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Von Hippel–Lindau disease (VHL) is a multineoplasm inherited disease manifesting with hemangioblastoma of the central nervous system and retina, adrenal pheochromocytoma, renal cell carcinoma, pancreatic neuroendocrine tumors and cysts, and neoplasms/cysts of the ear, broad ligament, and testicles. During 2018-2020, the VHL Alliance gathered several committees of experts in the various clinical manifestations of VHL to review the literature, gather the available evidence on VHL, and develop recommendations for patient management. The current report details the results of the discussion of a group of experts in the pancreatic manifestations of VHL along with their proposed recommendations for the clinical surveillance and management of patients with VHL. The recommendations subcommittee performed a comprehensive systematic review of the literature and conducted panel discussions to reach the current recommendations. The level of evidence was defined according to the Shekelle variation of the Grading of Recommendations, Assessment, Development, and Evaluation grading system. The National Comprehensive Cancer Network Categories of Evidence and Consensus defined the committee members' interpretation of the evidence and degree of consensus. The recommendations encompass the main aspects of VHL-related pancreatic manifestations and their clinical management. They are presented in a clinical orientation, including general planning of screening and surveillance for pancreatic neuroendocrine tumors, utility of biochemical biomarkers, the optimal choice for imaging modality, indirect risk stratification, indications for tissue sampling of VHL-related pancreatic neuroendocrine tumors, and interventions. These recommendations are designed to serve as the reference for all aspects of the screening, surveillance, and management of VHL-related pancreatic manifestations.

Dysregulation of epigenetic mechanisms, reflected by loss of expression of 5-hydroxymethylcytosine (5-hmC) is being increasingly recognized as a marker of aggressive behavior in several neoplasms; however, the role of such epigenetic modifiers in pancreatic neuroendocrine tumors (PanNETs) has not been studied. Annotated cohort of 60 PanNETs was evaluated for 5-hmC expression using immunohistochemistry. Univariable and multivariable analyses were performed. To determine intratumor heterogeneity of 5-hmC expression, 26 additional synchronous metastatic deposits of PanNETs from 8 patients were evaluated for 5-hmC expression. 5-hmC level showed significant association with the presence of distant metastases (P=0.02), female sex (P=0.04), and Ki-67 proliferation index (P=0.002). A multivariate model created using the stepwise logistic regression analysis showed the presence of nodal metastases (odds ratio=6.15), lymphovascular invasion (odds ratio=4.07) and lack of 5-hmC expression (odds ratio=5.34) were predictive of the risk of distant metastasis in PanNETs with a c-statistic of 0.845. Epigenetic intratumoral heterogeneity of 5-hmC expression was seen in 37.5% cases (3/8). Our work provides evidence that epigenetic regulators are involved in the pathobiology of PanNETs and immunohistochemical analysis of 5-hmC may be able to refine prognostic evaluation of these tumors.

Background: Progression trajectories of patients with mild cognitive impairment (MCI) are currently not well understood. Objective: To classify patients with incident MCI into different latent classes of progression and identify predictors of progression class. Methods: Participants with incident MCI were identified from the US National Alzheimer’s Coordinating Center Uniform Data Set (09/2005-02/2019). Clinical Dementia Rating (CDR®) Dementia Staging Instrument-Sum of Boxes (CDR-SB), Functional Activities Questionnaire (FAQ), and Mini-Mental State Examination (MMSE) score longitudinal trajectories from MCI diagnosis were fitted using growth mixture models. Predictors of progression class were identified using multivariate multinomial logistic regression models; odds ratios (ORs) and 95% confidence intervals (CIs) were reported. Results: In total, 21%, 22%, and 57% of participants (N = 830) experienced fast, slow, and no progression on CDR-SB, respectively; for FAQ, these figures were 14%, 23%, and 64%, respectively. CDR-SB and FAQ class membership was concordant for most participants (77%). Older age (≥86 versus≤70 years, OR [95% CI] = 5.26 [1.78–15.54]), one copy of APOE ɛ4 (1.94 [1.08–3.47]), higher baseline CDR-SB (2.46 [1.56–3.88]), lower baseline MMSE (0.85 [0.75–0.97]), and higher baseline FAQ (1.13 [1.02–1.26]) scores were significant predictors of fast progression versus no progression based on CDR-SB (all p

BACKGROUND: Small bowel neuroendocrine tumors (SB-NET) frequently metastasize to regional lymphatic or distant sites. While most prognostication of SB-NET focuses on lymph node involvement, findings from studies of NETs from other primary sites have suggested that preoperative serum chromogranin-A (CgA) levels may provide a more accurate metric. STUDY DESIGN: Using the National Cancer Database (2004–2016), we analyzed patients with locoregional SB-NET who underwent curative resection including an adequate lymphadenectomy (n = 1,274). A statistically optimized cut-point was used to dichotomize CgA cohort based on preoperative serum CgA levels. RESULTS: We determined that a CgA ≥139ng/mL identified patients with significantly shorter estimated mean overall survival (6.6 years vs. 7.6 years, log-rank p = 0.00001). These patients were also older (63 vs. 57 years, p < 0.001) and more likely to have poorly-differentiated tumors (2.1% vs. 0.7%, p = 0.04) or primary tumors >1cm (88.2% vs. 79.2%, p = 0.001). Clinical features associated with shorter overall survival included preoperative CgA ≥139ng/mL (HR = 2.19, 95% CI 1.22 – 3.92; p = 0.009), age at diagnosis (HR = 1.06, 95% CI 1.03 – 1.09; p < 0.001), Charlson-Deyo score ≥2 (HR = 3.93, 95% CI 1.71 – 9.01; p = 0.001), and poorly-differentiated tumors (HR = 11.22, 95% CI 4.16 – 30.24; p < 0.001). Neither lymph node metastasis nor T-stage were independently associated with shorter overall survival in patients with locoregional SB-NET. CONCLUSIONS: Elevated preoperative serum CgA is an adverse prognostic marker associated with shorter overall survival in patients with locoregional SB-NET.

Pancreatic neuroendocrine tumors (PNETs) are a rare group of neoplasms originating from the endocrine pancreas. PNETs are classified as functional or non-functional tumors. PNETs are more often diagnosed at a higher stage with distant metastases or advanced locoregional disease. The majority of individuals with hepatic metastases will ultimately die of liver failure; therefore, the treatment of liver tumor burden is critical to providing a survival impact. While surgical resection remains the only chance of cure for disease confined to the pancreas or for locoregional disease, the treatment of advanced or metastatic PNETs is more complex and often requires a multimodal approach. This review focuses on treatment options for well and moderately differentiated PNETs with metastatic disease to the liver. These include surgery, liver-directed therapies including ablative and intra-arterial therapies, and systemic therapies such as somatostatin analogues, targeted therapies, chemotherapy, and peptide receptor radionuclide therapy. Developing an individualized treatment strategy requires careful assessment of liver tumor burden and predicted biological behavior. Aggressive surgical resection of hepatic metastases secondary to PNET primary tumors is associated with improved survival in multiple retrospective studies. General goals of treatment for metastatic disease include prolonging overall survival and progression free survival, improving quality of life, and control of symptoms.

Noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) are follicular-patterned thyroid neoplasms defined by nuclear atypia and indolent behavior. They harbor RAS mutations, rather than BRAFV600E mutations as is observed in papillary thyroid carcinomas with extensive follicular growth. Reliably identifying NIFTPs aids in safe therapy de-escalation, but has proven to be challenging due to interobserver variability and morphologic heterogeneity. The genomic scoring system BRS (BRAF-RAS score) was developed to quantify the extent to which a tumor’s expression profile resembles a BRAFV600E or RAS-mutant neoplasm. We proposed that deep learning prediction of BRS could differentiate NIFTP from other follicular-patterned neoplasms. A deep learning model was trained on slides from a dataset of 115 thyroid neoplasms to predict tumor subtype (NIFTP, PTC-EFG, or classic PTC), and was used to generate predictions for 497 thyroid neoplasms within The Cancer Genome Atlas (TCGA). Within follicular-patterned neoplasms, tumors with positive BRS (RAS-like) were 8.5 times as likely to carry an NIFTP prediction than tumors with negative BRS (89.7% vs 10.5%, P

Osteoid osteoma is a painful, benign and common bone tumor that is prevalent in young adults. The typical clinical presentation consists of pain that becomes worse at night and is relieved by nonsteroidal anti-inflammatory drugs. The most common imaging finding is a lytic lesion, known as a nidus, with variable intralesional mineralization, accompanied by bone sclerosis, cortical thickening and surrounding bone marrow edema, as well as marked enhancement with intravenous contrast injection. When the lesion is located in typical locations (intracortical bone and the diaphyses of long bones), both characteristic clinical and radiological features are diagnostic. However, osteoid osteoma is a multifaceted pathology that can have unusual presentations, such as intraarticular osteoid osteoma, epiphyseal location, lesions at the extremities and multicentric nidi, and frequently present atypical clinical and radiological manifestations. In addition, many conditions may mimic osteoid osteoma and vice versa, leading to misdiagnosis. Therefore, it is essential to understand these musculoskeletal diseases and their imaging findings to increase diagnostic accuracy, enable early treatment and prevent poor prognosis.

Background Peptide receptor radionuclide therapy is a targeted therapy used to treat unresectable somatostatin receptor-positive neuroendocrine tumors. The objective of this study was to evaluate response rates among neuroendocrine tumors of different primaries and identify factors relevant to future treatment strategies. Methods We retrospectively reviewed patients who received peptide receptor radionuclide therapy for neuroendocrine tumors from 2018 to 2019 at our institution. Patients were assessed with computed tomography/magnetic resonance imaging and 68Ga-DOTATATE-positron emission tomography before and after 2 or 4 cycles of peptide receptor radionuclide therapy. Tumor response was evaluated by RECIST 1.1. Statistics included multinomial logistic regression models and Fisher exact test. Results Twenty-seven patients underwent 92 cycles of peptide receptor radionuclide therapy: pancreas (n = 11), small bowel (n = 7), and other (n = 9) neuroendocrine tumors. Overall, 30% (8 of 27) had partial response, 59% (16 of 27) stable disease, and 11% (3 of 27) progressed. Pancreatic neuroendocrine tumors responded differently from small bowel neuroendocrine tumors regardless of cycle number (P = .01). The majority of pancreatic neuroendocrine tumors (6 of 11) had partial response to peptide receptor radionuclide therapy, while all small bowel neuroendocrine tumors had stable disease. Pancreatic neuroendocrine tumors stable after 2 cycles were more likely to respond to additional cycles versus other neuroendocrine tumors (probability: 60% vs 11%). Conclusion Patients with unresectable advanced or metastatic pancreatic neuroendocrine tumors may benefit from a full course of peptide receptor radionuclide therapy, whereas other neuroendocrine tumors appear less likely to respond. Large prospective studies are needed to confirm these findings.

Positive resection margins are associated with worse survival after surgery for adrenocortical carcinoma (ACC). We aimed to identify risk factors for positive margins post-resection.The NCDB was queried for ACC patients from 2006 to 2015. Patients with positive versus negative resection margins post-surgery were compared using Chi-square tests. Survival based on adjuvant treatment was assessed using Kaplan-Meier curves.1,973 patients with ACC were identified, 217 (11.0%) with positive margins. Multivariable analysis identified extra-adrenal extension (HR 4.92, p 0.001), lymph node metastases (HR 2.64, p = 0.001), and distant metastases (HR 1.53, p = 0.03) as risk factors for positive margins. No significant difference in margin status existed between patients who had an open versus minimally invasive procedure (p = 0.6). Positive margin patients receiving adjuvant radiation (p = 0.007) or combined chemo-radiation (p = 0.001) had the longest survival.No modifiable risk factors were identified, but patients with positive margins receiving adjuvant radiation or chemo-radiation had the longest survival.

The Chicago Consensus Working Group provides multidisciplinary recommendations for the management of desmoplastic small round cell tumor, breast, and gastrointestinal stromal tumor specifically related to peritoneal surface malignancy. These guidelines are developed with input from leading experts including surgical oncologists, medical oncologists, pathologists, radiologists, palliative care physicians, and pharmacists. These guidelines recognize and address the emerging need for increased awareness in the appropriate management of peritoneal surface disease. They are not intended to replace the quest for higher levels of evidence.

The Chicago Consensus Working Group provides multidisciplinary recommendations for palliative care specifically related to peritoneal surface malignancies. These guidelines are developed with input from leading experts including surgical oncologists, medical oncologists, gynecologic oncologists, pathologists, radiologists, palliative care physicians, and pharmacists. These guidelines recognize and address the emerging need for increased awareness in the appropriate management of peritoneal surface disease. They are not intended to replace the quest for higher levels of evidence.

The Chicago Consensus Working Group provides multidisciplinary recommendations for the management of neuroendocrine tumors specifically related to the management of peritoneal surface malignancy. These guidelines are developed with input from leading experts, including surgical oncologists, medical oncologists, pathologists, radiologists, palliative care physicians, and pharmacists. These guidelines recognize and address the emerging need for increased awareness in the appropriate management of peritoneal surface disease. They are not intended to replace the quest for higher levels of evidence.

Surgical management of pancreatic neuroendocrine tumors (PNETS) is steadily evolving and is influenced by multiple factors. Sporadic PNETs are generally managed more aggressively than those occurring in the background of hereditary syndromes, and functioning PNETs are almost always resected if they are not metastatic. Localized nonfunctioning PNETs less than 2 cm can often be observed. Surgical resection for localized PNET greater than 2 cm comprises parenchymal sparing pancreas resections, such as enucleations, or formal anatomic resection, such as distal pancreatectomy or pancreaticoduodenectomy. PNETs commonly metastasize to the liver, and several systemic and liver-directed options to treat hepatic metastases are available.

