Clinical spectrum of eye malformations in four patients with Mowat-Wilson syndrome.

Mowat-Wilson syndrome (MWS) is a rare genetic syndrome characterized by a specific facial gestalt, intellectual deficiency, Hirschsprung disease and multiple congenital anomalies. Heterozygous mutations or deletions in the zinc finger E-box-binding homeobox2 gene (ZEB2) cause MWS. ZEB2 encodes for Smad-interacting protein 1, a transcriptional co-repressor involved in TGF-beta and BMP pathways and is strongly expressed in early stages of development in mice. Eye abnormalities have rarely been described in patients with this syndrome. Herein, we describe four patients (two males and two females; mean age 7 years) with MWS and eye malformations. Ocular anomalies included, iris/retinal colobomas, atrophy or absence of the optic nerve, hyphema, and deep refraction troubles, sometimes with severe visual consequences. All eye malformations were asymmetric and often unilateral and all eye segments were affected, similarly to the nine MWS cases with ophthalmological malformations previously reported (iris/chorioretinal/optic disc coloboma, optic nerve atrophy, retinal epithelium atrophy, cataract, and korectopia). In human embryo, ZEB2 is expressed in lens and neural retina. Using the present report and data from the literature, we set out to determine whether or not the presence of eye manifestations could be due to specific type or location of mutations. We concluded that the presence of eye malformations, although a rare feature in MWS, should be considered as a part of the clinical spectrum of the condition.

Necrobiotic xanthogranuloma occurring in an eyelid scar.

We present a case report of necrobiotic xanthogranuloma (NXG) in a 76-year-old Caucasian lady occurring as a nodule in a blepharoplasty scar. NXG is a rare histiocytic disease with progressive orbital and systemic features. Management options of excision biopsy or chemotherapy are discussed.

Results of the randomized phase IIB ARCTIC trial of low-dose rituximab in previously untreated CLL.

ARCTIC was a multicenter, randomized-controlled, open, phase IIB non-inferiority trial in previously untreated chronic lymphocytic leukemia (CLL). Conventional frontline therapy in fit patients is fludarabine, cyclophosphamide and rituximab (FCR). The trial hypothesized that including mitoxantrone with low-dose rituximab (FCM-miniR) would be non-inferior to FCR. A total of 200 patients were recruited to assess the primary end point of complete remission (CR) rates according to IWCLL criteria. Secondary end points were progression-free survival (PFS), overall survival (OS), overall response rate, minimal residual disease (MRD) negativity, safety and cost-effectiveness. The trial closed following a pre-planned interim analysis. At final analysis, CR rates were 76 FCR vs 55% FCM-miniR (adjusted odds ratio: 0.37; 95% confidence interval: 0.19-0.73). MRD-negativity rates were 54 FCR vs 44% FCM-miniR. More participants experienced serious adverse reactions with FCM-miniR (49%) compared to FCR (41%). There are no significant differences between the treatment groups for PFS and OS. FCM-miniR is not expected to be cost-effective over a lifetime horizon. In summary, FCM-miniR is less well tolerated than FCR with an inferior response and MRD-negativity rate and increased toxicity, and will not be taken forward into a confirmatory trial. The trial demonstrated that oral FCR yields high response rates compared to historical series with intravenous chemotherapy.

[Evaluation of the efficacy of aflibercept's in the treatment of neovascular age-related macular degeneration in treatment-naive and switched patients. Report of 86 cases]. / Évaluation de l'efficacité de l'aflibercept comme traitement de la dégénérescence maculaire liée à l'âge exsudative chez des patients naïfs et « switchés ¼. À propos de 86 cas.

INTRODUCTION: AMD (age-related macular degeneration) is the leading cause of legal blindness after age 50 in developed countries. Anti-VEGF therapy by intravitreal injection has become the standard for the treatment of neovascular AMD. Ranibizumab is the most currently used, but the arrival of aflibercept on the market 1 year ago is changing clinical practices in France. METHODS: The objective of this study is to evaluate the efficacy of aflibercept in AMD. All patients with neovascular AMD undergoing IVT (intra-vitreal injection) of aflibercept were included. All patients had at baseline and on follow-up visits a measurement of best corrected visual acuity (ETDRS), a fundus examination and an OCT. For statistical analysis, we analyzed the data at 0, 3, 6 and 12 months. An induction phase was carried out for treatment-naive patients, and follow-up was performed according to the PRN method (Pro Re Nata). The total number of injections over the entire follow-up period was recorded. RESULTS: Ninety-six eyes were included, with 17 treatment-naive patients and 69 patients who had previously received ranibizumab. At 1 year, all patients had a mean improvement of 5.4 ETDRS letters (P=0.0026). The OCT data showed a rapid decline in retinal thickness, from baseline to the third month, of 143 microns on average (P=5.6×10(-15)); between the 3rd and 6th month, this was slower, with an average decrease of 4.6 microns, and between the 6th and the 12th month, the difference was significant, with an average decrease of 36 microns (P=0.003). The number of injections over one year was 5.7 on average. CONCLUSION: The efficacy of aflibercept with a PRN protocol provides interesting results, with an improvement in visual acuity and central retinal thickness in all treated groups, and with fewer injections than advocated.

