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Although splenectomy is still considered the most effective curative treatment for immune thrombocytopenia (ITP), its use has significantly declined in the last decade, especially since the approval of thrombopoietin receptor agonists (TPO-RAs). The main objective of the study was to determine whether splenectomy was still as effective nowadays, particularly for patients with failure to respond to TPO-RAs. Our secondary objective was to assess, among patients who relapsed after splenectomy, the pattern of response to treatments used before splenectomy. This multicentre retrospective study involved adults who underwent splenectomy for ITP in France from 2011 to 2020. Response status was defined according to international criteria. We included 185 patients, 100 (54.1%) and 135 (73.0%) patients had received TPO-RAs and/or rituximab before the splenectomy. The median follow-up after splenectomy was 39.2 months [16.5-63.0]. Overall, 144 (77.8%) patients had an initial response and 23 (12.4%) experienced relapse during follow-up, for an overall sustained response of 65.4%, similar to that observed in the pre-TPO-RA era. Among patients who received at least one TPO-RA or rituximab before splenectomy, 92/151 (60.9%) had a sustained response. Six of 13 (46%) patients with previous lack of response to both TPO-RAs and rituximab had a sustained response to splenectomy. Among patients with relapse after splenectomy, 13/21 (61.2%) patients responded to one TPO-Ras that failed before splenectomy. In conclusion, splenectomy is still a relevant option for treating adult primary ITP not responding to TPO-RAs and rituximab. Patients with lack of response or with relapse after splenectomy should be re-challenged with TPO-RAs. This article is protected by copyright. All rights reserved.

Introduction Omalizumab is a high-cost therapy recommended for the treatment of severe allergic asthma. Objective To find clinical parameters that are related to the sustained response to omalizumab. Patients and methods This retrospective, real-life, 4-year follow-up was provided in Poland between March 2013 and May 2019. The success of omalizumab was assessed based on composed subjective and objective criteria. Simple/multiple regression analyses were performed to search for predictors of the response to omalizumab. Results A total of 989 severe allergic asthma patients were referred for omalizumab therapy, of whom 854 patients were considered eligible for treatment. At weeks 16 and 52, omalizumab was successful in 84% and 91% of patients, respectively. Treatment effectiveness was maintained up to the 4-year follow-up. Four predictors of the response to omalizumab were found at week 16 and two at week 52. The results at week 16 may be used as predictors of success at week 52 based on the model including baseline FEV1% and change in ACQ-7 and miniAQLQ score at week 16: the area under the ROC curve equals 0.746 [95% CI: 0.672-0.820]. Conclusion Omalizumab therapy is very effective, with this efficacy sustained after 4 years of treatment. Success of the therapy can be predicted from the baseline FEV1% and clinical improvement (based on ACQ-7 and miniAQLQ scores) at week 16.

BackgroundCongenital hyperinsulinism (CHI), a condition characterized by dysregulation of insulin secretion from the pancreatic β cells, remains one of the most common causes of hyperinsulinemic, hypoketotic hypoglycemia in the newborn period. Mutations in ABCC8 and KCNJ11 constitute the majority of genetic forms of CHI.Case presentationA term macrosomic male baby, birth weight 4.81 kg, born to non-consanguineous parents, presented on day 1 of life with severe and persistent hypoglycemia. The biochemical investigations confirmed a diagnosis of CHI. Diazoxide was started and progressively increased to 15 mg/kg/day to maintain normoglycemia. Sequence analysis identified compound heterozygous mutations in ABCC8 c.4076C>T and c.4119+1G>A inherited from the unaffected father and mother, respectively. The mutations are reported pathogenic. The patient is currently 7 months old with a sustained response to diazoxide.ConclusionsBiallelic ABCC8 mutations are known to result in severe, diffuse, diazoxide-unresponsive hypoglycemia. We report a rare patient with CHI due to compound heterozygous mutations in ABCC8 responsive to diazoxide.

Saksenaea vasiformis complex is an emerging cause of mucormycosis. We report a case of an immunocompetent patient presenting with a non-resolving lung mass who developed multiple skin nodules. Skin biopsy yielded Saksenaea vasiformis complex. This showcases an uncommon occurrence of disseminated Saksenaea infection without cutaneous inoculation that improved with posaconazole.

Background Treatment with onabotulinumtoxin A (BT-A) is safe and effective for chronic migraine (CM). Several studies assessed possible predictors of response to treatment with BT-A, but there is little knowledge on the frequency and predictors of sustained response. The aim of this study was to evaluate sustained response to BT-A in patients with CM. Main body In this prospective open-label study, 115 patients with CM and treated with BT-A were consecutively enrolled in two Italian headache centers and followed up for 15 months. Anytime responders were defined as those patients who achieved a ≥ 50% reduction in headache days during any three-month treatment cycle compared with the 3 months prior to initiation of BT-A treatment. Sustained responders were defined as those who achieved a ≥ 50% reduction in headache days within the third treatment cycle and maintained response until the end of follow-up. Non-responders were defined as those patients who never achieved a ≥ 50% reduction in headache days during the follow-up. Headache characteristics prior to BT-A treatment were assessed in order to evaluate their ability in predicting treatment response. The 115 enrolled patients (84.3% female; median age 50 years) had a median migraine duration of 30 years (interquartile range 22–38). At the end of follow-up, 66 patients (57.4%) were classified as anytime responders. Among the 51 patients who achieved a clinical response within the third month of treatment, 33 (64.7%) were sustained responders. Patients with sustained response had a lower CM duration (median 31 vs 65 months; P = 0.030) and a lower number of headache days (median 25 vs 30; P = 0.013) at baseline compared with non-responders. Conclusions About two thirds of patients who gain ≥50% response to BT-A within the third cycle of treatment maintain this positive response over time. More recent onset of CM and more headache-free days at baseline are associated with sustained response. We suggest not to delay preventive treatment of CM with BT-A, in order to increase the likelihood to achieve sustained clinical response.

Parkinsonism is one of the most common neurologic disorders in the aging population. Although Parkinson disease (PD) is the most common cause, there is a lengthy differential diagnosis. The diagnosis of PD hinges on recognizing its typical features, including bradykinesia, rest tremor, unilateral onset, cogwheel rigidity, and beneficial and sustained response to levodopa. Equally important is to be familiar with the "red flags," which are features not expected with PD and suggest an alternative diagnosis, usually a parkinsonian syndrome. In general, it is best to have the diagnosis confirmed by a neurologist, especially one with expertise in movement disorders.

Context: Melasma is a chronic, acquired hyperpigmentary disorder. Plethora of treatment options are available but none is promising and recurrence is common. Treatment of melasma using oral tranexamic acid is a novel concept. Aims: To compare the efficacy of oral tranexamic acid with conventional topical therapy for the treatment of melasma. Design: Prospective, parallel, randomized, comparative, clinical study. Methods and Material: It was a prospective, randomized controlled trial conducted among 104 melasma patients. Patients were assigned into two groups (group A and group B) consisting of 52 patients each. Group A was given routine treatment measures along with oral Tranexamic Acid and photoprotection while Group B was treated only with routine topical measures and photoprotection. Oral Tranexamic Acid was prescribed at a dose of 250 mg BD for three months and patients were followed for three months. Clinical response was evaluated on the basis of Melasma Assessment Severity Index (MASI). Mean scores between the two groups were then compared. Results: The MASI scores at baseline, 8 weeks and 12 weeks in group A were 18.24 + 1.05,6.13 + 4.9 and 2.19 + 2.3 respectively and in group B were 15.42 + 1.09,11.07 + 9.16 and 7.99 + 6.05. MASI score reduction percentage at the end of 12 weeks was 88% and 54.6% respectively indicating a greater decrease in the group taking Tranexamic acid and was statistically significant for both the groups with P< 0.05 Conclusion: Addition of oral tranexamic acid with the triple combination results in rapid and sustained response with less chances of relapse. So tranexamic acid is a great boon for the melasma patient as well as for the clinicians.

A 72-year-old man with metastatic clear cell renal carcinoma, who had progressed after previous treatment with Sunitinib and Axitinib, was given one dose of immunotherapy. He was initially unwell after treatment with fever, shortness of breath, chest pain and raised inflammatory markers. Following this he elected not to have any further immunotherapy. Before the treatment he had multiple pulmonary metastases and hilar and mediastinal lymph nodes on chest X-ray and suffered with a persistent cough. Chest X-ray 10 months after treatment showed normal appearances and his cough had largely resolved. The patient initially declined repeat computed tomography imaging but agreed to it 2 years after the immunotherapy, the results showed a maintained response. Some patients with renal cell carcinoma show a durable response to immunotherapy but we are not aware of other published cases where a patient has shown such a dramatic and sustained response to one dose.

