Long-Term Organ Function After HCT for SCD: A Report From the Sickle Cell Transplant Advocacy and Research Alliance.

Hematopoietic cell transplantation (HCT) is an established cure for sickle cell disease (SCD) supported by long-term survival, but long-term organ function data are lacking. We sought to describe organ function and assess predictors for dysfunction in a retrospective cohort (n = 247) through the Sickle cell Transplant Advocacy and Research alliance. Patients with <1-year follow-up or graft rejection/second HCT were excluded. Organ function data were collected from last follow-up. Primary measures were organ function, comparing pre- and post-HCT. Bivariable and multivariable analyses were performed for predictors of dysfunction. Median age at HCT was 9.4 years; the majority had HbSS (88.2%) and severe clinical phenotype (65.4%). Most received matched related (76.9%) bone marrow (83.3%) with myeloablative conditioning (MAC; 57.1%). Acute and chronic graft-versus-host disease (GVHD) developed in 24.0% and 24.8%. Thirteen patients (5.3%) died ≥1 year after HCT, primarily from GVHD or infection. More post-HCT patients had low ejection or shortening fractions than pre-HCT (0.6% â†’ 6.0%, P = .007 and 0% â†’ 4.6%, P = .003). The proportion with lung disease remained stable. Eight patients (3.2%) had overt stroke; most had normal (28.3%) or stable (50.3%) brain magnetic resonance imaging. On multivariable analysis, cardiac dysfunction was associated with MAC (odds ratio [OR] = 2.71; 95% confidence interval [CI], 1.09-6.77; P = .033) and severe acute GVHD (OR = 2.41; 95% CI, 1.04-5.62; P = .041). Neurologic events were associated with central nervous system indication (OR = 2.88; 95% CI, 2.00-4.12; P < .001). Overall organ dysfunction was associated with age ≥16 years (OR = 2.26; 95% CI, 1.35-3.78; P = .002) and clinically severe disease (OR = 1.64; 95% CI, 1.02-2.63; P = .043). In conclusion, our results support consideration of HCT at younger age and use of less intense conditioning.

Type 2 innate lymphoid cells from Id1 transgenic mice alleviate skin manifestations of graft-versus-host disease.

BACKGROUND: Acute graft-versus-host disease (aGVHD) is one of the most common causes of morbidity for patients undergoing allogeneic stem cell transplantation. There is preliminary evidence that activated Group 2 innate lymphoid cells (ILC2s) from wild type (WT) mice reduces the lethality of aGVHD and is effective in treating lower gastrointestinal (GI) tract manifestations of aGVHD. This raises the prospect that ILC2s may be used for cell-based therapy of aGVHD but vigorous investigation is necessary to assess their impacts on different aspects of aGVHD. Genetically engineered mice which either express Id1 protein (Id1tg/tg), an inhibitor of E protein transcription factors or have E protein genes knocked out (dKO) in the thymus produce massive numbers of ILC2s, thus allowing extensive evaluation of ILC2s. We investigated whether these ILC2s have protective effects in aGVHD as WT ILC2s do using an established mouse model of aGVHD. RESULTS: bone marrow transplant was performed by irradiating BALB/c strain of recipient mice and transplanting with bone marrow and T cells from the MHC-disparate C57BL/6 strain. We isolated ILC2s from Id1tg/tg and dKO mice and co-transplanted them to study their effects. Our results confirm that activated ILC2s have a protective role in aGVHD, but the effects varied depending on the origin of ILC2s. Co-transplantation of ILC2s from Id1tg/tg mice were beneficial in aGVHD and are especially helpful in ameliorating the skin manifestations of aGVHD. However, ILC2s from dKO mice were less effective at the protection and behaved differently depending on if the cells were isolated from dKO mice were pre-treated with IL-25 in vivo. CONCLUSION: These findings support the notion that thymus-derived ILC2s from Id1tg/tg mice are protective against aGVHD, with a significant improvement of skin lesions and they behave differently from dKO mice in the setting of aGVHD.

IDH1 mutated acute myeloid leukemia in a child with metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria.

D-2-hydroxyglutaric aciduria (D-2-HGA) is a rare metabolic disorder characterized by developmental delay, hypotonia, and bi-allelic mutations in D-2-hydroxyglutarate dehydrogenase (D2HGDH) or a single gain-of-function mutation in isocitrate dehydrogenase 2 (IDH2). Metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria (MC-HGA) is a type of D-2-HGA that has been previously reported in ten patients (OMIM 614875), three of whom had somatic mosaicism for R132 variants in isocitrate dehydrogenase 1 (IDH1). We describe a 3-year-old boy with MC-HGA who subsequently developed acute myeloid leukemia (AML) and was found to have an IDH1 R132C mutation in a leukemic bone marrow sample. Further testing revealed presence of somatic mosaicism for IDH1 R132C variant, suggesting an association of IDH1 in inducing myeloid leukemogenesis.