BackgroundIn rheumatoid arthritis (RA) trials, inclusion of patients on background treatment with glucocorticoids (GCs) might impact efficacy and safety outcomes.ObjectivesTo determine if inclusion of patients on background GC use influenced efficacy and safety outcomes of RA randomised clinical trials on initiation of tocilizumab (TCZ) or adalimumab (ADA) or methotrexate (MTX) monotherapy.MethodsData of four double-blind RA randomised controlled trials (AMBITION, ACT-RAY, ADACTA and FUNCTION) with in total four TCZ, one ADA and two MTX monotherapy arms were analysed. Analyses of covariance of changes from baseline to week 24 in efficacy endpoints and radiographic progression up to week 104 were performed, correcting for relevant covariates. Incidence rates of serious adverse events (SAEs) were assessed.ResultsNo statistically significant differences were found in efficacy parameters between background GC users and non-GC users, except for less radiographic progression associated with GC usage in one MTX arm. SAE rates were not statistically significantly different between GC users and non-GC users in the treatment arms.ConclusionNo effect of including patients on background GC treatment on efficacy and safety trial outcomes was found, with the exception of reduced radiological joint damage in one MTX arm.

Many current guidelines recommend nonoperative management for pancreatic neuroendocrine tumors2 cm. The objective of this study was to evaluate the utilization and outcomes of resection for these pancreatic neuroendocrine tumors in the United States.Using the National Cancer Database (2004-2014), 3,243 cases of T1 (≤2.0 cm) pancreatic neuroendocrine tumors were identified. Additional patient and tumor characteristics were examined. Multivariate models were used to identify factors that predicted resection and to assess patient survival after resection.75% of pancreatic neuroendocrine tumors measuring 0 to 1.0 cm and 80% of pancreatic neuroendocrine tumors measuring1.0 and ≤2.0 cm were resected. Eighty-four pancreatic neuroendocrine tumors were functional, of which 82% were resected. Variables influencing resection included positive lymph nodes, tumor in body or tail of pancreas, well or moderately differentiated tumors, and resection at academic medical centers (odds ratio 1.5-4.9). When controlling for other variables, patients with pancreatic neuroendocrine tumors 1 to 2 cm who underwent resection had a prolonged 5-year survival rate (hazard ratio 0.51, confidence interval 0.34-0.75) when compared with those who did not undergo resection. This survival benefit of resection was not found for pancreatic neuroendocrine tumors 0 to 1 cm (hazard ratio = 0.63, confidence interval 0.36-1.11).Contrary to many current recommendations, most patients with pancreatic neuroendocrine tumors ≤2.0 cm undergo surgical resection in the United States. A survival benefit was found for resection of pancreatic neuroendocrine tumors 1 to 2 cm, suggesting that current recommendations should perhaps be revised.

This manuscript is the result of the North American Neuroendocrine Tumor Society consensus conference on the surgical management of pancreatic neuroendocrine tumors from July 19 to 20, 2018. The group reviewed a series of questions of specific interest to surgeons taking care of patients with pancreatic neuroendocrine tumors, and for each, the available literature was reviewed. What follows are these reviews for each question followed by recommendations of the panel.

The only potential cure for neuroendocrine tumors (NETs) is operative resection, which may also offer a survival benefit for advanced disease. We aimed to assess the role of 68Ga-DOTATATE PET/CT in preoperative planning and compared its performance to CT with IV contrast and MRI with Eovist®, for abdominal NETs. Records of patients who underwent 68Ga-DOTATATE PET/CT in addition to MRI with Eovist® and/or CT with IV contrast were retrospectively evaluated. The effect of imaging findings on surgical management and characteristics of detected lesions were analyzed. Descriptive statistics were used. Of 21 patients who underwent 68Ga-DOTATATE PET/CT prior to surgical resection, five (24%) had a change in surgical management due to findings. In three patients, 68Ga-DOTATATE PET/CT identified the primary tumor. In two patients, 68Ga-DOTATATE PET/CT helped clarify equivocal hepatic lesions seen on MRI with Eovist®. MRI with Eovist® had the highest number of lesions found (median 13, versus 9 on CT and 9.5 on 68Ga-DOTATATE PET/CT). DOTATATE-avid lesions were on average larger than lesions seen only on MRI with Eovist® (1.6 cm versus 0.6 cm, p = 0.0002). The optimal cutoff point for detection by 68Ga-DOTATATE PET/CT was a size of 0.95 cm, with a sensitivity of 56% and specificity of 98%. Preoperative 68Ga-DOTATATE PET/CT is useful only in a subset of patients undergoing surgical resection for NETs. MRI with Eovist® is superior at identifying liver metastases when compared to 68Ga-DOTATATE PET/CT and should therefore be used routinely before hepatic cytoreduction of NETs.

Background The goal of gene therapy for patients with hemophilia A is to safely impart long-term stable factor VIII expression that predictably ameliorates bleeding with the use of the lowest possible vector dose. Methods In this phase 1-2 trial, we infused an investigational adeno-associated viral (AAV) vector (SPK-8011) for hepatocyte expression of factor VIII in 18 men with hemophilia A. Four dose cohorts were enrolled; the lowest-dose cohort received a dose of 5 × 1011 vector genomes (vg) per kilogram of body weight, and the highest-dose cohort received 2 × 1012 vg per kilogram. Some participants received glucocorticoids within 52 weeks after vector administration either to prevent or to treat a presumed AAV capsid immune response. Trial objectives included evaluation of the safety and preliminary efficacy of SPK-8011 and of the expression and durability of factor VIII. Results The median safety observation period was 36.6 months (range, 5.5 to 50.3). A total of 33 treatment-related adverse events occurred in 8 participants; 17 events were vector-related, including 1 serious adverse event, and 16 were glucocorticoid-related. Two participants lost all factor VIII expression because of an anti-AAV capsid cellular immune response that was not sensitive to immune suppression. In the remaining 16 participants, factor VIII expression was maintained; 12 of these participants were followed for more than 2 years, and a one-stage factor VIII assay showed no apparent decrease in factor VIII activity over time (mean [±SD] factor VIII activity, 12.9±6.9% of the normal value at 26 to 52 weeks when the participants were not receiving glucocorticoids vs. 12.0±7.1% of the normal value at >52 weeks after vector administration; 95% confidence interval [CI], -2.4 to 0.6 for the difference between matched pairs). The participants had a 91.5% reduction (95% CI, 88.8 to 94.1) in the annualized bleeding rate (median rate, 8.5 events per year [range, 0 to 43.0] before vector administration vs. 0.3 events per year [range, 0 to 6.5] after vector administration). Conclusions Sustained factor VIII expression in 16 of 18 participants who received SPK-8011 permitted discontinuation of prophylaxis and a reduction in bleeding episodes. No major safety concerns were reported. (Funded by Spark Therapeutics and the National Heart, Lung, and Blood Institute; ClinicalTrials.gov numbers, NCT03003533 and NCT03432520.).

