Feasibility of Narrow-Band Imaging, Intraductal Biopsy, and Laser Ablation During Mammary Ductoscopy: Protocol for an Interventional Study.

Introduction: Ductoscopy is a minimally invasive micro-endoscopic approach for direct visualization of intraductal lesions of the breast. Challenges of ductoscopy are low sensitivity for detecting malignancy, the lack of a proper intraductal biopsy device, and adequate treatment of intraductal lesions. This study will analyze three new approaches to enhance the effectiveness of interventional ductoscopy in patients with (premalignant) intraductal lesions: narrow-band imaging (NBI), new intraductal biopsy tools, and intraductal laser ablation. The main aims of the present study are to improve diagnostic accuracy and therapeutic efficacy of interventional ductoscopy in patients with pathological nipple discharge (PND) and to explore the feasibility of the new approaches in diagnosing and removing intraductal precursor lesions. Methods and analysis: This prospective, single-center, diagnostic feasibility study will include two patient groups. Group A: women with PND with no radiological suspicion for malignancy. Group B: women undergoing mastectomy (preventive or therapeutic). The primary endpoints for both groups are the technical feasibility of NBI ductoscopy, intraductal biopsy, and laser ablation, and as secondary endpoint the number of diagnosed and successfully treated intraductal lesions. Discussion: Enhanced ductoscopy with NBI, intraductal biopsy, and laser ablation could prevent unnecessary surgery in patients with PND. Ethics and dissemination: This study was approved by the Medical Research Ethics Committee UMC Utrecht in The Netherlands (METC protocol number 21-688/H-D). The results of this study will be published in peer-reviewed journals and presented at national and international conferences. Highlights: - Pathological nipple discharge (PND) is a common breast-related complaint in women.- Ductoscopy, a minimally invasive technique, is used in the treatment of PND.- This study will analyze three new approaches to enhance interventional ductoscopy of the breast: narrow-band imaging, new intraductal biopsy tools, and intraductal laser ablation in patients with (premalignant) intraductal lesions.

Robotic nipple-sparing mastectomy complication rate compared to traditional nipple-sparing mastectomy: a systematic review and meta-analysis.

Breast cancer is worldwide the most common cause of cancer in women and causes the second most common cancer-related death. Nipple-sparing mastectomy (NSM) is commonly used in therapeutic and prophylactic settings. Furthermore, (preventive) mastectomies are, besides complications, also associated with psychological and cosmetic consequences. Robotic NSM (RNSM) allows for better visualization of the planes and reducing the invasiveness. The aim of this study was to compare the postoperative complication rate of RNSM to NSM. A systematic search was performed on all (R)NSM articles. The primary outcome was determining the overall postoperative complication rate of traditional NSM and RNSM. Secondary outcomes were comparing the specific postoperative complication rates: implant loss, hematoma, (flap)necrosis, infection, and seroma. Forty-nine studies containing 13,886 cases of (R)NSM were included. No statistically significant differences were found regarding postoperative complications (RNSM 3.9%, NSM 7.0%, p = 0.070), postoperative implant loss (RNSM 4.1%, NSM 3.2%, p = 0.523), hematomas (RNSM 4.3%, NSM 2.0%, p = 0.059), necrosis (RNSM 4.3%, NSM 7.4%, p = 0.230), infection (RNSM 8.3%, NSM 4.0%, p = 0.054) or seromas (RNSM 3.0%, NSM 2.0%, p = 0.421). Overall, there are no statistically significant differences in complication rates between NSM and RNSM.

The association of socioeconomic status on treatment strategy in patients with stage I and II breast cancer in the Netherlands.

