Surgeons' physical workload in open surgery versus robot-assisted surgery and nonsurgical tasks.

BACKGROUND: Musculoskeletal disorders (MSDs) are common among surgeons, and its prevalence varies among surgical modalities. There are conflicting results concerning the correlation between adverse work exposures and MSD prevalence in different surgical modalities. The progress of rationalization in health care may lead to job intensification for surgeons, but the literature is scarce regarding to what extent such intensification influences the physical workload in surgery. The objectives of this study were to quantify the physical workload in open surgery and compare it to that in (1) nonsurgical tasks and (2) two surgeon roles in robot-assisted surgery (RAS). METHODS: The physical workload of 22 surgeons (12 performing open surgery and 10 RAS) was measured during surgical workdays, which includes trapezius muscle activity from electromyography, and posture and movement of the head, upper arms and trunk from inertial measurement units. The physical workload of surgeons in open surgery was compared to that in nonsurgical tasks, and to the chief and assistant surgeons in RAS, and to the corresponding proposed action levels. Mixed-effects models were used to analyze the differences. RESULTS: Open surgery constituted more than half of a surgical workday. It was associated with more awkward postures of the head and trunk than nonsurgical tasks. It was also associated with higher trapezius muscle activity levels, less muscle rest time and a higher proportion of sustained low muscle activity than nonsurgical tasks and the two roles in RAS. The head inclination and trapezius activity in open surgery exceeded the proposed action levels. CONCLUSIONS: The physical workload of surgeons in open surgery, which exceeded the proposed action levels, was higher than that in RAS and that in nonsurgical tasks. Demands of increased operation time may result in higher physical workload for open surgeons, which poses an increased risk of MSDs. Risk-reducing measures are, therefore, needed.

A Plasma Protein Biomarker Strategy for Detection of Small Intestinal Neuroendocrine Tumors.

BACKGROUND: Small intestinal neuroendocrine tumors (SI-NETs) are difficult to diagnose in the early stage of disease. Current blood biomarkers such as chromogranin A (CgA) and 5-hydroxyindolacetic acid have low sensitivity (SEN) and specificity (SPE). This is a first preplanned interim analysis (Nordic non-interventional, prospective, exploratory, EXPLAIN study [NCT02630654]). Its objective is to investigate if a plasma protein multi-biomarker strategy can improve diagnostic accuracy (ACC) in SI-NETs. METHODS: At the time of diagnosis, before any disease-specific treatment was initiated, blood was collected from patients with advanced SI-NETs and 92 putative cancer-related plasma proteins from 135 patients were analyzed and compared with the results of age- and sex-matched controls (n = 143), using multiplex proximity extension assay and machine learning techniques. RESULTS: Using a random forest model including 12 top ranked plasma proteins in patients with SI-NETs, the multi-biomarker strategy showed SEN and SPE of 89 and 91%, respectively, with negative predictive value (NPV) and positive predictive value (PPV) of 90 and 91%, respectively, to identify patients with regional or metastatic disease with an area under the receiver operator characteristic curve (AUROC) of 99%. In 30 patients with normal CgA concentrations, the model provided a diagnostic SPE of 98%, SEN of 56%, and NPV 90%, PPV of 90%, and AUROC 97%, regardless of proton pump inhibitor intake. CONCLUSION: This interim analysis demonstrates that a multi-biomarker/machine learning strategy improves diagnostic ACC of patients with SI-NET at the time of diagnosis, especially in patients with normal CgA levels. The results indicate that this multi-biomarker strategy can be useful for early detection of SI-NETs at presentation and conceivably detect recurrence after radical primary resection.

Highly proliferative anal neuroendocrine carcinoma: molecular and clinical features of a rare, recurrent case in complete remission.

