Treatment of keloids is a therapeutic challenge.To determine the outcome and the risk of recurrence after debulking cold steel surgery or carbon dioxide (CO2) laser ablation of earlobe keloids.The case records of 16 patients with earlobe keloids managed at Changi General Hospital, Singapore, from 2003 to 2009 were reviewed retrospectively.Fourteen patients were females, and the mean age at presentation was 20 years. Eight patients underwent CO2 laser ablation, six patients underwent cold steel surgery, one patient underwent both surgery and CO2 laser ablation, and one patient received only 40 mg/ml of intralesional triamcinolone acetonide. Fourteen patients were followed up for 1-24 months post procedure, and two patients defaulted. Both modalities were equally effective in debulking the earlobe keloids. All 13 patients who had either CO2 laser ablation or cold steel surgery had recurrence of keloid growth at 2-18 weeks post procedure. The patient who received intralesional triamcinolone acetonide therapy alone had only partial response to the therapy.Both the CO2 laser ablation and cold steel surgery were equally useful in reducing the size of the earlobe keloids, but were not effective in preventing regrowth of the keloids, even with adjunctive intralesional steroids. Patients should be clearly counselled regarding this.
The undruggable nature of oncogenic Myc transcription factors poses a therapeutic challenge in neuroblastoma, a pediatric cancer in which MYCN amplification is strongly associated with unfavorable outcome. Here, we show that CYC065 (fadraciclib), a clinical inhibitor of CDK9 and CDK2, selectively targeted MYCN-amplified neuroblastoma via multiple mechanisms. CDK9 — a component of the transcription elongation complex P-TEFb — bound to the MYCN-amplicon superenhancer, and its inhibition resulted in selective loss of nascent MYCN transcription. MYCN loss led to growth arrest, sensitizing cells for apoptosis following CDK2 inhibition. In MYCN-amplified neuroblastoma, MYCN invaded active enhancers, driving a transcriptionally encoded adrenergic gene expression program that was selectively reversed by CYC065. MYCN overexpression in mesenchymal neuroblastoma was sufficient to induce adrenergic identity and sensitize cells to CYC065. CYC065, used together with temozolomide, a reference therapy for relapsed neuroblastoma, caused long-term suppression of neuroblastoma growth in vivo, highlighting the clinical potential of CDK9/2 inhibition in the treatment of MYCN-amplified neuroblastoma.
Abstract Medulloblastoma (MB), the most common embryonal tumour of the Central Nervous System, occurs in the cerebellum. Treatment regimens involve surgery, craniospinal radiotherapy, and chemotherapy. The greatest mortality is associated with disseminated disease, almost exclusively found in the leptomeningeal space. Unfortunately, knowledge about the aetiology of MB spread is limited and the need for kinder and efficacious therapy remains an unmet goal. Of the four molecular classified MB groups, Group3 (Gr3) MB presents with a high frequency of metastasis at diagnosis, with the worst overall survival. Gr3 MB tumours are dominated by primitive progenitor-like cells and cMYC deregulation; often, p53 deficiency is observed at relapse. To dissect the biology of primary and metastatic Gr3 MB, we have developed a new germline genetically engineered mouse model (GEMM), harbouring cMYC amplification in a Tamoxifen-inducible p53 functional background (Trp53ERTAM strain). A novel LSL-cMYC-CopGFP-Luciferase transgene was integrated into the Rosa-26 locus of the mouse genome. Transgenic mice were crossed with a strain expressing Cre recombinase under the Blbp promoter targeting embryonic neural progenitors, and subsequently bred to Trp53ERTAM mice. As result, the cMYC overexpression was sufficient to generate tumours. Tumour penetrance was observed in all the expected tumour bearing genotypes, with increased aggressiveness in a non-functional p53 background. Bioluminescence imaging demonstrated tumour onset in the brain and dissemination along the spinal cord. CopGFP positive tumour cells were isolated from primary and metastatic tumours. Pathological interrogation confirmed that tumours present large cell/anaplastic (LCA) histology. Analysis of preliminary transcriptional profiling data proved that tumours cluster with human Gr3 MB. Ongoing methylation profiling and multi-omics approaches will inform on the tumour cells of origin and clonal divergence of primary tumour versus metastasis. In conclusion, we have successfully developed a novel immunocompetent mouse model of metastatic Gr3 MB with which we can investigate therapeutic vulnerabilities of MB.
Beauticians are exposed to many potential allergens in their occupation. To identify the sources of occupational skin and respiratory disease reported in beauticians, with an emphasis on acrylate chemicals, and to investigate the trends over time. We used the Health and Occupation Research (THOR) database to identify occupational disease in beauticians between 1996 and 2011. Trend analysis was carried out to look for any change in the allergens reported over this period. In total, 257 cases of contact dermatitis (CD) in beauticians were identified, which were associated with 502 suspected agents. The most frequently cited source of allergic CD was acrylate chemicals. The trend analysis showed a small average annual percentage increase in work‐related CD in beauticians for all agents (1.1%; 95% CI −2.5 to 4.9). There was a small decrease in cases in which acrylates were not cited (−1.7%; 95% CI −5.9 to 2.7), and a statistically significant increase when acrylates were cited (7.4%; 95% CI 0.9 to 14.4). There were 11 cases of occupational asthma. We found an increase in cases of occupational dermatitis associated with acrylates in beauticians over a 15‐year period, and describe other causes of occupational dermatitis.
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