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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.

Thrombopoietin receptor agonists (TPO-RAs) are currently indicated for continuous treatment of chronic primary immune thrombocytopenia (ITP). However, there is growing evidence that TPO-RAs can also trigger sustained response in 10-30% of cases after treatment tapering and discontinuation. Therefore, at least for selected responding patients, it might be rational to plan TPO-RA interruption to exploit off-treatment response. Intriguingly, complete or partial responses with TPO-RAs are frequently observed when treatments are initiated early, suggesting that unknown immune-related mechanisms may be involved in this phenomenon. The sustained responses observed after interruption of TPO-RAs may be interpreted as a recovery of immunological tolerance; thus, the re-establishment of immunological equilibrium might be primarily responsible for the observed off-treatment effect. Importantly, these findings may indicate that anticipated TPO-RA usage can lead to improved responses, and that optimized tapering and interruption in selected patients can furthermore improve prognoses. On the base of this rationale, a series of real-life considerations have been generated by a panel of Experts to elucidate possible novel criteria and modalities to identify subgroups of patients who can benefit from tapering and/or discontinuation of TPO-RAs. Towards this aim, the results of a survey of ITP experts are herein reported, reflecting a snapshot of current real-life experience on early discontinuation of TPO-RA-based therapy. The present manuscript also highlights the importance of future translational studies on novel prognostic and predictive biomarkers that can stratify patients and facilitate the clinical choice for second-line treatment of ITP.

Mediastinal germ cell tumors (GCTs) are a rare and heterogeneous group of neoplasms. Although histologically resembling their gonadal counterparts, they differ considerably in their clinical characteristics, biological behavior and prognostic outcome. The rarity of mediastinal GCTs has hindered their meaningful analysis, with most studies and clinical trials including them along with other extragonadal GCTs, which has led to a lack of consensus on optimal treatment strategies, and a lull in improvement in patient outcomes. Diagnosis of mediastinal GCT requires a multipronged approach, and encompasses multidisciplinary treatment including chemotherapy followed by surgery, with or without radiotherapy. In view of sustained response rates to current management protocols, the focus needs to be shifted to identifying patients in whom treatment regimens can be downscaled with the aim of decreasing long term morbidity and improving quality of life in low risk patient groups, while improving survival rates in poor risk patient subsets. In this scenario, better understanding of the molecular pathogenesis of these tumors may lead to identification of novel biomarkers and therapeutic targets, as well as improved disease segmentation and risk stratification, thus helping to avoid the toxicity and morbidity associated with current one-fits-all treatment strategies. Multi-institutional collaborations across continents are necessary to generate meaningful data, and are the face of future developments in this arena.

Background:Linaclotide is approved for the treatment of moderate-to-severe irritable bowel syndrome (IBS) with constipation (IBS-C) in adults. This study aimed to assess factors predictive of a clinical response and improvements in non-IBS symptoms with linaclotide treatment in a Spanish patient population.Methods:In this open-label phase IIIb study, patients with moderate-to-severe IBS-C received linaclotide 290 μg once daily for 12 weeks. The primary endpoint was clinical response at week 12, defined as >30% reduction in IBS symptom severity score (IBS-SSS) or IBS-SSS Results:A total of 96 patients were eligible; 91 were female and the mean age was 47.4 years. Mean (SD) baseline IBS-SSS was 371 (72.5). In the intention-to-treat and per-protocol populations, 22.9% and 31.7% were clinical responders at week 4, respectively, and 25.0% and 36.7% were clinical responders at week 12. Digestive nonintestinal and extra-digestive symptom scores were significantly improved at weeks 4 and 12. Baseline characteristic was not associated with week 12 clinical response; however, clinical response at week 4 was predictive of response at week 12 (OR: 6.5; 95%IC: 2.1–19.8). The most common adverse event was diarrhea inclusive of loose or watery stools (35.4%).Conclusions:Linaclotide improves IBS-C symptoms, including digestive nonintestinal and extra-digestive symptoms. A clinical response at week 4 may predict response at week 12.