BACKGROUND: Previous studies have shown that socioeconomic status (SES) influences breast cancer therapy. However, these studies were performed in countries with unequal access to healthcare. Therefore, the aim of this study is to investigate whether SES also contributes to the likelihood of receiving a certain therapy in the Netherlands, a country with supposedly equal access to healthcare. MATERIALS AND METHODS: From the Netherlands Cancer Registry, 105,287 patients with newly diagnosed stage I or II breast cancer diagnosed between 2011 and 2018 were selected for analysis. SES was calculated from the average incomes of each postal code, which were divided into 10 deciles. Primary outcome was the effect of SES on the likelihood of undergoing surgery and secondary outcome was the effect of SES on the likelihood of the type of surgery. Both outcomes were corrected for patient, tumor, and hospital characteristics and were expressed as odds ratio (OR) with 95% confidence interval (CI). RESULTS: SES did not affect the likelihood of a breast cancer patient to undergo surgery (OR 1.00 per 10% stratum). In contrast, increased age and higher tumor stage were the most important factors determining whether patients underwent surgery. Patients with higher SES were less likely to undergo mastectomy (OR 0.98). Additionally, more recently diagnosed patients were less likely to undergo mastectomy (OR 0.93 per year) while patients with higher tumor stage were more likely to undergo mastectomy (OR 3.42). CONCLUSION: SES does not affect whether a patient undergoes surgery; however, higher SES increased the likelihood of BCT.

Meta-analysis and cost-effectiveness of ductoscopy, duct excision surgery and MRI for the diagnosis and treatment of patients with pathological nipple discharge.

INTRODUCTION: Pathological nipple discharge (PND) is a common breast-related complaint for referral to a surgical breast clinic because of its association with breast cancer. The aim of this meta-analysis was to compare the diagnostic efficacy of magnetic resonance imaging (MRI) and ductoscopy in patients with PND. Additionally, we determined the most cost-efficient strategy for the treatment of PND and the detection of breast cancer in PND patient without radiological suspicion for malignancy. MATERIALS AND METHODS: PubMed and EMBASE were searched to collect the relevant literature from the inception of both diagnostic methods until January 27th 2020. The search yielded 815 original citations, of which 10 studies with 894 patients were finally included for analysis. Costs of ductoscopy, MRI and duct excision surgery were obtained from the UMC Utrecht as established in the year 2019. These costs included: medical personnel, overhead costs, material costs and sterilisation costs. RESULTS: The meta-analysis showed no significant difference in sensitivity between ductoscopy (44%) and MRI (76%) for the detection of malignancy in patients with PND. However, ductoscopy (98%) had a statistically significantly higher specificity than MRI (84%). Individual costs were €1401.33, €822.13 and €6494.27 for ductoscopy, MRI and duct excision surgery, respectively. Full diagnostic strategy involving ductoscopy was on average €1670.97, while with MRI it was €2070.27. CONCLUSION: Patients undergoing MRI are more often (false) positive which more often leads to duct excision surgery referrals compared to ductoscopy. This makes ductoscopy significantly more cost-effective compared MRI in patients with PND without radiological suspicion for malignancy.

Socioeconomic status significantly contributes to the likelihood of immediate postmastectomy breast reconstruction in the Netherlands: A nationwide study.

BACKGROUND: Previous studies have shown that breast cancer patients with a low socioeconomic status (SES) are less likely to undergo postmastectomy immediate breast reconstruction (IBR). However, these studies were performed in countries with unequal access to healthcare. Therefore, the aim of this study was to investigate whether SES also contributes to the likelihood of receiving IBR in a country with equal access to healthcare. MATERIALS AND METHODS: Patients with stage I or II breast cancer diagnosed between 2011 and 2018 who underwent mastectomy were selected from the Netherlands Cancer Registry. SES was calculated from the average incomes of each postal code which were divided into 10-deciles. Primary outcome was the effect of SES on the likelihood of receiving IBR, controlled for patient, tumour and hospital characteristics expressed as Odds Ratio (OR) with 95% confidence interval (CI). RESULTS: Higher SES significantly increased the probability of undergoing postmastectomy IBR (OR 1.05 per 10% SES stratum), just as larger hospital volume (average volume OR 1.89 and large volume 2.58), oestrogen positive tumours (OR 1.19) and neo-adjuvant therapy (OR 1.42). In contrast, factors significantly reducing the likelihood of receiving IBR were older age (OR 0.92 per year), stage II (OR 0.61 compared to stage I) and adjuvant therapy (OR 0.56). CONCLUSION: Women with lower SES undergoing mastectomy were less likely to receive postmastectomy IBR. More research is warranted to study whether lifestyle factors associated with lower SES such as smoking and higher BMI, language barrier, illiteracy and less access to internet explain these differences.