Patients with relapsed or primary resistant Hodgkin lymphoma (HL) who do not qualify for high-dose chemotherapy with a transplant of autologous hematopoietic stem cell transplantation (auto-HSCT) have poor prognosis. The use of new drugs such as brentuximab vedotin, anti-PD-L1 antibodies enables remission and sustained response in this difficult to treat group of patients. Brentuximab vedotin is a conjugate of anti-CD30 and auristatin E antibodies. The drug was registered by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in 2012 to treat patients with recurrent or resistant HL. In Poland, this drug is available in the National Health Fund drug program for patients after autologous peripheral blood stem cell transplantation or after at least two lines of chemotherapy, when auto-HSCT is not a valid treatment option. This case illustrates the effectiveness of brentuximab vedotin in the fourth line of primary resistant HL treatment.

Outcomes for children with high-grade gliomas (HGG) remain dismal despite aggressive treatment strategies. The use of targeted therapy for BRAFV600E mutated malignancies including HGG is being explored as a potentially well tolerated and effective therapeutic option. The results of adult melanoma studies demonstrating that combination therapy with BRAF inhibitors and MEK inhibitors results in prolonged survival led us to employ this treatment strategy in children with BRAFV600E mutated HGG. In this case series, we describe three pediatric patients with HGG with confirmed BRAFV600E mutation who demonstrated responses to combination therapy with dabrafenib and trametinib.

BackgroundThere is an urgent need for treatments to prevent the progression to severe COVID-19 and hospitalization.MethodsA randomized double-blind placebo-controlled clinical trial in 36 centers in the U.S. and Puerto Rico investigated the safety and effectiveness of oral nitazoxanide 600 mg twice daily for 5 days in outpatients with symptoms of mild or moderate COVID-19 enrolled within 72 hours of symptom onset. Key objectives were reduction of duration of symptoms (primary) and progression to severe illness (key secondary).Results1,092 subjects were enrolled, and 379 with laboratory-confirmed SARS-CoV-2 infection were analyzed. Overall, times to sustained clinical recovery were similar for the two arms. Nitazoxanide treatment was associated with an 85% reduction in the progression to severe COVID-19 (1/184, [0.5%] vs. 7/195, [3.6%], p=0.07) and 82% reduction in the rate of hospitalization, emergency room visit or death (1/184 [0.5%] vs. 6/195 [3.1%], p=0.12). In subjects with mild illness at baseline, treatment was also associated with a 3.1-day reduction in median time to sustained clinical recovery and a 5.2-day reduction in time to return to usual health. Nitazoxanide was safe and well tolerated.ConclusionsTreatment of mild or moderate COVID-19 with a five-day course of oral nitazoxanide was safe and well tolerated and was associated with an 85% reduction in the progression to severe illness and a 3- to 5-day reduction of the duration of mild illness.

espanolAntecedentes: la trombocitopenia inmunitaria secundaria (PTI) es una enfermedad heterogenea e impredecible asociada con diversas afecciones subyacentes. Objetivo: El objetivo del estudio fue investigar la evolucion clinica y los predictores de cronicidad en la PTI secundaria. Metodos: Los pacientes atendidos en un centro medico academico durante el periodo 2008-2019 fueron estratificados por edad en ninos 16 anos. Las respuestas a los esteroides, inmunoglobulina G intravenosa (IVIG), rituximab y eltrombopag se clasificaron como respuesta (R) y respuesta completa (CR). Los factores de riesgo para la PTI cronica se determinaron mediante regresion multiple con analisis univariante y multivariable. Resultados: Se incluyeron 83 pacientes, 37 ninos y 46 adultos. Las condiciones asociadas mas frecuentes fueron infecciones 53%, lupus eritematoso sistemico (LES) 24%, enfermedad tiroidea 9,6% y sindrome de Evans 3,6%. La respuesta al tratamiento de primera linea en toda la cohorte fue del 94%; CR 45,7%; y R 50,6%. La respuesta inicial a los esteroides solos fue del 91,3% (n = 21/23), rituximab mas dexametasona en dosis alta (HDD) del 93,3% (n = 14/15); ninos que reciben IgIV sola 100% (n = 12/12); y eltrombopag en adultos 100% (n = 3/3). Se documento recaida en el 19,4% de los ninos y el 34% de los adultos, con una mediana de tiempo de 15 y 2 meses, respectivamente; El 30,4% de los adultos (el 15,2% del grupo miscelaneo, el 10,9% asociado a LES y el 4,3% asociado a infeccion) y el 18,9% de los ninos siguieron un curso cronico; edad ≥10 anos y plaquetas ≥20 × 109 / L fueron factores de riesgo de PTI cronica en ninos. Conclusion: La evolucion fue heterogenea: se documento una respuesta mejor y mas sostenida en el grupo de infecciones en comparacion con el LES o el grupo miscelaneo. (REV INVEST CLIN. 2021; 73 (1): 31-8) EnglishBackground: Secondary immune thrombocytopenia (ITP) is a heterogeneous and unpredictable disease associated with various underlying conditions. Objective: The objective of the study was to investigate clinical evolution and chronicity predictors in secondary ITP. Methods: Patients treated at an academic medical center during 2008-2019 were stratified by age as children 16 years. Responses to steroids, intravenous immunoglobulin G (IVIG), rituximab, and eltrombopag were classified as response (R) and complete response (CR). Risk factors for chronic ITP were determined by multiple regression with uni- and multi-variate analysis. Results: Eighty-three patients were included, 37 children and 46 adults. The most frequent associated conditions were infections 53%, systemic lupus erythematosus (SLE) 24%, thyroid disease 9.6%, and Evans syndrome 3.6%. Response to first-line treatment in the whole cohort was 94%; CR 45.7%; and R 50.6%. Initial response to steroids alone was 91.3% (n = 21/23), rituximab plus high-dose dexamethasone (HDD) 93.3% (n = 14/15); children receiving IVIG alone 100% (n=12/12); and eltrombopag in adults 100% (n = 3/3). Relapse was documented in 19.4% of children and 34% of adults, at a median time of 15 and 2 months, respectively; 30.4% of adults (15.2% from the miscellaneous group, 10.9% SLE-associated, and 4.3% infection-associated) and 18.9% of children followed a chronic course; age ≥10 years and platelets ≥20 × 109/L were risk factors for chronic ITP in children. Conclusion: Evolution was heterogeneous: a better and more sustained response was documented in the infections group compared to SLE or the miscellaneous group. (REV INVEST CLIN. 2021;73(1):31-8)

Compliment activation has been implicated in Delayed Hemolytic Transfusion Reaction (DHTR) in patients with sickle cell disease, and eculizumab has been reported as an effective treatment for patients with DHTR. Previously reported patients with SCD and DHTR responded well after few doses of eculizumab. We report on the long-term use of eculizumab in a pediatric sickle cell patient with DHTR who had a slow and less sustained response. Long-term use of eculizumab in this SCD patient was effective and well tolerated.

Resumen Introducción: el dolor abdominal crónico es frecuente en consulta externa. El enfoque tradicional es investigar patologías viscerales. El 50 % de esos pacientes finalmente tiene dolor crónico de la pared abdominal (DCPA), generalmente secundario a atrapamiento del nervio cutáneo anterior. Esta entidad se identifica con el signo de Carnett. El tratamiento de elección es infiltrar con lidocaína los puntos dolorosos. Con una postinfiltración hay una mejoría significativa en el 85 %-90 % de los pacientes. Se desconoce la duración de la mejoría postinfiltración. El objetivo de este trabajo es determinar la respuesta sostenida en seguimientos a 1 y 2 años. Materiales y métodos: estudio de cohorte, retrospectivo, realizado en la unidad de gastroenterología de la Clínica Fundadores. Se incluyeron pacientes adultos mayores de 18 años que hubieran recibido tratamiento con inyección local con lidocaína al 2 % sin epinefrina y que hubieran respondido una encuesta telefónica para evaluar la intensidad del dolor en una escala análoga. Resultados: se identificaron 360 elegibles y, finalmente, atendieron la entrevista telefónica 324 pacientes (90 %). El 87 % era de sexo femenino. La edad promedio de la población era de 57 años. En la preinfiltración el dolor promedio era 8,7 puntos. En la postinfiltración los pacientes tuvieron una mejoría con una intensidad promedio de 2,38 (p < 0,05). En el 71 % de los pacientes la intensidad del dolor en el seguimiento hasta 2 años tuvo una intensidad promedio de 1,65 (p < 0,05), que representa una mejoría del 81 % en la intensidad (p = 0,001). La fibromialgia tuvo una asociación positiva con la mejoría sostenida del dolor (p = 0,008). Conclusiones: en los pacientes con DCPA, la infiltración de la pared con anestesia local produce una respuesta sostenida hasta 2 años después del tratamiento. Abstract Introduction: Chronic abdominal pain is frequently encountered at outpatient clinics where the traditional approach is to investigate visceral pathologies. Fifty percent of these patients are finally found to have abdominal wall pain which is generally secondary to entrapment of the anterior cutaneous nerve. This entity is identified by Carnett’s sign. The treatment of choice is to infiltrate the painful points with lidocaine following which there is significant improvement in 85% to 90% of these patients. The duration of post-infiltration improvement is unknown. The objective of this work is to determine sustained response in one and two-year follow-up examinations. Materials and Methods: This is a retrospective cohort study conducted in the gastroenterology unit of the Clínica Fundadores. We included adult patients over 18 years of age who had received local injection treatment with 2% lidocaine without epinephrine and who had answered a telephone survey to assess the intensity of pain on an analogous scale. Results: Of the 360 eligible patients identified, 324 patients (90%) were interviewed by telephone. The average age of those interviewed was 57 years, and 87% were women. The average pain level prior to infiltration was 8.7 points. Following infiltration, the average intensity was 2.38 points (p

