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Objective: Epigenetic changes contribute to pancreatic neuroendocrine tumor (PanNET) development. Hypermethylation of promoter DNA as a cause of tumor suppressor gene silencing is a well-established oncogenic mechanism that is potentially reversible and therefore an interesting therapeutic target. Multiple endocrine neoplasia type 1 (MEN1) is the most frequent cause of inherited PanNETs. The aim of this study was to determine promoter methylation profiles in MEN1-related PanNETs. Design and methods: Methylation-specific multiplex ligation-dependent probe amplification was used to assess promoter methylation of 56 tumor suppressor genes in MEN1-related (n = 61) and sporadic (n = 34) PanNETs. Differences in cumulative methylation index (CMI), individual methylation percentages and frequency of promoter hypermethylation between subgroups were analyzed. Results: We found promoter methylation of a large number of potential tumor suppressor genes. CMI (median CMI: 912 vs 876, P = 0.207) was the same in MEN1-related and sporadic PanNETs. We found higher methylation percentages of CASP8 in MEN1-related PanNETs (median: 59% vs 16.5%, P = 0.002). In MEN1-related non-functioning PanNETs, the CMI was higher in larger PanNETs (>2 cm) (median: 969.5 vs 838.5; P = 0.021) and in PanNETs with liver metastases (median: 1036 vs 869; P = 0.013). Hypermethylation of MGMT2 was more frequent in non-functioning PanNETs compared to insulinomas (median: 44.7% vs 8.3%; P = 0.022). Hypermethylation of the Von Hippel-Lindau gene promoter was observed in one MEN1-related PanNET and was associated with loss of protein expression. Conclusion: Promoter hypermethylation is a frequent event in MEN1-related and sporadic PanNETs. Targeting DNA methylation could be of therapeutic value in MEN1 patients with advanced PanNETs. [ABSTRACT FROM AUTHOR]

Background: Oxaliplatin and 5-fluorouracil (5-FU) currently form the backbone of conservative treatment in patients with metastatic colorectal cancer. Tumour responses to these agents are highly variable, but the underlying mechanisms are poorly understood. Our previous results have indicated that oncogenic KRAS in colorectal tumour cells sensitises these cells to chemotherapy.Methods: FACS analysis was used to determine cell-cycle distribution and the percentage of apoptotic and mitotic cells. A multiplexed RT-PCR assay was used to identify KRAS-controlled apoptosis regulators after exposure to 5-FU or oxaliplatin. Lentiviral expression of short-hairpin RNAs was used to suppress p53 or Noxa.Results: Oncogenic KRAS sensitised colorectal tumour cells to oxaliplatin and 5-FU in a p53-dependent manner and promoted p53 phosphorylation at Ser37 and Ser392, without affecting p53 stabilisation, p21 induction, or cell-cycle arrest. Chemotherapy-induced expression of the p53 target gene Noxa was selectively enhanced by oncogenic KRAS. Suppression of Noxa did not affect p21 induction or cell-cycle arrest, but reduced KRAS/p53-dependent apoptosis after exposure to chemotherapy in vitro and in tumour xenografts. Noxa suppression did not affect tumour growth per se, but strongly reduced the response of these tumours to chemotherapy.Conclusion: Oncogenic KRAS determines the cellular response to p53 activation by oxaliplatin or 5-FU, by facilitating apoptosis induction through Noxa. [ABSTRACT FROM AUTHOR]

The article presents a study on the short-term and mid-term results of robot-assisted thoracoscopic oesophagectomy (RTO) with two-field lymph node dissection. It notes that the method used was to gather clinical data from the 47 patients with oesophageal cancer who underwent RTO. The results prove that RTO was acceptable in oncology and suggests that operating time, blood loss, and pulmonary complications might decrease with more experience.

Aims: The mammalian target of rapamycin (mTOR), an important regulator of protein translation and cell proliferation, is activated in various malignancies. In a randomised controlled trial of advanced renal cell carcinoma patients, targeted therapy to mTOR by means of rapamycin analogues has been shown to significantly improve survival. An in vitro study has revealed that mTOR is activated in oesophageal squamous cell carcinoma (OSCC) cell lines and that mTOR expression is inhibited by rapamycin. The objectives of this histological study were to determine the proportion of OSCC tissues with activated mTOR (p-mTOR) expression, thereby assessing the percentage of patients with OSCC that would possibly benefit from neoadjuvant rapamycin therapy, and to identify the clinicopathological features of these potentially rapamycin-sensitive tumours. Methods: The expression of p-mTOR (Ser2448) was immunohistochemically assessed in a validated tissue microarray comprising triplicate tissue biopsy cores of 108 formalin-fixed, paraffin-embedded OSCCs. Staining results were correlated with clinicopathological data. Results: Normal oesophageal epithelium was negative for p-mTOR. Activated mTOR expression was located in the cytoplasm of oesophageal tumour cells. 26 (25%) of 105 assessable OSCCs showed tumour cells with positive staining for activated mTOR. Activated mTOR expression was associated with a lesser degree of differentiation only (p = 0.024). No correlation was detected between p-mTOR and the proliferation marker Ki-67. Conclusions: Activated mTOR can be detected in one-quarter of OSCCs. Since this subset of patients may potentially benefit from mTOR inhibiting therapy, a phase II clinical trial of neoadjuvant mTOR-inhibiting therapy in patients with OSCC may be considered. [ABSTRACT FROM AUTHOR]

