Menno R. Vriens

MicroRNA expression profiling is a potential diagnostic tool for thyroid cancer

Approximately 30% of fine‐needle aspiration (FNA) biopsies of thyroid nodules are indeterminate or nondiagnostic. Recent studies suggest microRNA (miRNA, miR) is differentially expressed in malignant tumors and may have a role in carcinogenesis, including thyroid cancer. The authors therefore tested the hypothesis that miRNA expression analysis would identify putative markers that could distinguish benign from malignant thyroid neoplasms that are often indeterminate on FNA biopsy.

Loss of ATRX or DAXX expression and concomitant acquisition of the alternative lengthening of telomeres phenotype are late events in a small subset of MEN-1 syndrome pancreatic neuroendocrine tumors

Approximately 45% of sporadic well-differentiated pancreatic neuroendocrine tumors harbor mutations in either ATRX (alpha thalassemia/mental retardation X-linked) or DAXX (death domain-associated protein). These novel tumor suppressor genes encode nuclear proteins that interact with one another and function in chromatin remodeling at telomeric and peri-centromeric regions. Mutations in these genes are associated with loss of their protein expression and correlate with the alternative lengthening of telomeres phenotype. Patients with multiple endocrine neoplasia-1 (MEN-1) syndrome, genetically defined by a germ line mutation in the MEN1 gene, are predisposed to developing pancreatic neuroendocrine tumors and thus represent a unique model for studying the timing of ATRX and DAXX inactivation in pancreatic neuroendocrine tumor development. We characterized ATRX and DAXX protein expression by immunohistochemistry and telomere status by telomere-specific fluorescence in situ hybridization in 109 well-differentiated pancreatic neuroendocrine lesions from 28 MEN-1 syndrome patients. The study consisted of 47 neuroendocrine microadenomas (<0.5 cm), 50 pancreatic neuroendocrine tumors (≥0.5 cm), and 12 pancreatic neuroendocrine tumor lymph node metastases. Expression of ATRX and DAXX was intact in all 47 microadenomas, and none showed the alternative lengthening of telomeres phenotype. ATRX and/or DAXX expression was lost in 3 of 50 (6%) pancreatic neuroendocrine tumors. In all three of these, tumor size was ≥3 cm, and loss of ATRX and/or DAXX expression correlated with the alternative lengthening of telomeres phenotype. Concurrent lymph node metastases were present for two of the three tumors, and each metastasis displayed the same changes as the primary tumor. These findings establish the existence of ATRX and DAXX defects and the alternative lengthening of telomeres phenotype in pancreatic neuroendocrine tumors in the context of MEN-1 syndrome. The observation that ATRX and DAXX defects and the alternative lengthening of telomeres phenotype occurred only in pancreatic neuroendocrine tumors measuring ≥3 cm and their lymph node metastases suggests that these changes are late events in pancreatic neuroendocrine tumor development.

Clinical Features and Genetic Predisposition to Hereditary Nonmedullary Thyroid Cancer

BACKGROUND Approximately 5% of the nonmedullary thyroid cancers are hereditary. Hereditary nonmedullary thyroid cancer may occur as a minor component of familial cancer syndromes (familial adenomatous polyposis, Gardners syndrome, Cowdens disease, Carneys complex type 1, Werners syndrome, and papillary renal neoplasia) or as a primary feature (familial nonmedullary thyroid cancer [FNMTC]). The goal of this article was to review our current knowledge on the hereditary nonmedullary thyroid cancer. SUMMARY Epidemiologic and clinical kindred studies have demonstrated that FNMTC is a unique clinical entity. Most studies suggest that FNMTC is associated with more aggressive disease than sporadic cases, with higher rates of multicentric tumors, lymph node metastasis, extrathyroidal invasion, and shorter disease-free survival. A hereditary predisposition to nonmedullary thyroid cancer is well established, but the susceptibility genes for isolated FNMTC have not been identified. However, additional susceptibility loci for FNMTC have been recently identified in classic isolated cases of FNMTC (1q21, 6q22, 8p23.1-p22, and 8q24). CONCLUSIONS More studies are needed to validate chromosomal susceptibility loci and identify the susceptibility genes for FNMTC. The discovery of the predisposing genes may allow for screening and early diagnosis, which could lead to improved outcomes for patients and their families.