The SF3B1 inhibitor spliceostatin A (SSA) elicits apoptosis in chronic lymphocytic leukaemia cells through downregulation of Mcl-1.

The pro-survival Bcl-2 family member Mcl-1 is expressed in chronic lymphocytic leukaemia (CLL), with high expression correlated with progressive disease. The spliceosome inhibitor spliceostatin A (SSA) is known to regulate Mcl-1 and so here we assessed the ability of SSA to elicit apoptosis in CLL. SSA induced apoptosis of CLL cells at low nanomolar concentrations in a dose- and time-dependent manner, but independently of SF3B1 mutational status, IGHV status and CD38 or ZAP70 expression. However, normal B and T cells were less sensitive than CLL cells (P=0.006 and P<0.001, respectively). SSA altered the splicing of anti-apoptotic MCL-1(L) to MCL-1(s) in CLL cells coincident with induction of apoptosis. Overexpression studies in Ramos cells suggested that Mcl-1 was important for SSA-induced killing since its expression inversely correlated with apoptosis (P=0.001). IL4 and CD40L, present in patient lymph nodes, are known to protect tumour cells from apoptosis and significantly inhibited SSA, ABT-263 and ABT-199 induced killing following administration to CLL cells (P=0.008). However, by combining SSA with the Bcl-2/Bcl-x(L) antagonists ABT-263 or ABT-199, we were able to overcome this pro-survival effect. We conclude that SSA combined with Bcl-2/Bcl-x(L) antagonists may have therapeutic utility for CLL.

[Gas-permeable scleral lens for management of severe keratoconjunctivitis sicca secondary to chronic graft-versus-host disease]. / Traitement des sécheresses oculaires sévères secondaires à la maladie du greffon contre l'hôte chronique par lentilles sclérales perméables à l'oxygène.

INTRODUCTION: Graft-versus-host disease is a major complication of allogeneic hematopoietic stem cell transplantation. Severe keratoconjunctivitis sicca is common in patients with chronic GVH disease. The goal of this study was to evaluate the safety and efficacy of a gas-permeable scleral lens in the management of severe dry eye disease associated with chronic GVH. PATIENTS AND METHODS: This is a retrospective study from June 2009 to November 2013. Patients fitted with scleral lenses for severe keratoconjunctivitis sicca associated with chronic GVH were included. The main outcomes measured were best-corrected visual acuity and quality of life (OSDI and NEI-VFQ25) composite scores before and six months after scleral lens fitting. RESULTS: Sixteen patients were included. The mean age was 52 years (19-69 years). Mean follow-up was 20 months (3-48 months). All patients reported improvement of their ocular symptoms. Best corrected visual acuity improved from 0.21 ± 0.26 to 0.1 ± 0.14 logMAR (P = 0.002), OSDI score improved from 92.1 ± 11.3 to 23.5 ± 11.2 (P = 0.002) and NEI-VFQ25 improved from 41.3 ± 7 to 83.1 ± 15.9 (P = 0.003), 6 months after scleral lens fitting. No serious adverse events, infectious, hypoxemic or allergic complications attributable to the scleral lens occurred. CONCLUSION: Gas-permeable scleral lens use appears to be safe and effective in patients with severe dry eye related to chronic GVH.

Monosomy 7 and Ph-positive acute lymphoblastic leukaemia: cytogenetic and molecular aspects.

A combination of monosomy 7 and translocation t(9;22) (q34;q11), rarely observed in acute lymphoblastic leukaemia (ALL), is here reported: a peculiarity of this case was that the "breakpoint cluster region" on chromosome 22 was not rearranged, as demonstrated by molecular analysis, and a new c-abl protein (p190) was found, instead of the usual p210 protein usually associated with the Ph chromosome; moreover a rearrangement of c-abl oncogene was found. The clinical course of this patient was, as expected, unfavorable: a few normal metaphases were observed during a short partial remission.

IL2 activated killer cells may contribute to cytomegalovirus induced marrow hypoplasia after bone marrow transplantation.