Background: Temporary vascular clamping during local ablation for colorectal liver metastases increases destruction volumes. However, it also causes ischaemia-reperfusion (IR) injury to the liver parenchyma and accelerates the outgrowth of microscopic tumour deposits. The aim of this study was to investigate the effects of selective portal clamping on hepatocellular damage and tumour growth. Methods: Mice carrying pre-established hepatic colorectal micrometastases underwent either simultaneous clamping of both the portal vein and the hepatic artery or selective clamping of the portal vein to the median and left liver lobes for 45 min. Sham-operated mice served as controls. Hepatic injury and tumour growth were assessed over time. Results: Standard inflow occlusion resulted in a rise in liver enzymes, a local inflammatory response and hepatocellular necrosis. The outgrowth of pre-established micrometastases was accelerated three- to fourfold in clamped compared with non-clamped liver lobes (27.4 versus 7.8 per cent, P < 0.010). Conversely, selective portal clamping induced minimal liver injury, tissue inflammation or hepatocellular necrosis, and completely stopped the accelerated outgrowth of micrometastases. Conclusion: Selective portal clamping does not induce liver tissue damage or accelerate micrometastasis outgrowth and may therefore be the preferable clamping method during local ablative treatment of hepatic metastases. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Robotically assisted laparoscopic transhiatal esophagectomy," by C. A. Galvani and colleagues in the January 2008 issue.

Background: Active efflux of irinotecan by ATP-binding cassette (ABC)-transporters, in particular ABCB1 and ABCG2, is a well-established drug resistance mechanism in vitro and in pre-clinical mouse models, but its relevance in colorectal cancer (CRC) patients is unknown. Therefore, we assessed the association between ABC-transporter expression and tumour response to irinotecan in patients with metastatic CRC., Methods: Tissue microarrays of a large cohort of metastatic CRC patients treated with irinotecan in a prospective study (CAIRO study; n=566) were analysed for expression of ABCB1 and ABCG2 by immunohistochemistry. Kaplan-Meier and Cox proportional hazard regression analyses were performed to assess the association of ABC transporter expression with irinotecan response. Gene expression profiles of 17 paired tumours were used to assess the concordance of ABCB1/ABCG2 expression in primary CRC and corresponding metastases., Results: The response to irinotecan was not significantly different between primary tumours with positive versus negative expression of ABCB1 (5.8 vs 5.7 months, p=0.696) or ABCG2 (5.7 vs 6.1 months, p=0.811). Multivariate analysis showed neither ABCB1 nor ABCG2 were independent predictors for progression free survival. There was a mediocre to poor concordance between ABC-transporter expression in paired tumours., Conclusion: In metastatic CRC, ABC-transporter expression in the primary tumour does not predict irinotecan response.

Thyroid cancer is the most common endocrine neoplasm accounting for approximately 1,7% of total cancer diagnoses. The gold standard for evaluation of thyroid nodules is cytology from fine needle aspiration. In 30% of biopsies there is no conclusive diagnosis and patients undergo a diagnostic hemithyroidectomy. Somatic mutations occur frequently in thyroid cancer, the value of testing FNA biopsies on different mutation is analyzed, it improves accuracy, but their sensitivity is low. Another class of molecules with potential diagnostic value are miRNAs (miRNA, miR). MiRNAs function as gene regulators thereby controlling many cellular processes including cell growth, differentiation, proliferation, and apoptosis. Several studies have analyzed the expression of miRNAs in thyroid cancer, either by performing microarray analyses or validating a set of miRNAs. Recent reports focused on the diagnostic value of miRNAs in indeterminate FNA biopsies. In this systematic review we will provide an overview of all miRNAs found to be up- or downregulated in the different types of thyroid carcinomas, give an overview of the value of validated sets of microRNAs or single microRNAs in distinguishing malignant from benign lesions and conclude with a clinical view on future study strategies.

Background: Although total parathyroidectomy with forearm autotransplantation is a widely accepted treatment for patients with secondary/tertiary hyperparathyroidism (HPT) some debate persists about the optimal surgical strategy. In particular, the question what to do when less than four parathyroid glands can be found during surgery has yet to be resolved. The aim of this retrospective study was to review the outcome of total parathyroidectomy with autotransplantation and to assess the proper procedure (to autotransplant or not) when finding less than 4 glands after extensive surgical exploration., Methods: Between 1995 and 2005, parathyroidectomy was performed in 74 patients in two affiliated centers. In this case-control study both clinical and biochemical outcomes of a total or subtotal parathyroidectomy were compared. The parathyroid hormone (PTH), serum calcium concentration, phosphate and alkaline phosphatase levels were monitored preoperatively, 1 and 12 months postoperatively., Results: Sixty five patients underwent a total parathyroidectomy and nine patients underwent a subtotal parathyroidectomy. Persistent HPT was seen in nine patients (12%). Recurrent HPT was seen in eight patients (11%). There were no significant differences between the group with > or = 4 glands excised and the group with three glands excised regarding serum PTH levels after 12 months and the number of patients with a hypo- or hyperparathyroidism (persistent or recurrent). Procedure related morbidity was minimal., Conclusions: Total parathyroidectomy with forearm autotransplantation is safe and effective for patients with secondary/tertiary hyperparathyroidism. In case of not finding a fourth gland after extensive surgical exploration, our general advice is to proceed as planned with the autotransplantation.

CT and ultrasound have been advocated to improve the diagnostic accuracy and management of appendicitis. However, these were single-centre studies, performed by specialised radiologists and with a low level of evidence. Most of the literature shows no increase in diagnostic accuracy or decrease of negative appendectomies if radiographic imaging techniques are applied. However these techniques do lead to disadvantages such as radiation load and unnecessary prolongation of the diagnostic phase. Therefore, CT or ultrasound are of no use in the diagnosis and management of acute appendicitis.