Chronic ataxic neuropathy with anti-disialosyl IgM antibodies (CANDA) is a rare disorder for which the pathological, neurophysiological, and therapeutic evidence remains anecdotal and controversial. This report on CANDA focuses on the neurophysiological patterns and treatment responses shared by two cases. One patient underwent nerve ultrasound follow-up. A comprehensive review of the literature highlighted the diverse experiences with different treatment options. Response to different therapies was similar in both patients: intravenous immunoglobulins achieved a favorable response albeit with significant wearing-off fluctuations; treatment with subcutaneous immunoglobulins (SCIg) was an effective alternative leading to a clinical response for at least 2 years. Rituximab, which was trialed in both patients, was not continued long enough to determine its efficacy in modifying the disease course and/or modulating responsiveness to immunoglobulins. Steroids caused clinical worsening in both patients. Immunoglobulin therapy appeared as the most effective in the treatment of these two patients. SCIg provided an effective treatment option for the long-term management of CANDA.

Aim of the study: To compare the efficacy of different treatment options for newly diagnosed ITP in pediatrics. Patients and methods: This is a retrospective observational study that reviewed data of 102 newly diagnosed ITP children. Treatment regimens received by patients were classified into 5 types: Type I: pulse intravenous methylprednisolone followed by oral prednisolone then gradual tapering. Type II: oral prednisolone 4 mg/kg/d × 4 days. Type III: oral prednisolone 2 mg/kg/d followed by gradual tapering. Type IV: intravenous immune globulin (IVIG) combined with intravenous methylprednisolone. Type V: no treatment. Platelet counts at presentation, after 1 week, at 1 month, 3 months and 6 months from initial presentation were analyzed. Results: Patients who received Type I, III or IV treatment showed statistically significant higher response to treatment at 1 week (96.1%, 93.3%, and 100% respectively) in comparison to those who received Type II or no treatment (Type V) in which less response was observed (58.8% and 75% respectively); (p-value = 0.001%). However, the overall response showed no statistically significant difference in response to treatment using different types of treatment at one month and 3 months, p-value = 0.086 and 0.335 respectively. When we evaluated the response overtime of each line of treatment at 3 months, Type I showed a statistically significant response (p = 0.009) with the biggest number of patients continuing to maintain response up to 3 months. Conclusion: We recommend the use of (methylprednisolone 20–30 mg/kg/d × 3–5 days) followed by oral (prednisolone 2 mg/kg/d) due to rapid and sustained response. Keywords: Purpura, Thrombocytopenia, Idiopathic, Methylprednisolone, Immunoglobulins, Intravenous, Prednisolone

// Gregorio J. Petrirena 1 , Julien Masliah-Planchon 2, 3 , Quentin Sala 4 , Bertrand Pourroy 5 , Didier Frappaz 6 , Emeline Tabouret 1, 7 , Thomas Graillon 8 , Jean-Claude Gentet 9 , Olivier Delattre 2, 3 , Olivier Chinot 1, 7 and Laetitia Padovani 10 1 Service de Neuro-Oncologie, Hopital La Timone, Assistance Publique-Hopitaux de Marseille, Marseille, France 2 Unite de Genetique Somatique, Departement de Genetique Oncologique, Institut Curie, Paris, France 3 INSERM_U830, Institut Curie, Paris, France 4 Service de Medecine Nucleaire, Hopital Nord, Assistance Publique-Hopitaux de Marseille, Marseille, France 5 Unite Oncopharma, Service Pharmacie, Hopital La Timone, Assistance Publique-Hopitaux de Marseille, Marseille, France 6 Service de Neuro-Oncologie Pediatrique et Adulte, Centre Leon Berard, Lyon, France 7 Aix-Marseille Universite, Marseille, France 8 Service de Neurochirurgie, Hopital La Timone, Assistance Publique-Hopitaux de Marseille, Marseille, France 9 Service d’Oncologie et Hematologie Pediatrique, Hopital La Timone, Assistance Publique-Hopitaux de Marseille, Marseille, France 10 Service de Radiotherapie, Hopital La Timone, Assistance Publique-Hopitaux de Marseille, Marseille, France Correspondence to: Gregorio J. Petrirena, email: gregorio.petrirena@ap-hm.fr Keywords: sonic hedgehog medulloblastoma; vismodegib; temozolomide; smoothened mutation; PIK3CA mutation Received: June 03, 2017 Accepted: November 01, 2017 Published: January 03, 2018 ABSTRACT Background: Response to targeting and non-targeting agents is variable and molecular information remains poorly described in patients with recurrent sonic-hedgehog-driven medulloblastoma (SHH-MB). Materials and Methods: Clinical and PET/CT findings during treatment with successive hedgehog antagonists and temozolomide monotherapies are described in a heavily pre-treated patient with recurrent extraneural metastases from PTCH1 mutated/ wild type smoothened ( SMO ) CNS SHH-MB. Molecular tests were prospectively performed in tissue from two extraneural sites at progression. Results: Sustained clinical/metabolic response was obtained to vi smo degib. At progression, itraconazole was ineffective, but salvage temozolomide treatment results in a response similar to vismodegib. At further progression, acquired SMO and PIK3CA mutations were identified in bone (G477L and H1047A, respectively) and epidural (L412P and H1065L, respectively) metastases. No response was observed with subsequent sonidegib treatment. Conclusions: This is the first clinical report of recurrent extraneural PTCH1 mutated SHH-MB exhibiting: 1) a sustained response to vismodegib and temozolomide, and 2) inter-metastatic molecular heterogeneity and acquired SMO-G477L, SMO-L412P, and PIK3CA-H1065L mutations at progression, highlighting the need for a multitarget treatment approach.

Introduction Although anti-TNF therapy has changed the scenery of pediatric inflammatory bowel diseases (IBD) immensely, there are still patients with an unfortunate outcome. Approximately one third of patients that initially respond to anti-TNF therapy will lose that response over time and need treatment optimization. Loss of response (LOR) is a big concern in IBD management and especially among pediatric patients where treatment options are more limited than in adults. In children it is even more important to sustain response with minimal toxicity. Therapeutic drug monitoring (TDM) is proposed as a tool to reach this goal. Areas covered This review focuses on the importance of TDM of anti-TNF and the role TDM has in clinical practice of pediatric IBD. Expert opinion Although TDM is not yet widely used in pediatric IBD, the available literature suggests it to be a promising tool, especially in patients with LOR to anti-TNF. There is increasing evidence that also in children, higher anti-TNF drug levels are associated with sustained response, and likewise low or undetectable trough levels increase the likelihood of LOR. TDM-based treat to target strategies are being designed in adult studies, but more prospective studies also in pediatric IBD populations looking at the role of proactive testing are needed.

Background/Objectives Accumulating evidence has shown that omalizumab is an effective and safe treatment for chronic spontaneous urticaria (CSU), but there is little information regarding the use of omalizumab to treat CSU in Taiwan. Reports on clinical experiences with using omalizumab for CSU for more than 6 months are also lacking. Methods A retrospective review of medical records of consecutive CSU patients receiving omalizumab treatment in the Urticaria Special Clinic of one tertiary referral center in Taiwan was conducted. We analyzed clinical features of the patients, treatment efficacy and safety, and also long-term outcomes after omalizumab treatment. An Urticaria Activity Score over 7 days (UAS7) was recorded at each visit. Results A total of 17 CSU patients were identified (11 females and 6 males, age range: 21–83 years) with a baseline mean UAS7 of 29.8 ± 8.9 despite antihistamine treatment. All patients were treated with at least 3 doses of monthly subcutaneous injections of omalizumab. Fifteen patients achieved a UAS7 of 6 or less after 3 doses of monthly omalizumab injections. Seven of those 15 patients received an additional 1 to 3 doses and all ended up with a UAS7 of less than 2 at the 24-week follow-up. A sustained response to maintenance treatment after 24 weeks was observed in 5 patients with individual tailoring of treatment duration and dosing interval. Conclusion Omalizumab is an effective and safe treatment for antihistamine refractory CSU. Maintenance therapy with individual tailoring of the treatment duration and interval is possible.