Patient-reported outcomes of ductoscopy procedures for pathologic nipple discharge.

BACKGROUND: Pathologic nipple discharge (PND) is a common complaint often associated with breast cancer. However, when ultrasound and mammography are negative, the chances of malignancy are lower than 5%. Currently, major duct excision and microdochectomy are often recommended to alleviate symptoms and definitely rule out malignancy, but can cause infections and breastfeeding problems. Ductoscopy is a minimally invasive endoscopy technique that allows visualization of the mammary ducts and may not only obviate surgery but also detect malignancy. The aim of this study was to determine quality of life (QOL) after ductoscopy in patients with PND. MATERIALS AND METHODS: All PND patients referred for ductoscopy between 2014 and 2015 to our hospital were included. Ductoscopy procedures were performed under local anaesthesia in the outpatient clinic. Patients were asked to fill out questionnaires (Breast-Q, EQ-5D-5L and SF-36) on the day of ductoscopy, and after 2 weeks, 3 and 6 months. Additionally, we performed reliability analysis to determine if these questionnaires were suitable for PND patients. RESULTS: Fifty consecutive patients underwent ductoscopy of whom 47 patients participated in this study. One domain of SF-36 (vitality) varied significantly over time. Breast-Q, SF-36 and EQ-5D-5L showed that QOL after ductoscopy for PND was unaffected by ductoscopy. Success of the ductoscopy procedure was a significant predictor for satisfaction with the result domain. CONCLUSION: Ductoscopy is a minimally invasive technique that does not seem to impact QoL of PND patients over time. Breast-Q, SF-36 and EQ-5D-5L seem to be suitable existing QOL tests for PND patients undergoing ductoscopy, whereas SF-36 would require modifications.

New national recommendations for the treatment of pediatric differentiated thyroid carcinoma in the Netherlands.

BACKGROUND: Currently, there are no European recommendations for the management of pediatric thyroid cancer. Other current international guidelines are not completely concordant. In addition, medical regulations differ between, for instance, the US and Europe. We aimed to develop new, easily accessible national recommendations for differentiated thyroid carcinoma (DTC) patients <18 years of age in the Netherlands as a first step toward a harmonized European Recommendation. METHODS: A multidisciplinary working group was formed including pediatric and adult endocrinologists, a pediatric radiologist, a pathologist, endocrine surgeons, pediatric surgeons, pediatric oncologists, nuclear medicine physicians, a clinical geneticist and a patient representative. A systematic literature search was conducted for all existing guidelines and review articles for pediatric DTC from 2000 until February 2019. The Appraisal of Guidelines, Research and Evaluation (AGREE) instrument was used for assessing quality of the articles. All were compared to determine dis- and concordances. The American Thyroid Association (ATA) pediatric guideline 2015 was used as framework to develop specific Dutch recommendations. Discussion points based upon expert opinion and current treatment management of DTC in children in the Netherlands were identified and elaborated. RESULTS: Based on the most recent evidence combined with expert opinion, a 2020 Dutch recommendation for pediatric DTC was written and published as an online interactive decision tree (www.oncoguide.nl). CONCLUSION: Pediatric DTC requires a multidisciplinary approach. The 2020 Dutch Pediatric DTC Recommendation can be used as a starting point for the development of a collaborative European recommendation for treatment of pediatric DTC.

Surgery for multiple endocrine neoplasia type 1-related insulinoma: long-term outcomes in a large international cohort.