Cytomegalovirus (CMV) infection remains the commonest cause of infective death following allogeneic bone marrow transplantation (BMT). CMV disease post-BMT occurs in the context of compromised cellular defence mechanisms and is associated with marrow hypoplasia and pneumonitis. However, CMV infection induces release of interleukin 2 (IL2) which in turn generates MHC unrestricted lymphokine activated killer (LAK) cells. We have investigated whether recruitment of IL2 activated MHC unrestricted defence mechanisms post-transplant can be implicated in the marrow hypoplasia that frequently accompanies CMV infection. The results show that IL2 activated peripheral blood mononuclear cells (PBMC) have substantial cytotoxicity against MHC matched and MHC mismatched marrow fibroblasts but that this activity is not specific for CMV infected fibroblasts; uninfected target cells are also equally killed. Furthermore, post-BMT PBMC show greater responsiveness to IL2 than normal PBMC in killing of marrow fibroblasts. We provide a hypothesis from these observations which may explain some of the consequences of CMV infection post-BMT. Local production of IL2 activated cytotoxic cells which would be generated during CMV infection would damage uninfected as well as infected marrow fibroblasts and thereby could compromise haemopoietic growth factor production by marrow fibroblasts. Similarly generated cytotoxicity in the lung may accompany CMV pneumonitis. Our results suggest that administration of anti-IL2 receptor antibody may have a therapeutic role in CMV disease post-BMT as has recently been shown in graft-versus-host disease.

Human recombinant GM-CSF in allogeneic bone marrow transplantation for leukaemia: double-blind placebo controlled trial.

A double-blind randomised trial compared 20 patients with leukaemia receiving human recombinant granulocyte macrophage colony stimulating factor (GM CSF), with 20 patients receiving placebo for 14 days after allogeneic matched sibling bone marrow transplantation. The median neutrophil count at 14 days was significantly higher in the GM CSF group (1.90 vs. 0.46 x 10(9)/l). The duration of hospital stay, the number of antibiotic days, and the number of fever days was the same for both patient groups. The lymphocyte count was significantly higher in the GM-CSF group than in the placebo group between days 10 and 15 after transplantation. The GM-CSF group had lower haemoglobin concentrations and platelets counts, and higher plasma urea creatinine and bilirubin, than the placebo group. There was no evidence that GM CSF was associated with a greater incidence of leukaemic relapse.

Fatal disseminated fusarium infection in acute lymphoblastic leukaemia in complete remission.

Fusarium species are increasingly recognised as serious pathogens in the immunocompromised. The outcome in the context of persistent severe neutropenia has been almost universally fatal. However, there have been several case reports of successful treatment if neutrophil recovery can be achieved. This report presents the case of a fatality that occurred despite neutrophil recovery. A 67 year old man developed disseminated fusariosis during the neutropenic phase of induction chemotherapy for acute lymphoblastic leukaemia. Fusarium dimerum was isolated from blood cultures. This species is highly unusual and very few case reports exist in the literature. An initial response to amphotericin treatment coincided with neutrophil recovery but a subsequent relapse occurred, despite adequate neutrophil counts, which proved fatal. It is postulated that reseeding of the blood from an occult site, namely the right vitreum in this case, led to this secondary relapse despite achieving complete leukaemic remission.

The number of prognostically detrimental mutations and prognosis in primary myelofibrosis: an international study of 797 patients.

We recently defined a high-molecular risk category (HMR) in primary myelofibrosis (PMF), based on the presence of at least one of the five 'prognostically detrimental' mutated genes (ASXL1, EZH2, SRSF2 and IDH1/2). Herein, we evaluate the additional prognostic value of the 'number' of mutated genes. A total of 797 patients were recruited from Europe (n=537) and the Mayo Clinic (n=260). In the European cohort, 167 (31%) patients were HMR: 127 (23.6%) had one and 40 (7.4%) had two or more mutated genes. The presence of two or more mutations predicted the worst survival: median 2.6 years (hazard ratio (HR) 3.8, 95% confidence interval (CI) 2.6-5.7) vs. 7.0 years (HR 1.9, 95% CI 1.4-2.6) for one mutation vs 12.3 years for no mutations. The results were validated in the Mayo cohort and prognostic significance in both cohorts was independent of International Prognostic Scoring System (IPSS; HR 2.4, 95% CI 1.6-3.6) and dynamic IPSS (DIPSS)-plus (HR 1.9, 95% CI 1.2-3.1), respectively. Two or more mutations were also associated with shortened leukemia-free survival (HR 6.2, 95% CI 3.5-10.7), also Mayo validated. Calreticulin mutations favorably affected survival, independently of both number of mutations and IPSS/DIPSS-plus. We conclude that the 'number' of prognostically detrimental mutations provides added value in the combined molecular and clinical prognostication of PMF.

[Severe pseudouveitis associated with moxifloxacin therapy]. / Pseudo-uvéite sévère associée à l'utilisation de moxifloxacine.