BACKGROUND: Poorly differentiated anal neuroendocrine carcinomas (ANECs) are rare lesions with poor prognosis, and the molecular etiology is only partially understood. CASE PRESENTATION: At our institution, we have treated and followed a patient with such a rare ANEC. He had primarily surgery followed by three rounds of repeated surgery for loco-regional recurrences. He also received three different combinations of chemotherapy and external beam radiation. At last follow-up 13 years since the primary diagnosis, the patient had been in complete remission for nine years. The patient's medical files were re-examined, including laboratory, radiology and clinical examinations. Histopathology was re-assessed, and expanded immunohistochemistry was performed from tissue specimens from the four surgical procedures. In addition, the molecular genetic status was evaluated through next-generation sequencing. The initial tumor was consistent with a 59 mm small cell neuroendocrine cancer with a Ki-67 index of 80%. Regional lymph node metastases were evident, and immunohistochemistry supported a neuroendocrine origin. A PCR screening detected human papilloma virus type 45 DNA (high-risk subtype), and focused next-generation sequencing found a missense mutation in the Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA) gene. In tissues representing subsequent recurrences, the Chromogranin A expression was lost, and the Ki-67 index increased to 90%. CONCLUSIONS: For the first time, we report the detection of HPV45 in a case of ANEC. To our belief, PIK3CA mutations have also not been previously demonstrated in this tumor entity. In highly malignant ANECs, cure can in rare cases be achieved. Although speculative, expression of HPV45 and/or the PIK3CA mutation may have contributed to the favorable outcome.

Operating hurts: a study of EAES surgeons.

BACKGROUND: Work-related pain and discomfort experienced by surgeons is widely reported in the literature. A survey was, therefore, conducted to explore this issue among members of the European Association for Endoscopic Surgery (EAES). METHODS: The survey was emailed to 2980 EAES members in 2017 enquiring about their working practice, musculoskeletal (MSK) pain and burnout. RESULTS: A total of 569 (19%) surgeons responded, of whom 556 were practicing surgeons; 86% were consultants, 84% were male, and 94% were right-handed. Respondents operated on average 3.3 days/week with 27% of their procedures lasting longer than 3 h. The 386 endoscopists surveyed reported performing an average of 5.3 procedures/day with 83% performing endoscopy at least once per week. Over half of practicing surgeons (62%) reported their worst pain score was 3 or higher (10-point scale) in the past 7 working days, encompassing 71% of their open, 72% laparoscopic, 48% robot-assisted cases and 52% of their endoscopies. Of the 120 surgeons who had ever sought medical help for aches, pain or discomfort, 38% were currently in pain and 16% had considered leaving surgery due to their MSK pain, 26% had reported work-related pain to their employer, 26% had been on short-term disability during their career and 4% long-term disability due to MSK disorders. A significant proportion of the respondents (49%) felt their physical discomfort would influence the ability to perform or assist with surgical procedures in the future. These surgeons reported significantly lower satisfaction from their work (p = 0.024), higher burnout (p = 0.005) and significantly higher callousness toward people (p < 0.001) than those not fearing loss of career longevity. CONCLUSION: The results show that MSK pain is prevalent amongst EAES members. Nearly half the respondents had career longevity fears from pain/discomfort which, in turn, correlated with more prevalent feelings of burnout. More emphasis should be placed on the aetiology, prevention and management of musculoskeletal pain in the surgical workforce.

Intraoperative workload in robotic surgery assessed by wearable motion tracking sensors and questionnaires.

