Dragon 1 Protocol Manuscript: Training, Accreditation, Implementation and Safety Evaluation of Portal and Hepatic Vein Embolization (PVE/HVE) to Accelerate Future Liver Remnant (FLR) Hypertrophy.

STUDY PURPOSE: The DRAGON 1 trial aims to assess training, implementation, safety and feasibility of combined portal- and hepatic-vein embolization (PVE/HVE) to accelerate future liver remnant (FLR) hypertrophy in patients with borderline resectable colorectal cancer liver metastases. METHODS: The DRAGON 1 trial is a worldwide multicenter prospective single arm trial. The primary endpoint is a composite of the safety of PVE/HVE, 90-day mortality, and one year accrual monitoring of each participating center. Secondary endpoints include: feasibility of resection, the used PVE and HVE techniques, FLR-hypertrophy, liver function (subset of centers), overall survival, and disease-free survival. All complications after the PVE/HVE procedure are documented. Liver volumes will be measured at week 1 and if applicable at week 3 and 6 after PVE/HVE and follow-up visits will be held at 1, 3, 6, and 12 months after the resection. RESULTS: Not applicable. CONCLUSION: DRAGON 1 is a prospective trial to assess the safety and feasibility of PVE/HVE. Participating study centers will be trained, and procedures standardized using Work Instructions (WI) to prepare for the DRAGON 2 randomized controlled trial. Outcomes should reveal the accrual potential of centers, safety profile of combined PVE/HVE and the effect of FLR-hypertrophy induction by PVE/HVE in patients with CRLM and a small FLR. TRIAL REGISTRATION: Clinicaltrials.gov: NCT04272931 (February 17, 2020). Toestingonline.nl: NL71535.068.19 (September 20, 2019).

ABC-Transporter Expression Does Not Correlate with Response to Irinotecan in Patients with Metastatic Colorectal Cancer.

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.

Maspin is a marker for early recurrence in primary stage III and IV colorectal cancer.

BACKGROUND: Little is known about the factors that drive metastasis formation in colorectal cancer (CRC). Here, we set out to identify genes and proteins in patients with colorectal liver metastases that correlate with early disease recurrence. Such factors may predict a propensity for metastasis in earlier stages of CRC. METHODS: Gene expression profiling and proteomics were used to identify differentially expressed genes/proteins in resected liver metastases that recurred within 6 months following liver surgery vs those that did not recur for >24 months. Expression of the identified genes/proteins in stage II (n=243) and III (n=176) tumours was analysed by immunohistochemistry on tissue microarrays. Correlation of protein levels with stage-specific outcome was assessed by uni- and multivariable analyses. RESULTS: Both gene expression profiling and proteomics identified Maspin to be differentially expressed in colorectal liver metastases with early (<6 months) and prolonged (>24 months) time to recurrence. Immunohistochemical analysis of Maspin expression on tumour sections revealed that it was an independent predictor of time to recurrence (log-rank P=0.004) and CRC-specific survival (P=0.000) in stage III CRC. High Maspin expression was also correlated with mucinous differentiation. In stage II CRC patients, high Maspin expression did not correlate with survival but was correlated with a right-sided tumour location. CONCLUSION: High Maspin expression correlates with poor outcome in CRC after spread to the local lymph nodes. Therefore, Maspin may have a stage-specific function possibly related to tumour cell dissemination and/or metastatic outgrowth.

Patient tailored resection planning in patients undergoing liver surgery for colorectal liver metastases; how and why should you do it?

BACKGROUND: A systematic preoperative evaluation to determine the individual resection strategy in patients with colorectal liver metastases (CRLM) was assessed as to its clinical value. PATIENTS AND METHODS: From 2009 to 2011, 75 patients with CRLM who were scheduled for surgery were prospectively included and received an additional preoperative systematic evaluation in the presence of a hepatobiliary radiologist and the hepatobiliary surgeon scheduled to perform the surgery. The following items were assessed in a standardized manner: lesion detection and characterization, presence of extrahepatic disease, vascular anatomy, and resection strategy. Intraoperative findings and histopathological results were prospectively recorded. RESULTS: Five out of 75 patients were not considered to be eligible for surgery due to additional findings, such as additional metastases or extrahepatic disease. Sensitivity and specificity for detection of individual CRLM were 80.9% (95% CI 75.7-86.1%) and 69.1% (95% CI 59.1-79.1%), respectively. Radical resections were performed in 87.1%. There was one futile laparotomy (1.4%). CONCLUSION: In patients with colorectal liver metastases, standardized preoperative work-up, with subsequent planning of an individualized resection in a jointed meeting of a hepatobiliary radiologist and the surgeon who will perform the operation, leads to a high level of radical resections and a low number of futile laparotomies.

The value of miRNA in diagnosing thyroid cancer: a systematic review.