Robot-assisted pancreatic surgery: a systematic review of the literature

BACKGROUND To potentially improve outcomes in pancreatic resection, robot-assisted pancreatic surgery has been introduced. This technique has possible advantages over laparoscopic surgery, such as its affordance of three-dimensional vision and increased freedom of movement of instruments. A systematic review was performed to assess the safety and feasibility of robot-assisted pancreatic surgery. METHODS The literature published up to 30 September 2011 was systematically reviewed, with no restrictions on publication date. Studies reporting on over five patients were included. Animal studies, studies not reporting morbidity and mortality, review articles and conference abstracts were excluded. Data were extracted and weighted means were calculated. RESULTS A total of 499 studies were screened, after which eight cohort studies reporting on a total of 251 patients undergoing robot-assisted pancreatic surgery were retained for analysis. Weighted mean operation time was 404 ± 102 min (510 ± 107 min for pancreatoduodenectomy only). The rate of conversion was 11.0% (16.4% for pancreatoduodenectomy only). Overall morbidity was 30.7% (n = 77), most frequently involving pancreatic fistulae (n = 46). Mortality was 1.6%. Negative surgical margins were obtained in 92.9% of patients. The rate of spleen preservation in distal pancreatectomy was 87.1%. CONCLUSIONS Robot-assisted pancreatic surgery seems to be safe and feasible in selected patients and, in left-sided resections, may increase the rate of spleen preservation. Randomized studies should compare the respective outcomes of robot-assisted, laparoscopic and open pancreatic surgery.

Efficacy and complications of nasojejunal, jejunostomy and parenteral feeding after pancreaticoduodenectomy.

BackgroundEuropean nutritional guidelines recommend routine use of enteral feeding after pancreaticoduodenectomy (PD) whereas American guidelines do not. Data on the efficacy and, especially, complications of the various feeding strategies after PD are scarce.MethodsRetrospective monocenter cohort study in 144 consecutive patients who underwent PD during a period wherein the routine post-PD feeding strategy changed twice. Patients not receiving nutritional support (n=15) were excluded. Complications were graded according to the Clavien-Dindo classification and the International Study Group of Pancreatic Surgery (ISGPS) definitions. Analysis was by intention-to-treat. Primary endpoint was the time to resumption of normal oral intake.Results129 patients undergoing PD (111 pylorus preserving) were included. 44 patients (34%) received enteral nutrition via nasojejunal tube (NJT), 48 patients (37%) via jejunostomy tube (JT) and 37 patients (29%) received total parenteral nutrition (TPN). Groups were comparable with respect to baseline characteristics, Clavien ≥II complications (P=0.99), in-hospital stay (P=0.83) and mortality (P=0.21). There were no differences in time to resumption of normal oral intake (primary endpoint; NJT/JT/TPN: median 13, 16 and 14 days, P=0.15) and incidence of delayed gastric emptying (P=0.30). Duration of enteral nutrition was shorter in the NJT- compared to the JT- group (median 8 vs. 12 days, P=0.02). Tube related complications occurred mainly in the NJT-group (34% dislodgement). In the JT-group, relaparotomy was performed in three patients (6%) because of JT-leakage or strangulation leading to death in one patient (2%). Wound infections were most common in the TPN group (NJT/JT/TPN: 16%, 6% and 30%, P=0.02).ConclusionNone of the analysed feeding strategies was found superior with respect to time to resumption of normal oral intake, morbidity and mortality. Each strategy was associated with specific complications. Nasojejunal tubes dislodged in a third of patients, jejunostomy tubes caused few but potentially life-threatening bowel strangulation and TPN doubled the risk of infections.

Clinical Spectrum of Pheochromocytoma

BACKGROUND Pheochromocytomas vary in presentation, tumor size, and in catecholamine production. Whether pheochromocytoma size correlates with hormone levels, clinical presentation, and perioperative complications is not known. The goal of this study was to determine if tumor size and hormone level correlate according to the clinical presentation at diagnosis. STUDY DESIGN We retrospectively analyzed all patients who underwent an adrenalectomy with a diagnosis of a pheochromocytoma from February 1996 to October 2008. We grouped patients according to their clinical presentation at diagnosis (routine biochemical screening, incidentaloma, classic symptoms, pheochromocytoma crisis) and obtained preoperative radiographic tumor size and catecholamine hormone levels. ANOVA was used for the group effects and the Kruskal-Wallis rank test was used for pairwise comparison between groups with the Sidak/Bonferroni method for multiplicity adjustment according to age, tumor size, and hormone level. The Pearson correlation coefficient was then calculated to determine if hormone level correlated with tumor size. RESULTS Eighty-one of 107 patients had data available for complete analysis. The average age at diagnosis for all patients was 47.1 years, and the average tumor size was 4.9 cm. The average highest hormone ratio among all patients was 27.4. Tumor size and hormone ratio levels differed among all groups (p < or = 0.03). A direct correlation (p = 0.014) was apparent between tumor size and hormone level. Complication rates also differed among the four groups of patients (p < or = 0.02). CONCLUSIONS Our study showed that tumor size directly correlates with hormone level. Smaller tumors tend to secrete lower levels of catecholamines, but larger tumors have a wider variation in secretory potential. Larger tumors, however, produced the highest hormone ratios.

