Control over progenitor proliferation and neurogenesis remains a key challenge for stem cell neurobiology and a prerequisite for successful stem cell replacement therapies for neurodegenerative diseases like Parkinson's disease (PD). Here, we examined the function of two nuclear receptors, liver X receptors (Lxralpha and beta) and their ligands, oxysterols, as regulators of cell division, ventral midbrain (VM) neurogenesis, and dopaminergic (DA) neuron development. Deletion of Lxrs reduced cell cycle progression and VM neurogenesis, resulting in decreased DA neurons at birth. Activation of Lxrs with oxysterol ligands increased the number of DA neurons in mouse embryonic stem cells (ESCs) and in wild-type but not Lxralphabeta(-/-) VM progenitor cultures. Likewise, oxysterol treatment of human ESCs (hESCs) during DA differentiation increased neurogenesis and the number of mature DA neurons, while reducing proliferating progenitors. Thus, Lxr ligands may improve current hESC replacement strategies for PD by selectively augmenting the generation of DA neurons.

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While allogeneic hematopoietic stem cell transplantation (alloHSCT) has extensively been studied in patients with AML <60 years of age, AML predominantly affects older individuals (median age at diagnosis of 71 years). The majority of older patients receiving intensive induction treatment may obtain a first complete remission (CR1), but the probability of relapse is very high necessitating effective post-remission treatment (PRT). AlloHSCT is the most effective PRT to prevent relapse, although non-relapse mortality (NRM) may compromise that beneficial effect, especially in the elderly. The development of reduced intensity conditioning (RIC) regimens, however, has enabled the application of alloHSCT in older patients with acceptable NRM. In the present study, we set out to compare alloHSCT following RIC with other PRTs including no further chemotherapy by time-dependent analysis in patients with AML aged 60 years and older. A total number of 640 patients with newly diagnosed AML were included, with a median age of 66 years, who participated in consecutive, prospective HOVON-SAKK phase II/III trials (AML42/42A, AML43, AML81, and AML92) between May 2001 and February 2010 and who obtained CR1 after induction chemotherapy. PRT consisted of RIC alloHSCT (n=97), gemtuzumab ozogamicin (n=110), chemotherapy (n=38), autologous HSCT (autoHSCT) (n=23), or no further treatment (n=372). RIC regimens contained either busulfan and fludarabine, or 2.0 Gy total body irradiation preceded by fludarabine. Endpoints of this study were 5 year overall survival (OS), relapse-free survival (RFS), relapse and non-relapse mortality (NRM) measured from start of consolidation. Patients were classified by leukemia risk, based on the latest European Leukemia NET (ELN) risk classification. To perform a time-dependent statistical analysis of alloHSCT versus non-alloHSCT, a multivariable cox regression model with time-dependent covariates autoHSCT and alloHSCT was applied with adjustment for the different types of non-alloHSCT treatment, leukemia risk, white blood cell count at diagnosis, late CR, age, sex, and year of consolidation. Recipients of alloHSCT were significantly younger as compared to patients who were not consolidated with alloHSCT (64 (range: 60-74) versus 67 (range: 60-82) years, respectively, p<0.001). Leukemia risk, white blood cell count at diagnosis, karyotyping, and CR reached after first or second cycle of chemotherapy, was not significantly different between the two groups. A trend towards improved OS was found for RIC alloHSCT recipients as compared to patients receiving no alloHSCT (35±5% versus 23±2% at 5 years, respectively, p=0.09), while OS was significantly improved in patients with adverse risk AML receiving an alloHSCT (34±10% versus 8±3% at 5 years, p=0.002). Recipients of RIC alloHSCT showed improved relapse-free survival (RFS), as compared to non-transplant approaches (32±5% versus 17±2% at 5 years, p=0.02), which effect was similarly exerted among intermediate and adverse risk AMLs. Following multivariable analysis with adjustment for covariates, RIC AlloHSCT was associated with better OS (HR 0.68, p=0.006), better RFS (HR 0.59, p<0.001), and less relapse (HR 0.44, p<0.001) as compared to non-transplant approaches (Figure 1). The cumulative incidence of NRM was 18±4% in the present study, demonstrating the feasibility of RIC alloHSCT in elderly patients. In the non-transplanted patients the estimated cumulative incidence of NRM was 10±1%. Collectively, these results indicate that RIC alloHSCT significantly improves survival in elderly patients with AML in CR1 who are eligible for PRT upon achieving remission following induction chemotherapy. Subgroup analysis showed that, similar to results in younger patients, alloHSCT was not associated with better outcome in favorable risk patients, but both OS and RFS appeared improved in intermediate and poor risk patients. Our findings suggest that RIC alloHSCT is a feasible and effective PRT in elderly patients. Future studies including comorbidities and geriatric assessment may more reliably give insight into eligibility criteria other than age for alloHSCT in elderly patients. Our results underscore the importance of a prospective randomized study such as currently is being performed in Europe (http://clinicaltrials.gov/show/NCT00766779). Figure 1A Figure 1A. Figure 1B Figure 1B. Disclosures No relevant conflicts of interest to declare.