INTRODUCTION: Moxifloxacin is an antibiotic of the fluoroquinolone class, marketed in France since 2002. It is used primarily in the treatment of bacterial sinusitis and acute exacerbations of chronic bronchitis. The purpose of this study is to report a possible severe ocular side effect following the systemic use of moxifloxacin. PATIENT AND METHODS: Case report of a patient who presented with the appearance of a severe acute uveitis after being treated with systemic moxifloxacin. Eleven days after initiation of moxifloxacin treatment, the patient developed simultaneous bilateral eye pain, pigment dispersion and diffuse iris transillumination. This case was further complicated by ocular hypertension. Etiologic investigations for other causes of the uveitis were negative. In particular, an anterior chamber tap was performed and PCR for herpes viruses (HSV, VZV, EBV, CMV) was negative. DISCUSSION: Drug-induced uveitis is relatively rare. The relationship between systemic fluoroquinolone treatment and the occurrence of uveitis has been considered "possible", according to World Health Organization criteria, in a recent retrospective analysis of 40 case reports. Moxifloxacin was suspected in 25 of these cases. The presence of both iris transillumination and pigment dispersion appears specific to the uveitis in question. CONCLUSION: It appears that practitioners prescribing moxifloxacin and ophthalmologists should be informed of this possible adverse effect, so that it may be quickly recognized, managed and reported.

Mutations and prognosis in primary myelofibrosis.

Patient outcome in primary myelofibrosis (PMF) is significantly influenced by karyotype. We studied 879 PMF patients to determine the individual and combinatorial prognostic relevance of somatic mutations. Analysis was performed in 483 European patients and the seminal observations were validated in 396 Mayo Clinic patients. Samples from the European cohort, collected at time of diagnosis, were analyzed for mutations in ASXL1, SRSF2, EZH2, TET2, DNMT3A, CBL, IDH1, IDH2, MPL and JAK2. Of these, ASXL1, SRSF2 and EZH2 mutations inter-independently predicted shortened survival. However, only ASXL1 mutations (HR: 2.02; P<0.001) remained significant in the context of the International Prognostic Scoring System (IPSS). These observations were validated in the Mayo Clinic cohort where mutation and survival analyses were performed from time of referral. ASXL1, SRSF2 and EZH2 mutations were independently associated with poor survival, but only ASXL1 mutations held their prognostic relevance (HR: 1.4; P=0.04) independent of the Dynamic IPSS (DIPSS)-plus model, which incorporates cytogenetic risk. In the European cohort, leukemia-free survival was negatively affected by IDH1/2, SRSF2 and ASXL1 mutations and in the Mayo cohort by IDH1 and SRSF2 mutations. Mutational profiling for ASXL1, EZH2, SRSF2 and IDH identifies PMF patients who are at risk for premature death or leukemic transformation.

[Role of intravitreal bevacizumab for resistant macular edema due to central retinal vein occlusion after failure of intravitreal triamcinolone acetonide]. / Intérêt du bevacizumab dans le traitement des occlusions de la veine centrale de la rétine après échec de la triamcinolone.

PURPOSE: To evaluate the efficacy of bevacizumab injection used secondarily in patients with macular edema due to central retinal vein occlusion after failure of intravitreal triamcinolone acetonide injection. PATIENTS AND METHODS: The present study represents a retrospective review of eight patients presenting with central retinal vein occlusion complicated by macular edema with central foveolar thickness greater than 350 µm by Cirrus-OCT, Zeiss. Between 4 and 6 months after the central vein occlusion, all patients initially underwent intravitreal triamcinolone acetonide injection (4 mg/0.1 ml). In the case of functional or anatomic failure, three monthly bevacizumab injections (1.25mg/0.05 ml) were administered. Prior to each injection, an ophthalmic examination was performed, documenting visual acuity (ETDRS), biomicroscopy, IOP and central foveolar thickness (OCT 3). RESULTS: After three intravitreal bevacizumab injections, we found no improvement in visual acuity (M0 = 45.56 ± 13 letters; M3 = 44.2 ± 8.6 letters), and no decrease in macular thickness (M0 = 559 µm ± 193; M3 = 543 µm ± 263). No intraocular pressure spikes or endophthalmitis were observed. DISCUSSION: The lack of anatomic and functional efficacy observed in our study does not appear to be related to the method, dosage or timing of injection, nor to the presence of subretinal macroaneurysms. It may be due to a cross-resistance to these two drugs. In any event, recent approval of ranibizumab and intraocular dexamethasone implants will likely change our therapeutic approach. CONCLUSION: In case of recalcitrant macular edema secondary to central vein occlusion after failed intravitreal triamcinolone acetonide injection, secondary intravitreal bevacizumab does not appear beneficial.

British Society of Haematology, Slide Session presented at the Annual Scientific Meeting, Brighton 2009.

Seven cases were discussed by an expert panel at the 2009 Annual Scientific Meeting of the British Society of Haematology. These cases are presented in a similar format to that adopted for the meeting. There was an initial discussion of the presenting morphology, generation of differential diagnoses and then, following display of further presenting and diagnostic information, each case was concluded with provision of a final diagnosis.