BACKGROUND: Insulinomas are found in 10-15 per cent of patients with multiple endocrine neoplasia type 1 (MEN1) and lead to life-threatening hypoglycaemia. Surgical outcome and the optimal surgical strategy for MEN1-related insulinoma are unknown. METHODS: Patients with MEN1-related insulinomas were identified in 46 centres in Europe and North America between 1990 and 2016. Insulinomas were considered localized if the lesion was in the pancreatic head or body/tail. Patients with pancreatic neuroendocrine tumours throughout the pancreas were suspected of having multifocal insulinoma. The primary outcome was postoperative hypoglycaemia, defined as persistent hypoglycaemia, or recurrent hypoglycaemia caused by a new insulinoma or insulin-producing liver metastases. Hypoglycaemia-free survival was estimated by the Kaplan-Meier method. RESULTS: Ninety-six patients underwent resection for MEN1-related insulinoma. Sixty-three and 33 patients had localized and multifocal insulinomas respectively. After a median follow-up of 8 (range 1-22) years, one patient (1 per cent) had persistent disease and six (6 per cent) had developed recurrent disease, of whom four had a new insulinoma. The 10-year hypoglycaemia-free survival rate was 91 (95 per cent c.i. 80 to 96) per cent. Of those with localized disease, 46 patients underwent pancreatic resection and 17 enucleation. One of these patients had persistent disease and one developed recurrent insulinoma. Among patients with multifocal disease, three developed new insulinomas and two developed insulin-producing liver metastases. CONCLUSION: Surgery for MEN1-related insulinoma is more successful than previously thought.

ANTECEDENTES: Del 10% al 15% de los pacientes con MEN1 presentan insulinomas que pueden desencadenar una hipoglucemia potencialmente mortal. Se desconoce el resultado de la cirugía y la estrategia quirúrgica óptima para el tratamiento del insulinoma relacionado con el MEN1. MÉTODOS: Se identificaron los pacientes con insulinomas relacionados con el MEN1 en 46 centros de Europa y América del Norte entre 1990 y 2016. Los insulinomas se consideraron localizados si el tumor se localizaba en la cabeza o en el cuerpo/cola del páncreas. Se sospechó la existencia de un insulinoma multifocal en los pacientes con tumores neuroendocrinos pancreáticos (pNETs). El objetivo primario de este estudio fue evaluar la hipoglucemia postoperatoria, definida como hipoglucemia persistente, hipoglucemia recidivante causada por un nuevo insulinoma o debida a metástasis hepáticas productoras de insulina. La supervivencia libre de hipoglucemia se estimó mediante el método de Kaplan-Meier. RESULTADOS: A 96 se les realizó una resección por insulinoma en el contexto del MEN1. Un total de 63 y 33 pacientes presentaron insulinomas localizados y multifocales, respectivamente. Después de una mediana de seguimiento de 7,8 años (rango 1-22), un paciente (1%) tenía enfermedad persistente y seis pacientes (6%) presentaron enfermedad recidivante, de los cuales cuatro desarrollaron un nuevo insulinoma. La supervivencia libre de hipoglucemia fue del 91% a los 10 años (i.c. del 95%, 80%-96%). De los pacientes con enfermedad localizada, 46 fueron sometidos a resección pancreática y 17 pacientes a enucleación. Entre éstos, un paciente tenía enfermedad persistente y uno desarrolló insulinoma recidivante, respectivamente. De los pacientes con enfermedad multifocal, tres desarrollaron nuevos insulinomas y dos desarrollaron metástasis hepáticas productoras de insulina. CONCLUSIÓN: La cirugía para el insulinoma en el contexto del MEN1 es más exitosa de lo que parecía en principio.

Molecular prognostic factors in small-intestinal neuroendocrine tumours.