Background Adrenocortical carcinoma (ACC) is a rare malignancy with a dismal prognosis. Two landmark trials published in 2007 and 2012 showed efficacy for adjuvant mitotane in resectable ACC and etoposide/doxorubicin/cisplatin plus mitotane for unresectable ACC, respectively. In this study, we used the National Cancer Database to examine whether treatment patterns and outcomes changed after these trials. Methods The National Cancer Database was used to examine treatment patterns and survival in patients diagnosed with ACC from 2006 to 2015. Treatment modalities were compared within that group and with a historical cohort (1985 to 2005). χ2 tests were performed, and Cox proportional hazards models were created. Results From 2006 to 2015, 2752 patients were included; 38% of patients (1042) underwent surgery alone, and 31% (859) underwent surgery with adjuvant therapy. Overall 5-year survival rates for all stages after resection were 43% (median, 41 months) in the contemporary cohort and 39% (median, 32 months) in the historical cohort. After 2007, patients who underwent surgery were more likely to receive adjuvant chemotherapy (P = 0.005), and 5-year survival with adjuvant chemotherapy improved (41% vs 25%; P = 0.02). However, survival did not improve in patients with unresectable tumors after 2011 compared with 2006 to 2011 (P = 0.79). Older age, tumor size ≥10 cm, distant metastases, and positive margins were associated with lower survival after resection (hazard ratio range: 1.39 to 3.09; P < 0.03). Conclusions Since 2007, adjuvant therapy has been used more frequently in patients with resected ACC, and survival for these patients has improved but remains low. More effective systemic therapies for patients with ACC, especially those in advanced stages, are desperately needed.

Objectives Methotrexate (MTX), often combined with low moderately dosed prednisone, is still the cornerstone of initial treatment for early rheumatoid arthritis (RA). It is not known how this strategy compares with initial treatment with a biological. We therefore compared the effectiveness of tocilizumab (TCZ), or TCZ plus MTX (TCZ+MTX) with MTX plus 10 mg prednisone (MTX+pred), all initiated within a treat-to-target treatment strategy in early RA. Methods Using individual patient data of two trials, we indirectly compared tight-controlled treat-to-target strategies initiating TCZ (n=103), TCZ+MTX (n=106) or MTX+pred (n=117), using initiation of MTX (n=227) as reference. Primary outcome was Disease Activity Score assessing 28 joints (DAS28) over 24 months. To assess the influence of acute phase reactants (APRs), a disease activity composite outcome score without APR (ie, modification of the Clinical Disease Activity Index (m-CDAI)) was analysed. Secondary outcomes were remission (several definitions), physical function and radiographic progression. Multilevel models were used to account for clustering within trials and patients over time, correcting for relevant confounders. Results DAS28 over 24 months was lower for TCZ+MTX than for MTX+Pred (mean difference: −0.62 (95% CI −1.14 to −0.10)). Remission was more often achieved in TCZ+MTX and in TCZ versus MTX+pred (p=0.02/0.05, respectively). Excluding APRs from the disease activity outcome score, TCZ-based strategies showed a slightly higher m-CDAI compared with MTX+pred, but this was not statistically significant. Other outcomes were also not statistically significantly different between the strategies. Conclusions In patients with early RA, although TCZ-based strategies resulted in better DAS28 and remission rates compared with MTX+pred, at least part of these effects may be due to a specific effect of TCZ on APRs.

Altres ajuts: CIBERONC/CB16/12/00363 Malignant tumours show a marked degree of morphological, molecular and proteomic heterogeneity. This variability is closely related to microenvironmental factors and the location of the tumour. The activation of genetic alterations is very tissue-dependent and only few tumours have distinct genetic alterations. Importantly, the activation state of proteins and signaling factors is heterogeneous in the primary tumour and in metastases and recurrences. The molecular diagnosis based only on genetic alterations can lead to treatments with unpredictable responses, depending on the tumour location, such as the tumour response in melanomas versus colon carcinomas with mutations. Therefore, we understand that the correct evaluation of tumours requires a system that integrates both morphological, molecular and protein information in a clinical and pathological context, where intratumoral heterogeneity can be assessed. Thus, we propose the term 'tissunomics', where the diagnosis will be contextualised in each tumour based on the complementation of the pathological, molecular, protein expression, environmental cells and clinical data.

Venous thromboembolism (VTE) occurs at high incidence in abdominal cancer surgery; therefore, a 4-week postoperative VTE prophylaxis is advocated. However, most patients with neuroendocrine tumors (NETs) have more favorable prognoses. This study aimed to determine the incidence of VTE in patients with abdominal NETs, compare these rates to other abdominal malignancies, and identify VTE risk factors. The ACS-NSQIP database was queried to identify patients with abdominal NETs and other abdominal malignancies who underwent surgery from 2008 to 2015. A 30-day postoperative VTE incidence for each group was compared. Univariable and multivariable analyses were used to identify VTE risk factors. Of the 7226 operations for patients with benign (2154) and malignant (5072) abdominal NETs, 144 patients experienced a VTE without significant differences between groups. Subgroup analysis revealed a spectrum of VTE rates. Compared to VTE rates of other abdominal malignancies, patients with benign (1.1% vs. 2.4%, p

Background 68Gallium-DOTATATE positron emission tomography–computed tomography (PET CT) has shown superior accuracy in detecting grade 1 and 2 neuroendocrine tumors over previous imaging modalities and was recently included in National Comprehensive Cancer Network guidelines. It remains unclear which patients benefit most from this imaging modality. We therefore reviewed our initial experience with 68Gallium-DOTATATE PET CT to evaluate its usefulness in diagnosing, staging, and surveilling neuroendocrine tumors. Methods Records of patients who underwent 68Gallium-DOTATATE PET CT from March to December 2017 were prospectively evaluated. The primary endpoint was whether 68Gallium-DOTATATE PET CT changes treatment in patients with neuroendocrine tumors. Descriptive statistics, Fisher exact tests, and nested logistic regressions were conducted. Results A total of 50 consecutive patients were included. Of these, 41 patients (82%) had a biopsy-proven neuroendocrine tumor at the time of imaging. The remaining 9 patients (18%) had symptoms or biochemistry suggestive of a neuroendocrine tumor with negative cross-sectional imaging. 68Gallium-DOTATATE PET CT changed management in 33 patients (66%). There were 24 patients with intermodality changes in management and 9 patients with intramodality changes in management. Patients with scans performed for staging had a higher likelihood of a change in management (P = .006). Conclusion Performing 68Gallium-DOTATATE PET CT should be considered for staging and surveillance of neuroendocrine tumors because it is frequently associated with changes in management.