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.

Retroperitoneal endoscopic adrenalectomy is safe and effective.

BACKGROUND: The aim of this study was to review an experience with retroperitoneal endoscopic adrenalectomy (REA). This is the procedure of choice for adrenal tumours at this institution. METHODS: Between 1997 and 2008, 112 REAs were performed in a single university centre. Data were retrieved retrospectively from a prospectively collected database, including information on patient demographics, surgical procedure, complications and hospital stay. RESULTS: One hundred and twelve REAs were carried out successfully in 105 patients, including seven bilateral adrenalectomies. Thirty-nine patients with unilateral adrenal disease had a phaeochromocytoma, of whom 16 had multiple endocrine neoplasia syndrome type 2, 21 patients had Cushing's disease and 20 had Conn's disease. Median body mass index was 27 (interquartile range 23-29) kg/m(2). The median duration of unilateral operations was 100 (90-130) min with a median blood loss of 5 ml. Median tumour size was 3.1 (2.0-4.4) cm. Conversion from REA to open surgery was needed in two patients. Seven patients experienced postoperative complications (2 major, 5 minor). One patient needed a reoperation. The median postoperative hospital stay was 3 days. A learning curve with a significant decrease in operating time was observed over the years. CONCLUSION: REA appears to be a safe and effective surgical technique for adrenal gland tumours up to 6 cm in diameter, with a minimal complication rate.

Surgical strategy in patients with secondary and tertiary hyperparathyroidism. A bi-institutional series.

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.

Multiple endocrine neoplasia type 1 (MEN1): its manifestations and effect of genetic screening on clinical outcome.

OBJECTIVE: Effect of genetic screening on outcome in multiple endocrine neoplasia type 1 (MEN1) remains unclear. Expression of MEN1 is described using currently available diagnostic techniques. Manifestations and outcome are compared in patients diagnosed because of clinical expression with those diagnosed by genetic screening. DESIGN: Retrospective cohort study. Patients are divided into two groups: patients with a (i) clinical MEN1 diagnosis and (ii) MEN1 diagnosis by genetic screening. PATIENTS AND MEASUREMENTS: Demographic and clinical data were collected on MEN1 patients treated in the UMCU up to 1 January 2008. Results of mutation analysis were obtained from the Department of Medical Genetics. RESULTS: A total of 74 patients was included (median follow-up 5.5 year); 78% had hyperparathyroidism, 46% a pancreatic neuro-endocrine tumour (NET), 38% a pituitary abnormality, 8% a NET of other origin and 16% an adrenal adenoma at the end of follow-up. Of the patients 18% had no manifestation. All five MEN1-related tumours were seen as first manifestation. Compared with patients identified by genetic screening, patients with a clinical MEN1 diagnosis had significantly more manifestations at diagnosis (P < 0.001) and at end of follow-up (P = 0.002). Eleven of 30 patients with a genetic MEN1 diagnosis (mean age at diagnosis 30.0 years) already had manifestations at diagnosis. No malignancy or death was seen in genetically diagnosed patients. CONCLUSIONS: MEN1 is a syndrome with high morbidity. Genetic diagnosis is associated with less morbidity at diagnosis and at follow-up. Early genetic diagnosis might therefore lead to improvement of long-term outcome.

mTOR in squamous cell carcinoma of the oesophagus: a potential target for molecular therapy?

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.

Virtual reality training for endoscopic surgery: voluntary or obligatory?

INTRODUCTION: Virtual reality (VR) simulators have been developed to train basic endoscopic surgical skills outside of the operating room. An important issue is how to create optimal conditions for integration of these types of simulators into the surgical training curriculum. The willingness of surgical residents to train these skills on a voluntary basis was surveyed. METHODS: Twenty-one surgical residents were given unrestricted access to a VR simulator for a period of four months. After this period, a competitive element was introduced to enhance individual training time spent on the simulator. The overall end-scores for individual residents were announced periodically to the full surgical department, and the winner was awarded a prize. RESULTS: In the first four months of study, only two of the 21 residents (10%) trained on the simulator, for a total time span of 163 minutes. After introducing the competitive element the number of trainees increased to seven residents (33%). The amount of training time spent on the simulator increased to 738 minutes. CONCLUSIONS: Free unlimited access to a VR simulator for training basic endoscopic skills, without any form of obligation or assessment, did not motivate surgical residents to use the simulator. Introducing a competitive element for enhancing training time had only a marginal effect. The acquisition of expensive devices to train basic psychomotor skills for endoscopic surgery is probably only effective when it is an integrated and mandatory part of the surgical curriculum.

[Ancillary diagnostic imaging is undesirable if there is evidence of appendicitis]. / Aanvullend beeldvormend onderzoek is ongewenst bij aanwijzingen voor appendicitis.

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.