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.

Prospective Study on the Performance of 18F-DOPA Positron Emission Tomography/Computed Tomography in Patients with Medullary Thyroid Carcinoma

Purpose 18F-DOPA Positron Emission Tomography/Computed Tomography (18F-DOPA PET/CT) is a sensitive functional imaging method (65-75%) for detecting disease localization in medullary thyroid cancer (MTC). We aimed: i) to assess the clinical usefulness of 18F-DOPA PET/CT in patients with MTC and elevated calcitonin (Ctn) and CEA levels and, ii) to evaluate changes in disease management secondary to the findings encountered with this methodology. Methods thirty-six patients with MTC and Ctn levels ≥150 pg/ml were prospectively included. Neck ultrasound, chest contrast-enhanced CT, liver magnetic resonance imaging/ abdominal 3-phase contrast-enhanced CT and bone scintigraphy were carried out up to 6 months before the 18F DOPA PET/CT. Results 77.7% were female and 27% had hereditary MTC. Median Ctn level was 1450 pg/ml [150-56620], median CEA level 413 ng/ml [2.9-7436]. Median Ctn DT was 37.5 months [5.7-240]; median CEA DT was 31.8 [4.9-180]. 18F-DOPA PET/CT was positive in 33 patients (91.6%); in 18 (56%) uptake was observed in lymph nodes in the neck or mediastinum, in 7 cases (22%) distant metastases were diagnosed, and in 8 additional patients (24%) both locoregional and distant sites of disease were found. Ctn and CEA levels were higher in patients with ≥ 3 foci of distant metastases. In 14 patients (38.8%), findings on 18F-DOPA PET/CT led to changes in management; surgery for locoregional lymph nodes was the most frequent procedure in 8 patients (22%). Conclusion 18F-DOPA PET/CT was useful for the detection of recurrent disease in MTC and provided helpful information for patient management.

Perioperative Management of Pheochromocytomas and Sympathetic Paragangliomas

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors arising from chromaffin cells of the adrenal medulla or extra-adrenal paraganglia, respectively. PPGLs have the highest degree of heritability among endocrine tumors. Currently, ~40% of PPGL individuals have a genetic germline and there exist at least 12 different genetic syndromes related to these tumors. Metastatic PPGLs are defined by the presence of distant metastases at sites where chromaffin cells are physiologically absent. Approximately 10% of pheochromocytomas and ~40% of sympathetic paragangliomas are linked to metastases explaining why complete surgical resection is the first-choice treatment for all PPGL patients. The surgical approach is a high-risk procedure requiring perioperative management by a specialized multidisciplinary team in centers with broad expertise. In this review, we summarize and discuss the most relevant aspects of perioperative management in patients with pheochromocytomas and sympathetic paragangliomas.

PET metabolic tumor volume as a new prognostic factor in childhood rhabdomyosarcoma

Purpose Childhood RMS is a rare malignant disease in which evaluation of tumour spread at diagnosis is essential for therapeutic management. F-18 FDG-PET imaging is currently used for initial RMS disease staging. Materials and methods This multicentre retrospective study in six French university hospitals was designed to analyse the prognostic accuracy of MTV at diagnosis for patients with RMS between 1 January 2007 and 31 October 2017, for overall (OS) and progression-free survival (PFS). MTV was defined as the sum of the primitive tumour and the largest metastasis, where relevant, with a 40% threshold of the primary tumour SUVmax. Additional aims were to define the prognostic value of SUVmax, SUVpeak, and bone lysis at diagnosis. Results Participants were 101 patients with a median age of 7.4 years (IQR [4.0-12.5], 62 boys), with localized disease (35 cases), regional nodal spread (43 cases), or distant metastases (23). 44 patients had alveolar subtypes. In a univariate analysis, a MTV greater than 200 cm3 was associated with OS (HR = 3.47 [1.79;6.74], p<0.001) and PFS (HR = 3.03 [1.51;6.07], p = 0.002). SUVmax, SUVpeak, and bone lysis also influenced OS (respectively p = 0.005, p = 0.004 and p = 0.007) and PFS (p = 0.029, p = 0.019 and p = 0.015). In a multivariate analysis, a MTV greater than 200 cm3 was associated with OS (HR = 2.642 [1.272;5.486], p = 0.009) and PFS (HR = 2.707 [1.322;5.547], p = 0.006) after adjustment for confounding factors, including SUVmax, SUVpeak, and bone lysis. Conclusion A metabolic tumor volume greater than 200 cm3, SUVmax, SUVpeak, and bone lysis in the pre-treatment assessment were unfavourable for outcome.