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

Purpose The HERBERT study was a dose-finding feasibility study of a high-dose rate endorectal brachytherapy (HDREBT) boost after external beam radiotherapy (EBRT) in elderly patients with rectal cancer who were unfit for surgery. This analysis evaluates the association of patient, tumor and dosimetric parameters with tumor response and toxicity after HDREBT in definitive radiotherapy for rectal cancer. Patients and methods The HERBERT study included 38 inoperable patients with T2-3N0-1 rectal cancer. Thirteen fractions of 3 Gy EBRT were followed by three weekly HDREBT applications of 5–8 Gy per fraction. Clinical and dosimetric parameters were tested for correlation with clinical complete response (cCR), sustained partial/complete response (SR), patient reported bowel symptoms, physician reported acute and late proctitis (CTCAE v3) and endoscopically scored toxicity. Results Thirty-five patients completed treatment and were included in the current analyses. Twenty of 33 evaluable patients achieved a cCR, the median duration of a sustained response was 32 months. Tumor volume at diagnosis showed a strong association with clinical complete response (OR 1.15; p = 0.005). No dose–response correlation was observed in this cohort. Prescribed dose to the brachytherapy CTV (D90) correlated with acute and late physician reported proctitis while CTV volume, CTV width and high dose regions in the CTV (D1cc/D2cc) were associated with endoscopic toxicity at the tumor site. Conclusion Tumor volume is the most important predictive factor for tumor response and a higher dose to the brachytherapy CTV increases the risk of severe clinically and endoscopically observed proctitis after definitive radiotherapy in elderly patients with rectal cancer.

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.

To understand visual motion processing underlying the optokinetic response (OKR), we developed a biomimetic model that reproduces the findings from behavioral experiments. We recorded OKRs induced by drifting gratings with different spatiotemporal frequencies from humans and non-human primates. The characteristics of the initial open-loop responses and the closed-loop eye velocity gains were analyzed using a model developed in this study. The model consists of two pathways with different dynamics. One mediates the transient response (transient pathway) and the other the sustained response (sustained pathway). Each pathway has a different spatiotemporal frequency dependence. Assuming there are different visual sensitivities for these pathways, one tuned to lower spatial and higher temporal frequencies on the retina and the other tuned to stimulus velocity, we successfully reproduced the course of OKRs. Our results suggest that two different neural circuitries/populations contribute to visual processing in the different stages of OKRs.

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.

Metastatic breast cancer (MBC) entails an overall 5-year survival of approximately 25%. The choice of therapy is influenced by expression of the HER2 gene and hormone receptors, by a disease-free interval, and by age. The use of paclitaxel combined with gemcitabine (doublet protocol) has shown efficacy as first-line treatment for MBC in either initial or maintenance therapy when compared to monotherapy with paclitaxel. There is evidence showing that the doublet protocol is a good alternative to maintenance therapy in women under 50 years old. Nevertheless, there is a lack of information concerning individuals above that age. We report the case of an 81-year-old patient presenting with recurrence of MBC, with lung and skin metastases both positive for hormone receptor and negative for HER2. We implemented a therapy based on the combination of gemcitabine and paclitaxel for 12 cycles, when complete response was achieved. Currently, 16 months after this achievement, the patient is receiving maintenance treatment under the doublet protocol, presenting acceptable parameters of toxicity since the beginning of treatment, which shows satisfactory tolerability and management of chemotherapy in an elderly patient. We suggest that the maintenance treatment protocol with a doublet might be an alternative with a satisfactory response in patients with MBC.

Delivery of nucleic acids is the most promising therapy for many diseases that remain untreatable. Therefore, many research efforts have been put on finding a safe and efficient delivery system able to provide a sustained response. Viral vectors have proved to be the most efficient for delivery of nucleic acids and, thus, stand as the foremost vector used in current clinical trials. However, safety issues arise as a main concern and mitigate their use, impelling the improvement of non-viral alternatives. This review focuses on the recent advances in pre-clinical development of non-viral polyplexes and lipoplexes for nucleic acid-based delivery, in contrast with vectors being used in present clinical trials. Nucleic acid vectors for neurodegenerative ataxias, Parkinson's disease, retinitis pigmentosa, cystic fibrosis, hemophilia, pancreatic and lung cancer, and rheumatoid arthritis are discussed to illustrate current state of pre-clinical and clinical studies. Thereby, denoting the prospects for treatment of genetic diseases and elucidating the trend in non-viral vector development and improvement which is expected to significantly increase disease rescue exceeding the modest clinical successes observed so far.

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.

