Absence of mutations of the BRAF gene in malignant melanoma of soft parts (clear cell sarcoma of tendons and aponeuroses)

Malignant melanoma of soft parts (MMSP), also called clear cell sarcoma of tendons and aponeuroses, is cytogenetically characterized by the t(12;22)(q13;q12) resulting in the chimeric EWSR1/ATF1 gene. MMSP shares a number of morphologic, histologic, and immunohistochemical features with malignant melanoma of the skin, causing diagnostic difficulties in the distinction between MMSP and metastatic malignant melanoma with an unknown primary site. Recently, a high incidence of activating mutations in the kinase domain of the BRAF gene has been reported in malignant melanoma of the skin. The most common mutation (V599E) is the T1796A substitution in exon 15, leading to an exchange of valine for glutamic acid at position 599. Because of the extensive clinical, histologic, and immunohistochemic similarities with melanoma, we decided to analyze whether MMSP also has mutations in the BRAF gene. Eight MMSP with an EWSR1/ATF1 chimeric transcript, one soft tissue metastasis of a malignant melanoma of the skin, and one malignant melanoma cell line were examined. Both conventional melanomas had the exon 15 T1796A (V599E) mutation, but none of the MMSP was found to harbor any mutation in exon 11 or 15 of the BRAF gene. Our data further emphasize that MMSP and conventional malignant melanoma develop through different genetic pathways

Primary Burkitt lymphoma of the thyroid gland in a 28-year-old female

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Functional temozolomide sensitivity testing of patient-specific glioblastoma stem cell cultures is predictive of clinical outcome

Serum-free culturing of patient-derived glioblastoma biopsies enrich for glioblastoma stem cells (GSCs) and is recognized as a disease-relevant model system in glioblastoma (GBM). We hypothesized that the temozolomide (TMZ) drug sensitivity of patient-derived GSC cultures correlates to clinical sensitivity patterns and has clinical predictive value in a cohort of GBM patients. To this aim, we established 51 individual GSC cultures from surgical biopsies from both treatment-naive primary and pretreated recurrent GBM patients. The cultures were evaluated for sensitivity to TMZ over a dosing range achievable in normal clinical practice. Drug efficacy was quantified by the drug sensitivity score. MGMT-methylation status was investigated by pyrosequencing. Correlative, contin-gency, and survival analyses were performed for associations between experimental and clinical data. We found a heterogeneous response to temozolomide in the GSC culture cohort. There were significant differences in the sensitivity to TMZ between the newly diagnosed and the TMZ-treated recurrent disease (pPeer reviewe

Midline carcinoma with t(15;19) and BRD4-NUT fusion oncogene in a 30-year-old female with response to docetaxel and radiotherapy

BACKGROUND: Poorly differentiated midline carcinoma with a translocation between chromosomes 15 and 19, i.e. t(15;19), has been recognized as a distinct clinical entity for over a decade. This tumor affects young individuals, shows a rapidly fatal clinical course despite intensive therapy. The t(15;19) results in the fusion oncogene BRD4-NUT. Information concerning treatment of this rare disorder is scarce. CASE PRESENTATION: A 30-year-old woman was admitted with a rapidly progressing tumor in the mediastinum, cervical lymph nodes, vertebral column and the epidural space. Pathological, cytogenetic, FISH and PCR analysis revealed a glycogenated carcinoma rarely expressing cytokeratins and showing t(15;19) and BRD4-NUT gene rearrangement. The patient was initially treated with a Ewing sarcoma chemotherapy regimen, but had rapid progression after two cycles. She then received docetaxel and radiotherapy, which resulted in almost complete disappearance of the tumor. CONCLUSION: Docetaxel may be considered for initial chemotherapy in young patients presenting with a midline carcinoma with bone marrow involvement and cytogenetic and molecular genetic finding of a t(15;19)/BRD4-NUT-rearrangement. We herein describe, in detail, the laboratory methods by which the BRD4-NUT -rearrangement can be detected

Patient outcomes following surgical management of thyroid nodules classified as Bethesda category III (AUS/FLUS)

Introduction: The Bethesda classification system for reporting thyroid cytopathology is the standard for interpreting fine needle aspirate (FNA). Because of its heterogeneity and inconsistent reporting, atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS), known as Bethesda category III, is the most controversial category. Thyroid nodules that fall within Bethesda categories III–IV have an overall risk of malignancy of between 15 and 40%. The aim of this study was to determine the malignancy rate in Bethesda III nodules. Material and methods: A retrospective study was performed for 1166 patients who underwent thyroid surgery for multinodular goitre (MNG) or solitary nodular goitre (SNG) in our institution between June 2010 and May 2020. Data retrieved included demographic characteristics of the patients, FNB cytology, thyroid function test results, type of thyroidectomy, and final histology results. Results: During the study period, 29.5% (344/1166) of patients with an FNA categorized as AUS/FLUS underwent thyroid surgery. Of these 344 patients, 190 were diagnosed with MNG and 154 with SNG. Incidental malignancy was found in 35 of 190 cases of MNG (18.42%) and 31 of 154 cases of SNG (20.13%). The most common malignant tumour type in either category was the follicular variant of papillary thyroid carcinoma. Conclusions: The current study demonstrates that patients with a FNA categorized as AUS/FLUS may have a higher risk of malignancy than traditionally believed. Reconsideration may be necessary to guidelines that recommend observation or repeat FNA in this category of patients

Bone marrow ectopic expression of a non-coding RNA in childhood T-cell acute lymphoblastic leukemia with a novel t(2;11)(q11.2;p15.1) translocation

Chromosomal translocations play a crucial role in tumorigenesis, often resulting in the formation of chimeric genes or in gene deregulation through position effects. T-cell acute lymphoblastic leukemia (T-ALL) is associated with a large number of such rearrangements. We report the ectopic expression of the 3' portion of EST DA926692 in the bone marrow of a childhood T-ALL case showing a t(2;11)(q11.2;p15.1) translocation as the sole chromosome abnormality. The breakpoints, defined at the sequence level, mapped within HPS5 ( Hermansky Pudlak syndrome 5) intron 1 at 11p15.1, and DA926692 exon 2 at 2q11.2. The translocation was accompanied by a submicroscopic inversion that brought the two genes into the same transcriptional orientation. No chimeric trancript was detected. Interestingly, Real-Time Quantitative (RQ)-PCR detected, in the patient's bone marrow, expression of a 173 bp product corresponding to the 3' portion of DA926692. Samples from four T-ALL cases with a normal karyotype and normal bone marrow used as controls were negative. It might be speculated that the juxtaposition of this genomic segment to the CpG island located upstream HPS5 activated DA92669 expression. RQ-PCR analysis showed expression positivity in 6 of 23 human tissues examined. Bioinformatic analysis excluded that this small non-coding RNA is a precursor of micro-RNA, although it is conceivable that it has a different, yet unknown, functional role. To the best of our knowledge, this is the first report, in cancer, of the activation of a small non-coding RNA as a result of a chromosomal translocation