Targeted next-generation sequencing of cancer genes in poorly differentiated thyroid cancer

Poorly differentiated thyroid carcinoma (PDTC) is a rare malignancy with higher mortality than well-differentiated thyroid carcinoma. The histological diagnosis can be difficult as well as the therapy. Improved diagnosis and new targeted therapies require knowledge of DNA sequence changes in cancer-relevant genes. The TruSeq Amplicon Cancer Panel was used to screen cancer genomes from 25 PDTC patients for somatic single-nucleotide variants in 48 genes known to represent mutational hotspots. A total of 4490 variants were found in 23 tissue samples of PDTC. Ninety-eight percent (4392) of these variants did not meet the inclusion criteria, while 98 potentially pathogenic or pathogenic variants remained after filtering. These variants were distributed over 33 genes and were all present in a heterozygous state. Five tissue samples harboured not a single variant. Predominantly, variants in P53 (43% of tissue samples) were identified, while less frequently, variants in APC, ERBB4, FLT3, KIT, SMAD4 and BRAF (each in 17% of tissue samples) as well as ATM, EGFR and FBXW7 (each in 13% of tissue samples) were observed. This study identified new potential genetic targets for further research in PDTC. Of particular interest are four observed ERBB4 (alias HER4) variants, which have not been connected to this type of thyroid carcinoma so far. In addition, APC and SMAD4 mutations have not been reported in this subtype of cancer either. In contrast to other reports, we did not find CTNNB1 variants

Transforming growth factor-β activated kinase 1 (Tak1) is activated in hepatocellular carcinoma, mediates tumor progression, and predicts unfavorable outcome

Although knowledge on inflammatory signaling pathways driving cancer initiation and progression has been increasing, molecular mechanisms in hepatocarcinogenesis are still far from being completely understood. Hepatocyte-specific deletion of the MAPKKK Tak1 in mice recapitulates important steps of hepatocellular carcinoma (HCC) development, including the occurrence of cell death, steatohepatitis, dysplastic nodules, and HCCs. However, overactivation of Tak1 in mice upon deletion of its deubiquitinase Cyld also results in steatohepatitis and HCC development. To investigate Tak1 and Cyld in human HCCs, we created a tissue microarray to analyze their expression by immunohistochemistry in a large and well-characterized cohort of 871 HCCs of 561 patients. In the human liver and HCC, Tak1 is predominantly present as its isoform Tak1A and predominantly localizes to cell nuclei. Tak1 is upregulated in diethylnitrosamine-induced mouse HCCs as well as in human HCCs independent of etiology and is further induced in distant metastases. A high nuclear Tak1 expression is associated with short survival and vascular invasion. When we overexpressed Tak1A in Huh7 cells, we observed increased tumor cell migration, whereas overexpression of full-length Tak1 had no significant effect. A combined score of low Cyld and high Tak1 expression was an independent prognostic marker in a multivariate Cox regression model

Epidemiology of thymomas and thymic carcinomas in the United States and Germany, 1999-2019

Introduction Mediastinal tumors, particularly non-neuroendocrine thymic epithelial tumors (TET) are relatively uncommon, posing challenges for extensive epidemiological studies. This study presents a comprehensive analysis of these tumors in the United States (US) and Germany (GER) from 1999 to 2019. Methods Patients aged 0-19 (n=478) and ≥20 years (n=17,459) diagnosed with malignant tumors of the anterior mediastinum were identified from the Surveillance, Epidemiology, and End Results registry (SEER) and the Zentrum für Krebsregisterdaten (ZfKD) databases. Results Among patients aged ≥20 years, TETs accounted for the most prevalent anterior mediastinal tumors (US/GER: 63%/64%), followed by lymphomas (14%/8%). For patients <20 years, predominant tumors included germ cell tumors (42%/14%), lymphomas (38%/53%), and TETs (10%/27%). The overall annual incidence of thymoma was 2.2/2.64 (US/GER) per million inhabitants and for thymic carcinomas 0.48/0.42. The male-to-female ratio was 1:1.09/1.03, and the mean age 59.48 ± 14.89/61.33 ± 13.94. Individuals with thymomas, but not thymic carcinomas, exhibited a 21%/29% significantly heightened risk of developing secondary malignancies compared to controls with non-thymic primary tumors. Discussion This study provides a comparative analysis of anterior mediastinal tumors, particularly TETs, in the US and GER over the past two decades. Furthermore, it highlights a significantly elevated incidence of secondary malignancies in thymoma patients