Mepolizumab was the first anti-interleukin-5 (anti-IL-5) monoclonal antibody licensed for the treatment of severe asthma, recommended as add-on treatment in patients with frequent exacerbations or requiring maintenance oral corticosteroids (OCS) despite optimal inhaled therapy [1, 2]. In clinical trials it reduced exacerbation rates and OCS use, and improved lung function, asthma control and health-related quality of life over the first year of treatment [3–6]. Current guidance states that anti-IL-5 biologics should be continued long term if benefit is demonstrated over the first year, yet little is known about whether initial responses are sustained, or whether they can be predicted by clinical characteristics., This study found that 30% of patients stopped mepolizumab in the second year of treatment. Those with a sustained response had lower blood eosinophils and better asthma control questionnaire scores prior to starting mepolizumab. https://bit.ly/3ChWN63

Background:Time-to-relapse after rituximab for ANCA-associated vasculitis (AAV) is variable and optimal retreatment strategy has been unclear. We previously showed that repopulation of naïve B-cells at 6 months predicts sustained response [1].Objectives:In AAV following rituximab induction, to evaluate clinical and B-cell predictors of relapse in order to develop a retreatment algorithm.Methods:An observational study was conducted in 60 rituximab-treated AAV patients followed for over 10 years. Complete response (CR) was defined as Birmingham Vasculitis Activity Score v3.0 = 0. Retreatment was given on clinical relapse, defined as new features or worsening of persistent disease (not by biomarker status). Peripheral B-cell subsets were measured using highly sensitive flow cytometry. Predictors were tested using multivariable Cox-Regression.Results:Median times-to-retreatment for rituximab cycles 1-5 were 87, 71, 65, 59 and 86 weeks. Over 417 patient-years follow-up, 137 relapses occurred in 50 patients; 16 (in 14 patients) were major (renal=7, neurological=4, ENT=3 and respiratory=2). The major-relapse rate was 3.8/100 patient-years. In multivariable analysis, concomitant immunosuppressant [HR 0.48 (95% CI 0.24–0.94)], achieving CR [0.24 (0.12–0.50)] and naïve B-cell repopulation at 6 months [0.43 (0.22–0.84)] were associated with longer time-to-relapse. Higher baseline memory B-cells [1.01 (1.00–1.02)] were associated with a shorter time-to-relapse. AUROC for prediction of time-to-relapse was greater if guided by naïve B-cell repopulation than if ANCA and/or CD19+ return at 6 months had been used, 0.82 and 0.52 respectively.Conclusion:These data suggest that all patients should receive concomitant oral immunosuppressant. Those with incomplete response or with absent naïve B-cells should be retreated at 6 months. Patients with complete response and naïve repopulation at 6 months should not receive fixed retreatment. This algorithm could reduce hypogammaglobulinaemia due to unnecessary retreatment.Figure 1.A personalised retreatment algorithm for rituximab in ANCA-associated vasculitisReferences:[1]Md Yusof et al. Annals of rheumatic diseases (2015) PMID: 25854586.Disclosure of Interests:Jack Arnold: None declared, Edward Vital Speakers bureau: Roche, GSK and AstraZeneca, Consultant of: Roche, GSK and AstraZeneca, Grant/research support from: Roche, GSK and AstraZeneca, Shouvik Dass Speakers bureau: Roche and GSK, Aamir Aslam: None declared, Andrew Rawstron: None declared, Sinisa Savic: None declared, Paul Emery Speakers bureau: BMS, Abbott, Pfizer, MSD, Novartis, Roche and UCB, Consultant of: BMS, Abbott, Pfizer, MSD, Novartis, Roche and UCB, Grant/research support from: Abbott, BMS, Pfizer, MSD and Roche., Md Yuzaiful Md Yusof: None declared

This paper prospectively evaluates the long-term follow-up [mean ± standard deviation (SD) duration: 89.7±19.4 months] data of 15 patients (13 females and 2 males) with refractory symptomatic immune thrombocytopenia (ITP) treated with rituximab.Rituximab was administered at 375 mg/m2 weekly for a total of 4 doses. Complete response (CR) was defined as a platelet count of ≥100,000/mm3 and partial response (PR) as a platelet count of ≥30,000/mm3 but less than 100,000/mm3. Early response (ER) and late response (LR) were defined as response within 42 days and after 42 days of initiation of rituximab therapy, respectively. Sustained response (SR) was defined as response lasting for at least 6 months.Mean age (±SD) at the start of rituximab was 46.6±11.3 years. Mean platelet count (±SD) prior to rituximab treatment was 17,400±8878/mm3. The mean time (±SD) between rituximab therapy and response to rituximab in early responders and late responders was 1.8±1.3 weeks and 10±2.8 weeks, respectively. Mean durations (±SD) of ER and LR were 51±47.2 months and 6±4.2 months, respectively. Seven of the 15 patients (46.7%) showed an initial response to rituximab (5 ER and 2 LR). The rate of SR over 6 months was 26.7% (4/15). Among the responders to rituximab, 3 (3/7, 42.9%) maintained their response 1 year after rituximab treatment and 2 (2/7, 28.6%) had ongoing response 5 years after initiation of rituximab. Two of the 7 patients (28.6%) still maintained their response 98 months after initiation of rituximab. All 5 initial responders with subsequent relapse achieved response from subsequent treatment modalities (3 CR, 2 PR).Our data confirm, over a long period of observation, that rituximab is safe and effective in the management of patients with chronic refractory primary ITP.Amaç: Çalışmamızda rituksimab ile tedavi edilen refrakter semptomatik immün trombositopeni (İTP) tanılı 15 olgunun (13 kadın ve 2 erkek) uzun süreli izlemi sonucundaki [ortalama ± SD (standart deviasyon) süresi: 89,7±19,4 ay] verileri incelenmiştir. Gereç ve Yöntemler: Rituksimab haftada bir 375 mg/m2 dozunda toplam 4 doz uygulanmıştır. Tam yanıt (TY) trombosit sayısının ≥100,000/mm3 olması ve parsiyel yanıt (PY) trombosit sayısının ≥30,000/mm3 olması fakat 100,000/mm3’ün altında olması olarak tanımlanmıştır. Erken yanıt (EY) ve geç yanıt (GY) ise sırasıyla rituksimab başlangıcından 42 gün içinde ve 42 gün sonra yanıt elde edilmesi olarak tanımlanmıştır. Sürekli yanıt (SY), yanıtın en az 6 ay sürmesi olarak tanımlanmıştır. Bulgular: Rituksimab tedavisinin başladığı sırada ortalama yaş (±SD) 46,6±11,3 yıldır. Rituksimab tedavisi öncesinde ortalama trombosit sayısı (±SD) 17,400±8878/mm3’dür. Erken ve geç yanıt edilen olgularda rituksimab başlangıcı ile yanıta kadar geçen ortalama süre (±SD) sırasıyla 1,8±1,3 hafta ve 10±2,8 hafta olarak saptanmıştır. EY ve GY elde edilen olgularda ortalama yanıt süresi sırasıyla 51±47,2 ay ve 6±4,2 aydır. On beş olgunun 7’sinde (%46,7) rituximab tedavisine başlangıçta yanıt elde edilmiştir (5 EY, 2 GY). SY oranı %26,7’dir (4/15). Rituksimab tedavisine yanıt veren olgular arasında 3’ü (3/7, %42,9) yanıtını bir yıldan fazla ve 2’si (2/7, %28,6) yanıtını 5 yıldan fazla sürdürmüştür. Yedi olgunun ikisi (%28,6) rituksimab başlangıcından 98 ay sonra halen yanıtını korumaktadır. Başlangıçta yanıt veren 5 olgunun hepsi relaps sonrasında ardışık tedavilere yanıt vermiştir (3 TY, 2 PY). Sonuç: Çalışmamız uzun bir gözlem sonucunda kronik refrakter primer İTP olgusunda rituksimab tedavisinin güvenilir ve etkili olduğunu desteklemektedir.

