractory esophageal stenosis induced by nivolumab and responding to personalized treatment.
Authors: Michel Obeid
Journal: Journal of Clinical Oncology (2019)

113 Background: The prevalence of esophageal stenosis caused by ICI in the context of induced immune mucositis and esophagitis is extremely rare. Methods: NA. Results: Case presentation: We report the case of a patient with stage IV pulmonary adenocarcinoma treated for 6 months with nivolumab who developed bilateral conjunctivitis followed by oropharyngeal mucositis and esophagitis complicated by a severe esophageal stenosis. The laryngeal margin and hypopharyngeal mucosa appeared highly inflammatory. Esophagogastroduodenoscopy revealed mucositis with a scar-like stricture immediately below the upper esophageal sphincter with nonulcerative mucosa and an inflammatory aspect of the entire esophagus. No involvement of the stomach was observed. Oropharynx biopsies displayed marked lymphocytic T cell-infiltration with several foci of monocellular necrosis in the squamous epithelium. A blood sample revealed a discrete increase in the ESR with no eosinophilia or leukocytosis. Liver and kidney function panel tests were normal. A CT scan reported no evidence of disease recurrence. Despite multiple boluses of methylprednisolone and high doses of prednisone continued for several months, the patient experienced very rapid symptomatological reappearance during three steroid tapering attempts and aggravation of his esophageal stenosis to an aphagic stage, requiring a nasogastric tube. This long course of high-dose corticosteroid treatment was complicated with osteoporosis-induced fractures with several spontaneous compressions of thoracolumbar vertebrae requiring an enlarged T10 to L5 cementoplasty. Anti-IL-6 blockade therapy with tocilizumab resulted in excellent response, allowing the total resolution of the irAEs leading to successful steroid tapering. Conclusions: Herein, we describe the first case of a patient who developed autoimmune mucositis and esophagitis complicated by a severe refractory esophageal stenosis induced during treatment by nivolumab, which completely resolved after personalized treatment with tocilizumab, suggesting a role of IL-6 blockade in the management of severe steroid refractory irAEs.
Real-world time to next treatment (TTNT) for first-line (1L) targeted and immuno-oncology therapies for BRAF-mutated metastatic melanoma (MM) by lactate dehydrogenase (LDH) level.
Authors: Jason J. Luke, Sameer R. Ghate, Jonathan Kish, Choo Hyung Lee, Briana Ndife, Lindsay McAllister, Sonam Mehta, Antonio Reis Nakasato, Bruce A. Feinberg
Journal: Journal of Clinical Oncology (2019)

141 Background: Dabrafenib plus trametinib (D+T), ipilimumab plus nivolumab (I+N), and both nivolumab and pembrolizumab (“PD-1 mono”) are approved for the 1L treatment of MM. This study reports real world 1L TTNT for patients receiving these therapies by LDH status. Methods: This was a retrospective, observational study. MM patients initiating 1L treatment with D+T, I+N, or PD-1 monotherapy from Jan-2014 through Jun-2017 were identified from community oncology practices in the U.S. Patients treating oncologist abstracted patient date into case report forms. LDH at initiation of treatment was classified by the provider as normal or abnormal ( &gt; 1x and &lt; 2x ULN or ≥ 2x ULN) according to the reference laboratory. TTNT was calculated from 1L initiation to initiation of second-line (2L). Cox proportional hazard models estimated the risk of initiating 2L (proxy for progression) between groups adjusted for age, gender, brain/liver metastases (mets), number of mets and ECOG-PS. Results: Data for 332 patients were submitted by 53 providers including 51.6% who initiated 2L. Abnormal LDH: D+T = 60.3%, ipi/nivo = 53.0%, PD-1 mono = 35.4%. No differences in the frequency of patients with stage IV M1c, brain mets, ECOG, or discontinuation due to toxicity (8.4% of all patients) were noted between cohorts. TTNT was significantly longer in both normal and abnormal LDH cohorts for D+T (14.1 and 11.6 mo.) vs. ipi/nivo (10.1 and 10.2 mo.) but not PD-1 mono (13.3 and 10.6). Adjusted for confounding variables in the abnormal LDH cohort the hazard ratio (HR) for risk of 2L initiation was significantly higher (2.08, p &lt; 0.01) for ipi/nivo vs. D+T but not significant different among normal LDH patients (HR = 1.89, p = 0.054). No significant difference in the risk of 2L initiation between D+T and ipi/nivo were noted in either the normal or abnormal cohorts. Conclusions: For normal and abnormal LDH cohorts 1L TTNT was longer for patients receiving D+T vs. ipi/nivo (but not vs. PD-1 mono). Using the multivariate model we observed the risk of 2L initiation, a proxy for progression, was higher for ipi/nivo treated vs. D+T adjusted for clinical factors for abnormal LDH patients.