Extracranial Medulloblastoma With Myogenic Differentiation: Report of a Rare Event.

Medulloblastoma accounts for nearly 10% of childhood primary central nervous system (CNS) malignancies. However, it is rare in adults. Extracranial metastasis is commonly documented to involve bones but rarely involves lymph nodes. Herein, we present an unusual case of primary CNS medulloblastoma in an adult patient with extracranial metastasis to a lymph node, which exhibits a myogenic differentiation. To the best of our knowledge, this is the fourth reported case of medulloblastoma in an adult with extracranial metastasis to the lymph node and the first reported case of extracranial metastatic medulloblastoma with myogenic differentiation that involves a lymph node.

Acute reversible rhabdomyolysis during direct-acting antiviral hepatitis C virus treatment: a case report.

INTRODUCTION: Treatment of hepatitis C infection has evolved dramatically since 2011. Previous conventional therapy with interferon and ribavirin used to have a low sustained virological response rate of less than 40%. In the new direct-acting antiviral therapy era, a sustained virological response can be achieved in more than 90% of cases. CASE PRESENTATION: We report a rare case of severe reversible acute rhabdomyolysis in a 31-year-old Saudi male patient with very long-chain acyl-coenzyme A dehydrogenase deficiency and chronic hepatitis C infection. The patient was clinically asymptomatic with no signs of decompensated liver disease. The patient received new direct-acting antiviral agents: sofosbuvir and daclatasvir. Fourteen days after initiation of direct-acting antiviral agents, the patient was found to have asymptomatic rhabdomyolysis. His creatine kinase peaked at 2572 IU/l, and he was treated conservatively; the direct-acting antiviral agents were discontinued and within 7 days, the patient's creatine kinase levels normalized. CONCLUSION: This case highlights possible direct-acting antiviral agent-induced rhabdomyolysis in a patient with very-long-chain acyl-CoA dehydrogenase deficiency, presumably through alteration of mitochondrial membrane potential. Further studies are required to assess the possible impact and associations.

Profiling Activins and Follistatin in Colorectal Cancer According to Clinical Stage, Tumour Sidedness and Smad4 Status.

This study explored the roles of activins and follistatin in colorectal cancers. Paired malignant and normal colonic tissues were collected from archived paraffin-embedded (n = 90 patients) alongside fresh (n = 40 patients) specimen cohorts. Activin ß-subunits, follistatin and Smad4 mRNAs and proteins were measured by real-time PCR and immunohistochemistry (IHC). Mature activin-A, -B, -AB and follistatin proteins were measured by ELISA. Cancer tissues having ≤ the 20th percentile of the Smad4 IHC score were considered as low (L-S4) group. The Smad4-intact SW480 and Smad4-null HT29 colon cancer cell lines were treated with activins and follistatin, and cell cycle was analysed by flow cytometry. The cell cycle inducing (CCND1/CCND3) and inhibitory (p21/p27) proteins alongside the survival (survivin/BCL2) and pro-apoptosis (Casp-8/Casp-3) markers were measured by immunofluorescence. Thirty-nine patients had right-sided cancers (30%) and showed higher rates of L-S4 tumours (n = 17; 13.1%) alongside worse clinicopathological characteristics relative to left-sided cancers. The ßA-subunit and activin-A increased, whilst ßB-subunit and activin-AB decreased, in malignant sites and the late-stage cancers revealed the greatest abnormalities. Interestingly, follistatin declined markedly in early-stage malignant tissues, whilst increased significantly in the advanced stages. All activin molecules were comparable between the early stage right- and left-sided tumours, whereas the late-stage right-sided cancers and L-S4 tumours showed more profound deregulations. In vitro, activin-A increased the numbers of the SW480 cells in sub-G1 and G0/G1-phases, whereas reduced the HT29 cell numbers in the sub-G1 phase with simultaneous increases in the G0/G1 and S phases. The p21/p27/Casp-8/Casp-3 proteins escalated, whilst CCND1/CCND3/BCL2/survivin declined in the SW480 cells following activin-A, whereas activin-A only promoted p21 and p27 alongside reduced CCND3 in the HT29 cells. By contrast, activin-AB increased the numbers of SW480 and HT29 cells in Sub-G1 and G0/G1-phases and promoted the anti-cancer and reduced the oncogenic proteins in both cell lines. In conclusion, activins and follistatin displayed stage-dependent dysregulations and were markedly altered during the advanced stages of right-sided and L-S4 cancers. Moreover, the activin-A actions in CRC could be Smad4-dependent, whereas activin-AB may act as a Smad4-independent tumour suppressor protein.

Evaluation of the Idylla KRAS and NRAS mutation test in colorectal cancer tissue.