Simultaneous B and T cell acute lymphoblastic leukemias in zebrafish driven by transgenic MYC: implications for oncogenesis and lymphopoiesis.

Precursor-B cell acute lymphoblastic leukemia (pre-B ALL) is the most common pediatric cancer, but there are no useful zebrafish pre-B ALL models. We describe the first highly- penetrant zebrafish pre-B ALL, driven by human MYC. Leukemias express B lymphoblast-specific genes and are distinct from T cell ALL (T-ALL)-which these fish also develop. Zebrafish pre-B ALL shares in vivo features and expression profiles with human pre-B ALL, and these profiles differ from zebrafish T-ALL or normal B and T cells. These animals also exhibit aberrant lymphocyte development. As the only robust zebrafish pre-B ALL model and only example where T-ALL also develops, this model can reveal differences between MYC-driven pre-B vs. T-ALL and be exploited to discover novel pre-B ALL therapies.

Management of Candida glabrata infectious crystalline keratopathy with endophthalmitis following penetrating keratoplasty.

A 33-year-old male underwent an optical keratoplasty elsewhere in the right eye following which he developed endophthalmitis and subsequently underwent a pars plana vitrectomy and lensectomy. At presentation, he had a deep stromal crystalline infiltration along the graft-host junction. A large therapeutic keratoplasty was performed, and the excised corneal button was evaluated. Histopathology revealed gram-positive round-to-oval budding structures and microbiology identified the organism as Candida glabrata. He was treated with antifungals in the postoperative period. At 4 months after therapeutic keratoplasty, the patient developed recurrent endophthalmitis, following stoppage of antifungals. The treatment was reinstituted for another year, and the patient did well with a clear graft at 18-month-follow-up period after the recurrence episode. Management of infectious crystalline keratopathy with endophthalmitis is a challenging situation and requires long-term treatment.

Encephalocraniocutaneous Lipomatosis.

A 5-year-old boy presented with worsening headaches for 3 months. On examination, he was found to have a hairless fatty tissue nevus of the scalp (nevus psiloliparus), subcutaneous soft tissue masses on the right side of his face, neck, mandible and right buttock and epibulbar dermoid of the right eye (choristoma) (). Magnetic resonance imaging revealed a large suprasellar mass, which was debulked and found to be a pilocytic astrocytoma. Testing was not performed for the BRAF/KIAA1549 fusion or BRAFV600E mutation. Seven years later, he was started on adjuvant chemotherapy for gradual tumor progression. Over the ensuing 3 years, he had further disease progression despite treatment with 3 frontline chemotherapy regimens: vinblastine, carboplatin/vincristine, and irinotecan/bevacizumab. Targeted sequencing of tissue from the right gluteal mass, revealed a mosaic activating FGFR1 c.1966A>G (p.Lys656Glu) mutation, absent in normal left gluteal tissue, confirming the diagnosis of encephalocraniocutaneous lipomatosis (ECCL), belonging to the family of RASopathies (including neurofibromatosis type I, Noonan syndrome, Costello syndrome), with constitutive activation of the mitogen-activated protein kinase (MAPK) pathway, and an increased risk of developing neoplasms. He was started on trametinib, a MEK inhibitor, off-label, targeting the MAPK pathway downstream from FGFR1, with stable tumor size at last follow-up, after 6 months on therapy.

A novel homozygous VPS45 p.P468L mutation leading to severe congenital neutropenia with myelofibrosis.

VPS45-associated severe congenital neutropenia (SCN) is a rare disorder characterized by life-threating infections, neutropenia, neutrophil and platelet dysfunction, poor response to filgrastim, and myelofibrosis with extramedullary hematopoiesis. We present a patient with SCN due to a homozygous c.1403C>T (p.P468L) mutation in VPS45, critical regulator of SNARE-dependent membrane fusion. Structural modeling indicates that P468, like the T224 and E238 residues affected by previously reported mutations, cluster in a VPS45 "hinge" region, indicating its critical role in membrane fusion and VPS45-associated SCN. Bone marrow transplantation, complicated by early graft failure rescued with stem cell boost, led to resolution of the hematopoietic phenotype.