BACKGROUND: Small-intestinal neuroendocrine tumours (SI-NETs) represent a heterogeneous group of rare tumours. In recent years, basic research in SI-NETs has attempted to unravel the molecular events underlying SI-NET tumorigenesis. AIM: We aim to provide an overview of the current literature regarding prognostic and predictive molecular factors in patients with SI-NETs. METHOD: A PubMed search was conducted on (epi)genetic prognostic factors in SI-NETs from 2000 until 2019. RESULTS: The search yielded 1522 articles of which 20 reviews and 35 original studies were selected for further evaluation. SI-NETs are mutationally quiet tumours with a different genetic make-up compared to pancreatic NETs. Loss of heterozygosity at chromosome 18 is the most frequent genomic aberration (44-100%) followed by mutations of CDKN1B in 8%. Prognostic analyses were performed in 16 studies, of which 8 found a significant (epi)genetic association for survival or progression. Loss of heterozygosity at chromosome 18, gains of chromosome 4, 5, 7, 14 and 20p, copy gain of the SRC gene and low expression of RASSF1A and P16 were associated with poorer survival. In comparison with genetic mutations, epigenetic alterations are significantly more common in SI-NETs and may represent more promising targets in the treatment of SI-NETs. CONCLUSION: SI-NETs are mutationally silent tumours. No biomarkers have been identified yet that can easily be adopted into current clinical decision making. SI-NETs may represent a heterogeneous disease and larger international studies are warranted to translate molecular findings into precision oncology.

DNA methylation profiling in MEN1-related pancreatic neuroendocrine tumors reveals a potential epigenetic target for treatment.

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.

Multicentre study evaluating the surgical learning curve for posterior retroperitoneoscopic adrenalectomy.

BACKGROUND: Posterior retroperitoneoscopic adrenalectomy has gained international popularity in the past decade. Despite major advantages, including shorter duration of operation, minimal blood loss and decreased postoperative pain, many surgeons still prefer laparoscopic transperitoneal adrenalectomy. It is likely that the unfamiliar anatomical environment, smaller working space and long learning curve impede implementation. The present study assessed the number of procedures required to fulfil the surgical learning curve for posterior retroperitoneoscopic adrenalectomy. METHODS: The first consecutive posterior retroperitoneoscopic adrenalectomies performed by four surgical teams from university centres in three different countries were analysed. The primary outcome measure was duration of operation. Secondary outcomes were conversion to an open or laparoscopic transperitoneal approach, complications and recovery time. The learning curve cumulative sum (LC-CUSUM) was used to assess the learning curves for each surgical team. RESULTS: A total of 181 surgical procedures performed by four surgical teams were analysed. The median age of the patients was 57 (range 15-84) years and 61·3 per cent were female. Median tumour size was 25 (range 4-85) mm. There were no significant differences in patient characteristics and tumour size between the teams. The median duration of operation was 89 (range 29-265) min. There were 35 perioperative and postoperative complications among the 181 patients (18·8 per cent); 17 of 27 postoperative complications were grade 1. A total of nine conversions to open procedures (5·0 per cent) were observed. The LC-CUSUM analysis showed that competency was achieved after a range of 24-42 procedures. CONCLUSION: In specialized endocrine surgical centres between 24 and 42 procedures are required to fulfil the entire surgical learning curve for the posterior retroperitoneoscopic adrenalectomy.

Expression of p27Kip1 and p18Ink4c in human multiple endocrine neoplasia type 1-related pancreatic neuroendocrine tumors.