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A previously healthy 20-year-old woman was diagnosed with chronic myeloid leukaemia (CML) in chronic phase in November 2010. She participated in a multi-centre, singlearm study of nilotinib 300 mg twice daily as frontline treatment of patients with Philadelphia-positive CML in chronic phase.Within 1 week of initiation of nilotinib she reported episodes of cold, white hands and blue discoloration of the nails. The image shows the hands of our patient (on the right) and her mother (on the left) during these episodes, which occurred several times per week and were characterized by a sudden onset and recovery within 5-10 min. There was no obvious provocation, especially no association with changes in temperature, position of the arm, physical activity or time after intake of nilotinib. The symptoms were completely reversible. There were no signs of arterial insufficiency of the upper extremities and sensation was found to be intact. No antinuclear antibody or cryoglobulin was present.After consultation with the principal investigator, nilotinib was stopped and imatinib 400 mg once daily was started. Within 2 weeks of initiation of imatinib she reported a diminishing frequency of occurrence of these episodes. However, imatinib resulted in side effects, especially disabling (grade 3) bone pain, arthralgia and nausea. Nilotinib was restarted and continued in an adjusted dose of 150 mg twice daily. The episodes of cold, white fingers and blue nails reappeared in a non-disabling and low frequency. She achieved a major molecular response within 3 months of re-starting nilotinib.The second patient, a 40-year-old female with CML who participated in the same trial, reported, immediately after starting nilotinib 300 mg twice daily, the sudden onset of cold fingers in association with sharply demarcated color changes of skin pallor or sometimes cyanotic skin discoloration. With rewarming, the ischaemic phase usually lasted for about 15 min. The attacks were exaggerated by cold but also occurred spontaneously and no other manifestations of vascular insufficiency were detected, either clinically or serologically. She decided not to stop her medication and these Raynaud-like complaints are occurring much less frequently after 18 months of treatment. She has achieved a major molecular response.Nilotinib is an oral ATP-competitive inhibitor of protein kinase activity of BCR-ABL1. Nilotinib also inhibits FIP1L1-PDGFRA tyrosine kinase and the stem cell factor receptor, KIT-kinase. Side effects resembling peripheral arterial insufficiency as described in these two patients have not previously been reported with nilotinib, although similar features occur with imatinib.The exact pathogenesis of the cold, white hands and blue discoloration of the nails in these patients is not clear. In the second patient the findings resembled Raynaud's phenomenon at first sight, while in the first patient they lacked the typical triphasic course of Raynaud's syndrome. The clinical presentation does seem to suggest an arterial cause, possibly transient ...

Background Chronic Graft-versus-Host Disease (cGVHD) can impact quality of life, especially in patients with oral involvement. Half of the patients with cGVHD do not respond to first-line therapy with corticosteroids and calcineurin inhibitors. Ruxolitinib is effective in steroid-refractory (SR)-cGVHD cases, but the long-term effects of ruxolitinib on the oral mucosa are unknown. Objective(s) This study aims to assess the effect of ruxolitinib on the oral mucosa of SR-cGVHD patients with oral involvement. Materials and methods An observational longitudinal patient study was conducted in 53 patients with SR-cGVHD and oral involvement who were treated with ruxolitinib. The baseline condition of the oral mucosa was compared to its condition at 4 and 12 weeks after starting ruxolitinib. Results The overall response was 81% (43/53), with a complete response in 53% (28/53) and partial response in 28% (15/53) after 12 weeks (p < 0.001). Men and patients concurrently using immunosuppressive therapy responded better than women (p = 0.005) and patients with ruxolitinib monotherapy (p = 0.02), respectively. At a longer follow-up (median 20 months), oral symptoms were comparable to the 12-week symptoms (p = 0.78), regardless of ruxolitinib use (p = 0.83). Conclusion Ruxolitinib treatment of SR-cGVHD patients with oral involvement was associated with a significant response of the oral manifestations at 12 weeks. Clinical relevance The oral mucosa of SR-cGVHD patients is likely to improve after 4 and 12 weeks of ruxolitinib treatment. Symptom severity at baseline does not affect the response of the oral mucosa.