INTRODUCTION: The currently approved techniques for RAS mutations testing in colorectal cancer (CRC) tissue are labor-intensive and time consuming. The Idylla technology (IT) is a rapid and fully automated diagnostics system. The primary aim of this study is to compare the Idylla performance against that of conventional techniques (CT). METHODOLOGY: Archival CRC tumor samples from 2 hospitals were tested for KRAS and NRAS mutations using the IT. Results were compared to those obtained earlier by CT performed in accredited laboratories. Unexplained discordant results were verified locally by next generation sequencing (NGS) to ascertain the accuracy of IT. RESULTS: Forty five samples were processed. All samples underwent dual testing (CT & IT) for KRAS mutations. IT identified mutations in 2 samples that were not detected by CT. Primary concordance rate for KRAS was 93.3% and the accuracy rate improved to 100% after verification and explanation of discordant results. Only 18 samples underwent dual testing for NRAS. Primary concordance and accuracy rates for NRAS were 94.4%. The mean time from dispatching the specimen for RAS testing by CT until receipt of results was 12 (7-28) days compared to few hours when IT was used. CONCLUSION: IT provides a quick and reliable mean for RAS testing. In addition, it identifies mutations that are not detected by CT and thus may provide better guidance to treatment choices.

Immunodeficiency and EBV-induced lymphoproliferation caused by 4-1BB deficiency.

BACKGROUND: The tumor TNF receptor family member 4-1BB (CD137) is encoded by TNFRSF9 and expressed on activated T cells. 4-1BB provides a costimulatory signal that enhances CD8+ T-cell survival, cytotoxicity, and mitochondrial activity, thereby promoting immunity against viruses and tumors. The ligand for 4-1BB is expressed on antigen-presenting cells and EBV-transformed B cells. OBJECTIVE: We investigated the genetic basis of recurrent sinopulmonary infections, persistent EBV viremia, and EBV-induced lymphoproliferation in 2 unrelated patients. METHODS: Whole-exome sequencing, immunoblotting, immunophenotyping, and in vitro assays of lymphocyte and mitochondrial function were performed. RESULTS: The 2 patients shared a homozygous G109S missense mutation in 4-1BB that abolished protein expression and ligand binding. The patients' CD8+ T cells had reduced proliferation, impaired expression of IFN-γ and perforin, and diminished cytotoxicity against allogeneic and HLA-matched EBV-B cells. Mitochondrial biogenesis, membrane potential, and function were significantly reduced in the patients' activated T cells. An inhibitory antibody against 4-1BB recapitulated the patients' defective CD8+ T-cell activation and cytotoxicity against EBV-infected B cells in vitro. CONCLUSION: This novel immunodeficiency demonstrates the critical role of 4-1BB costimulation in host immunity against EBV infection.

Congenital Neurofibromatosis in a Saudi Neonate who Presented with Neck Mass, Esophageal and Airway Obstruction.

We are presenting a case of a neonate presented with a neck mass, airway and esophageal obstruction, the tumor has a brain extension; treated with partial surgical excision; the pathological studies revealed plexiform Neurofibromatosis. The patient also has café au lait spots.

TdT expression in Merkel cell carcinoma: potential diagnostic pitfall with blastic hematological malignancies and expanded immunohistochemical analysis.

Merkel cell carcinoma is an uncommon aggressive primary cutaneous neuroendocrine carcinoma. Histologically, the differential diagnosis includes the 'small round cell' tumor group, particularly metastatic small cell carcinoma and blastic hematological malignancies involving skin/soft tissues. Terminal deoxynucleotidyl transferase (TdT) is a DNA polymerase, which is a sensitive and specific antibody for acute lymphoblastic lymphoma with a small proportion of acute myeloid leukemia showing positivity. This study investigates the expression of TdT in 20 cases with initial diagnosis of Merkel cell carcinoma. Archival blocks and slides were retrieved and reviewed and clinical information obtained from patient charts. Immunohistochemistry was performed and graded as: 0, no staining; 1+, less than 50% staining in the cells; 2+, 50% or more staining in the cells. After review, 15 cases were confirmed as Merkel cell carcinoma. Immunohistochemical positivity was as follows: 8/15 cases were positive for TdT with strong nuclear staining, morphologically resembling 'blasts', AE1AE3, CAM5.2 (15/15) (both membrane and paranuclear dot positivity), CD56 and BCL-2 (15/15), Synaptophysin (13/15), Chromogranin A (11/15), NSE (15/15), CK20 (14/15), CK7 (3/15), both CK7 and CK20 (3/15), CD117 (8/15), CD99 (2/15), CD10 (1/15). One case was negative for CK7/CK20. All 15 cases were negative for thyroid transcription factor-1, LCA, CD20, CD3 and CD34. Expanded immunohistochemical panel with positive staining for epithelial/neuroendocrine markers, CK20, negative staining for hematolymphoid markers and awareness of TdT expression and other markers that show overlap with blastic hematological malignancies avoids misinterpretation in the diagnosis of Merkel cell carcinoma. This aids in further diagnosis of Merkel cell carcinoma, avoiding the potential diagnostic pitfall with other small round cell tumors and hematological malignancies primary or metastatic to the skin.