Image_3_Epidemiology of thymomas and thymic carcinomas in the United States and Germany, 1999-2019.tif

IntroductionMediastinal tumors, particularly non-neuroendocrine thymic epithelial tumors (TET) are relatively uncommon, posing challenges for extensive epidemiological studies. This study presents a comprehensive analysis of these tumors in the United States (US) and Germany (GER) from 1999 to 2019.MethodsPatients aged 0-19 (n=478) and ≥20 years (n=17,459) diagnosed with malignant tumors of the anterior mediastinum were identified from the Surveillance, Epidemiology, and End Results registry (SEER) and the Zentrum für Krebsregisterdaten (ZfKD) databases.ResultsAmong patients aged ≥20 years, TETs accounted for the most prevalent anterior mediastinal tumors (US/GER: 63%/64%), followed by lymphomas (14%/8%). For patients DiscussionThis study provides a comparative analysis of anterior mediastinal tumors, particularly TETs, in the US and GER over the past two decades. Furthermore, it highlights a significantly elevated incidence of secondary malignancies in thymoma patients.</p

Image_2_Epidemiology of thymomas and thymic carcinomas in the United States and Germany, 1999-2019.tif

IntroductionMediastinal tumors, particularly non-neuroendocrine thymic epithelial tumors (TET) are relatively uncommon, posing challenges for extensive epidemiological studies. This study presents a comprehensive analysis of these tumors in the United States (US) and Germany (GER) from 1999 to 2019.MethodsPatients aged 0-19 (n=478) and ≥20 years (n=17,459) diagnosed with malignant tumors of the anterior mediastinum were identified from the Surveillance, Epidemiology, and End Results registry (SEER) and the Zentrum für Krebsregisterdaten (ZfKD) databases.ResultsAmong patients aged ≥20 years, TETs accounted for the most prevalent anterior mediastinal tumors (US/GER: 63%/64%), followed by lymphomas (14%/8%). For patients DiscussionThis study provides a comparative analysis of anterior mediastinal tumors, particularly TETs, in the US and GER over the past two decades. Furthermore, it highlights a significantly elevated incidence of secondary malignancies in thymoma patients.</p

Image_1_Epidemiology of thymomas and thymic carcinomas in the United States and Germany, 1999-2019.tif

IntroductionMediastinal tumors, particularly non-neuroendocrine thymic epithelial tumors (TET) are relatively uncommon, posing challenges for extensive epidemiological studies. This study presents a comprehensive analysis of these tumors in the United States (US) and Germany (GER) from 1999 to 2019.MethodsPatients aged 0-19 (n=478) and ≥20 years (n=17,459) diagnosed with malignant tumors of the anterior mediastinum were identified from the Surveillance, Epidemiology, and End Results registry (SEER) and the Zentrum für Krebsregisterdaten (ZfKD) databases.ResultsAmong patients aged ≥20 years, TETs accounted for the most prevalent anterior mediastinal tumors (US/GER: 63%/64%), followed by lymphomas (14%/8%). For patients DiscussionThis study provides a comparative analysis of anterior mediastinal tumors, particularly TETs, in the US and GER over the past two decades. Furthermore, it highlights a significantly elevated incidence of secondary malignancies in thymoma patients.</p

SWI/SNF-deficient undifferentiated/rhabdoid carcinoma of the gallbladder carrying a POLE mutation in a 30-year-old woman: a case report