PURPOSE: Pancreatic neuroendocrine tumors are a major manifestation of multiple endocrine neoplasia type 1 (MEN1). This tumor syndrome is caused by germline mutations in MEN1, encoding menin. Insight into pathogenesis of these tumors might lead to new biomarkers and therapeutic targets for these patients. Several lines of evidence point towards a role for p27Kip1 and p18Ink4c in MEN1-related tumor development in animal models for MEN1, but their contribution to human MEN1-related pancreatic neuroendocrine tumor development is not known. METHODS: In this study, we characterized protein expression of p27Kip1 and p18Ink4c in human MEN1-related PanNETs by immunohistochemistry. From the nationwide DutchMEN1 Study Group database including > 90% of the Dutch MEN1 population, MEN1-patients, who underwent pancreatic surgery, were selected. A tissue micro-array was constructed with available paraffin tissue blocks, and PanNETs from 61 MEN1 patients were eligible for analysis. RESULTS: Expression of p27Kip1 was high in 57 (93%) PanNETs and 67% of the tumors showed low expression of p18Ink4c (67.3%). No association was found between expression of either p27Kip1 or p18Ink4c and clinic-pathological characteristics. CONCLUSIONS: These findings indicate that loss of p18Ink4c, but not p27Kip1, is a common event in the development of MEN1-related PanNETs. Restoration of p18Ink4c function through CDK4/6 inhibitors could be a therapeutic option for MEN1-related PanNETs.

Laparoscopic anterior versus endoscopic posterior approach for adrenalectomy: a shift to a new golden standard?

PURPOSE: There has been an increased utilization of the posterior retroperitoneal approach (PRA) for adrenalectomy alongside the "classic" laparoscopic transabdominal technique (LTA). The aim of this study was to compare both procedures based on outcome variables at various ranges of tumor size. METHODS: A retrospective analysis was performed on 204 laparoscopic transabdominal (UMC Groningen) and 57 retroperitoneal (UMC Utrecht) adrenalectomies between 1998 and 2013. We applied a univariate and multivariate regression analysis. Mann-Whitney and chi-squared tests were used to compare outcome variables between both approaches. RESULTS: Both mean operation time and median blood loss were significantly lower in the PRA group with 102.1 (SD 33.5) vs. 173.3 (SD 59.1) minutes (p < 0.001) and 0 (0-200) vs. 50 (0-1000) milliliters (p < 0.001), respectively. The shorter operation time in PRA was independent of tumor size. Complication rates were higher in the LTA (19.1%) compared to PRA (8.8%). There was no significant difference in recovery time between both approaches. CONCLUSIONS: Application of the PRA decreases operation time, blood loss, and complication rates compared to LTA. This might encourage institutions that use the LTA to start using PRA in patients with adrenal tumors, independent of tumor size.

Health-related quality of life after pancreatic resection for malignancy.

BACKGROUND: Health-related quality of life (QoL) is of major importance in pancreatic cancer, owing to the limited life expectation. The aim of this prospective longitudinal study was to describe QoL in patients undergoing resection for pancreatic or periampullary malignancy. METHODS: QoL was measured on a scale of 0-100 in patients who underwent pancreatic resection for malignancy or premalignancy at the University Medical Centre Utrecht before resection, and 1, 3, 6 and 12 months after surgery. Measures consisted of the RAND-36, the European Organization for Research and Treatment of Cancer (EORTC) core questionnaire (QLQ-C30) and the EORTC pancreatic cancer-specific module (QLQ-PAN26). RESULTS: Between March 2012 and November 2013, 68 consecutive patients with a malignancy (59 patients) or premalignancy (9) were included. Physical role restriction, social and emotional domains showed a significant and clinically relevant deterioration directly after operation in 53 per cent (RAND-36, P < 0.001), 63 and 78 per cent (QLQ-C30 and RAND-36 respectively, P < 0.001) and 37 per cent (RAND-36, P < 0.001) of patients respectively. Most domains demonstrated recovery to preoperative values or better at 3 months, except for physical functioning. Emotional functioning at 3, 6 and 12 months was better than at baseline (P < 0.001). Symptom scores revealed a deterioration in vitality, pain (P = 0.002), fatigue (P < 0.001), appetite loss (P < 0.001), altered bowel habit (P = 0.001) and side-effects (P < 0.001) after 1 month. After 3 months, only side-effects were worse than preoperative values (P < 0.001). CONCLUSION: QoL after pancreatic resection for malignant and premalignant tumours decreased considerably in the early postoperative phase. Full recovery of QoL took up to 6 months after the operation.

