Phase I study of the aurora A kinase inhibitor alisertib with induction chemotherapy in patients with acute myeloid leukemia

Aberrant expression of aurora kinase A is implicated in the genesis of various neoplasms, including acute myeloid leukemia. Alisertib, an aurora A kinase inhibitor, has demonstrated efficacy as monotherapy in trials of myeloid malignancy, and this efficacy appears enhanced in combination with conventional chemotherapies. In this phase I, dose-escalation study, newly diagnosed patients received conventional induction with cytarabine and idarubicin, after which alisertib was administered for 7 days. Dose escalation occurred via cohorts. Patients could then receive up to four cycles of consolidation, incorporating alisertib, and thereafter alisertib maintenance for up to 12 months. Twenty-two patients were enrolled. One dose limiting toxicity occurred at dose level 2 (prolonged thrombocytopenia), and the recommended phase 2 dose was established at 30mg twice daily. Common therapy-related toxicities included cytopenias and mucositis. Only three (14%) patients had persistent disease at mid-cycle, requiring “5+2” reinduction. The composite remission rate (complete remission and complete remission with incomplete neutrophil recovery) was 86% (nineteen of twenty-two patients; 90% CI 68–96%). Among those over age 65 and those with high-risk disease (secondary acute leukemia or cytogenetically high-risk disease), the composite remission rate was 88% and 100%, respectively. The median follow up was 13.5 months. Of those treated at the recommended phase 2 dose, the 12-month overall survival and progression-free survival were 62% (90% CI 33–81%) and 42% (90% CI 17–65%), respectively. Alisertib is well tolerated when combined with induction chemotherapy in acute myeloid leukemia, with a promising suggestion of efficacy. (clinicaltrials.gov Identifier:01779843)

An unusual orbital tumor in an adult: Granuloma annulare

Purpose: Granuloma annulare (GA) is a rare clinical entity that does not classically arise from the peri-orbital area in adults. The purpose of this case report is to present a 69-year-old female with GA of the orbit. As well, the pathological and immunohistochemical features of these tumors will be discussed. Observations: One case of GA of the orbit was identified from a tertiary ophthalmology referral centre. Clinical and histopathological features of the case were reviewed. Other cases of GA were also retrieved from the literature and addressed in this report. Conclusion and importance: Granuloma annulare is a rare orbital lesion in adults. It is known to typically arise on the hands and feet of children. This lesion must be distinguished from necrobiotic xanthogranuloma (NXG), which is a progressive peri-orbital dermatosis seen in middle age men and women. GA is thought to be a benign, often self-resolving condition, whereas NXG tends to be linked to other systemic conditions and may have a poorer prognosis.Differentiating this rare orbital tumor from necrobitotic xanthogranuloma (NXG) is essential, as both a systemic work-up and follow-up must be appropriately arranged. A comprehensive description of pathognomonic microscopic features of GA and NXG is reviewed to achieve the correct diagnosis. Keywords: Granuloma annulare, Necrobiotic xanthogranuloma, Orbi

Fusion Winter 2012

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Structure of the magnetosome-associated actin-like MamK filament at subnanometer resolution

Magnetotactic bacteria possess cellular compartments called magnetosomes that sense magnetic fields. Alignment of magnetosomes in the bacterial cell is necessary for their function, and this is achieved through anchoring of magnetosomes to filaments composed of the protein MamK. MamK is an actin homolog that polymerizes upon ATP binding. Here, we report the structure of the MamK filament at ∼6.5 Å, obtained by cryo‐Electron Microscopy. This structure confirms our previously reported double‐stranded, nonstaggered architecture, and reveals the molecular basis for filament formation. While MamK is closest in sequence to the bacterial actin MreB, the longitudinal contacts along each MamK strand most closely resemble those of eukaryotic actin. In contrast, the cross‐strand interface, with a surprisingly limited set of contacts, is novel among actin homologs and gives rise to the nonstaggered architecture

A nonrandomized phase I and biomarker trial of regorafenib in advanced myeloid malignancies

Abstract We conducted a single‐center, open‐label, dose escalation, and expansion phase I trial of the antiangiogenic multikinase inhibitor regorafenib in patients with advanced myeloid neoplasms. We enrolled 16 patients with relapsed/refractory acute myeloid leukemia (AML), myeloproliferative neoplasms (MPN), chronic myelomonocytic leukemia (CMML), or myelodysplastic syndrome (MDS). A 3 + 3 dose escalation design was used with two planned dose levels (120 or 160 mg daily) and one de‐escalation level (80 mg daily). An additional 10 patients were treated on an expansion cohort. The recommended phase two dose of regorafenib was 160 mg daily, with no dose‐limiting toxicities. The best overall disease response by International Working Group criteria included one partial and stable disease in 11 patients. Tissue studies indicated no change in Ras/mitogen‐activated protein kinase (MAPK) pathway activation in responders. Pharmacodynamic changes in plasma VEGF, PlGF, and sVEGFR2 were detected during treatment. Baseline proinflammatory and angiogenic cytokine levels were not associated with clinical response. Single‐agent regorafenib demonstrated an acceptable safety profile in relapsed/refractory myeloid malignancy patients. Most patients achieved stable disease, with modest improvements in cell counts in some MDS patients. Biomarker studies were consistent with on‐target effects of regorafenib on angiogenesis. Future studies should investigate the role of regorafenib in combination therapy approaches