PURPOSE OF REVIEW Anaemia is a common haematological presentation in patients with bone marrow failure, yet a challenging condition to treat. As anaemia has a direct impact on the patient's symptoms, managing anaemia in the common bone marrow failure conditions, such as myelodysplastic syndrome will help to improve the quality of life. This review discusses the available treatment options and the benefit of improving the haemoglobin level. RECENT FINDINGS Managing anaemia effectively has shown to improve the patient outcome, yet treatment option remain limited. Recently, activin inhibitors such as Luspatercept have shown to be effective in patients' refractory to ESAs and further clinical trials are ongoing to explore this further. SUMMARY Transfusion still remains the mainstay of treatment in patients not suitable, lost response or refractory to erythropoiesis-stimulating agents (ESAs). Majority of these patients are not suitable for definite treatment options such as bone marrow transplantation. The aim of treatment remains improving the quality of life and newer therapeutic options may offer better and more sustained response.

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

We present a case of a 15-year-old girl with an allogenic renal transplant secondary to chronic glomerulonephritis of unknown etiology who presented with treatment refractory molluscum contagiosum of the lower extremities and perineum. Treatment of mollusca with pulsed dye laser resulted in a clinically significant and sustained response. To our knowledge, this is the first report of a successful treatment of molluscum contagiosum with pulsed dye laser in the setting of a renal transplant.

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.

BACKGROUND: Treating high-grade gliomas in pediatric patients involves multimodal therapy with significant long-term sequelae. Despite this approach, these tumors have a high rate of recurrence. Genetic testing has allowed for targeted therapies to be investigated in tumors with BRAF(V600E) mutations. While BRAF inhibitors have improved survival among patients with BRAF(V600E) mutated melanoma, resistance develops quickly leading to trials combining BRAF and MEK inhibitors. The efficacy and side effect profile of this combination has yet to be determined in pediatric high-grade glioma patients. CASES: We describe three cases: a 12 year-old female with a high-grade glioma, a 13 year-old male with an astroblastoma and a 6 year-old female with an anaplastic ganglioglioma. All tumors demonstrated a BRAF(V600E) mutation, and each patient received combined dabrafenib and trametinib therapy. The 12 year-old patient experienced a significant partial response and remains progression-free after a year of combination therapy. The 13 year-old remains disease free post radiation on combination therapy for 8 months. The final patient received combination targeted therapy upfront and after significant tumor response at 3 months, remains progression-free at 1 year. All patients were strictly monitored for side effects and remain free of complications. CONCLUSIONS: To our knowledge, this is the first report of sustained responses in pediatric patients with high-grade gliomas following combined BRAF and MEK inhibitor therapy. These responses highlight the potential use of these targeted agents in this population and suggest that targeted combination therapy is a well-tolerated option in pediatric patients with documented BRAF(V600E) mutated high-grade gliomas.

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

Background Biologic drugs have demonstrated efficacy and safety in the treatment of psoriasis. Frequently, label doses tend to be reduced in clinical practice when a sustained response has been reached. Purpose To assess the proposals of a committee for psoriasis according to drug serum levels and symptoms. Material and methods A retrospective study of patients with psoriasis and etanercept, adalimumab or infliximab screened by a multidisciplinary committee for psoriasis from January 2016 to August 2017 was developed. The multidisciplinary committee based its proposal on drug serum level and symptoms of psoriasis, and the maintenance, suspension/change or optimised doses of drug. The etanercept serum level was (2–7 µg/ml), adalimumab (5–12 µg/ml) and infliximab (3–10 µg/ml). Results Ninety-eight patients with psoriasis were included: 44 patients with etanercept of whom 22 were out of range (one over range and 21 below the range). Of the 22 patients within range: five maintained, one suspended/changed and 16 optimised the drug. Of the other 22 patients out of range: 12 maintained, eight suspended/changed and two optimised the drug. Thirty-five patients with adalimumab, of whom 21 were out of range (all below the range). Of the 14 patients within range: six maintained, one suspended/changed and seven optimised the drug. Of the other 21 patients out of range: nine maintained, nine suspended/changed and three optimised the drug. Nineteen patients with infliximab, of whom 12 were out of range (two over range and 10 below the range). Of the seven patients within range, all maintained the drug. Of the other 12 patients out of range: four maintained, six suspended/changed and two optimised the drug. Conclusion The proposals of the committee were not always strictly correlated with drug serum levels but clinic evolution influences its decision. Possession of the drug serum levels is one more tool in helping find the best treatment for the patient, but it is also necessary to look for other new tools. No conflict of interest