Reappraisal of Grading in Intestinal-Type Sinonasal Adenocarcinoma: Tumor Budding as an Independent Prognostic Parameter

Since sinonasal intestinal-type adenocarcinomas (ITAC) show resemblance to colorectal adenocarcinomas, we aimed to investigate novel prognostic factors of outcome, with particular focus on the role of tumor budding (TB). Retrospective clinico-pathological single-institution study on consecutive ITAC patients between 1996 and 2020. Histopathological parameters including conventional subtypes and TB features (low, intermediate, high) were evaluated with the aid of pancytokeratin (AE1/AE3) immunohistochemical staining. Parameters were correlated to clinical data and outcome. A total of 31 ITAC patients were included. Overall, 19/31 patients (61.3%) presented with stage III/IV disease. Presence of lymph node or distant metastases was rare (1/31 patient, 3.2%). Treatment protocols consisted of tumor resection in 30/31 patients (96.8%) and primary radiochemotherapy in 1/31 patient (3.2%). Adjuvant radiation therapy was conducted in 20/30 surgically treated patients (66.7%). The 3- and 5-year overall survival (OS) was 83.9% and 78.3% and the 3- and 5-years disease-specific survival (DSS) 83.7% % and 78.5%, respectively. The presence of intermediate/high TB (defined as ≥ 5 buds) was associated with both, worse DSS (log rank p = 0.03) and OS (log rank p = 0.006). No patient with low TB revealed progressive disease or died of the disease. No association between TB and tumor stage or conventional tumor subtype was found. Tumor budding seems to be an independent prognostic factor of worse outcome in ITAC.

Circulating Tumor Cell Transcriptomics as Biopsy Surrogates in Metastatic Breast Cancer

Background Metastatic breast cancer (MBC) and the circulating tumor cells (CTCs) leading to macrometastases are inherently different than primary breast cancer. We evaluated whether whole transcriptome RNA-Seq of CTCs isolated via an epitope-independent approach may serve as a surrogate for biopsies of macrometastases. Methods We performed RNA-Seq on fresh metastatic tumor biopsies, CTCs, and peripheral blood (PB) from 19 newly diagnosed MBC patients. CTCs were harvested using the ANGLE Parsortix microfluidics system to isolate cells based on size and deformability, independent of a priori knowledge of cell surface marker expression. Results Gene expression separated CTCs, metastatic biopsies, and PB into distinct groups despite heterogeneity between patients and sample types. CTCs showed higher expression of immune oncology targets compared with corresponding metastases and PB. Predictive biomarker (n = 64) expression was highly concordant for CTCs and metastases. Repeat observation data post-treatment demonstrated changes in the activation of different biological pathways. Somatic single nucleotide variant analysis showed increasing mutational complexity over time. Conclusion We demonstrate that RNA-Seq of CTCs could serve as a surrogate biomarker for breast cancer macrometastasis and yield clinically relevant insights into disease biology and clinically actionable targets. Visual Abstract Primary tumor cells (left side) disseminate via the blood stream to seed distant metastases (right side). Peripheral blood can be used for enrichment of CTCs (potentially representative of the full heterogeneity of a patient’s cancer) as a liquid biopsy. RNA-Seq can identify predictive biomarker expression in enriched CTCs as a surrogate for macrometastatic tissue biopsies. Different colored circles represent different cancer cell clones, representing heterogeneity in the primary tumor, and increased heterogeneity in metastatic tumors.

Circulating Lymphocyte Subsets are Prognostic Factors in Patients with Nasopharyngeal Carcinoma

Background: Nasopharyngeal carcinoma (NPC) is a geographically and racially variable disease which has a high incidence in Southeast China. According to previous studies on tumor immunity, we compared multiple clinical parameters and blood indexes to find its relationship with prognosis in NPC patients.Methods: According to the load of EBV at diagnosis, 220 NPC patients receiving concurrent chemoradiotherapy (CRT) were divided into two groups. We compared clinical parameters, peripheral blood mononuclear cells, lymphocyte subsets and biochemical indexes between them. We analyzed distant metastases and overall survival rate between them.Results: In most cases, the two groups showed the same trend. Most blood indexes were decreased during CRT, the decrease in absolute count was more significant than in percentage. The younger age showed the higher CD3+ and CD3+CD8+ percentage. Patients whose EBV DNA≥1500 copies/mL at first diagnosis showed higher pN grade. Among them, higher CD3+CD8+ percentage or lower CD3-CD56+ percentage had batter OS rates. Patients whose EBV DNA<1500 copies/mL at first diagnosis had higher survival rate and longer survival time.Conclusions: CRT cause overall decrease of blood cells in NPC patients. The initial EBV load was related to prognosis. Among all the blood indexes, CD3+CD8+ percentage showed correlation with age and OS rates in patients whose EBV DNA≥1500 copies/mL at first diagnosis, which is worthy of further study.

Imaging Evaluation of Thymoma and Thymic Carcinoma

Imaging is integral in the management of patients with thymoma and thymic carcinoma. At initial diagnosis and staging, imaging provides the clinical extent of local invasion as well as distant metastases to stratify patients for therapy and to determine prognosis. Following various modalities of therapy, imaging serves to assess treatment response and detect recurrent disease. While imaging findings overlap, a variety of CT, MRI, and PET/CT characteristics can help differentiate thymoma and thymic carcinoma, with new CT and MRI techniques currently under evaluation showing potential.