Abstract Background Undifferentiated carcinoma of the biliary tract are highly aggressive malignancies. In other organs, a subgroup of undifferentiated carcinoma related to SWI/SNF complex–deficiency have been described. Case presentation A 30-year-old woman presented with rising inflammatory markers (C-reactive protein (CRP)). Ultrasound examination revealed a large tumor of the liver. A computed tomography scan was performed and was primarily interpreted as a tumor-forming liver abscess, possibly caused by gallbladder perforation. Subsequent liver segment resection was performed. Microscopic examination showed an undifferentiated carcinoma with rhabdoid morphology and prominent inflammatory infiltrate in the gallbladder base. With SWI/SNF immunohistochemistry, intact expression of SMARCB1, SMARCA4, ARID1A, but loss of SMARCA2 and PBRM1 was detected. Next-generation-sequencing detected KRAS, PBRM1 and ARID1B mutations, a deleterious splice-site mutation in the POLE-gene and a mutation in the TP53-gene. Conclusions We were able to demonstrate loss of SMARCA2 expression and mutations characteristic of an SWI/SNF-deficient carcinoma in a tumor derived from the gallbladder. This is the first reported case of an undifferentiated carcinoma with rhabdoid features in the gallbladder carrying a POLE mutation and SWI/SNF-deficiency of PBRM1 and SMARCA2

Clinicopathological Significance of Syndecan-1 in Cholangiocarcinoma: A Study Based on Immunohistochemistry and Public Sequencing Data

Background: Syndecan-1 (CD138; SDC1) is a heparan sulfate proteoglycan that has been attributed a key role in cancer progression in ductal adenocarcinoma of the pancreas. We therefore aimed to investigate the role of syndecan-1 in cholangiocarcinoma. Methods: We analyzed syndecan-1 expression in a large, clinicopathologically well-characterized collective of 154 intrahepatic cholangiocarcinoma, 221 extrahepatic cholangiocarcinomas, and 95 gallbladder carcinomas as well as respective normal tissues and precursor lesions by immunohistochemistry with digital image analysis and correlated with recurrence-free survival and prognostic markers. Furthermore, we conducted an analysis of cancer genes in the cholangiocarcinoma cohort of The Cancer Genome Atlas (TCGA). Results: During cholangiocarcinogenesis, syndecan-1-expression decreased when compared to normal bile ducts and biliary intraepithelial neoplasia; however, syndecan-1 levels were found to be elevated in lymph node metastases. In the TCGA cohort, high mRNA SDC1 levels were associated with poor prognosis in intrahepatic cholangiocarcinoma. However, in our large cohort, the immunohistochemical syndecan-1 expression did not significantly correlate with recurrence-free survival. Conclusions: Syndecan-1 was found to be downregulated during cholangiocarcinogenesis, yet we could not show significant effects on prognosis on protein level. Further analyses are needed to further depict its specific role

In vitro testing of a funnel-tip catheter with different clot types to decrease clot migration in mechanical thrombectomy

Background Mechanical thrombectomy is the standard treatment for acute ischemic stroke in patients with large vessel occlusion and can be performed up to 24h after symptom onset. Despite high recanalization rates, embolism in new territories has been reported in 8.6% of the cases. Causes for this could be clot abruption during stent retrieval into the smaller opening of a standard distal access catheter, and antegrade blood flow via collaterals despite proximal balloon protection. A funnel-shaped tip with a larger internal diameter was developed to increase the rate of first-pass recanalization and to improve the safety and efficacy of mechanical thrombectomy. Methods This in vitro study compared the efficacy of a funnel-shaped tip with a standard tip in combination with different clot compositions. Mechanical thrombectomy was performed 80 times for each tip, using two stent retrievers (Trevo XP ProVue 3/20 mm, 4/20 mm) and four different clot types (hard vs. soft clots, 0–24h vs. 72h aged clots). Results Significantly higher first-pass recanalization rates (mTICI 3) were observed for the funnel-shaped tip, 70.0% versus 30.0% for the standard tip (absolute difference, 32; relative difference 57.1%; P < .001), regardless of the clot type and stent retriever. Recanalization could be increased using harder Chandler loop clots versus softer statically generated clots, as well as 0–24h versus 72h aged clots, respectively. Conclusion The funnel-shaped tip achieved higher first-pass recanalization rates than the smaller standard tip and lower rates of clot abruption at the tip. Clot compositions and aging times impacted recanalization rates