Thoracic and duodenopancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1: natural history and function of menin in tumorigenesis.

Mutations of the multiple endocrine neoplasia type 1 (MEN1) gene lead to loss of function of its protein product menin. In keeping with its tumor suppressor function in endocrine tissues, the majority of the MEN1-related neuroendocrine tumors (NETs) show loss of heterozygosity (LOH) on chromosome 11q13. In sporadic NETs, MEN1 mutations and LOH are also reported, indicating common pathways in tumor development. Prevalence of thymic NETs (thNETs) and pulmonary carcinoids in MEN1 patients is 2-8%. Pulmonary carcinoids may be underreported and research on natural history is limited, but disease-related mortality is low. thNETs have a high mortality rate. Duodenopancreatic NETs (dpNETs) are multiple, almost universally found at pathology, and associated with precursor lesions. Gastrinomas are usually located in the duodenal submucosa while other dpNETs are predominantly pancreatic. dpNETs are an important determinant of MEN1-related survival, with an estimated 10-year survival of 75%. Survival differs between subtypes and apart from tumor size there are no known prognostic factors. Natural history of nonfunctioning pancreatic NETs needs to be redefined because of increased detection of small tumors. MEN1-related gastrinomas seem to behave similar to their sporadic counterparts, while insulinomas seem to be more aggressive. Investigations into the molecular functions of menin have led to new insights into MEN1-related tumorigenesis. Menin is involved in gene transcription, both as an activator and repressor. It is part of chromatin-modifying protein complexes, indicating involvement of epigenetic pathways in MEN1-related NET development. Future basic and translational research aimed at NETs in large unbiased cohorts will clarify the role of menin in NET tumorigenesis and might lead to new therapeutic options.

Surgery for adrenocortical carcinoma in The Netherlands: analysis of the national cancer registry data.

OBJECTIVE: Adrenocortical carcinoma (ACC) is a rare disease with an estimated incidence of one to two cases per 1 million inhabitants. The Dutch Adrenal Network (DAN) was initiated with the aim to improve patient care and to stimulate scientific research on ACC. Currently, not all patients with ACC are treated in specialized DAN hospitals. The objective of the current investigation was to determine whether there are differences in survival between patients operated on in DAN hospitals and those operated on in non-DAN hospitals. DESIGN: The study was set up as a retrospective and population-based survival analysis. METHODS: Data on all adult ACC patients diagnosed between 1999 and 2009 were obtained from The Netherlands Cancer Registry (NCR). Overall survival was calculated and a comparison was made between DAN and non-DAN hospitals. RESULTS: The NCR contained data of 189 patients. The median survival of patients with European Network for the Study of Adrenal Tumors stages I-III disease was significantly longer for patients operated on in a DAN hospital (n=46) than for those operated on in a non-DAN hospital (n=37, 5-year survival 63 vs 42%). Survival remained significantly different after correction for sex, age, year of diagnosis, and stage of disease in the multivariate analysis (hazard ratio 1.96 (95% CI 1.01-3.81), P=0.047). CONCLUSION: The results associate surgery in a DAN center with a survival benefit for patients with local or locally advanced ACC. We hypothesize that a multidisciplinary approach for these patients explains the observed survival benefit. These findings should be carefully considered in view of the aim for further centralization of ACC treatment.

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.

Unintentional weight loss is the most important indicator of malnutrition among surgical cancer patients.