Background Daratumumab, a human CD38 monoclonal antibody that has direct on-tumor and immunomodulatory mechanisms of action, demonstrated clinical benefit as monotherapy or in combination with established regimens in patients with multiple myeloma with one or more prior lines of therapy. Case presentation A male patient, who was 70 years of age at the time of diagnosis of multiple myeloma in 2011, relapsed after five lines of therapy, including autologous stem cell transplantation. The patient’s disease, which was considered high risk with a deletion of chromosome 17p, advanced quickly and was triple refractory 2 years after diagnosis leaving few treatment options. He was treated with daratumumab monotherapy in the SIRIUS clinical trial resulting in a stringent complete response and clearance of minimal residual disease. The duration of the patient’s clinical response is now over 3.5 years without relapse, compared with a median of 7.6 months for similarly treated patients. The patient’s immunophenotype revealed CD8+ T-cell expansion, clonal expansion of the T-cell receptor repertoire, and decreases in regulatory T cells during daratumumab therapy, suggesting a robust adaptive immune response. This immune response was still present 32 months into daratumumab therapy. Conclusions The results from this case report showed that a patient with advanced multiple myeloma, who had exhausted all treatment options with existing regimens, mounted an ongoing, deep, and durable response to daratumumab monotherapy. Further investigation of the immunologic profile provided additional patient-level evidence of an immunomodulatory mechanism of action of daratumumab. Trial registration ClinicalTrials.gov Identifier number NCT01985126. Submitted 22 July 2013

Purpose: To identify factors associated with sustained response to interleukin (IL)-1 inhibition among demographic, clinical and therapeutic data in patients with Behcet disease (BD).Method...

In this issue of Blood, Miklos et al present results from a prospective phase 1b/2 study on the Bruton tyrosine kinase (BTK) inhibitor ibrutinib in patients in need of salvage immunosuppressive treatment for chronic graft-versus-host disease (GVHD). High sustained response rates among other findings led for the first time to US Food and Drug Administration (FDA) approval of an agent in refractory chronic GVHD.1

Local therapy for in-transit melanoma (ITM) is a treatment alternative for patients who are not good candidates for systemic therapy, regional therapy, or surgical management. In this case report, we describe 3 patients with ITM who were treated with intralesional Bacillus Calmette-Guerin (ILBCG) and/or topical imiquimod. Treatment course was dictated by the clinical response. Patient 1's response to ILBCG monotherapy was not sufficient to cause disease regression; however, transition to topical imiquimod therapy resulted in complete and sustained response. Although patient 2 responded to ILBCG and imiquimod, she developed a hypersensitivity reaction to ILBCG; when topical imiquimod was continued as monotherapy, her clinical response was complete. Patient 3 responded completely to ILBCG monotherapy in injected lesions, but expired shortly thereafter from unrelated disease. Reports like this one are needed to define the success measures of local therapy in the treatment of ITM.

Introduction: Chromophobe renal cell carcinoma is universally accepted as a distinct subtype of renal cell carcinoma. There are conflicting reports on prognosis, and few data on response to treatment exist. Currently, we do not have any effective treatment for the metastatic disease apart from surgical procedures. We report unexpectedly high efficacy of temsirolimus in a patient, with metastatic chromophobe renal cell carcinoma of right kidney. Case Report: We present the case of a 50-year-old female patient with advanced chromophobe renal cell carcinoma of right kidney, relapsing after radical nephrectomy; she was diagnosed of mRCC (metastatic renal cell carcinoma) with multiple lung metastasis. Treatment with temsirolimus resulted in a stable disease for 48 cycles. Conclusion: Mammalian target of rapamycin inhibitors like temsirolimus have been an option in the management of such cases. The case presented here impresses that temsirolimus could be a viable option for patients with metastatic chromophobe renal cell carcinoma.

Ming Dong Gu and Jianping Guo The essay by Fan Meijun and Wang Zhihe has sparked broad reflection by Ming Dong Gu and Jianping Guo in the form of a sustained response to the philosophical issues in the intellectual encounter between East and West. While agreeing with the thesis and major ideas of Fan and Wang, Gu and Guo offer a critique of some issues and continue to reflect on a series of questions relevant to the exchanges between Eastern and Western thought, which include: Is there an intellectual divide between East and West? What are the intellectual barriers to genuine dialogue? Do the intellectual barriers identified by Fan and Wang accurately mirror the real conditions of Eastern and Western thought? If they are true, have they formed a paradigm in East-West studies? If yes, what is the conceptual ground for the paradigm? Which is more responsible for the intellectual barriers, Western-centrism or Eastern-centrism? Besides Western process thought, is there any Eastern thought that can be appropriated to overcome the intellectual barriers? Gu and Guo’s reflections are summarized in a general question: under what conditions can East meet West in intellectual thought? Identifying some common ground in Eastern and Western thought, they reveal blind spots in current efforts to cross the East-West divide and examine some successful cases of East-West dialogue. Based on their meditations, they suggest new dimensions to the Second Enlightenment and call for transcultural intellectual empowerment for all cultural traditions.