BACKGROUND: The introduction of robotic technology has revolutionized radical prostatectomy surgery. However, the potential benefits of robotic techniques may have trade-offs in increased mental demand for the surgeon and the physical demand for the assisting surgeon. This study employed an innovative motion tracking tool along with validated workload questionnaire to assess the ergonomics and workload for both assisting and console surgeons intraoperatively. METHODS: Fifteen RARP cases were collected in this study. Cases were performed by 10 different participants, six primarily performed console tasks and four primarily performed assisting tasks. Participants had a median 12 (min-3, max-25) years of surgical experience. Both console and assisting surgeons performed robotic prostatectomy cases while wearing inertial measurement units (IMUs) that continuously track neck, shoulder, and torso motion without interfering with the sterile environment. Postoperatively, participants completed a workload questionnaire (SURG-TLX) and a body part discomfort questionnaire. RESULTS: Twenty-six questionnaires were completed from 13 assisting and 13 console surgeons over the 15 cases. Postoperative pain was reported highest for the right shoulder and neck. Mental demands were 41 % higher for surgeons at the console than assisting (p < 0.05), while physical demands were not significantly different. Assisting surgeons worked in demanding neck postures for 58 % of the procedure compared to 24 % for the console surgeon (p < 0.01). Surgeons at the console were primarily static and showed 2-5 times fewer movements than assisting surgeons (p < 0.01). CONCLUSIONS: Postures were more ergonomic during console tasks than when assisting by the bedside; however, the console may constrain postures leading to static loads that have been associated with musculoskeletal symptoms for the neck, torso, and shoulders. The IMU sensors were effective at quantifying ergonomics in robotic prostatectomies, and these methods and findings have broad applications to other robotic procedures.

Magseed application for detecting recurrent lymph node metastasis in papillary thyroid cancer: A novel minimally invasive Approach.

Papillary thyroid cancer is associated with lymph node metastasis and tumor recurrence that need repeated surgery, entailing surgical challenges with a high risk of complications such as nerve damage and bleeding. Magseed is a metal coil used to detect non-palpable lesions and is an established modality in breast cancer surgery. In this case series, we explore the feasibility of Magseed in metastasis surgery of papillary thyroid cancer. Under the guidance of ultrasonography, Magseed is injected into the target tissue and intraoperatively detected with a handheld magnetometer probe, Sentimag®. Five patients with recurrence of papillary thyroid cancer were operated on with focused Magseed-guided localization. All patients had repeated surgery and radioiodine treatments. Four of the patients had lymph node metastasis hidden in the fibrosis, and one patient had recurrent tumor tissue on the left side of the larynx. Magseed was easy to use, safe, and precise in detecting the target tissue.

Copy number alterations in small intestinal neuroendocrine tumors determined by array comparative genomic hybridization.

BACKGROUND: Small intestinal neuroendocrine tumors (SI-NETs) are typically slow-growing tumors that have metastasized already at the time of diagnosis. The purpose of the present study was to further refine and define regions of recurrent copy number (CN) alterations (CNA) in SI-NETs. METHODS: Genome-wide CNAs was determined by applying array CGH (a-CGH) on SI-NETs including 18 primary tumors and 12 metastases. Quantitative PCR analysis (qPCR) was used to confirm CNAs detected by a-CGH as well as to detect CNAs in an extended panel of SI-NETs. Unsupervised hierarchical clustering was used to detect tumor groups with similar patterns of chromosomal alterations based on recurrent regions of CN loss or gain. The log rank test was used to calculate overall survival. Mann-Whitney U test or Fisher's exact test were used to evaluate associations between tumor groups and recurrent CNAs or clinical parameters. RESULTS: The most frequent abnormality was loss of chromosome 18 observed in 70% of the cases. CN losses were also frequently found of chromosomes 11 (23%), 16 (20%), and 9 (20%), with regions of recurrent CN loss identified in 11q23.1-qter, 16q12.2-qter, 9pter-p13.2 and 9p13.1-11.2. Gains were most frequently detected in chromosomes 14 (43%), 20 (37%), 4 (27%), and 5 (23%) with recurrent regions of CN gain located to 14q11.2, 14q32.2-32.31, 20pter-p11.21, 20q11.1-11.21, 20q12-qter, 4 and 5. qPCR analysis confirmed most CNAs detected by a-CGH as well as revealed CNAs in an extended panel of SI-NETs. Unsupervised hierarchical clustering of recurrent regions of CNAs revealed two separate tumor groups and 5 chromosomal clusters. Loss of chromosomes 18, 16 and 11 and gain of chromosome 20 were found in both tumor groups. Tumor group II was enriched for alterations in chromosome cluster-d, including gain of chromosomes 4, 5, 7, 14 and gain of 20 in chromosome cluster-b. Gain in 20pter-p11.21 was associated with short survival. Statistically significant differences were observed between primary tumors and metastases for loss of 16q and gain of 7. CONCLUSION: Our results revealed recurrent CNAs in several candidate regions with a potential role in SI-NET development. Distinct genetic alterations and pathways are involved in tumorigenesis of SI-NETs.