Background:Among treatment options for PsA, IL-12/23 inhibition with UST was the first new biologic mode of action after TNFi. Few real-world data comparing UST with TNFi are available.Objectives:Comparison of UST and TNFi treatment effectiveness within the prospectively followed PsABio cohort at 12-month (mo) follow-up.Methods:The PsABio study (NCT02627768) evaluates effectiveness, tolerability and persistence of 1st, 2nd or 3rd-line UST or TNFi in PsA. Proportions of patients (pts) reaching MDA/very low disease activity (VLDA) and clinical Disease Activity index for PSoriatic Arthritis (cDAPSA) LDA/remission are described. Comparison across UST and TNFi cohorts was done on last observation carried forward up to 12 (±3) mo, with non-response imputation for pts who had stopped/switched initial treatment. Logistic regression analysis was used, including propensity score (PS) analysis to adjust for imbalanced prognostic baseline (BL) covariates: country, age, sex, BMI, smoking (yes/no), comorbidities (cardiovascular/metabolic syndrome), PsA type (axial, polyarticular, oligoarticular), psoriasis body surface area (BSA), disease duration, cDAPSA, 12-item PsA Impact of Disease (PsAID-12), dactylitis, enthesitis, Fibromyalgia Rapid Screening Tool (FiRST) score, line of biologic (b)DMARD, synthetic DMARD use, and steroid or NSAID use.Results:Of 929 eligible pts, 893 had evaluable data at BL and at follow-up; 438 (95.6%) were treated with UST and 455 (96.6%) with TNFi (including stoppers/switchers). UST and TNFi groups had BL differences in mean age (51.0 vs 48.5 years, respectively), concurrent comorbidities (68.7% vs 60.9%), time since diagnosis (7.5 vs 6.2 years), line of treatment (1st-line 45.0% vs 55.2%; 3rd-line 20.5% vs 12.1%), NSAID use (54.8% vs 68.8%), concomitant MTX use (29.9% vs 42.0%) and psoriasis skin involvement (BSA >10% in 26.6% vs 14.8%).In 714 pts with available data, mean (standard deviation) BL cDAPSA was 30.6 (20.2; n=358) for UST and 29.3 (18.6; n=356) for TNFi. Observed data showed differences in proportion of pts achieving MDA/VLDA and cDAPSA LDA/remission in favour of TNFi, but after PS adjustment for BL differences (such as line of therapy, skin psoriasis, concomitant conventional DMARD, etc.), odds ratios for reaching targets at 12 mo did not significantly differ between UST and TNFi groups (Fig. 1).Comparison of 6- and 12-mo unadjusted data showed sustained MDA/VLDA responses with both UST (21.8%) and TNFi (29.5%), with comparable proportions of additional pts achieving these targets between 6 and 12 mo (17.0% and 20.3%, respectively). Sustained efficacy became lower with successive lines of treatment (data not shown).Conclusion:Various factors, including patient characteristics such as comorbidities, influence the physician’s selection of treatment modality for patients needing a bDMARD. Our real-world results demonstrate differences in observed clinical effectiveness between UST and TNFi. However, after PS adjustment for a number of BL differences, clinical results at 12 mo were comparable between UST and TNFi groups. Data at 12 mo also show sustained response with both UST and TNFi treatment, as well as a similar rate of pts achieving targets after 6 to 12 mo of treatment.Acknowledgments:This study was funded by Janssen.Disclosure of Interests:Josef S. Smolen Grant/research support from: AbbVie, AstraZeneca, Celgene, Celltrion, Chugai, Eli Lilly, Gilead, ILTOO, Janssen, Novartis-Sandoz, Pfizer Inc, Samsung, Sanofi, Consultant of: AbbVie, AstraZeneca, Celgene, Celltrion, Chugai, Eli Lilly, Gilead, ILTOO, Janssen, Novartis-Sandoz, Pfizer Inc, Samsung, Sanofi, Stefan Siebert Grant/research support from: BMS, Boehringer Ingelheim, Celgene, GlaxoSmithKline, Janssen, Novartis, Pfizer, UCB, Consultant of: AbbVie, Boehringer Ingelheim, Janssen, Novartis, Pfizer, UCB, Speakers bureau: AbbVie, Celgene, Janssen, Novartis, Tatiana Korotaeva Grant/research support from: Pfizer, Consultant of: Abbvie, BIOCAD, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck Sharp & Dohme, Novartis, Novartis-Sandoz, Pfizer, UCB, Speakers bureau: Abbvie, BIOCAD, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck Sharp & Dohme, Novartis, Novartis-Sandoz, Pfizer, UCB, Paul Bergmans Shareholder of: Johnson & Johnson, Employee of: Janssen, Kurt de Vlam Consultant of: Celgene Corporation, Eli Lilly, Novartis, Pfizer, UCB – consultant, Speakers bureau: Celgene Corporation, Eli Lilly, Novartis, Pfizer, UCB – speakers bureau and honoraria, Elisa Gremese Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck Sharp & Dohme, Novartis, Sanofi, UCB, Roche, Pfizer, Speakers bureau: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck Sharp & Dohme, Novartis, Sanofi, UCB, Roche, Pfizer, Beatriz Joven-Ibáñez Speakers bureau: Abbvie, Celgene, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, Wim Noel Employee of: Janssen Pharmaceuticals NV, Michael T Nurmohamed Grant/research support from: Abbvie, Bristol-Myers Squibb, Celltrion, GlaxoSmithKline, Jansen, Eli Lilly, Menarini, Merck Sharp & Dohme, Mundipharma, Pfizer, Roche, Sanofi, USB, Consultant of: Abbvie, Bristol-Myers Squibb, Celltrion, GlaxoSmithKline, Jansen, Eli Lilly, Menarini, Merck Sharp & Dohme, Mundipharma, Pfizer, Roche, Sanofi, USB, Speakers bureau: Abbvie, Bristol-Myers Squibb, Celltrion, GlaxoSmithKline, Jansen, Eli Lilly, Menarini, Merck Sharp & Dohme, Mundipharma, Pfizer, Roche, Sanofi, USB, Petros Sfikakis Grant/research support from: Grant/research support from Abvie, Novartis, MSD, Actelion, Amgen, Pfizer, Janssen Pharmaceutical, UCB, Elke Theander Employee of: Janssen-Cilag Sweden AB, Laure Gossec Grant/research support from: Lilly, Mylan, Pfizer, Sandoz, Consultant of: AbbVie, Amgen, Biogen, Celgene, Janssen, Lilly, Novartis, Pfizer, Sandoz, Sanofi-Aventis, UCB

Objective To report our experience concerning sustained response (SR) after TPO-RAs discontinuation in adult pITP patients and to identify possible predictive factors for outcome. Methods Thirty-nine pITP patients who received a TPO-RA were evaluated. Response (R) was defined as a platelet count ≥30x109/L and at least a two-fold increase of the baseline count and complete response (CR) as a platelet count ≥100x109/L, in absence of bleeding. Durable response (DR) was defined as a R/CR persisting ≥4 weeks with a stable dose of TPO-RA, and SR as the first assessed platelet count ≥30x109/L, available at more than 4 weeks after discontinuation of TPO-RA, in absence of other concomitant or rescue therapies. RESULTS: Twenty-nine/39 (74%) were responders: 18 (46%) reached a CR and 11 (28%) a R. A DR was observed in 16/29 (55%) responders. Seven SR (18%) were reached: 5/7 patients achieved a SR from a prior DR. CR was statistically associated with the achievement of a subsequent DR: 13/18 (72%) CR patients obtained a DR, while only 3/11 (27%) R ones did (p=0.027). Conclusions CR was a significant prognostic factor for the achievement of a DR. Moreover, we observed a trend for DR patients to obtain a subsequent SR. This article is protected by copyright. All rights reserved.

Deep brain stimulation (DBS) is at present, a useful treatment for patients with advanced Parkinson's disease and motor complications. The crucial step toward consistent DBS outcomes remains careful patient selection; several conditions must be fulfilled including excellent levo dopa response. We report two cases of early onset Parkinson's disease with severe intolerance to levo dopa but excellent and sustained response to DBS. DBS can be a useful alternative for parkinsonian patients with severe intolerance to levo dopa, provided a positive acute response to levo dopa or apomorphine is obtained.

Care of patients with chronic immune thrombocytopenia (ITP) who are refractory to available treatments can be quite challenging. Fostamatinib, an oral Syk inhibitor, is the newest FDA-approved agent for ITP. Phase 3 clinical trials demonstrated an overall response in 43% of patients treated with fostamatinib and use for two years has been reported. Herein, we report two patients with long histories of ITP without lasting responses to numerous first-, second- and third-line therapies with prolonged responses to ongoing fostamatinib. This shows that patients unresponsive to other agents may respond to fostamatinib and can have sustained benefit.

