Inhibitor development after liver transplantation in congenital factor VII deficiency.

Congenital factor VII (FVII) deficiency is the commonest type of the rare bleeding disorders. Very few cases of congenital FVII deficiency developed inhibitor and liver transplant is considered as definitive treatment. In the literature, twelve patients with congenital FVII deficiency developed inhibitors. Two had spontaneous resolution of inhibitors and one did not respond to high dose recombinant factor VIIa (rFVIIa) and died. Regarding liver transplant in congenital FVII patients, seven patients underwent liver transplant with good prognosis. We report a 5-year-old girl with confirmed severe congenital FVII deficiency since neonatal period. She suffered from recurrent intracranial bleeding despite rFVIIa replacement. After auxiliary liver transplant at the age of 4, she continued to show persistent deranged clotting profile and was found to have inhibitor towards FVII. Interestingly, she was still responsive to rFVIIa replacement.

Remission With Donor Lymphocyte Infusion in a Child With Marrow Relapse After Haploidentical Stem Cell Transplantation for Relapsed Stage 4 Neuroblastoma.

A 7-year-old male with Stage 4 neuroblastoma was treated with chemotherapy and autologous hematopoietic stem cell transplantation (HSCT), resulting in partial response with residual bone and marrow disease. He proceeded to haploidentical-HSCT with his mother as donor and achieved remission. The patient developed marrow relapse 2 years after haploidentical-HSCT with cytopenia and dropping donor chimerism. Donor lymphocyte infusion (DLI) using mother's whole blood was given resulting in clearance of marrow disease, resolution of cytopenia, and full donor chimerism. This is the first report of successful treatment for neuroblastoma relapse after haploidentical-HSCT using DLI alone, supporting the role of adoptive cell therapy post-HSCT in neuroblastoma.

Defective phenotype of mesenchymal stem cells in patients with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) has been considered as stem cell disorder. The objective of this study was to examine the phenotype, growth and immunomodulatory effect of mesenchymal stem cells (MSCs) from SLE patients compared with those from age- and sex-matched healthy donors. MSCs were expanded from bone marrow aspirate and were examined for morphological appearance, quantified in different passages to determine growth rate and evaluated for ability of adipogenesis and osteogenesis. Telomerase activity was measured by telomerase repeat amplification protocol. The immunomodulatory effect of MSCs was evaluated by mixed lymphocyte reaction. MSCs from SLE patients were found to be bigger and flattened in appearance after passage 3 and demonstrated slower growth rate compared with fibroblast-like MSCs from normal controls. These cells were not able to reach confluence after passage 4. Telomerase activity was upregulated in five SLE patients mostly with active disease compared with two with negative expression with lesser activity. MSCs from SLE patients were, otherwise, comparable to normal controls in terms of their surface marker (CD73, CD90 and CD105) expression and extent of suppression on proliferation of allogeneic T lymphocytes. In conclusion, MSCs from SLE demonstrated early signs of senescence which may be a corollary of active lupus or a contributory factor to disease pathogenesis.

Congenital Rosai-Dorfman disease presenting with anemia, thrombocytopenia, and hepatomegaly.

Rosai-Dorfman disease (RDD) is a rare entity of non-Langerhans cell histiocytoses (non-LCH) which usually presents with bilateral painless cervical lymphadenopathy. We describe a neonate with RDD who presented with anemia, thrombocytopenia and hepatomegaly. He recovered spontaneously with conservative management. This represents an atypical presentation of RDD. Conservative management with close monitoring can be adopted for some with systemic involvement.

Quality of life in patients with transfusion-dependent thalassemia after hematopoietic SCT.