BACKGROUND: Disease-related malnutrition is highly prevalent in hospital patients and varies from 25-40%. Early nutritional screening of patients at admission helps to improve recognition of malnourished patients to allow early interventions and enhance clinical outcomes. METHOD: A total of 104 preoperative surgical patients with oesophageal (34), stomach (17) or pancreatic cancer (53) were recruited in our study. The risk of malnutrition was examined using the quick-and-easy Malnutrition Universal Screening Tool (MUST). Anthropometric data and information on percent weight change over the past six months, unintentional weight loss, dietician referrals, and history of nutritional intervention were collected. RESULTS: A total of 75% of our participants were at high malnutrition risk with a mean (±SD) percentage weight loss of 5.18 (±6.23)%, despite a mean BMI of 26.09 (±5.73) kgm-2. Participants with a significantly higher percent weight loss, unintentional weight loss, dietician referral and nutritional intervention had a higher risk of malnutrition (p<0.05). Presence of unintentional weight loss was the only significant predictor (OR 3.22; 95%CI 1.23, 8.40) associated with risk of malnutrition after adjusted for all confounders. CONCLUSION: In conclusion, our findings highlight the importance of routine screening of malnutrition in oncology patients. Medical personnel must be aware that unintentional weight loss is an important predictor of malnutrition risks even if the patient's BMI is not suggestive of malnutrition.

Not the number but the location of lymph nodes matters for recurrence rate and disease-free survival in patients with differentiated thyroid cancer.

BACKGROUND: Several Japanese studies have focused on identifying prognostic factors in patients with positive lymph nodes to predict recurrence rate and disease-free survival (DFS). However, different treatment protocol is followed in Japan compared with the European and American approach. This study was designed to investigate whether the number and/or location of lymph nodes predicts prognosis in patients with DTC treated with total thyroidectomy, lymph node dissection, and postoperative radioactive iodine ablation. METHODS: All 402 patients who were treated at the Department of Nuclear Medicine between 1998 and 2010 for DTC were reviewed. Patients were treated with (near) total thyroidectomy, lymph node dissection on indication, and postoperative I-131 ablation. Median follow-up was 49 (range, 10-240) months. Outcome measures were recurrence rate, disease-free survival, and mean time to recurrence. RESULTS: Ninety-seven patients had proven lymph node metastases. Recurrence rate was significantly higher in patients with positive lymph nodes in the lateral compartment vs. patients with lymph node metastasis in the central compartment (60 vs. 30%, p = 0.007). Disease-free survival and mean time to recurrence also were significantly shorter (30 vs. 52 months, p = 0.035 and 7 vs. 44 months, p = 0.004, respectively). The number of lymph nodes and extranodal growth were not significantly associated with the outcome measures used. CONCLUSIONS: The location of positive lymph nodes was significantly correlated with the risk of recurrence and a shorter DFS. Hence, the TNM criteria are useful in subdividing patients based on risk of recurrence and DFS.

Care for patients with multiple endocrine neoplasia type 1: the current evidence base.

Multiple endocrine neoplasia type 1 (MEN1) is a rare disease caused by mutations in the MEN1 gene on chromosome 11. It is characterized by the occurrence of primary hyperparathyroidism (pHPT), duodenopancreatic neuroendocrine tumours (pNET), pituitary tumours (PIT), adrenal adenomas (ADR) and neuroendocrine tumours (NET) of the stomach, bronchus and thymus. MEN1 is a syndrome with high penetrance and high morbidity. Malignant NETs are the most important cause of MEN1-related death. Since 1997 the diagnosis can be made by genetic screening. MEN1 is a complex syndrome and the endocrine manifestations cannot be viewed upon as coinciding sporadic tumours. Differences in epidemiology and pathology between MEN1-related tumours and their sporadic counterparts show that a unique approach is needed. Therefore the care for MEN1 patients should be provided by a centre of expertise. Early genetic diagnosis and periodic screening are important pillars of care. For primary hyperparathyroidism surgery is the most important treatment modality, with a subtotal parathyroid gland resection as the procedure of choice. In neuroendocrine tumours surgery also is the most important treatment modality. Selective tumour enucleation has no place in the surgical treatment of MEN1-related pNETs; the exact procedure depends on the functionality of the tumour. In MEN1-associated pituitary and adrenal adenomas, watchful waiting and medical therapy play more important roles. In the twenty-first century new developments will impact the care for MEN1 patients. These developments should be critically evaluated in clinical research with the ultimate goal of optimizing the care for MEN1 patients on an evidence base.