Molecular genetics of childhood, adolescent and young adult non-Hodgkin lymphoma.

Molecular genetic abnormalities are ubiquitous in non-Hodgkin lymphoma (NHL), but genetic changes are not yet used to define specific lymphoma subtypes. Certain recurrent molecular genetic abnormalities in NHL underlie molecular pathogenesis and/or are associated with prognosis or represent potential therapeutic targets. Most molecular genetic studies of B- and T-NHL have been performed on adult patient samples, and the relevance of many of these findings for childhood, adolescent and young adult NHL remains to be demonstrated. In this review, we focus on NHL subtypes that are most common in young patients and emphasize features actually studied in younger NHL patients. This approach highlights what is known about NHL genetics in young patients but also points to gaps that remain, which will require cooperative efforts to collect and share biological specimens for genomic and genetic analyses in order to help predict outcomes and guide therapy in the future.

N-acetylcysteine renoprotection in methotrexate induced nephrotoxicity and its effects on B-cell lymphoma.

BACKGROUND: Nephrotoxicity is one of the known side effects of methotrexate (MTX) therapy despite the use of conventional protective measures. Our objectives were to evaluate the effects of N-acetylcysteine (NAC) on MTX-induced toxicity in renal tubular cells and to evaluate whether adjunctive use of NAC interferes with MTX antitumor activity in the B-cell lymphoma. METHODS: Kidney Epithelial (Madin-Darby canine kidney [MDCK]) cells were exposed to MTX (10 µM or 100 µM) alone and with NAC (0.2 mM or 0.4 mM). Reactive oxygen species (ROS) generation at 1, 2, 4, and 24 h was measured by flow cytometer. Quantification of total glutathione (GSH) was performed by using GSH assay kit. To measure the impact of NAC on the antitumor activity of MTX, B lymphoma cells were exposed to MTX alone and with NAC. A percentage of apoptosis was measured using fluorescein isothiocyanate in both cell lines. Quantitative data was presented as a means ± standard deviation, and P values were analyzed using the Student's t-test. RESULTS: Apoptosis in MDCK cells were observed after 24 h of incubation with both 10 µM and 100 µM MTX. Maximum ROS generation was observed at 4 h and corresponded to GSH production. Treatment with 0.2 and 0.4 mM of NAC led to decrease percentages of apoptotic MDCK cells. NAC did not change either proliferation or apoptosis of B-cell lymphoma. CONCLUSION: Using NAC for kidney protection may not interfere with the antitumor activity of MTX. Further in vivo studies are warranted to confirm noninterference between MTX and NAC and assess synergistic antitumor effects.

Conjunctival keratoacanthoma.

An 83-year-old man presented with a 1-month history of a rapidly enlarging conjunctival mass. On examination, slit lamp biomicroscopy revealed a leukoplakic tumour at the temporal limbus. The lesion was excised with cryotherapy application to the limbus and conjunctival margins. Histopathology revealed a keratoacanthoma (KA). KA typically occurs on sun-exposed areas of the skin. Conjunctival KA is very rare, and differentiation between conventional squamous cell carcinoma (SCCA) and KA can be challenging. The present case highlights the indication for excisional surgery in patients with conjunctival KA using the no touch technique, cryotherapy, amniotic membrane and the histopathological differentiation between KA and SCCA.

N-acetylcysteine rescue protocol for nephrotoxicity in children caused by ifosfamide.

Nephrotoxicity is a serious side effect associated with ifosfamide use. It can affect up to 30% of children who are treated with this chemotherapeutic drug, and treatment may necessitate lifelong supplementations, renal dialysis, renal transplant, and in severe cases may result in death. The antioxidant n-acetylcysteine is a promising strategy for mitigating this renal toxicity. It is currently used in children for acetaminophen overdose in the 21-hour IV protocol, a dose which has also been suggested to provide renal protection against ifosfamide. Of significance, both in vitro and in vivo studies suggest n-acetylcysteine does not interfere with the antitumor actions of ifosfamide. Most importantly, n-acetylcysteine has successfully protected against ifosfamide-induced nephrotoxicity in both cell and rodent models, as well as in several paediatric cases, suggesting it should be evaluated as a treatment option for children on ifosfamide who present with renal dysfunction. The purpose of this paper is to outline strategies and recommendations for treating patients at risk or suffering from nephrotoxicity during ifosfamide therapy. These recommendations may be used when deciding who to treat, how and when to treat, as well as several considerations when exact recommendations cannot be met. They have been created to increase both the quality of care and quality of life of paediatric oncology patients.