Current guidelines recommend total thyroidectomy (TT) and radioablation for most papillary thyroid cancer (PTC) in children. These guidelines have been criticized as aggressive, especially for early-stage PTC, as it likely does not influence patient survival and results in life-long thyroid hormone replacement. We sought to study whether the extent of thyroidectomy (TT vs thyroid lobectomy [TL]) influences overall and disease-specific survival in children with localized PTC.The National Cancer Database and the Surveillance, Epidemiology, and End Results registries were queried. Patients 18 years or younger with low-risk PTC between 2004 and 2016 were included. Using a 1:1 propensity score matching, patients who underwent TT were matched for age, sex, race, year of diagnosis, and tumor size with a similar cohort of patients who underwent TL. Primary end points were overall survival and disease-specific survival.There were 3,500 patients identified as surgically treated for PTC, of which 1,325 patients met inclusion criteria for matching. Three hundred and twenty-six patients were matched. One hundred and sixty-three patients had TT; 140 were female and mean age was 16 years (interquartile range [IQR] 13 to 17 years). One hundred and sixty-three patients had TL; 140 were female and mean age was 16 years (IQR 14 to 17 years). Median follow-up was 5.0 years (IQR 2.8 to 8 years) and 8.3 years (IQR 3.6 to 14.4 years) in the National Cancer Database and Surveillance, Epidemiology, and End Results cohorts, respectively. There was no statistically significant difference in overall survival or disease-specific survival in patients with PTC4 cm, regardless of whether patients underwent TT or TL (p = 0.32 for National Cancer Database registry and p = 0.67 for Surveillance, Epidemiology, and End Results registry).This study suggests that the extent of thyroidectomy does not influence survival for pediatric patients with early-stage PTC and that TL might be adequate in this patient population.

Appendiceal neuroendocrine tumors (NETs) are rare with an incidence rate of 0.15–0.6 cases per 100,000 each year. The majority of appendiceal neuroendocrine tumors are diagnosed retrospectively after appendectomy that was performed for other indications. Workup includes histopathology review, biochemical laboratory studies, and cross-sectional and/or functional imaging. The extent of surgical resection, appendectomy versus right hemicolectomy with mesenteric lymphadenectomy, depends upon assessment of tumor size, location, and other high risk features. The management of advanced or metastatic disease is more complex and often requires a multidisciplinary approach but can include hepatic debulking, local ablative therapies, and/or medical therapies including somatostatin analogues, targeted therapies, and cytotoxic chemotherapies. Patients with locoregional disease have excellent survival, while patients with advanced and metastatic disease have a worse prognosis. The purpose of this text is to review the diagnosis and surgical management of well-differentiated appendiceal NETs.

Background Despite thyroid hormone replacement, some euthyroid patients with Hashimoto thyroiditis will continue to experience persistent symptoms that reduce their quality of life. Recent studies indicate that total thyroidectomy is superior to medical therapy alone in improving these symptoms. However, there is a high complication rate after total thyroidectomy in patients with Hashimoto thyroiditis. This study evaluates the cost-effectiveness of total thyroidectomy for euthyroid patients who have Hashimoto thyroiditis with persistent symptoms. Methods We utilized a Markov model to compare total thyroidectomy and medical therapy alone over the lifetime of the cohort. Costs, probabilities, and utility parameters were derived from literature and Medicare cost data. A willingness-to-pay threshold of $100,000/quality-adjusted life years was used. We performed sensitivity analyses to ascertain model uncertainty. Results On average, medical therapy alone costs $12,845, produced 16.9 quality-adjusted life years, and was dominated. Total thyroidectomy costs $1,490 less and produced 1.4 more quality-adjusted life years. Probabilistic sensitivity analysis confirmed total thyroidectomy as the optimal strategy in 89% of cases. Medical therapy alone will become cost-effective if the cost of uncomplicated thyroidectomy increases by 25%, if the probability of permanent complication after total thyroidectomy increases 12-fold, or if there is no gain in quality of life after thyroidectomy. Conclusion Total thyroidectomy is more cost-effective than medical therapy alone for the management of euthyroid patients who have Hashimoto thyroiditis with persistent symptoms.

Background We sought to identify immunoglobin G autoantibodies predictive of early treatment response to methotrexate, the recommended first-line therapy for patients with newly diagnosed rheumatoid arthritis, and to the interleukin-6 receptor inhibitor biologic tocilizumab, initiated as the first disease-modifying anti-rheumatic drug. Materials and methods In baseline sera of a subset of patients with newly diagnosed rheumatoid arthritis in the U-Act-Early study, selected based on specific responder/non-responder criteria using the Disease Activity Score assessing 28 joints (DAS28) within the first 20 weeks, we measured immunoglobin G antibody reactivity against 463 protein antigens and performed supervised cluster analysis to identify predictive autoantibodies for treatment response. The analysis subset comprised 56 patients in the methotrexate arm (22 responders, 34 non-responders) and 50 patients in the tocilizumab arm (34 responders, 16 non-responders). For comparison, these analyses were also performed in 50 age- and gender-matched healthy controls. Results Increased reactivity in responders versus non-responders was found in the methotrexate arm against two antigens—DOT1-like histone lysine methyltransferase (p = 0.009) and tropomyosin (p = 0.003)—and in the tocilizumab arm against one antigen—neuro-oncological ventral antigen 2 (p = 0.039). Decreased reactivity was detected against two antigens in the methotrexate arm—G1 to S phase transition 2 (p = 0.023) and the zinc finger protein ZPR1 (p = 0.021). Reactivity against the identified antigens was not statistically significant in either treatment arm for patients with rheumatoid factor–positive versus–negative or anti-cyclic citrullinated test–positive versus test–negative rheumatoid arthritis (p ≥ 0.06). Conclusions Comprehensive profiling of baseline sera revealed several novel immunoglobin G autoantibodies associated with early treatment response to methotrexate and to tocilizumab in disease-modifying anti-rheumatic drug-naive patients with rheumatoid arthritis. These findings could eventually yield clinically relevant predictive markers, if corroborated in different patient cohorts, and may facilitate future benefit in personalised healthcare.

Context Patients with von Hippel–Lindau (vHL) disease caused by a missense VHL mutation have a more severe phenotype compared with other VHL mutation types. Objective To define pancreatic neuroendocrine tumor (PNET) aggressiveness according to VHL genotype. Design A prospective natural history study. Setting The National Institutes of Health clinical center. Patients Patients with vHL disease, pancreatic manifestations, and germline missense VHL gene mutations. Intervention In-silico prediction of VHL mutation via five computational prediction models. Patients with >80% prediction for disease-causing mutations in all models [high predicted risk (HPR)] were compared with others [low predicted risk (LPR)]. Main Outcome Measure Rates of metastases, surgical intervention, and disease progression. Results Sixty-nine patients were included: 2 developed metastases, 12 needed surgery, and 31 had disease progression during a median follow-up of 60 months (range 13 to 84 months). Thirteen patients were excluded for low prediction reliability. In the remaining 56 patients (45 with PNETs, 11 with pancreatic cysts), the HPR group (n = 13) had a higher rate of disease progression than the LPR group (n = 43) in multivariable analysis (hazard ratio 3.6; 95% confidence interval, 1.1 to 11.9; P = 0.037). The HPR group also had a higher risk of developing metastases (P = 0.015). Among patients with codon 167 hotspot mutations (n = 26), those in the HPR group had a higher risk for disease progression (P = 0.03) than other patients. Conclusions Computational models for predicting the impact of missense VHL gene mutations may be used as a prognostic factor in patients with PNETs in the context of vHL disease.