SummaryIn nonsevere haemophilia A (HA) patients the presence of an inhibitor may exacerbate the bleeding phenotype dramatically. There are very limited data on the optimal therapeutic approach to eradicate inhibitors in these patients. We aimed to describe inhibitor eradication treatment in a large cohort of unselected nonsevere HA patients with inhibitors. We included 101 inhibitor patients from a source population of 2,709 nonsevere HA patients (factor VIII 2–40 IU/dl), treated in Europe and Australia (median age 37 years, interquartile range (IQR) 15–60; median peak titre 7 BU/ml, IQR 2–30). In the majority of the patients (71 %; 72/101) the inhibitor disappeared; either spontaneously (70 %, 51/73) or after eradication treatment (75 %, 21/28). Eradication treatment strategies varied widely, including both immune tolerance induction and immunosuppression. Sustained success (no inhibitor after rechallenge with factor VIII concentrate after inhibitor disappearance) was achieved in 64 % (30/47) of those patients rechallenged with FVIII concentrate. In high-titre inhibitor patients sustained success was associated with eradication treatment (unadjusted relative risk 2.3, 95 % confidence interval 1.3–4.3), compared to no eradication treatment. In conclusion, in nonsevere HA patients most inhibitors disappear spontaneously. However, in 35 % (25/72) of these patients an anamnestic response still can occur when rechallenged, thus disappearance in these patients does not always equal sustained response. Treatment for those requiring eradication has to be decided case by case, as one single approach is unlikely to be appropriate for all.Study was carried out in: Emma Children’s Hospital, Academic Medical Center, Amsterdam, the Netherlands.

Clostridium difficile colitis is a substantial cause of in-hospital morbidity. Since the mortality attributable may be as high as 10%, a prompt and effective treatment is advisable. Fidaxomicin is a well-documented effective drug for the treatment of C. difficile colitis and it is particularly effective in the treatment of recurrences. We report a case of a 92-year-old woman with prolonged hospitalization and recurrent episodes (three in a three-month period) of C. difficile diarrhea. Each episode initially responded to vancomycin. However, after the third episode fidaxomicin was given, with a sustained response (5 months without further episodes). In this patient fidaxomicin was safe and effective in treating recurrence of C. difficile colitis. The use of fidaxomicin as a therapy of first episode of C. difficile colitis should be considered for those patients with a predictable high risk of recurrent C. difficile colitis.

Resume Contexte Environ un melanome sur deux presente une mutation sur le codon 600 du gene BRAF. Les patients dont la tumeur est mutee V600 ont une reponse aux traitements par des inhibiteurs de BRAF (vemurafenib ou dabrafenib) le plus souvent rapide et spectaculaire, avec un gain significatif en termes de survie sans progression ou en survie globale. Cependant, s�il existe de rares patients longs repondeurs aux agents anti-BRAF en monotherapie, une resistance au traitement se developpe dans la plupart des cas dans un delai median de 6 mois. Objectifs Il est essentiel de comprendre les mecanismes de resistance aux therapies anti-BRAF afin d�optimiser leur efficacite et d�ameliorer les taux de reponse, ainsi que la duree du benefice clinique. Cette revue de la litterature decrit les voies de signalisation impliquant BRAF. Les principaux mecanismes de resistance a ces traitements identifies a ce jour sont decrits, ainsi que les strategies therapeutiques alternatives potentielles. Methodes Les mots cles (resistance, BRAF, melanoma, targeted therapy, vemurafenib, et dabrafenib) renseignes dans la base de donnees Pubmed/Medline ont permis de selectionner les principales references scientifiques utiles a l�elaboration de ce travail. Cette selection a pris fin le 31 janvier 2014. Discussion Le decryptage et la meilleure comprehension des mecanismes de resistance aux inhibiteurs de BRAF devraient permettre le developpement de nouvelles strategies therapeutiques destinees a contourner ces resistances et ainsi a ameliorer les taux et les durees de reponse. Summary Context In patients with melanoma positive for the BRAF V600 mutation, clinical response to specific BRAF inhibitors is usually rapid and striking, with significant benefits in terms of progression-free survival and overall survival. However, resistance to treatment almost invariably arises, typically within a median timeframe of 6 months. Indeed, very few patients exhibit long-lasting response to these targeted therapies. Aims It is essential to better understand the mechanisms of resistance to targeted anti-BRAF therapies in order to increase both response rates and the duration of clinical response to treatment. This literature review describes the signaling pathways involving BRAF and presents recent data from clinical trials with these molecules. Furthermore, we aim to describe the main resistance mechanisms linked with targeted anti-BRAF therapies. Methods The keywords (resistance, BRAF, melanoma, targeted therapy, vemurafenib, and dabrafenib) were used to extract relevant articles in the Medline/Pubmed database published before 31 January 2014. Discussion Improved knowledge and understanding of the mechanisms of resistance to targeted anti-BRAF therapies should enable the development of new therapeutic strategies in order to overcome such resistance and allow more significant and sustained response rates to be achieved among melanoma patients. Mots cles Mutation; BRAF; Melanome; Therapie ciblee; Vemurafenib; Dabrafenib; Resistance Keywords BRAF; Mutation; Melanoma; Targeted therapy; Vemurafenib; Dabrafenib; Resistance

