Multidisciplinary treatment of thymic neuroendocrine tumors: surgery remains a key component.

BACKGROUND: Thymic neuroendocrine tumors (NETs) are rare malignancies often treated in a multidisciplinary fashion. However, evidence for adjunctive therapy is limited, and predictors of survival and recurrence are not well established. METHODS: Patients treated for thymic NETs at a single center from 1975 to 2018 were reviewed. Variables collected pertained to tumor factors, stage, and treatments, including surgery. Univariate and multivariate regression analyses were used to determine predictors of overall survival (OS) and recurrence. RESULTS: We identified treated 49 patients, among whom 36 (73%) were male with a median age of 46 years. Surgical resection was pursued in 41 (84%) patients, and chemotherapy and radiation therapy were used in 27 (55%) and 21 (43%) instances as either neoadjuvant, adjuvant, or definitive therapy. Median tumor size was 6.5 centimeters and most tumors were intermediate-grade. During a median follow-up time of 60.8 months following surgical resection, disease recurrence was observed in 29 (71%) patients and median survival time was 83.7 months. In Kaplan-Meier analysis for survival, surgical resection was associated with a longer survival time (P=0.002), while receipt of neoadjuvant therapy was associated with poorer survival. Larger tumor size was associated with recurrence following resection (P=0.047). CONCLUSIONS: Thymic NETs represent a heterogeneous disease with variable survival. While we are unable to report clear evidence that supports the use of adjunctive therapies, surgery is important to survival. Additionally, it is likely that those receiving induction chemotherapy represent a unique cohort with advanced or aggressive disease. Among surgical candidates, tumor size predicts disease recurrence.

Identification of cancer stem cells in human gastrointestinal carcinoid and neuroendocrine tumors.

BACKGROUND & AIMS: Metastatic gastrointestinal neuroendocrine tumors (NETs) frequently are refractory to chemotherapy. Chemoresistance in various malignancies has been attributed to cancer stem cells (CSCs). We sought to identify gastrointestinal neuroendocrine CSCs (N-CSCs) in surgical specimens and a NET cell line and to characterize novel N-CSC therapeutic targets. METHODS: Human gastrointestinal NETs were evaluated for CSCs using the Aldefluor (Stemcell Technologies, Vancouver, Canada) assay. An in vitro, sphere-forming assay was performed on primary NET cells. CNDT2.5, a human midgut carcinoid cell line, was used for in vitro (sphere-formation) and in vivo (tumorigenicity assays) CSC studies. N-CSC protein expression was characterized using Western blotting. In vivo, systemic short interfering RNA administration targeted Src. RESULTS: By using the Aldefluor assay, aldehyde dehydrogenase-positive (ALDH+) cells comprised 5.8% ± 1.4% (mean ± standard error of the mean) of cells from 19 patient samples. Although many primary cell lines failed to grow, CNDT96 ALDH+ cells formed spheres in anchorage-independent conditions, whereas ALDH- cells did not. CNDT2.5 ALDH+ cells formed spheres, whereas ALDH- cells did not. In vivo, ALDH+ CNDT2.5 cells generated more tumors, with shorter latency than ALDH- or sham-sorted cells. Compared with non-CSCs, ALDH+ cells demonstrated increased expression of activated Src, Erk, Akt, and mammalian target of rapamycin (mTOR). In vivo, anti-Src short interfering RNA treatment of ALDH+ tumors reduced tumor mass by 91%. CONCLUSIONS: CSCs are present in NETs, as shown by in vitro sphere formation and in vivo tumorigenicity assays. Src was activated in N-CSCs and represents a potential therapeutic target in gastrointestinal NETs.

Clinical implications of DNA methylation in hepatocellular carcinoma.

BACKGROUND: Epigenetics is a rapidly evolving field of genetic study applicable to nearly every aspect of genome-related research. The importance of epigenetics has been recognised in human hepatocellular carcinoma (HCC). Changes in DNA methylation patterns, including global hypomethylation and promoter hypermethylation, are thought to be early events in hepatocarcinogenesis. OBJECTIVES: This review aimed to summarise the role of epigenetics in HCC, to describe the mechanisms of epigenetic changes in HCC and to examine the clinical relevance of epigenetics in HCC. METHODS: This review examines the role of CpG-rich regions and DNA methylation, and describes an epigenetic model of cancer, tumour type-specific methylation, the relationships among methylation, cirrhosis and hepatocarcinogenesis, and the role of DNA methylation in HCC. The clinical implications of epigenetics in HCC are discussed. RESULTS: A multivariate predictor model based on traditional clinical factors and DNA methylation profile may have important applications in the early detection of neoplastic transformation in populations at high risk for HCC. CpG methylation may be valuable in HCC prognostics. DNA methylation profiles may enable clinical prediction in pre-therapy patient biopsies, paraffin-embedded samples or plasma DNA. CONCLUSIONS: Epigenetic changes and profiles may correlate to the biological behaviour of tumours and clinical outcome of HCC patients. The use of DNA methylation profiles as a surrogate biomarker remains an active area of clinical cancer research.

Pancreatic adenocarcinoma in a patient with situs inversus: a case report of this rare coincidence.

BACKGROUND: Situs inversus (SI) is a relatively rare occurrence in patients with pancreatic adenocarcinoma. Pancreatic resection in these patients has rarely been described. CT scan imaging is a principle modality for detecting pancreatic cancer and its use in SI patients is seldom reported. CASE PRESENTATION: We report a 48 year old woman with SI who, despite normal CT scan 8 months earlier, presented with obstructive jaundice and a pancreatic head mass requiring a pancreaticoduodenectomy. The surgical pathology report demonstrated pancreatic adenocarcinoma. CONCLUSION: SI is a rare condition with concurrent pancreatic cancer being even rarer. Despite the rarity, pancreaticoduodenectomy in these patients for resectable lesions is safe as long as special consideration to the anatomy is taken. Additionally, radiographic imaging has significantly improved detection of early pancreatic cancer; however, there continues to be a need for improved detection of small neoplasms.