Caffeine is a widely consumed stimulant with the potential to enhance physical performance through multiple mechanisms. However, recent in vitro findings have suggested that caffeine may block skeletal muscle anabolic signaling through AMP-activated protein kinase (AMPK)-mediated inhibition of mechanistic target of rapamycin (mTOR) signaling pathway. This could negatively affect protein synthesis and the capacity for muscle growth. The primary purpose of this study was to assess the effect of caffeine on in vivo AMPK and mTOR pathway signaling, protein synthesis, and muscle growth. In cultured C2C12 muscle cells, physiological levels of caffeine failed to impact mTOR activation or myoblast proliferation or differentiation. We found that caffeine administration to mice did not significantly enhance the phosphorylation of AMPK or inhibit signaling proteins downstream of mTOR (p70S6k, S6, or 4EBP1) or protein synthesis after a bout of electrically stimulated contractions. Skeletal muscle-specific knockout of LKB1, the primary AMPK activator in skeletal muscle, on the other hand, eliminated AMPK activation by contractions and enhanced S6k, S6, and 4EBP1 activation before and after contractions. In rats, the addition of caffeine did not affect plantaris hypertrophy induced by the tenotomy of the gastrocnemius and soleus muscles. In conclusion, caffeine administration does not impair skeletal muscle load-induced mTOR signaling, protein synthesis, or muscle hypertrophy.

ObjectiveTo determine the association between neuroendocrine tumor (NET) biomarker levels and the extent of disease as assessed by68Ga DOTATATE PET/CT imaging.DesignA retrospective analysis of a prospective database of patients with NETs.MethodsFasting plasma chromogranin A (CgA), neuron-specific enolase (NSE), gastrin, glucagon, vasoactive intestinal peptide (VIP) and pancreatic polypeptide (PP), and 24-h urinary 5-hydroxyindoleacetic acid (5-HIAA) levels were measured. Correlation between biomarkers and total68Ga-DOTATATE-avid tumor volume (TV) was analyzed.ResultsThe analysis included 232 patients. In patients with pancreatic NETs (n = 112),68Ga-DOTATATE TV correlated with CgA (r = 0.6,P = 0.001, Spearman). In patients with multiple endocrine neoplasia type 1 (n = 39),68Ga-DOTATATE TV correlated with glucagon (r = 0.5,P = 0.01) and PP levels (r = 0.5,P = 0.049). In patients with von Hippel–Lindau (n = 24), plasma VIP (r = 0.5,P = 0.02) and PP levels (r = 0.7,P 68Ga-DOTATATE TV. In patients with small intestine NET (SINET,n = 74),68Ga-DOTATATE TV correlated with CgA (r = 0.5,P = 0.02) and 5-HIAA levels (r = 0.7,P P = 0.001).68Ga-DOTATATE TV in patients with NET of unknown primary (n = 16) and those with NET of other primary location (n = 30) correlated with 5-HIAA levels (r = 0.8,P = 0.002 andr = 0.7,P = 0.02 respectively).ConclusionsOur data supports the use of specific NET biomarkers based on the site of the primary NET and the presence of hereditary syndrome-associated NET. High urinary 5-HIAA levels indicate the presence of metastatic disease in patients with SINET.

The Chicago Consensus Working Group provides multidisciplinary recommendations for the management of peritoneal mesothelioma. These guidelines are developed with input from leading experts, including surgical oncologists, medical oncologists, pathologists, radiologists, palliative care physicians, and pharmacists. These guidelines recognize and address the emerging need for increased awareness of the appropriate management of peritoneal surface disease. They are not intended to replace the quest for higher levels of evidence.

The Chicago Consensus Working Group provides the following multidisciplinary recommendations for the care of patients with peritoneal surface malignancies. This article focuses on the standards of a peritoneal surface malignancy center, standards of billing and coding, standards of operative reports for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy, standards of cytoreductive surgery training, and standards of intraoperative chemotherapy preparation. These guidelines are developed with input from leading experts, including surgical oncologists, medical oncologists, pathologists, radiologists, palliative care physicians, and pharmacists. These guidelines recognize and address the emerging need for increased awareness in the appropriate management of peritoneal surface disease. They are not intended to replace the quest for higher levels of evidence.

The Chicago Consensus Working Group provides multidisciplinary recommendations for the management of ovarian neoplasms specifically related to the management of peritoneal surface malignancy. These guidelines are developed with input from leading experts, including surgical oncologists, medical oncologists, gynecologic oncologists, pathologists, radiologists, palliative care physicians, and pharmacists. These guidelines recognize and address the emerging need for increased awareness in the appropriate management of peritoneal surface disease. They are not intended to replace the quest for higher levels of evidence.

Background: The role of perioperative systemic therapy (PST) in the management of localized pancreatic neuroendocrine neoplasms (PanNEN) is unclear. Objectives: We aimed to evaluate the benefit of PST compared to surgery alone (SA) in patients with localized PanNEN. Method: We selected patients with stages I–III PanNEN who underwent curative-intent surgical resection in National Cancer Database from 2006 to 2014. Patients who had both PST and surgical resection were matched with patients who received SA by propensity score at 1-to-1 ratio with nearest neighbor method. Results: Four thousand eight hundred and ninety-two patients were included in this study with median age of 60 years. Factors associated with significant more use of PST compared to SA included age p = 0.037). This finding was confirmed by multivariable Cox proportional hazards regression in the original cohort (hazard ratio [HR] 1.45, 95% CI 1.11–1.89, p = 0.006). Subgroup analyses showed that adjuvant therapy was not associated with improved OS in grades 1–2 PanNEN (HR 2.03, 95% CI 1.31–3.16, p = 0.002). Conclusions: PST stratified by grade and neoadjuvant or adjuvant therapy compared to SA was not associated with improved OS in patients with localized PanNEN. PST for localized PanNEN should be used with caution until prospective data are available.

Background. Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are commonly present with metastatic disease, and the liver is the most frequent metastatic site. Herein, we studied whether primary tumor site affects survival in patients with GEP-NETs and liver metastases (NELM). As a secondary endpoint, we studied whether extrahepatic disease and surgical resection impact survival in this patient population. Methods. Patients with NELM diagnosed from 2006 to 2014 were identified from the National Cancer Database. Kaplan-Meier curves and nested Cox proportional hazards were used to assess variables associated with survival. Results. 2947 patients with well- or moderately differentiated GEP-NETs and NELM met the inclusion criteria for this study. Patients with small bowel NETs survived the longest of all GEP-NETs with NELM (median not reached). Rectal and gastric NETs with NELM had the shortest survival (median 31 months). Patients with extrahepatic metastases who underwent any operation survived longer than those managed nonoperatively (median survival 38.7 months vs. 18.6 months, p=0.01). On multivariable analysis, operations on the primary tumor and distant metastatic site (HR 0.23-0.43 vs. no surgery), treatment at an academic/research hospital, Charlson comorbidity index of 0, no extrahepatic metastases, and younger age were associated with prolonged survival (p<0.01). Conclusions. Primary tumor site affects survival in patients with GEP-NETs and NELM. Surgical resection seems beneficial for all GEP-NETs with NELM, even in the presence of extrahepatic metastases.