Background The efficacy of SC abatacept (ABA) in patients (pts) with polyarticular-course juvenile idiopathic arthritis (pJIA) was shown in a 2-year (yr), Phase III, open-label international study (NCT01844518).1 However, it is unknown whether each individual pt within a treatment group consistently achieves the same efficacy endpoint at all time points. Objectives To investigate whether ABA efficacy is maintained by individual pts with pJIA over time. Methods In this subgroup analysis, pts in two age cohorts (2–5 yrs and 6–17 yrs) who achieved clinical response to weekly SC ABA (10 to Results A total of 219 pts entered the study (46 [21.0%] 2–5 yrs; 173 [79.0%] 6–17 yrs) and a subgroup of these pts achieved a clinical response at Day 113 (Table). Most pts who achieved JIA-ACR70, JIA-ACR100, JADAS71 MDA and JADAS71 ID at Day 113 sustained their response at Day 393 and at Days 393 and 645 in the 2–5-yr and 6–17-yr cohorts (Figure). Across cohorts, more than 75% and 60% of pts maintained a JIA-ACR 70 and JADAS71 MDA response through Day 645, respectively. Prior biologic (b)DMARD use was an important prognostic factor. In pts aged 6–17 yrs, sustained JIA-ACR70 response rate at Days 393 and 645 was 81% (57/70) in pts who did not have prior bDMARDs vs 57% (12/21) in pts who had prior bDMARDs (p=0.0715); sustained JADAS71 MDA response rate was 71% (37/52) vs 37% (7/19; p=0.0320). Prognostic factors for JIA-ACR100 response and JADAS71 ID in pts aged 6–17 yrs and for all outcomes in pts aged 2–5 yrs could not be determined due to low pt numbers. Conclusion The majority of individuals with pJIA who achieved stringent efficacy endpoints with weekly SC abatacept by Day 113 sustained that clinical endpoint over time. Prior bDMARD use may be a prognostic factor for sustained response over 2 yrs. Reference [1] Brunner HI, et al. Arthritis Rheumatol2018;70:1144–54. Acknowledgement Professional medical writing: Stacey Reeber, PhD, Caudex; funding: Bristol-Myers Squibb Disclosure of Interests Nicolino Ruperto Grant/research support from: The Gaslini Hospital, where NR works as full-time public employee, has received contributions (> 10.000 USD each) from the following industries in the last 3 years: BMS, Eli-Lilly, GlaxoSmithKline, F Hoffmann-La Roche, Janssen, Novartis, Pfizer, Sobi. This funding has been reinvested for the research activities of the hospital in a fully independent manner, without any commitment with third parties., Consultant for: Received honoraria for consultancies or speaker bureaus ( I perform consultancy activities on behalf of the Gaslini Institute for the companies listed below: AbbVie, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, EMD Serono, Janssen, Novartis, Pfizer, R-Pharm. The money received for these activities are directly transferred to the Gaslini Institute’s bank account. Before March 2016, I was the head of the Pediatric Rheumatology Department at the G. Gaslini Hospital, where the PRINTO Coordinating Centre is located. For the coordination activity of the PRINTO network, the Gaslini Hospital received contributions from the industries listed in this section. This money has been reinvested for the research activities of the hospital in fully independent manners besides any commitment with third parties., Daniel J Lovell Consultant for: Consulting fees and/or honoraria from Astra Zeneca, Wyeth Pharma, Amgen, Abbott, Pfizer, F. Hoffmann-La Roche, Novartis, UBC, Takeda, GSK, Boehringer, and Celgene

Background: In MONARCH (NCT02332590), sarilumab monotherapy (200 mg subcutaneously [SC] every 2 weeks [q2w]) demonstrated superiority to adalimumab monotherapy (40 mg SC q2w) in DAS28-ESR, ACR20/50/70 response, HAQ-DI, and CDAI in pts with RA and inadequate response/intolerance to methotrexate. Objectives: To assess long-term safety/efficacy in RA pts continuing sarilumab or switching from adalimumab to sarilumab monotherapy in the ongoing OLE of MONARCH. Methods: Pts completing MONARCH were eligible for the OLE, in which they received sarilumab 200 mg SC q2w. Efficacy and safety data were reported up to OLE Wk 48 and March 2017, respectively. Responder rates were based on the intent-to-treat population. Continuous efficacy endpoints were based on the observed population. Results: Of 369 pts enrolled in MONARCH, 320 (87%) entered OLE (switch: n=155; continuation: n=165). By safety data cut-off, pt attrition was similar in switch (24; 15.5%) and continuation groups (22; 13.3%), as were treatment-emergent adverse events (AEs) (switch: 76.1%, 267.4/100 PY; continuation: 70.9%, 230.2/100 PY) and infections (switch: 41.9%; continuation: 35.8%). For DAS28-ESR and CDAI endpoints, >40% of switch pts achieved a minimally important difference (MID) improvement from OLE baseline by OLE Wk 12, increasing to >50% by OLE Wk 48. Additionally, >40% of switch pts achieved a MID in DAS28-CRP and a minimally clinically important difference (MCID) in HAQ-DI from OLE baseline to OLE Wk 48 (Fig). Of pts achieving CDAI ≤10 from baseline OLE to Wk 24 of the OLE, 70.7% (switch group) and 83.5% (continuation group) achieved sustained response at OLE Wks 36 and 48. In the randomized controlled phase, response rates were higher in sarilumab-treated than adalimumab-treated pts, hence fewer pts in the continuation group achieved additional MID during OLE (data not shown). AEs of special interest are reported (Table). Two deaths occurred in the switch group (malignancy; cerebrovascular accident) versus one in the continuation group (subarachnoid hemorrhage). No GI-related AEs (ulcerations/perforations/diverticulitis) were observed. Conclusion: Pts switched from adalimumab to sarilumab experienced clinically meaningful improvements in signs and symptoms of RA. Safety observations in OLE were generally consistent with those in MONARCH. Acknowledgement: Study funding and editorial support (Helen Johns, Adelphi) were provided by Sanofi Genzyme and Regeneron Pharmaceuticals, Inc. These data have been submitted to the 2019 APLAR-ARA and SER meetings. Disclosure of Interests: Gerd Rdiger Burmester Consultant for: Roche, Sanofi-Genzyme, Speakers bureau: Roche, Sanofi-Genzyme, Howard Amital Grant/research support from: Pfizer, AbbVie, Janssen, Grant/research support from: Pfizer, AbbVie, Janssen, Consultant for: Pfizer, Merck Sharp & Dohme, Consultant for: Pfizer, Merck Sharp & Dohme, Speakers bureau: Pfizer, Merck Sharp & Dohme, Janssen, Sanofi, Bristol-Myers Squibb, Abbvie, Neopharm, Speakers bureau: Pfizer, Merck Sharp & Dohme, Janssen, Sanofi, Bristol-Myers Squibb, Abbvie, Neopharm, Andrea Rubbert-Roth Consultant for: Chugai, Eli Lilly, Roche, and Sanofi, Speakers bureau: AbbVie, Bristol-Myers Squibb, Chugai, Hexal/Novartis, Janssen, Eli Lilly, Merck Sharp & Dohme, Pfizer, Roche, and Sanofi, Hubert van Hoogstraten Shareholder of: Sanofi, Regeneron, Novartis, Grant/research support from: Zambon, Employee of: Sanofi, Leon M. Gervitz Shareholder of: Sanofi, Union Chimique Belge, Abbvie, Celgene, Amgen, Employee of: Sanofi, Karthinathan Thangavelu Shareholder of: Sanofi, Employee of: Sanofi, Gregory St John Shareholder of: Regeneron Pharmaceuticals Inc, Employee of: Regeneron Pharmaceuticals Inc, Mark C. Genovese Grant/research support from: Sanofi/Genzyme, Genentech/Roche, RPharm, Consultant for: Sanofi/Genzyme, Genentech/Roche, RPharm

Hypothyroidism is common, with an extreme manifestation of myxedema coma if untreated. Hematologic consequences of myxedema coma include mild leukopenia and anemia, rarely pancytopenia. We present a patient with typical symptoms of myxedema coma, but found to be pancytopenic, with sustained response to levothyroxine and blood transfusion for anemia.

Background: Breast pain or mastalgia is one of the most common symptoms presenting to general surgeons. Approximately 60-70% of the women experience some type of breast pain at some point of their lives. Mastalgia may be classified as cyclical and non-cyclical. In cyclical mastalgia the pain intensity is changing during the menstrual cycle. In non-cyclical mastalgia there is no other obvious cause present, the pain is considered to be originating from the breast and the pain remains unchanged during the menstrual cycle. If the pain persists there are a variety of pharmacological agents for treatment of mastalgia. These include 3-6 months course of low dose tamoxifen (10 mg) or evening primrose oil. Other agents include bromocriptine and danazol but are obsolete now days. Newer treatments include centchroman and topical non-steroidal anti-inflammatory preparations. In pursuit of finding an effective safe and economical agent to treat it, plan to compare centchroman to evening primrose oil as treatment of mastalgia.Methods: In this study, two groups with 40 patients each will be taken and treatment will be given for 12 weeks and follow up to 24 weeks will be done without medication to assess sustained response or recurrence of mastalgia.Results: Centchroman is a non-steroidal drug found to be effective in the treatment of mastalgia with early and better relief in a time period of 3 months with minimal side effects as compared to evening primrose oil.Conclusions: This study has demonstrated that Centchroman therapy offers safe, effective and economical alternative to Evening Primrose oil for treatment of mastalgia.