In this cross-sectional study, we compared the quality of life (QOL) in transfusion-dependent thalassemic patients who survived matched sibling hematopoietic SCT (HSCT, n=24) with patients treated conventionally with transfusion and iron chelation (n=74). WHOQOL-BREF(HK) and PedsQL questionnaires were administered to patients aged >18 years and 5-12 years, respectively. Patients aged 12-18 years received both questionnaires. WHOQOL-BREF(HK) revealed post transplant patients rated overall health better than those treated conventionally (score 3.67 vs 3.06, P=0.01). They are less dependent on medical aids (3.87 vs 2.96, P=0.006), having higher activity level (4.00 vs 3.36, P=0.026) and better personal relationships (4.13 vs 3.69, P=0.014). Physical health domain score was better (75.20 vs 63.94, P=0.007). These differences remained significant after adjustment for comorbidities. PedsQL revealed post transplant patients rated better for running (3.53 vs 2.72, P=0.001) and sports (3.20 vs 2.64, P=0.038), even after adjustment for comorbidities, but were less satisfied for school absence to attend hospital (2.53 vs 3.29, P=0.03). Post transplant patients were significantly more likely to consider marriage (100 vs 75.7%, P=0.033), but not childbearing (66.7 vs 51.4%, P=0.28). In conclusion, transplanted thalassemic patients enjoy better QOL, mainly in physical health, compared with conventionally treated patients. This information is important to patients considering HSCT.

Self-assembled collagen-human mesenchymal stem cell microspheres for regenerative medicine.

Mesenchymal stem cells (MSCs)-based therapy is a promising approach in regenerative medicine and tissue engineering. However, the outcomes of existing treatments have not been satisfactory owing to suboptimal localization to implantation site, poor viability, low engraftment efficacy and lack of functional remodeling of the delivered cells. Therefore, adopting an effective cell delivery modality is among the biggest technological challenges for successful clinical applications of MSC-based therapy. We developed a novel microencapsulation technique producing self-assembled collagen-MSC microspheres and demonstrated that these microspheres could serve as excellent cell delivery devices as they were stable, injectable and able to provide a protective, growth- and migration-supporting matrix to MSCs. We also showed that MSCs could preserve their stem cell nature upon microencapsulation and easily be localized with retained viability upon in vivo implantation. These microspheres present novel cell delivery devices with optimal biological and functional profile that may facilitate clinical applications of MSC-based therapy.

Risk factors and mortality predictors of hepatic veno-occlusive disease after pediatric hematopoietic stem cell transplantation.

A cohort of 138 children with 144 hematopoietic stem cell transplantation (HSCT) performed in 1997-2006 were analyzed to evaluate risk factors and mortality predictors of hepatic veno-occlusive disease (VOD). Nineteen patients (13.2%) developed VOD (nine boys, median age 3.5 years) at 1-21 days after HSCT (median 13 days). Age < or =2 years at transplant (odds ratio (OR)=5.25, P=0.011), BU-CY conditioning (OR=5.16, P=0.001), thalassemia major (OR=3.97, P=0.015), platelet engraftment beyond day +21 (OR=8.67, P=0.025) were univariate risk factors for VOD. The first two remained significant in multivariate regression. Seven patients (36.8%) with VOD died, at a median of 44 days post transplant (range, 30-421 days). The 5-year survival was 62%. All surviving patients had normal liver function on follow-up at 0.5-9 years. Patients with VOD had higher 100-day mortality (16.3 vs 9.6%, P=0.024). Mortality predictors included donors other than autologous or matched sibling (hazard ratio (HR)=23.6, P=0.006), hepatic and cutaneous GVHD (HR=8.15, P=0.038), maximal weight gain >9% (HR=6.81, P=0.023), pleural effusion, intensive care unit admission, peak bilirubin >300 micromol l(-1) (HR=13.6, P=0.016), day +21 bilirubin >200 micromol l(-1) (HR=33.9, P=0.001), and rise of bilirubin >15 micromol l(-1) per day within the first week (HR=19.8, P=0.006). Mortality was substantially higher if >3 predictors were present (HR=33.9, P=0.001). Meticulous monitoring in high-risk patients and early treatment should be considered before VOD progresses beyond salvage.

Complete recovery from acute encephalopathy of late-onset ornithine transcarbamylase deficiency in a 3-year-old boy.