Background We previously identified, in newly diagnosed rheumatoid arthritis (RA) patients, networks of co-expressed genes and proteomic biomarkers associated with achieving sustained drug-free remission (sDFR) after treatment with tocilizumab- or methotrexate-based strategies. The aim of this study was to identify, within the same patients, metabolic pathways important for achieving sDFR and to subsequently study the complex interactions between different components of the biological system and how these interactions might affect the therapeutic response in early RA. Methods Serum samples were analyzed of 60 patients who participated in the U-Act-Early trial (ClinicalTrials.gov number NCT01034137) and initiated treatment with methotrexate, tocilizumab, or the combination and who were thereafter able to achieve sDFR (n = 37); as controls, patients were selected who never achieved a drug-free status (n = 23). Metabolomic measurements were performed using mass spectrometry on oxidative stress, amine, and oxylipin platforms covering various compounds. Partial least square discriminant analyses (PLSDA) were performed to identify, per strategy arm, relevant metabolites of which the biological pathways were studied. In addition, integrative analyses were performed correlating the previously identified transcripts and proteins with the relevant metabolites. Results In the tocilizumab plus methotrexate, tocilizumab, and methotrexate strategy, respectively, 19, 13, and 12 relevant metabolites were found, which were subsequently used for pathway analyses. The most significant pathway in the tocilizumab plus methotrexate strategy was “histidine metabolism” (p

BackgroundParenchymal-sparing hepatectomies (PSH) are liver resections with preservation of as much liver parenchyma as possible. PSH can be performed laparoscopically (LPSH), but access to the posterosuperior segments is difficult and they are challengingwhen there are multiple bilobar lesions; the procedure may require repositioning and may be long and cumbersome. The objective of this systematic review is to analyze the feasibility and limitations of laparoscopic PSH in the literature.MethodsA systematic review of the literature was performed by searching Medline/PubMed, Scopus, and Cochrane databases. Resections were categorized by segment(s), and data regarding operative time, blood loss, length of hospital stay, complications, and R0 resection were analyzed.ResultsOf 351 studies screened for relevance, 48 studies were reviewed. Ten publications fulfilled inclusion criteria, reporting data from 579 patients undergoing LPSH. The most common indication was CRLM (58%) followed by hepatocellular carcinoma (16%). Only 92 patients were reported to have resections of more than one tumor; the maximum number of lesions resected was seven. Of resected lesions, 21.5% were located in the cranial segments. Mean operating time was 335.2min, estimated blood loss was 462cc, and hospital stay was 7.6days. Conversion rate was 9.7%, and complications occurred in 19.4% of cases. No perioperative mortality was reported. R0 resections were achieved in 87.7% of cases.ConclusionLaparoscopic PSH is performed and reported, but the data quality is low so far. The main limitation of LPSH is the low number of lesions resected, especially for bilobar, metastatic disease. Prospective reports with tumor-specific oncological data are desirable.

A missense point mutation in nerve growth factor (NGFR100W) is associated with hereditary sensory autonomic neuropathy V (HSAN V), originally discovered in a Swedish family. These patients develop severe loss of perception to deep pain but with apparently normal cognitive functions. To better understand the disease mechanism, we have generated the first NGFR100Wknockin mouse model of HSAN V. Mice homozygous for the NGFR100Wmutation (NGFfln/fln) showed significant structural deficits in intra-epidermal nerve fibers (IENFs) at birth. These mice had a total loss of pain perception at ∼2 months of age and they often failed to survive to full adulthood. Heterozygous mice (NGF+/fln) developed a progressive degeneration of small sensory fibers both behaviorally and functionally: they showed a progressive loss of IENFs starting at the age of 9 months accompanied with progressive loss of perception to painful stimuli such as noxious temperature. Quantitative analysis of lumbar 4/5 dorsal root ganglia (DRG) revealed a significant reduction in small size neurons positive for calcitonin gene-related peptide, while analysis of sciatic nerve fibers revealed the mutant NGF+/flnmice had no reduction in myelinated nerve fibers. Significantly, the amount of NGF secreted from fibroblasts were reduced in heterozygous and homozygous mice compared to their wild-type littermates. Interestingly, NGF+/flnshowed no apparent structural alteration in the brain: neither the anterior cingulate cortex nor the medial septum including NGF-dependent basal forebrain cholinergic neurons. Accordingly, these animals did not develop appreciable deficits in tests for central nervous system function. Our study provides novel insights into the selective impact of NGFR100Wmutation on the development and function of the peripheral sensory system.

Context: Insulinomas are usually due to a solitary tumor, but they can be challenging to localize. Case Description: A 66-year-old woman presented with a 1-year history of episodic neuroglycopenic hypoglycemia and was suspected of having an insulinoma. On a supervised fast, she was found to be hypoglycemic at 39 mg/dL, with an insulin of 40 μU/mL 26 hours into the fast and a proinsulin of 35 pmol/L. Contrast-enhanced computed tomography and magnetic resonance imaging did not localize a pancreatic lesion. Intra-arterial calcium stimulation testing showed a step-up of venous insulin levels at injection of the superior mesenteric artery and proximal and mid-splenic artery, and a 68Ga-DOTATATE positron emission tomography/computed tomography showed focal uptake in the neck of the pancreas with a standardized uptake value of 12. Despite negative intraoperative pancreatic palpation and ultrasound, the patient underwent an extended distal pancreatectomy with normalization of biochemical levels and resolution of ...

Pancreatic neuroendocrine tumors (pNETs) are rare tumors that have a better prognosis than their exocrine counterpart, but frequently present with advanced disease. Management of pNETs has evolved considerably over the past decade. Surgical resection remains the only potentially curative option for patients with pNETs. Patients who have locoregionally advanced and/or metastatic pNETs require additional treatments. These include liver-directed (transarterial (chemo)-embolization, selective intraarterial radio therapy) and systemic therapies (somatostatin analogs, targeted therapy such as tyrosine-kinase inhibitors and mammalian target of rapamycin inhibitor, peptide receptor radionuclide therapy and cytotoxic chemotherapy). The aim of this article is to review the current treatment options as well as potential future therapeutic perspectives for patients with pNETs.

