Metastatic intradural primary spinal osteosarcoma: illustrative case.

BACKGROUND: Osteosarcomas are a common primary bone neoplasm among adolescents but represent 0.2% of all malignancies with an incidence of two to four cases per million persons annually worldwide. Although known to have significant metastatic potential, its rare incidence, treatment resistance, and poor prognosis have rendered it a poorly understood and infrequently documented pathology. OBSERVATIONS: Herein the authors present the first documented case of lumbosacral intradural metastasis of a primary osteosarcoma in a young patient, possibly via intradural dissemination following pinhole durotomy in a prior thoracic surgery. LESSONS: Osteosarcomas remain a difficult pathology to treat, particularly upon metastatic dissemination. The utility of adjuvant radiotherapy after resection of an osteosarcoma is increasingly evident in the reduction of local recurrence. In the context of intraoperative pinhole durotomies in resections of high-grade lesions, due consideration should be given to whole-spine radiation, although this remains an evidence-free zone.

Intensive monitoring for post-transplant diabetes mellitus and treatment with dipeptidyl peptidase-4 inhibitor therapy.

AIM: Current monitoring practices fail to diagnose patients with post-transplant hyperglycaemia and tend to delay initiation of treatment, which potentially results in adverse graft and morbidity outcomes. This real-world study set out to assess the impact on insulin resistance indices of a new clinical pathway for diagnosis and treatment of hyperglycaemia following renal transplantation. METHODS: A hundred and forty-seven adult renal transplant recipients, without pre-existing diabetes, from a single centre were included. Patients transplanted between January 2008 to September 2015 formed the historical cohort. Patients transplanted between October 2015 and February 2018 were subject to a new clinical pathway - if they had fasting blood sugar levels more than 7 mmol/L or random blood glucose levels more than 11.1 mmol/L, they had early introduction of oral therapy, using the DPP-4 inhibitor linagliptin. RESULTS: In the historical cohort, 19.8% were diagnosed with PTDM, compared to 46.3% in the protocol cohort. Amongst patients with PTDM, there was a significant difference in HOMA-IR (p = 0.02) between the historical cohort (median HOMA-IR 3.33) and the protocol cohort (median HOMA-IR 2.21). There was a significant difference at each time point (0,1,2-h measurements) of blood glucose levels form oral glucose tolerance testing between patients with and without PTDM in the historical cohort (p < 0.001), but no difference between patients in the protocol cohort. CONCLUSION: Detection of PTDM was higher with the new clinical pathway. Early treatment of hyperglycaemia resulted in better insulin resistance scores. Larger prospective controlled studies focussing on early detection and management of PTDM with linagliptin are warranted.

Waking up dormant tumor suppressor genes with zinc fingers, TALEs and the CRISPR/dCas9 system.

The aberrant epigenetic silencing of tumor suppressor genes (TSGs) plays a major role during carcinogenesis and regaining these dormant functions by engineering of sequence-specific epigenome editing tools offers a unique opportunity for targeted therapies. However, effectively normalizing the expression and regaining tumor suppressive functions of silenced TSGs by artificial transcription factors (ATFs) still remains a major challenge. Herein we describe novel combinatorial strategies for the potent reactivation of two class II TSGs, MASPIN and REPRIMO, in cell lines with varying epigenetic states, using the CRISPR/dCas9 associated system linked to a panel of effector domains (VP64, p300, VPR and SAM complex), as well as with protein-based ATFs, Zinc Fingers and TALEs. We found that co-delivery of multiple effector domains using a combination of CRISPR/dCas9 and TALEs or SAM complex maximized activation in highly methylated promoters. In particular, CRISPR/dCas9 VPR with SAM upregulated MASPIN mRNA (22,145-fold change) in H157 lung cancer cells, with accompanying re-expression of MASPIN protein, which led to a concomitant inhibition of cell proliferation and induction of apoptotic cell death. Consistently, CRISPR/dCas9 VP64 with SAM upregulated REPRIMO (680-fold change), which led to phenotypic reprogramming in AGS gastric cancer cells. Altogether, our results outlined novel sequence-specific, combinatorial epigenome editing approaches to reactivate highly methylated TSGs as a promising therapy for cancer and other diseases.