Congenital X-linked neutropenia with myelodysplasia and somatic tetraploidy due to a germline mutation in SEPT6.

Septins play key roles in mammalian cell division and cytokinesis but have not previously been implicated in a germline human disorder. A male infant with severe neutropenia and progressive dysmyelopoiesis with tetraploid myeloid precursors was identified. No known genetic etiologies for neutropenia or bone marrow failure were found. However, next-generation sequencing of germline samples from the patient revealed a novel, de novo germline stop-loss mutation in the X-linked gene SEPT6 that resulted in reduced SEPT6 staining in bone marrow granulocyte precursors and megakaryocytes. Patient skin fibroblast-derived induced pluripotent stem cells (iPSCs) produced reduced myeloid colonies, particularly of the granulocyte lineage. CRISPR/Cas9 knock-in of the patient's mutation or complete knock-out of SEPT6 was not tolerated in non-patient-derived iPSCs or human myeloid cell lines, but SEPT6 knock-out was successful in an erythroid cell line and resulting clones revealed a propensity to multinucleation. In silico analysis predicts that the mutated protein hinders the dimerization of SEPT6 coiled-coils in both parallel and antiparallel arrangements, which could in turn impair filament formation. These data demonstrate a critical role for SEPT6 in chromosomal segregation in myeloid progenitors that can account for the unusual predisposition to aneuploidy and dysmyelopoiesis.

Potential Impact of the Interval Between Imaging and Whole-brain Radiotherapy in Patients With Relatively Favorable Survival Prognoses.

BACKGROUND/AIM: The interval between diagnostic imaging and whole-brain radiotherapy (WBRT) had no significant impact on survival in our previous study of WBRT for brain metastases. Since median survival time was only 2 months, a potentially negative impact by delaying treatment could have been missed. Therefore, we performed an additional analysis of patients surviving at least 4 months following irradiation. PATIENTS AND METHODS: The interval between diagnosis of brain metastases and WBRT and ten other factors were retrospectively analyzed for survival in 191 patients surviving 4 months or longer following WBRT. RESULTS: On univariate analyses, Eastern Cooperative Oncology Group (ECOG) performance score of 0-1, 1-3 brain metastases and absence of extra-cerebral metastases were significantly associated with longer survival, whereas the interval from diagnostic imaging to WBRT was not. On multivariate analysis, ECOG performance score remained significant, and extra-cerebral metastases showed a trend towards a longer survival. CONCLUSION: The interval between diagnostic imaging and WBRT didn't have a significant impact on patients surviving 4 months or longer. Depending on the need for symptom relief, WBRT may be postponed for very important reasons such as obtaining a multidisciplinary tumor board decision or definitive histology.

Whole-Brain Radiotherapy (WBRT) for Brain Metastases: Does the Interval Between Imaging and Treatment Matter?

BACKGROUND/AIM: Many patients with brain metastases receive whole-brain radiotherapy (WBRT). An important question is whether a delay between diagnosis of brain metastases and treatment impairs the patient's prognosis. PATIENTS AND METHODS: This retrospective study investigated the impact of the interval between diagnosis of brain metastases and WBRT plus ten additional factors on overall survival (OS) in 573 patients. Prospective trials cannot be performed due to ethical concerns. RESULTS: On univariate analyses, age (p<0.001), performance status (p<0.001), controlled primary tumor (p=0.047), metastases outside the brain (p<0.001) and completion of WBRT (p<0.001) were associated with OS. The interval between diagnosis and WBRT had no significant impact (p=0.84). On multivariate analysis, age (p=0.047), performance status (p<0.001), metastases outside the brain (p=0.029) and completion of WBRT (p<0.001) maintained significance. CONCLUSION: WBRT may be postponed for good reasons (multidisciplinary coordination of treatment, missing histology). OS was significantly associated with previously identified factors, which demonstrates consistency of the present data.