Venetoclax and hypomethylating agents in FLT3-mutated acute myeloid leukemia

FMS-like tyrosine kinase 3 (FLT3) mutations are prevalent in acute myeloid leukemia (AML), and their presence confers adverse risk. FLT3-mutated (FLT3m) AML is a challenging leukemia to manage, particularly in older and unfit patients as well as patients with relapsed/refractory (r/r) disease. We retrospectively analyzed the outcomes of 50 FLT3m AML patients (17 treatment-naïve, 33 r/r) treated with venetoclax (VEN) and hypomethylating agents (HMA). The overall CR/CRi rate with VEN-HMA was 60% (94% in treatment-naïve AML and 42% in r/r AML). Early (60-days) treatment related mortality was 2%. The r/r AML setting was an independent predictor of lower complete response (OR: 0.08; 95%CI: 0.00-0.60, P = .03). Cytogenetics-molecular risk, concurrent mutations, the type of FLT3 mutation (ITD vs TKD), the ITD allelic ratio, the type of HMA, age, prior exposure to HMA and receipt of prior allogeneic transplant did not independently impact response or leukemia-free survival (LFS). Concurrent IDH mutations were associated with lower CR/CRi (P = .01), while ASXL1 or TET2 mutations showed a non-significant association toward higher CR/CRi (P = .07, for both). However, none of the concurrent mutations were an independent predictor for response when adjusted to AML setting. In conclusion, VEN-HMA is associated with encouraging efficacy in FLT3m AML among both newly diagnosed unfit and r/r patients.     

Molecular characterisation of TP53 mutated squamous cell carcinomas of the lung to identify putative targets for therapy

Personalised cancer treatment depends on identification of therapeutically relevant biological subgroups of patients for assessing effect of treatment and to discover new therapeutic options. By analyses in heterogeneous patient populations, the effects may be lost in noise. Squamous cell carcinoma of the lung is a major killer worldwide. Despite recent advances, mortality is high and response to therapies varies greatly from patient to patient. Target search in biologically relevant subgroups may identify treatment options not so far discovered. A total of 198 patients undergoing surgery for squamous cell carcinomas of the lung were included in the study. The tumours were analysed for copy number alterations (n = 152) and gene expression from tumour (n = 188) and normal lung (n = 21), with both data levels present in 140 patients. We studied alterations in tumours harbouring mutations in TP53 and in previously published gene expression subtypes. Genes with consistent alterations in both genomic levels were identified as putative biomarkers. Results were validated in TCGA. The most convincing biomarker in TP53 mutated squamous cell carcinomas of the lung was BIRC5 with amplification in 36% of mutated samples, 5% in wild-type samples and a 17%-fold change of expression between TP53 mutated tumours and normal lung tissue. BIRC5 was significantly altered in the classical and primitive subtypes. We suggest BIRC5 as a putative predictive biomarker and putative druggable target in squamous cell lung carcinomas harbouring TP53 mutation or classified as classical and primitive subtypes.     

Autoradiographic evaluation of circadian periodicity in cell proliferation in the periodontal ligament of the young mouse

Five-week-old BNL male mice were maintained on a 12-h light/dark cycle, subcutaneously injected with [3H]-thymidine 1 h before death and killed every 3 h for 24 h. Autoradiographs were made from demineralized, paraffin-wax embedded sagittal sections of maxillae. The labelling index was calculated for fibroblast-like cells of the periodontal ligament mesial to the first molar. A bimodal distribution of labelled cells was seen. Labelling index was highest at 0900 h (light period); a second, lower, peak was seen at 2400 h (dark period). Cell proliferation was significantly increased during the light period. The increased activity during the dark period may represent a superimposed secondary, ultradian, rhythm, differences in periodontal cell subtypes or may be related to the feeding and activity cycle of the mouse. Thus there is a 24-h cyclic rhythmicity in the proliferation of periodontal-ligament cells in the mouse.     

The blood-brain barrier models to study apolipoprotein E genotypes in Alzheimer’s disease

Alzheimer’s disease(AD)is a neurodegenerative disease that is characterized by an age-dependent progressive decline of memory,impairment of cognitive functions and changes in personality and behavior.Despite the improvement in understanding of the mechanisms underlying the disease,AD remains an incurable complex disorder with multifaceted pathophysiology to date.Apolipoprotein E(ApoE)is the main cholesterol carrier in the brain that supports lipid transport between brain cells.The individuals carrying the APOE4 allele are known to be at increased risk of developing AD compared with those carrying the more common APOE3 allele.     