Case report. A 41-year-old man presented with anemia, lymphocytosis and splenomegaly. T-cell large granular lymphocyte leukemia was diagnosed based on lymphocytosis of T-cell large granular lymphocytes, characteristic immunophenotype (CD3+, CD8+, CD16+, CD57+) of the lymphocytes and clonally rearranged T-cell receptor genes. Therapy indication was transfusion-dependent anemia. Initial cyclosporine therapy and low-dose oral methotrexate failed to control anemia and lymphocytosis. Yet, a complete clinical and hematological response (without molecular remission) was achieved and sustained when cyclosporine was reintroduced into the therapy. Conclusion. Our case confirms that cyclosporine therapy is effective in treating T-cell large granular lymphocyte leukemia and suggests that indefinite treatment may not be needed to maintain the response.

In primary chronic immune thrombocytopenia, long-term response to splenectomy, with 60% of patients enjoying a treatment-free life, is higher when compared with rituximab and similar to that with continuous thrombopoietin-receptor agonists (TPO-RA) administration. Splenectomy should continue to be offered to patients failing initial treatments in the absence of increased surgery-related risks. The higher lifelong safety concerns with splenectomy (increased risk of infection, shared in part with rituximab, and of thrombosis, in common with TPO-RA) and a mortality

Dapsone is recommended as a second line therapy in immune thrombocytopenia (ITP), but is underused because of its potential side effects. The medical charts of 42 ITP patients treated with dapsone (100 mg/day) were retrospectively reviewed in order to assess its efficacy and safety in daily clinical practice. The overall response rate was 54.8% (n = 22, with a complete response in 38.1%) with a median time to response of 29 days (24-41 days). Patients with complete response had shorter disease duration whereas no difference was observed between responders and non-responders regarding age, sex or previous treatments received. Importantly, after dapsone withdrawal, a sustained response was observed in 5 patients, representing 12% of the whole cohort. Twenty percent of patients (n = 8) relapsed on therapy after 8.1 (6.5-13.6) months. Side effects occurred in 31% (n = 13) of patients, and required dapsone withdrawal in 22% (n = 9) or dosage reduction in 10% (n = 4) of the cases. Side effects resolved in all but one case. Overall, these data support dapsone as an interesting second line therapy in ITP, with a good safety and efficacy profile at a low cost.

The authors report a case of a patient with bilateral orbital necrobiotic xanthogranuloma and no associated systemic paraproteinemia. Orbital biopsy showed strong expression of CD20-positive cells. The patient was treated with systemic rituximab monotherapy, with excellent clinical response and marked regression of the orbital lesions on imaging. At the time of writing, the patient has been treated with bimonthly rituximab maintenance therapy for 22 months and has stable clinical and imaging findings with sustained response to treatment and no reported side effects. To the authors' knowledge, this is the first reported case of orbital necrobiotic xanthogranuloma successfully treated with rituximab monotherapy. They hope that this well-documented case will encourage clinicians to consider rituximab monotherapy as a possible treatment option, albeit one entailing an off-label use of this drug, for patients with necrobiotic xanthogranuloma of the orbit.