[A survey on surgical training during residency in Sweden - description of the current state]. / Kirurgisk träning under ST ­ en enkätundersökning.

Practical training for new surgeons differs between institutions, and standards are mostly lacking. The largest problems seem to occur during the first years, when novices begin their specialty training, (specialisttjänstgöring in Swedish). A large number of scientific publications are available, but the they are usually limited to one specific procedure or one surgical specialty, and the results are rarely applied in practice. Scientifically validated and systematic methods for basic training outside the operating room have been called for over the last decade, but the main part of the training still takes place during surgery on patients. In order to evaluate the practising of manual skills among doctors doing their training within surgical specialties, a survey with fourteen questions was carried out. The results show shortcomings that seem easy to remedy in the short term, but long term studies on the subject are required to better understand and systematize surgical training.

Ergonomics and performance of using prismatic loupes in simulated surgical tasks among surgeons - a randomized controlled, cross-over trial.

Introduction: Recently developed prismatic loupes may mitigate the high physical workload and risk of neck disorders associated with traditional surgical loupes among surgeons. However, research in this area, particularly among surgeons, is sparse. This study examines the impact of prismatic loupes on surgeons' physical workload, musculoskeletal discomfort, and performance during simulated surgical tasks. Materials and methods: Nineteen out of twenty recruited surgeons performed three tasks in a fixed-order with their own loupes and both low-tilt (LT) and high-tilt (HT) prismatic loupes, in a randomized order. The primary outcomes were the median inclination angles and velocities of the head, trunk, and upper arms, along with the median muscle activity of the cervical erector spinae (CES), upper trapezius (UT), and lumbar erector spinae (LES) for each pair of loupes. The secondary outcomes included performance (completion time and errors), perceived body-part discomfort, and subjective evaluation of the three pairs of loupes. Results: Using prismatic loupes, either LT or HT, compared with the surgeons' own loupes yielded lower head inclinations (all p < 0.001), lower neck muscle activity (all p < 0.05), and lower neck discomfort in indirect comparisons (p < 0.01) with no significant difference in surgical errors (p = 0.628). However, HT loupes resulted in a longer task completion time in two tasks (p < 0.001). Most surgeons preferred LT loupes (N = 12) for their comfort and visual functions. Discussion: The results indicate that prismatic loupes can reduce physical workload in the neck during simulated surgical task, with no significant difference in surgical errors. Future studies are needed to investigate the long-term effects of prismatic loupes among surgeons.

Synchronous lateral lymph node metastases from papillary and follicular thyroid carcinoma: case report and review of the literature.

BACKGROUND: Follicular thyroid carcinomas (FTCs) rarely metastasize to regional lymph nodes, and descriptions of synchronous lateral lymph node metastases of FTC and papillary thyroid carcinoma (PTC) are lacking. CASE PRESENTATION: We describe a 43-year-old female with a preoperative cytology indicating a right-sided PTC with lateral lymph node metastases. She underwent a total thyroidectomy and central and lateral lymph node dissection, and histopathology confirmed a multifocal tall cell variant PTC together with a 12 mm minimally invasive FTC in the ipsilateral lobe. While the central compartment demonstrated metastatic PTC, the lateral compartment contained PTC metastases alongside a 15 mm large follicular-patterned mass in a separate lymph node. As the cells lacked PTC associated nuclear changes, the possibility of a lateral lymph node metastasis of FTC was considered, with the possibility of ectopic thyroid tissue as a differential diagnosis. By utilizing next-generation sequencing, a Q61R NRAS mutation was pinpointed, thus proving the tissue as tumorous. The patient underwent radioiodine treatment and is currently monitored following a negative whole-body scan. CONCLUSIONS: This is probably the first case report of a patient with co-existing lateral lymph node PTC and FTC metastases. Consulting previous publications, there is currently a gap of knowledge in terms of how patients with regional FTC metastases should be followed-up and treated, especially when co-occurring with spread high-risk PTC subtypes. Moreover, what guides a seemingly indolent FTC to spread via the lymphatic system remains to be defined from a molecular standpoint.