Ornithine transcarbamylase deficiency is the commonest urea cycle disorder which is transmitted in X-linked inheritance. It is mainly characterized in males by acute encephalopathy and hyperammonaemia with fatal outcomes in both classical neonatal and late-onset types. We report a 3-year-old healthy Hong Kong Chinese boy who presented with acute encephalopathy and coma after three days of gastroenteritis. He had no focal neurological deficit and brain CT imaging was normal. His plasma ammonia (54 micromol/L) and glutamine (747 micromol/L) concentrations were normal. The only biochemical abnormalities detected were marked orotic aciduria (700 micromol/mmol creatinine) and elevated urinary uracil. He regained consciousness spontaneously after three days under intensive care with parenteral fluid therapy. He recovered completely without any neurological deficits. Five months after discharge, urinary uracil concentration remained elevated despite normalized orotic acid concentration. Finally, ornithine transcarbamylase deficiency was diagnosed by DNA analysis. A missense mutation of arginine-to-glutamine substitution on amino acid 277 (p.R277Q) was revealed to be a late-onset mutant. Our case strengthens the argument that in any child with coma or acute encephalopathy of undetermined cause, genetic analysis of the OTC gene and the measurement of urinary uracil concentration remain the most reliable indicators of late-onset OTCD during acute and even quiescent phases. Existing neonatal screening programmes for inheritable metabolic disorders fail to detect late-onset variants. Therefore, a high clinical suspicion is a key to correct and timely diagnosis, especially in those patients with atypical presentations.

Improved outcome of acute lymphoblastic leukaemia treated by delayed intensification in Hong Kong children: HKALL97 study.

OBJECTIVE: To study the outcome of children with acute lymphoblastic leukaemia who were treated using a protocol including one or two delayed intensifications. DESIGN: Prospective single-arm multicentre study. SETTING: Five designated children cancer units of the Hospital Authority of Hong Kong. PATIENTS: Children aged between 1 and 17.9 years with newly diagnosed acute lymphoblastic leukaemia seen from November 1997 to December 2002. INTERVENTION: Chemotherapy was modified from a German Berlin-Frankfurt-Muenster 95 (BFM95) protocol that included a delayed intensification similar to the induction phase repeated 5 months after diagnosis. High-risk patients were given double delayed intensification. MAIN OUTCOME MEASURES: Overall survival and event-free survival of the whole group and the three risk groups (standard-, intermediate-, and high-risk groups), and comparison with historical controls. RESULTS: A total of 171 patients were recruited with a median age at diagnosis of 5.57 years (range, 1.15-17.85 years). The induction remission rate was 95.3% and non-leukaemia mortality during remission was 2.3%. At 4 years, the relapse rate of this (HKALL97) study was significantly lower than that of the HKALL93 study (15.7 vs 37.3%; P<0.001). The 4-year overall survival of HKALL97 and HKALL93 studies were 86.5% and 81.8%, respectively (P=0.51). The 4-year event-free survival for HKALL97 and HKALL93 studies were 79% and 65%, respectively (P=0.007). Nonetheless the difference of event-free survival was most remarkable in the intermediate-risk group: 75.6% and 53.1% for HKALL97 and HKALL93 studies, respectively (P=0.06). CONCLUSION: A more intensive delayed consolidation phase improved the outcome for children with acute lymphoblastic leukaemia by reducing relapses at 4 years. The early treatment complications were manageable and non-leukaemia mortality during remission remained low.

Prokineticin signaling is required for the maintenance of a de novo population of c-KIT⁺ cells to sustain neuroblastoma progression.

High cellular heterogeneity within neuroblastomas (NBs) may account for the non-uniform response to treatment. c-KIT(+) cells are frequently detected in NB, but how they influence NB behavior still remains elusive. Here, we used NB tumor-initiating cells to reconstitute NB development and demonstrated that c-KIT(+) cells are de novo generated and dynamically maintained within the tumors to sustain tumor progression. c-KIT(+) NB cells express higher levels of neural crest and stem cell markers (SLUG, SOX2 and NANOG) and are endowed with high clonogenic capacity, differentiation plasticity and are refractory to drugs. With serial transplantation assays, we found that c-KIT expression is not required for tumor formation, but c-KIT(+) cells are more aggressive and can induce tumors ninefold more efficiently than c-KIT(-/low) cells. Intriguingly, c-KIT(+) cells exhibited a long-term in vivo self-renewal capacity to sustain the formation of secondary and tertiary tumors in mice. In addition, we showed that Prokineticin signaling and mitogen-activated protein kinase pathways are crucial for the maintenance of c-KIT(+) cells in tumor to promote NB progression. Our results highlight the importance of this de novo population of NB cells in sustainable growth of NB and reveal specific signaling pathways that may provide targets leading to more effective NB therapies.