Recent studies identified the presence of ALK/ROS/NTRK/MET alterations in a subset of infantile hemispheric gliomas. We report a case of GOPC-ROS1 fused congenital hemispheric glioma with a sustained response to crizotinib. An infant born at 28 weeks gestation was diagnosed with a large hemispheric mass at 2 weeks of life. The tumor was partially resected at 7 weeks of life. Histological evaluation confirmed a neoplasm with a spindle cell growth pattern, hypercellularity, nuclear pleomorphism, endothelial proliferation and necrosis consistent with glioblastoma. Fresh tissue was submitted for targeted panel sequencing (Oncopanel) which identified the presence of a GOPC-ROS1 fusion (exon 36:intron 4). This was confirmed by copy number analysis which showed a focal intragenic deletion with a breakpoint in ROS1 on 6q22. Given the lack of preclinical native models for ROS1 and other congenital kinase-driven gliomas, live cells were utilized to attempt to establish a patient derived cell line (organoid/neurosphere model) and intracranial patient derived xenograft model, the results of which are pending and will be reported. The GOPC-ROS1 rearrangement was structurally predicted to respond to kinase inhibitors with activity against ROS1 and crizotinib was started at 280 mg/m2/dose twice daily at 6 months of life with progressive tumor noted on imaging. Three months after initiating therapy, a 56% reduction in the tumor size and subsequent imaging revealed additional response. Our report is the first to demonstrate clinical response to crizotinib in a GPOC-ROS1 fused congenital glioblastoma and describe the development of a renewable resources for future analysis.

Background Few data are available that describe response patterns in patients with chronic idiopathic urticaria (CIU)/chronic spontaneous urticaria (CSU) treated with omalizumab. Objective We sought to describe response patterns by using data from the 3 pivotal omalizumab CIU/CSU trials. Methods Every 4 weeks, randomized patients received dosing with placebo or 75, 150, or 300 mg of omalizumab (ASTERIA I: n = 318, 24 weeks; ASTERIA II: n = 322, 12 weeks) or placebo or 300 mg of omalizumab (GLACIAL: n = 335, 24 weeks). Response was defined as well-controlled urticaria (weekly Urticaria Activity Score [UAS7] ≤ 6) or complete response (UAS7 = 0). Results Response rates were dose dependent and highest with 300 mg of omalizumab. Some patients responded early (before week 4). At week 12, a higher proportion of patients treated with 300 mg of omalizumab reported a UAS7 ≤ 6 (26.0% [75 mg of omalizumab], 40.0% [150 mg of omalizumab], 51.9% [300 mg of omalizumab], and 11.3% [placebo] for ASTERIA I; 26.8% [75 mg of omalizumab], 42.7% [150 mg of omalizumab], 65.8% [300 mg of omalizumab], and 19.0% [placebo] for ASTERIA II; and 52.4% [300 mg of omalizumab] and 12.0% [placebo] for GLACIAL) or a UAS7=0 (11.7% [75 mg of omalizumab], 15.0% [150 mg of omalizumab], 35.8% [300 mg of omalizumab], and 8.8% [placebo] for ASTERIA I; 15.9% [75 mg of omalizumab], 22.0% [150 mg of omalizumab], 44.3% [300 mg of omalizumab], and 5.1% [placebo] for ASTERIA II; and 33.7% [300 mg of omalizumab] and 4.8% [placebo] for GLACIAL). In patients receiving 300 mg of omalizumab with 24 weeks of treatment, median time to achieve a UAS7 ≤ 6 was 6 weeks (ASTERIA I and GLACIAL) and median time to achieve a UAS7=0 was 12 or 13 weeks (ASTERIA I and GLACIAL, respectively). Some patients who achieved well-controlled urticaria or complete response sustained response throughout the treatment period. Conclusion Benefits of omalizumab treatment were evident early (before week 4) in some patients and persisted to week 24. Use of 300 mg of omalizumab demonstrated best results in controlling CIU/CSU symptoms.

The advent of lenalidomide has fundamentally changed the treatment of patients with myelodysplastic syndrome (MDS) and deletion of the long arm of chromosome 5 (del(5q)), inducing high rates of red blood cell transfusion independence and cytogenetic response. We report a case of an 84-year-old patient with International Prognostic Scoring System (IPSS)-defined low-risk MDS with isolated del(5q), who has received continuous lenalidomide treatment for the past 8 years and whose treatment is ongoing. Grade 3 or 4 neutropenia and thrombocytopenia, which occurred in approximately 60 % of the patients during the first weeks of treatment, did not occur in our patient. Also, there were no thromboembolic events or a progression to acute myeloid leukemia. This case highlights the role of lenalidomide in modifying the course of low-risk del(5q) MDS in long-term responders by inducing a durable hematologic response and thereby contributing to control iron overload and improving long-term outcomes in selected patients.

The addition of tyrosine kinase inhibitors (TKI) to treatment regimens of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) has significantly improved overall survival.160 However, allogeneic stem cell transplantation (allo-SCT) offers the only curative option

Dopa-responsive dystonia (DRD) encompasses a group of clinically and genetically heterogeneous disorders that typically manifest as limb-onset, diurnally fluctuating dystonia presenting in early life and exhibits a robust and sustained response to levodopa treatment. DRD is one of the treatable dystonia syndromes of childhood. It starts with the involvement of lower limb and associated with characteristic diurnal variation. Many times it is misdiagnosed as cerebral palsy due to selective lower limb preference. We report a series of three cases of DRD which were previously misdiagnosed. The first case presented as myelopathy and other two were diagnosed as cerebral palsy. It is a treatable condition with very good response to drugs. Early diagnosis and adequate therapy can prevent from catastrophic complications.

TO THE EDITOR: Peripheral T-cell lymphomas (PTCLs) are heterogeneous diseases resulting from the malignant transformation of mature T or natural killer cells. Their epidemiology varies widely, but PTCLs that derive from T follicular helper (TFH) cells, which include angioimmunoblastic T-cell

Background: Anemia remains one cardinal symptom associated with reduced quality of life (QoL) in patients (pts) with myelofibrosis (MF) which is normally not being addressed by ruxolitinib (RUX). In our previous MPNSG-0109 trial, single-agent pomalidomide (POM) improved cytopenia in 14% (POM 0.5 mg QD) and 29% (POM 2.0 mg QD) of MF pts, respectively. In the MPNSG-0212 study, we sought to investigate the potential synergism of RUX plus POM to improve anemia and QoL in MF pts. Study Design: MPNSG-0212 is an ongoing multicenter, open-label, single-arm phase-Ib/II trial with a target population of 90 pts following a two-stage design (NCT01644110). Pts 1-40 in cohort 1 (co1) were treated with RUX (10 mg BID) plus low-dose POM (0.5 mg QD), while pts 41-90 in cohort 2 (co2) receive a step-wise dose increase of POM from 0.5 mg to 1 mg and 2 mg QD after 3 and 6 28-day-cycles, respectively. Primary endpoints are safety of the combination therapy, anemia response after 12 cycles (according to IWG-MRT and RBC transfusion independence [RBC-TI] criteria), and clinical benefit (CB) defined as stable disease plus i) hemoglobin (Hb) increase ≥1 g/dL in pts with RBC-TI or ii) doubling of RBC transfusion intervals and/or iii) significant (>25%) improvement of QoL as measured by the MPN-SAF questionnaire. Main inclusion criterion is MF with anemia (Hb Results: At data cut-off (31-May-2019), 79 pts were included. Data from 67 pts were available for evaluation (co1, n=40; co2, n=27). Baseline characteristics of the pts were as follows: median age 72 years (range 49-84), prior treatment in 53% (RUX in 22%, POM in 4%), median Hb level at study start 8.6 g/dL (range 5.4-11.7), RBC-TD in 28%, median spleen diameter measured by ultrasound 17.7 cm (range 12-36), presence of constitutional symptoms in 76%, and 91% intermediate-2 (61%) or high-risk (30%) pts according to DIPSS; 55% of pts in co1 had ≥1 high molecular risk mutation (ASXL1, SRSF2, EZH2, and/or IDH1/2). Median number of cycles until data cut-off was 12 (range 2-63) in co1 and 11 (range 2-21) in co2. In total, 502 adverse events (AE) mainly grade 1/2 were recorded: AE grade 1/2 in >20% of pts were fatigue (in 27% of pts), dyspnea (24%), diarrhea (22%), and muscle cramps (21%); AE grade ≥3 in >3% of pts was Hb decrease in the first weeks of treatment occurring in 25% of pts. In total, 87 serious AE (SAE), were recorded: most common SAE (in ≥3 pts) were pneumonia (in 15% of pts), leukemic transformation (9%), worsening of general condition (6%), CNS ischemia, and sepsis (4% each); 7 SAE (in 10% of pts) were grade 5. Number or severity of (S)AE was not increased in co2. Treatment interruptions of RUX and/or POM were necessary in 11 pts (27%) of co1 and 3 pts (11%) of co2; 2 pts stopped treatment permanently due to hematotoxicity. Increase of the POM dose to 1 mg and 2 mg QD was feasible in the majority of pts after 3 and 6 cycles, respectively. In co1, 18/40 pts (45%) continued treatment beyond cycle 12 because of an objective anemia response (7/40, 18%: clinical improvement [CI, Hb increase ≥2 g/dL] n=5, partial remission and RBC-TI n=1 each) or CB (11/40, 27%): Hb increase ≥1 g/dL and/or doubling of RBC transfusion intervals (n=4) or improvement of QoL according to MPN-SAF (n=7). In co2, 17/27 pts (63%) reached cycle 12 and 10/17 (59%) continued treatment: 2/10 (20%) experienced CI, whereas 8/10 (80%) fulfilled the CB criterion; 19/27 pts (70%) were still on treatment at the time of data cut-off. Among all 67 pts analyzed, 42% (28/67) were on treatment for more than 12 cycles and 24% (16/67) for more than 24 cycles; 3 pts (4%) were treated for more than 60 cycles due to sustained response or CB. Of note, mean Hb increased from 8.7 g/dL at baseline to 9.6 g/dL at end of cycle 18 and remained stable thereafter (Figure 1). Conclusions: Combination treatment using RUX plus POM is feasible in pts with poor-risk MF and resulted in an objective anemia response rate of 18% in co1. Of note, 42% of pts were treated with >12 cycles and showed a longer lasting stabilization of their disease with sustained improvement of Hb and QoL. Step-wise increase of the POM dose in co2 is safe and feasible with 70% of pts still on study treatment. Updated efficacy results of co2 with longer follow-up data will be presented at the meeting. Figure 1 Disclosures Stegelmann: Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Koschmieder:Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers-Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Foundation: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AOP Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; CTI: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Isfort:Novartis: Consultancy, Honoraria, Other: Travel reimbursement; Pfizer: Consultancy, Honoraria, Other: Travel reimbursement; Ariad: Consultancy, Honoraria; BMS: Honoraria; Hexal: Other: Travel reimbursement; Amgen: Other: Travel reimbursement; Mundipharma: Other: Travel reimbursement; Roche: Other: Travel reimbursement; Alexion: Other: Travel reimbursement. Hochhaus:Pfizer: Research Funding; Novartis: Research Funding; BMS: Research Funding; Incyte: Research Funding; MSD: Research Funding. Göthert:Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel support; Incyte: Consultancy, Honoraria, Other: Travel support; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Travel support; Proteros Biostructures: Consultancy; AOP Orphan Pharmaceuticals: Honoraria, Other: Travel support. Schafhausen:Incyte: Consultancy, Equity Ownership, Honoraria; Novartis: Consultancy, Honoraria. Radsak:Daiichi Sankyo: Other: Travel Support, Advisory Boards; Novartis: Other: Travel Support, Advisory Boards; JAZZ: Other: Travel Support; Celgene: Other: Travel Support, Advisory Boards; Takeda: Other: Advisory Boards; Otsuka: Other: Advisory Boards. von Bubnoff:Novartis: Research Funding. Reiter:Blueprint: Consultancy, Honoraria, Other: Travel reimbursement; Novartis: Consultancy, Honoraria, Other: Travel reimbursement, Research Funding; Deciphera: Consultancy, Honoraria, Other: Travel reimbursement. Döhner:Celgene, Novartis, Sunesis: Honoraria, Research Funding; AbbVie, Agios, Amgen, Astellas, Astex, Celator, Janssen, Jazz, Seattle Genetics: Consultancy, Honoraria; AROG, Bristol Myers Squibb, Pfizer: Research Funding. Griesshammer:Novartis: Consultancy, Honoraria, Speakers Bureau. Döhner:Daiichi: Honoraria; Jazz: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Janssen: Honoraria; CTI Biopharma: Consultancy, Honoraria.