Plasma protein biomarkers for the detection of pancreatic neuroendocrine tumors and differentiation from small intestinal neuroendocrine tumors.

There is an unmet need for novel biomarkers to diagnose and monitor patients with neuroendocrine neoplasms. The EXPLAIN study explores a multi-plasma protein and supervised machine learning strategy to improve the diagnosis of pancreatic neuroendocrine tumors (PanNET) and differentiate them from small intestinal neuroendocrine tumors (SI-NET). At time of diagnosis, blood samples were collected and analyzed from 39 patients with PanNET, 135 with SI-NET (World Health Organization Grade 1-2) and 144 controls. Exclusion criteria were other malignant diseases, chronic inflammatory diseases, reduced kidney or liver function. Prosed Oncology-II (i.e., OLink) was used to measure 92 cancer related plasma proteins. Chromogranin A was analyzed separately. Median age in all groups was 65-67 years and with a similar sex distribution (females: PanNET, 51%; SI-NET, 42%; controls, 42%). Tumor grade (G1/G2): PanNET, 39/61%; SI-NET, 46/54%. Patients with liver metastases: PanNET, 78%; SI-NET, 63%. The classification model of PanNET versus controls provided a sensitivity (SEN) of 0.84, specificity (SPE) 0.98, positive predictive value (PPV) of 0.92 and negative predictive value (NPV) of 0.95, and area under the receiver operating characteristic curve (AUROC) of 0.99; the model for the discrimination of PanNET versus SI-NET providing a SEN 0.61, SPE 0.96, PPV 0.83, NPV 0.90 and AUROC 0.98. These results suggest that a multi-plasma protein strategy can significantly improve diagnostic accuracy of PanNET and SI-NET.

Altered expression of the IGF2­H19 locus and mitochondrial respiratory complexes in adrenocortical carcinoma.

Abnormalities of the insulin­like growth factor 2 (IGF2)­H19 locus with the overexpression of IGF2 are frequent findings in adrenocortical carcinoma (ACC). The present study assessed the expression of RNAs and microRNAs (miRNAs/miRs) from the IGF2­H19 locus using PCR­based methods in ACC and adrenocortical adenoma (ACA). The results were associated with proteomics data. IGF2 was overexpressed in ACC, and its expression correlated with that of miR­483­3p and miR­483­5p hosted by IGF2. The downregulated expression of H19 in ACC compared to ACA correlated with miR­675 expression hosted by H19. Several proteins exhibited an inverse correlation in expression and were predicted as targets of miR­483­3p, miR­483­5p or miR­675. Subsets of these proteins were differentially expressed between ACC and ACA. These included several proteins involved in mitochondrial metabolism. Among the mitochondrial respiratory complexes, complex I and IV were significantly decreased in ACC compared to ACA. The protein expression of NADH:ubiquinone oxidoreductase subunit C1 (NDUFC1), a subunit of mitochondrial respiratory complex I, was further validated as being lower in ACC compared to ACA and normal adrenals. The silencing of miR­483­5p increased NDUFC1 protein expression and reduced both oxygen consumption and glycolysis rates. On the whole, the findings of the present study reveal the dysregulation of the IGF2­H19 locus and mitochondrial respiration in ACC. These findings may provide a basis for the further understanding of the pathogenesis of ACC and may have potential values for diagnostics and treatment.