Acquisition and Cross-Transmission of Staphylococcus aureus in European Intensive Care Units

OBJECTIVE To study the acquisition and cross-transmission of Staphylococcus aureus in different intensive care units (ICUs). METHODS We performed a multicenter cohort study. Six ICUs in 6 countries participated. During a 3-month period at each ICU, all patients had nasal and perineal swab specimens obtained at ICU admission and during their stay. All S. aureus isolates that were collected were genotyped by spa typing and multilocus variable-number tandem-repeat analysis typing for cross-transmission analysis. A total of 629 patients were admitted to ICUs, and 224 of these patients were found to be colonized with S. aureus at least once during ICU stay (22% were found to be colonized with methicillin-resistant S. aureus [MRSA]). A total of 316 patients who had test results negative for S. aureus at ICU admission and had at least 1 follow-up swab sample obtained for culture were eligible for acquisition analysis. RESULTS A total of 45 patients acquired S. aureus during ICU stay (31 acquired methicillin-susceptible S. aureus [MSSA], and 14 acquired MRSA). Several factors that were believed to affect the rate of acquisition of S. aureus were analyzed in univariate and multivariate analyses, including the amount of hand disinfectant used, colonization pressure, number of beds per nurse, antibiotic use, length of stay, and ICU setting (private room versus open ICU treatment). Greater colonization pressure and a greater number of beds per nurse correlated with a higher rate of acquisition for both MSSA and MRSA. The type of ICU setting was related to MRSA acquisition only, and the amount of hand disinfectant used was related to MSSA acquisition only. In 18 (40%) of the cases of S. aureus acquisition, cross-transmission from another patient was possible. CONCLUSIONS Colonization pressure, the number of beds per nurse, and the treatment of all patients in private rooms correlated with the number of S. aureus acquisitions on an ICU. The amount of hand disinfectant used was correlated with the number of cases of MSSA acquisition but not with the number of cases of MRSA acquisition. The number of cases of patient-to-patient cross-transmission was comparable for MSSA and MRSA.

Low accuracy of tumor markers for diagnosing pancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1 patients

CONTEXT The assessment of tumor markers for diagnosing pancreatic neuroendocrine tumors (pNET) in multiple endocrine neoplasia type 1 (MEN1) patients is advised in the current guidelines but has never been validated for this purpose. OBJECTIVE The objective of the study was to assess the diagnostic accuracy of chromogranin A (CgA), pancreatic polypeptide (PP), and glucagon for pNET in MEN1. DESIGN This was a diagnostic study. SETTING The study was conducted at Dutch university medical centers from 2008 to 2011, representing 90% of the total Dutch MEN1 population. PATIENTS AND METHODS Patients for whom data on tumor markers in combination with the reference standard (ie, radiological imaging) were available between 2008 and 2011 were included. The reference standard for the presence of pNET was pathology or detection on magnetic resonance imaging, computed tomography, or endoscopic ultrasound confirmed on subsequent imaging, irrespective of modality at follow-up. MAIN OUTCOME MEASURES The area under the receiver-operating characteristic curve (AUC), positive predictive value, negative predictive value, positive likelihood ratio, negative likelihood ratio, sensitivity, and specificity were calculated for each marker. RESULTS For the analysis of PP, CgA, and glucagon, 73, 81, and 94 patients were available, respectively. The AUC for CgA was 0.48 [95% confidence interval (CI) 0.35-0.61] with a sensitivity 0.33 and a specificity 0.73; the AUC for glucagon was 0.58 (95% CI 0.46-0.70) with a sensitivity 0.43 and a specificity 0.73; and the AUC for PP was 0.64 (95% CI 0.50-0.77) with a sensitivity 0.36 and a specificity 0.74. Age, imaging modality, tumor size, and number did not influence the outcomes. CONCLUSION The diagnostic accuracy of the tumor markers CgA, PP, and glucagon for pNET in MEN1 is low.

Role of fine-needle aspiration biopsy and frozen section examination in determining the extent of thyroidectomy.

Abstract. Traditionally the extent of thyroidectomy in patients with nodular thyroid disease has been based on peroperative frozen section examination (FS). Fine-needle aspiration biopsy (FNAB) and FS were evaluated with regard to the reliability to determine whether an operation for cancer is necessary. Both methods were performed in 240 patients operated for nodular thyroid disease and compared with the final histology on paraffin sections. Altogether 72 (30%) patients were found to have a malignant lesion on final histology. Only a malignant FNAB diagnosis and a malignant FS diagnosis were considered positive results for determining the extent of thyroidectomy. The test characteristics were equal: the sensitivity of FNAB and FS was 67%, the specificity 99%, and the accuracy 89%. The positive predictive value was 96% for FNAB and 98% for FS; the negative predictive values were 88% and 87%, respectively. Further analysis of the results indicates that FS is not necessary for patients with a malignant FNAB result. These patients should undergo a therapeutic operation for malignancy. When the FNAB result is uncertain, patients should undergo diagnostic surgery, and definitive surgery should be based on the final histology. Routine use of FS can be omitted.

Clinical and molecular features of papillary thyroid cancer in adolescents and young adults

Age disparities in thyroid cancer incidence and outcome among adolescents and young adults (AYAs) with thyroid cancer are under reported. In this study, the authors compared the molecular and clinical features of papillary thyroid cancer (PTC) in AYAs with the same features among patients in other age groups.