Urothelial carcinoma (UC) is a common and frequently lethal cancer. Despite the presence of genomic alterations creating dependency on particular signaling pathways, the use of targeted therapies in advanced and metastatic UC has been limited. We performed an integrated analysis of whole-exome and RNA sequencing of primary and metastatic tumors in a patient with platinum-resistant UC. We found a strikingly high ERBB2 mRNA expression and enrichment of downstream oncogenic ERBB2 signaling in this patient’s tumors compared with tumors from an unselected group of patients with UC (N=17). This patient had an exceptional sustained response to trastuzumab. Our findings show that oncogenic addiction to ERBB2 signaling potentially predicts response to ERBB2-directed therapy of UC.

Background Observational studies provide important insights into therapeutic response during daily clinical practice, including data on the effects of long-term treatment. Objectives To evaluate treatment responses in rheumatoid arthritis (RA) patients during 5 years of adalimumab (ADA) therapy. Methods We analysed data from a large German multicenter observational study of patients with active RA who initiated ADA therapy during routine clinical care (the AGIL study). Outcomes of interest included Disease Activity Score-28 joints (DAS28), DAS28 therapeutic response as assessed by the statistical critical difference (dcrit,),1 Health Assessment Questionnaire-Disability Index (HAQ-DI), and patient-reported global health and pain. Results A total of 4283 patients had data available for analysis at baseline. The mean age was 55.2 years, 74% of patients were female, the mean disease duration was 9.3 years, and 26% had received previous treatment with one or more biologic drugs. At month 60, 726 patients (17%) of patients remained in the study. During the 5 year study, 41.3% of patients were lost to follow-up, 22.3% discontinued due to lack of effectiveness (about half within the first 6 months), and 4.0% discontinued due to adverse events. Mean values in patients treated with ADA showed a rapid response to treatment by both objective and patient-reported measures. Responses were maintained over 5 years in patients remaining on therapy (table 1). ADA was well tolerated and no unexpected safety signals were observed. Conclusions The AGIL study is one of the largest observational cohorts to provide long-term data on ADA therapy. Both objective and subjective measures support the effectiveness and safety of ADA in patients with RA during 5 years of therapy. Approximately 43% of patients experienced a therapeutic response to treatment at 6 months as assessed by statistical methods (DAS28-dcrit),1 and this level of response increased to 60% at 5 years in patients remaining on therapy. About one-third of patients recovered full functional ability (HAQ-DI remission) at the 6 month and subsequent visits. Our data indicate that ADA is an effective and safe long-term therapy in RA patients who continue on treatment. Reference [1] Behrens F, et al. Arthritis Care Res. 2013;65:1608–16. Acknowledgements This study was sponsored by AbbVie Deutschland GmbH and Co KG. AbbVie contributed to the study design, data analysis, and in the writing, revision, and approval of the abstract. Sharon L. Cross, Ph.D. provided medical writing services on behalf of CIRI, Frankfurt am Main, Germany, under contract with AbbVie for medical writing services and Holger Gnann, GKM Gesellschaft fur Therapieforschung, Munich, Germany, provided statistical analyses as a paid consultant. Disclosure of Interest F. Behrens Grant/research support from: AbbVie Deutschland GmbH and Co KG, Consultant for: AbbVie Deutschland GmbH and Co KG, Speakers bureau: AbbVie Deutschland GmbH and Co KG, M. Schmalzing Grant/research support from: AbbVie Deutschland GmbH and Co KG, Consultant for: AbbVie Deutschland GmbH and Co KG, M. Koehm Grant/research support from: AbbVie Deutschland GmbH and Co KG, Consultant for: AbbVie Deutschland GmbH and Co KG, E. Schwaneck Grant/research support from: AbbVie Deutschland GmbH and Co KG, Consultant for: AbbVie Deutschland GmbH and Co KG, G. Greger Employee of: AbbVie Deutschland GmbH and Co KG, T. Mosch Employee of: AbbVie Deutschland GmbH and Co KG, H. Burkhardt: None declared, H.-P. Tony Grant/research support from: AbbVie Deutschland GmbH and Co KG, Consultant for: AbbVie Deutschland GmbH and Co KG

A 10 year old presented in 2014 with left sided weakness and numbness and was found to have a large infiltrating mass involving the right perisylvian frontal and temporal cortex and causing mass effect. It was biopsied and shown to be an anaplastic oligodendroglioma (WHO Grade III) with no LOH 1p19q. The patient underwent 60 Gy cranial radiation with temozolomide and the MRI following radiation showed the mass had progressed with increased enhancement. The patient was then started on maintenance temozolomide, bevacizumab, and irinotecan but 7 months later further progressed. The patient was switched to procarbazine, lomustine and vincristine (PCV) but after 4 months showed further progression. Patient was wheel chair bound and was made do not resuscitate. Foundation One testing was sent and revealed mutations in EGFR, a receptor tyrosine kinase, and FBXW7, a member of the SCF complex predicted to sensitize cells to rapamycin. As a consequence, the patient was started on erlotinib, an EGFR inhibitor, and rapamycin, a mTOR inhibitor. The patient showed immediate response and tumor regression and continues to remain on these medications with sustained response for 2.5 years. Immunofluorescent analyses of fixed tumor specimens indicates that EGFR-positive cells in the pre-treatment tumor frequently also exhibit high levels of p-S6, an indicator of mTOR activity, suggesting that a majority of cells within this tumor may be targeted by both inhibitors simultaneously, rather than two independent populations being present. This regimen has potential to be an effective regimen in those with similar mutations.

This post-hoc analysis of the DURATION-3 study aimed to identify factors associated with sustained glycaemic response with exenatide once weekly (QW) or insulin glargine (IG) among patients with type 2 diabetes. Response was defined as achieving treatment target of HbA1c