A possible revival of population-representing digital human manikins in static work situations - exemplified through an evaluation of a prototype console for robotic surgery.

BACKGROUND: In the 90s, digital human manikins (DHMs) were introduced in planning of workstations, by static or semi-static simulations. Modern DHMs can simulate dynamic work and offer a rapid way for a virtual pre-production ergonomic evaluation. Work-related musculoskeletal disorders may affect surgical performance and patient safety. A prototype of an open console, which is contrary to the conventional closed consoles and may be seen as a representative for a new generation, has been designed to reduce workload for robotic surgery surgeons. OBJECTIVE: The aim of this project was to test a new DHM tool with improved usability to evaluate the ergonomics of a console of a robotic surgical system in a pre-production stage. METHODS: The DHM tool IMMA was used together with a 3D model of the prototype console. Twelve manikins who represented females and males from two national populations were introduced. Manikin-console distances, after console adjustments per manikin, were compared with a US checklist and Swedish standard for VDU work. RESULTS: The DHM tool was useful for this case, but the distances of the checklist and the standard were needed to be obtained "manually". The automatic functions of the DHM worked smoothly but were not optimized for VDU work. The prototype fulfilled most, but not all, of the ergonomic criteria of the checklist and the standard. CONCLUSIONS: There is room for improvements of the adjustable ranges of the console prototype. DHMs may facilitate rapid pre-production evaluation of workstations for static work; if ergonomic assessment models for VDU work are built-in, there may be a revival of DHMs in static work situations.

Portal vein resection during pancreaticoduodenectomy for pancreatic neuroendocrine tumors. An international multicenter comparative study.

BACKGROUND: The role of portal vein resection for pancreatic cancer is well established but not for pancreatic neuroendocrine neoplasms. Evidence from studies providing information on long-term outcome after venous resection in pancreatic neuroendocrine neoplasms patients is lacking. METHODS: This is a multicenter retrospective cohort study comparing pancreaticoduodenectomy with vein resection with standard pancreaticoduodenectomy in patients with pancreatic neuroendocrine neoplasms. The primary endpoint was to evaluate the long-term survival in both groups. Progression-free survival and overall survival were calculated using the method of Kaplan and Meier, but a propensity score-matched cohort analysis was subsequently performed to remove selection bias and improve homogeneity. The secondary outcome was Clavien-Dindo ≥3. RESULTS: Sixty-one (11%) patients underwent pancreaticoduodenectomy with vein resection and 480 patients pancreaticoduodenectomy. Five (1%) perioperative deaths were recorded in the pancreaticoduodenectomy group, and postoperative clinically relevant morbidity rates were similar in the 2 groups (pancreaticoduodenectomy with vein resection 48% vs pancreaticoduodenectomy 33%). In the initial survival analysis, pancreaticoduodenectomy with vein resection was associated with worse 3-year progression-free survival (48% pancreaticoduodenectomy with vein resection vs 83% pancreaticoduodenectomy; P < .01) and 5-year overall survival (67% pancreaticoduodenectomy with vein resection vs 91% pancreaticoduodenectomy). After propensity score matching, no significant difference was found in both 3-year progression-free survival (49% pancreaticoduodenectomy with vein resection vs 59% pancreaticoduodenectomy; P = .14) and 5-year overall survival (71% pancreaticoduodenectomy with vein resection vs 69% pancreaticoduodenectomy; P = .98). CONCLUSION: This study demonstrates no significant difference in perioperative risk with a similar overall survival between pancreaticoduodenectomy and pancreaticoduodenectomy with vein resection. Tumor involvement of the superior mesenteric/portal vein axis should not preclude surgical resection in patients with locally advanced pancreatic neuroendocrine neoplasms.

Preoperative 99Tc(m)-sestamibi scintigraphy with SPECT localizes most pathologic parathyroid glands.