Two patients with an anti-N-methyl-D-aspartate receptor antibody syndrome-like presentation and negative results of testing for autoantibodies.

We describe two boys whose distinct and remarkable clinical pictures suggested the possibility of anti-N-methyl-d-aspartate receptor antibody encephalitis. Both patients responded to immunotherapy, but neither manifested that antibody. Patient 1 exhibited florid encephalopathy with psychotic manifestations including inappropriate affect, intermittent delirium, visual hallucinations, severe anorexia, agitation, paranoid ideation, and abnormal electroencephalogram results. He responded to intravenous immunoglobulin, with steady improvement over 3 months to almost complete remission for 1 year, followed by a relapse that again responded, more quickly, to intravenous immunoglobulin. A second relapse occurred 1 month later, and again responded to intravenous immunoglobulin. Patient 2 exhibited progressive, severely debilitating limb dystonia that worsened over 1.5 years, with milder psychiatric symptoms including mood instability, aggressiveness, impulsivity, and depression. When he developed thymic hyperplasia 1.5 years into his illness, he underwent a thymectomy, and improved significantly on a regimen of plasmapheresis and intravenous immunoglobulin. Patients presenting with symptoms suggestive of autoimmune encephalitis, but without antibodies, may still respond to immunotherapy.

Ocular status and functional adaptation of visually challenged children of a special school in Oman.

INTRODUCTION: We assessed the ocular status and visual adaptation among children studying at a school for visually disabled children in Muscat, Oman. MATERIALS AND METHODS: This descriptive study was conducted in 2009-2010. We assessed the visual and ocular status of the participants. They were interviewed to elicit the past history of eye problems and management. They also expressed their visual adaptation in their 'day-to-day' life, and their ambitions. RESULT: We examined and interviewed 47 participants (29 male and 18 female). The mean age of the participants was 19.7 years (Standard deviation 5.9 years). Twenty-six of them were blind since birth. Phthisical eyes, disfigured eyes and anophthalmic sockets were noted in 19, 58, and six eyes of participants. Twenty-six (55.5%) participants had visual disabilities due to genetic causes, since birth. In 13 participants, further investigations were needed to confirm diagnosis and determine further management After low vision training, 13 participants with residual vision could be integrated in the school with normal children. One participant was recommended stem cell treatment for visual restoration. Five children were advised reconstructive orbital surgery. The participants were not keen to use a white cane for mobility. Some participants, 16 / 28 (57%), with absolute blindness, were not able to read the Braille language. Singing and playing music were not very well-accepted hobbies among the participants. Nineteen participants were keen to become teachers. CONCLUSIONS: Children with visual disabilities need to be periodically assessed. The underlying causes of visual disabilities should be further explored to facilitate prevention and genetic counseling. Participants had visual adaptation for daily living and had ambitions for the future.

Contact Lens Induced Corneal Ulcer Management in a Tertiary Eye Unit in Oman - A descriptive study.

OBJECTIVES: The corneal disease is a priority problem in Oman. We present patients with contact lens (CL) induced severe keratitis, admitted in the corneal unit of Al Nahdha Hospital in Oman. METHODS: The study was conducted in 2005-2006. Ophthalmologists examined the eyes using slit lamp bio-microscope. Visual acuity was noted using Snellen's distance vision chart. Specimens of corneal scraping and CLs were sent for culture and sensitivity tests. Patients with severe keratitis were admitted and treated with medicines. Corneal and visual statuses were noted at the time of discharge from hospital and after six weeks. Numbers, percentages and their 95% confidence intervals were calculated. Pre- and post-treatment vision were compared using a scattergram. RESULTS: The 52 eyes of 15 males and 37 female patients with corneal ulcers were examined. Thirty-two patients were between 20 to 30 years of age. Only 13 (25%) patients had visited an ophthalmologist within 24 hours of developing severe keratitis. Seventeen (33%) had central ulcers and six (11.5%) had ulcer ≥5 mm in size. Pseudomonas was found in 29 (55.8%) of CL and corneal material scraped from the eyes of 15 (28.8%) patients. Vision was <6/60 (legally blind) in 12 (23.1%) eyes before and in five (9.6%) eyes after treatment. Twenty-six (50%) patients were lost to follow up. CONCLUSION: CL related severe keratitis causes visual disabilities. Prevention and proper records are essential. Treatment improves vision and hence facilities for management should be strengthened.