Current concepts in intervertebral disc restoration

A current focus of treatment for degenerative disk disease is the restoration of the intervertebral disk. This article summarizes the structure and function of the intervertebral disk, the pathogenesis of its degeneration, and the clinical relevance of degenerative disk disease. Current literature relating to intervertebral disk replacement and regeneration is reviewed.     

Gene therapy for spinal applications

Gene therapy is a promising drug delivery mechanism for the treatment of spinal disorders. Currently, the technique has been most useful in enhancing growth factor therapy for spinal fusion, intervertebral disc regeneration, and spinal cord injury healing. Gene therapy allows for the high-level local production of growth factors, obviating the need for slow release carriers or continuous infusion pumps that are otherwise necessary because of the short half-lives of most peptide growth factors. Although continuous expression is desirable, growth factor therapy is usually intended to be transient. The typical expression profile of Ad vectors--at a high level over 2 weeks or so--has been ideal, leading to its widespread use in these applications. Despite the ability of Ad to deliver genes directly in vivo, however, the cell-based ex vivo approach has been used widely in spinal applications. In spinal cord injury, cells such as peripheral nerve or Schwann cells may provide a permissive substrate for axonal growth [51]. For spinal fusion and IVD regeneration, ex vivo manipulation of cells facilitates gene transfer, because bone and IVD tissue are too dense to be penetrated by injection of Ad or other vectors. The use of cells may be advantageous in these applications in which new tissue formation is the goal. Finally, the use of genetically modified cells may decrease the inflammatory reaction induced by Ad vectors. Although gene therapy for spinal disorders has been centered around Ad-mediated transfer of single growth factor genes, the options for candidate genes and vectors are growing rapidly. Ad vectors are being improved by decreasing their immunogenicity and altering their tropism [2]. Vectors based on other viruses (such as herpes, adeno-associated virus, and lentivirus) are being developed, also with lower immunogenicity and with longer durations of expression [26,67]. Regulated expression, such as with the tetracycline regulated promoter, is being developed so that genes can be turned on or off as needed. Such regulation may be sensitive even to physiologic cues in the future [68,69]. Finally, the high throughput technologies, such as the gene chip, are elucidating thousands of genes that may be good candidates for the enhancement of bone healing and IVD and spinal cord regeneration. Genes whose products not only support bone, fibrocartilage, or axon growth but also neutralize natural inhibitors or promote tissue remodeling and maturation may be good future candidates. In the future, a series of vectors with multiple genes that are regulated by physiologic cues might be used to enhance spinal fusion, restore IVD tissue, or support spinal cord healing.     

Incidental durotomy in spine surgery

STUDY DESIGN: Retrospective review of a large series of patients who underwent spinal surgery at a single institution during a 10-year period. OBJECTIVES: To further clarify the frequency of incidental durotomy during spine surgery, its treatment, associated complications, and results of long-term clinical follow-up. SUMMARY OF BACKGROUND DATA: Incidental durotomy is a relatively common occurrence during spinal surgery. There remains significant concern about it despite reports of good associated clinical outcomes. There have been few large clinical series on the subject. METHODS: A retrospective review was conducted of clinical and surgical records and radiographic data for consecutive patients who underwent spinal surgery performed by the two senior surgeons from January 1989 through December 1998. RESULTS: A total of 2144 patients were reviewed, and 74 were found to have dural tears occurring during or before surgery. Incidental durotomy occurred at the time of surgery in 66 patients (3.1% overall incidence). Incidence varied according to the specific procedure performed but was highest in the group that underwent revision surgery. The incidence of clinically significant durotomies occurring during surgery but not identified at the time was 0.28%. All dural tears that occurred during surgery and were recognized (60 of 66) were repaired primarily. Pseudomeningoceles developed in five of the remaining six patients. All six patients had subsequent surgical repair of dural defects because of failure of conservative therapy. A mean follow-up of 22.4 months was available and showed good long-term clinical results for all patients. CONCLUSIONS: Incidental durotomy, if recognized and treated appropriately, does not lead to long-term sequelae.