BACKGROUND AND AIMS: Surgery is the only curative treatment for primary hyperparathyroidism. Focused surgical techniques are being practiced with increasing frequency. Preoperative imaging, such as scintigraphy, is a prerequisite for focused surgery. There is controversy about which preoperative imaging method should be used. The sensitivity reported for parathyroid scintigraphy varies considerably. This study was designed to determine the accuracy of the preoperative imaging routinely used at our institution. MATERIAL AND METHODS: This retrospective study included consecutive patients who underwent a routine dual-phase sestamibi-SPECT (single photon emission computed tomography) scintigraphy and subsequent operation with follow-up. Scintigraphy results were evaluated by comparing the results to surgical findings and histopathology. RESULTS: Two hundred and sixty-four individuals entered the study. Sensitivity for scintigraphy was 84%, specificity 91%, positive predictive value 91%, and negative predictive value 84%. CONCLUSIONS: Sestamibi-SPECT scintigraphy is a sensitive preoperative modality with high positive predictive value. Scintigraphy is a good indicator for when to perform a focused surgical approach and could often correctly guide the actual operation.

Telomerase activation in small intestinal neuroendocrine tumours is associated with aberrant TERT promoter methylation, but not hot-spot mutations.

Telomere maintenance is a critical requirement for enabling replicative immortality and tumour development. Here, telomerase expression and activity, telomere length (TL) and potential regulatory factors that can underlie telomerase machinery alterations in small intestinal neuroendocrine tumours (SI-NETs) were analyzed. Telomerase activity assessed by TRAP assay was increased in SI-NETs compared to normal ileum (P < 0.001). The telomerase reverse transcriptase gene (TERT) was over-expressed in SI-NETs vs. normal ileal samples (P = 0.01). Furthermore, relative TL assessed by qPCR was found shorter in tumours compared with normal ileum (P = 0.02) and in distant metastasis samples compared to primary tumours and local metastases (P= 0.02). TERT promoter hotspot mutations were not present and TERT copy number gain was only observed in 3/70 tumour samples. TERT or chromosome 18 copy number alterations were not associated with telomerase expression and activity or TL. However, hypermethylation of TERT promoter in Region B - in the proximity of the transcription start site - was inversely correlated with TERT expression and telomerase activity and positively correlated with TL. Global LINE1 methylation was positively correlated with TERT promoter Region B methylation and was inversely correlated with telomerase activity, TERT expression and the upstream Region A methylation. The results show that telomerase activation, TERT expression and shorter telomeres are commonly found in SI-NETs. Aberrant DNA methylation of TERT promoter and of LINE1 can be implicated in abnormal regulation of TERT in SI-NETs.

Proteomics identifies neddylation as a potential therapy target in small intestinal neuroendocrine tumors.

Patients with small intestinal neuroendocrine tumors (SI-NETs) frequently develop spread disease; however, the underlying molecular mechanisms of disease progression are not known and effective preventive treatment strategies are lacking. Here, protein expression profiling was performed by HiRIEF-LC-MS in 14 primary SI-NETs from patients with and without liver metastases detected at the time of surgery and initial treatment. Among differentially expressed proteins, overexpression of the ubiquitin-like protein NEDD8 was identified in samples from patients with liver metastasis. Further, NEDD8 correlation analysis indicated co-expression with RBX1, a key component in cullin-RING ubiquitin ligases (CRLs). In vitro inhibition of neddylation with the therapeutic agent pevonedistat (MLN4924) resulted in a dramatic decrease of proliferation in SI-NET cell lines. Subsequent mass spectrometry-based proteomics analysis of pevonedistat effects and effects of the proteasome inhibitor bortezomib revealed stabilization of multiple targets of CRLs including p27, an established tumor suppressor in SI-NET. Silencing of NEDD8 and RBX1 using siRNA resulted in a stabilization of p27, suggesting that the cellular levels of NEDD8 and RBX1 affect CRL activity. Inhibition of CRL activity, by either NEDD8/RBX1 silencing or pevonedistat treatment of cells resulted in induction of apoptosis that could be partially rescued by siRNA-based silencing of p27. Differential expression of both p27 and NEDD8 was confirmed in a second cohort of SI-NET using immunohistochemistry. Collectively, these findings suggest a role for CRLs and the ubiquitin proteasome system in suppression of p27 in SI-NET, and inhibition of neddylation as a putative therapeutic strategy in SI-NET.

Initial clinical presentation and spectrum of pheochromocytoma: a study of 94 cases from a single center.

BACKGROUND: With the increasing access to imaging more pheochromocytomas are diagnosed in the workup of adrenal incidentalomas. This may have changed the occurrence of the classic presentation with hypertension and the classic triad (headaches, sweating and palpitation). METHODS: We reviewed 94 consecutive cases of pheochromocytomas. Two cases of ectopic ACTH-syndrome were subsequently excluded. RESULTS: Of the 92 cases included 64% had presented as an incidentaloma, 32% as a suspected pheochromocytoma and 4% had been screened because of previously diagnosed MEN2A. Those screened were youngest while those with incidentalomas were oldest. The females were more common in the incidentaloma and the screening groups, and males in the suspected pheochromocytoma group. Measurements of noradrenaline/normetanephrine levels were highest in the suspected pheocromocytoma group and lowest in the screening group. Hypertension was present in 63% of the incidentalomas, 79% of suspected pheochromocytomas and in none of the screening group. Paroxysmal symptoms were present in almost all with suspected pheochromocytoma while only in half of the other groups. The suspected pheocromocytoma group had most symptoms and the screening group least. The classic triad was present in 14% of the incidentalomas, in 28% of the suspected and in none of the screening group, while no symptoms at all was present in 12%, 0% and 25%, respectively. Pheochromocytoma crisis occurred in 5%. There was a positive correlation between tumor size vs hormone levels, and catecholamine levels vs blood pressure. CONCLUSION: Clinicians need to be aware of the modern presentation of pheochromocytomas since early identification can be life-saving.

Treatment and outcomes in pheochromocytomas and paragangliomas: a study of 110 cases from a single center.

PURPOSE: Many pheochromocytomas and paragangliomas (PPGLs) are nowadays diagnosed as incidentalomas or by screening. This may have changed outcomes. METHODS: We reviewed 110 consecutive cases of PPGLs. Two cases with concurrent ectopic ACTH-syndrome were excluded. RESULTS: Sixty-five percent had presented as incidentalomas, 30% as symptomatic PPGLs, and 5% had been screened (previously diagnosed MEN2A). Doxazosin was used in 79%, phenoxybenzamine in 18%, intravenous phentolamine in 1%, and no alpha-blockade in the rest. Laparoscopic surgery was performed in 70%, but 11% were converted to open surgery. Complications of surgery were seen in 20%, and length of stay after surgery was 4 days (2-8) with no correlation with alpha-blockade dose or time. In the whole cohort glycemic disturbances decreased by surgery (47% vs. 9%, P < 0.001). During 9.6 ± 7.2-year (median 8[4-13]) follow-up, 7% developed a new PPGL, 5% a PPGL-metastasis (KI67 > 2% n = 2; KI67 ≤ 1% n = 3; tumor size ≥ 95 mm n = 4), and 13% died (metastatic pheochromocytoma n = 2, hypertensive crisis n = 1, heart failure n = 2, other malignancies n = 5, and unclear n = 4). Surgery improved blood pressure and glycemic disturbances in the incidentaloma and the symptomatic PPGL. Recurrence was more common in the screening group. The symptomatic PPGL group was more likely to die of a PPGL-related cause. Surgery was more challenging in the paragangliomas, with less improvement in glycemic control than in the pheochromocytoma group. However, blood pressure and long-term outcomes were similar. CONCLUSION: The outcomes seemed slightly better than previous studies. Long-term prognosis was similar between pheochromocytomas and paragangliomas.