Malignant-functioning pancreatic neuroendocrine tumors (mFpNETs) are rare. Research analyzing the presentation, biological behavior, and patient outcomes of these tumors is limited.We used the Surveillance, Epidemiology, and End Results database to identify patients with malignant insulinomas, gastrinomas, glucagonomas, vasoactive intestinal peptide secreting tumors (VIPomas), somastatinomas, and mixed islet cell tumors (MICTs). The primary endpoint of this study was to identify factors affecting survival.We identified 401 patients with mFpNETs. Between histologic subtypes, there were significant differences in sex and age, and in tumor size, grade, location, and stage. Median survival time for insulinomas was 12.7 years; gastrinomas, 10.2 years; glucagonomas, 7.7 years; VIPomas, 7.9 years; and MICTs, 3.4 years. Multivariable analysis showed that histology (insulinoma, gastrinoma, and VIPoma; P = .009), absence of distant metastases (P = .002), age50 years (P = .001), surgical intervention (P = .001), and stage I/II disease (P = .011) were independently associated with prolonged survival. Subgroup analysis demonstrated that removal of the primary tumor in stage IV mFpNETs was associated with significantly prolonged survival (P = .01).mFpNETs are rare tumors that commonly present at an advanced stage despite hormonal secretion. Primary tumor resection is associated with longer survival in stages I-III as well as stage IV tumors.

Nonfunctioning pancreatic neuroendocrine tumors (NFpNET) present with distant metastases in up to 50% of patients. It is unknown whether removal of the primary tumor in patients with NFpNET and metastases is beneficial.We used the Surveillance, Epidemiology, and End Results database to identify patients with NFpNET and distant metastases. The primary outcome measure in this study was overall survival.We identified 882 patients with metastatic NFpNET who had survival data; 303 (34%) patients had operative removal of their primary tumor of which 243 (80%) were grade I or II. Median survival of patients undergoing resection of the primary site was 65 (95% confidence interval 60-86) versus 10 (8-12) months for those without resection (P.0001). Patients diagnosed after 2003 (n = 625, 71%) were more likely to undergo an operation than those diagnosed earlier (P = .001). Multivariable analysis showed that a lesser tumor grade (P.0001), younger age (P.0001), diagnosis during or after 2003 (P = .0003), tumor site in the body/tail (P = .009), and operative resection of the primary tumor site (P.0001) were associated with prolonged survival of patients with NFpNET and distant metastases.This study suggests that resection of the site of the primary NFpNET is associated with greater survival in patients with distant metastases and could therefore be considered as a additional treatment option in this patient population.

ObjectiveTo identify and validate clinical baseline predictors associated with inadequate response (IR) to methotrexate (MTX) therapy in newly diagnosed patients with rheumatoid arthritis (RA).MethodsIn U-Act-Early, 108 disease-modifying antirheumatic drug (DMARD)-naive patients with RA were randomised to initiate MTX therapy and treated to target until sustained remission (disease activity score assessing 28 joints (DAS28) ResultsWithin 1 year, 56/108 (52%) patients in U-Act-Early showed IR to ‘MTX+’. DAS28 (adjusted OR (ORadj) 2.1, 95% CI 1.4 to 3.2), current smoking (ORadj 3.02, 95% CI 1.1 to 8.0) and alcohol consumption (ORadj 0.4, 95% CI 0.1 to 0.9) were identified as baseline predictors. The area under the receiver operator characteristic curve (AUROC) of the prediction model was 0.75 (95% CI 0.66 to 0.84); the positive (PPV) and negative predictive value (NPV) were 65% and 80%, respectively. When applying the model to the validation cohort, the AUROC slightly decreased to 0.67 (95% CI 0.55 to 0.79) and the PPV and NPV to 54% and 80%, respectively.ConclusionHigher DAS28, current smoking and no alcohol consumption are predictive factors for IR to step-up ‘MTX+’ in DMARD-naive patients with new-onset RA.Trial registrationNCT01034137; Post-results, ISRCTN26791028; Post-results.

Atrial fibrillation (AF) is a frequent arrhythmia after conventional coronary artery bypass grafting. With the advent of minimally invasive technique for left internal mammary artery-left anterior descending coronary artery (LIMA-LAD) grafting, we analyzed the incidence and the risk factors of postoperative AF in this patient population. This prospective study involves all patients undergoing isolated LIMA-LAD grafting with minimally invasive technique between January 1994 and June 2000. Twenty-four possible risk factors for postoperative AF were entered into univariate and multivariate logistic regression analyses. Postoperative AF occurred in 21 of the 90 patients (23.3%) analyzed. Double- or triple-vessel disease was present in 12/90 patients (13.3%). On univariate analysis, right coronary artery disease (p

Patients with gastroenteropancreatic neuroendocrine tumors often present with stage IV disease. Primary tumor resection in these patients remains controversial. Herein, we studied the impact of primary tumor removal, identified variables associated with prolonged survival for each neuroendocrine tumor subtype, and determined factors that influence surgeons to perform primary tumor resection.Patients with metastatic gastroenteropancreatic neuroendocrine tumors diagnosed from 2004 to 2014 were identified from the National Cancer Database. Nested Cox proportional hazards and logistic regression models were used to assess variables associated with survival and primary resection.A total of 14,510 patients met inclusion criteria. On multivariable analysis, resection of the primary tumor and grade 1 or 2 tumors was associated with prolonged survival in all subtypes (P.001). Organ-specific variables associated with prolonged survival in patients undergoing primary tumor resection included the following: low grade for all organs; young age for pancreatic, small intestinal, colonic, and rectal neuroendocrine tumor; tumor size for colonic and rectal neuroendocrine tumor; and tumor location for colonic neuroendocrine tumor. Low tumor grade was found to be significantly associated with removal of the primary tumor across all organs.This study is the first suggesting that primary tumor resection is associated with prolonged survival for all gastro-entero-pancreatic NETs. Additional variables related to survival for each NET subtype were identified and might help select patients who benefit from primary tumor removal.

Background In disease modifying anti-rheumatic drug (DMARD)-naive early rheumatoid arthritis (RA) patients, we previously identified networks of differentially co-expressed genes associated with achieving sustained drug-free remission (sDFR).[1 A better understanding of processes involved with translation of mRNA into proteins might be used to develop personalised treatment for early RA patients. Objectives To identify inflammatory proteins associated with achieving sDFR by performing multi-analyte profiling in pre-treatment serum and subsequently to study significantly enriched biological pathways and compare these with the pathways previously found in the transcriptomic analyses. Methods In this exploratory study, baseline serum was analysed of 24 patients (n=13 achieved sDFR, n=11 controls) treated-to-target with tocilizumab (TCZ) therapy in the U-Act-Early trial. TCZ (intravenously, 8 mg/kg) was given every 4 weeks; if no remission, hydroxychloroquine (HCQ) was added and if subsequently remission was still not achieved, HCQ was replaced by (oral) methotrexate. Thereafter, if the target, remission, still was not achieved, patients switched to standard of care (e.g. tumour necrosis factor inhibitor). Provided remission persisted, therapy was tapered and subsequently discontinued. sDFR was reached when patients remained ≥3 months in remission while being drug-free until the end of the study period; those not able to discontinue therapy were selected as controls. Luminex® multi-analyte profiling (xMAP)® was used to measure 85 inflammatory proteins; partial least square discriminant analyses (PLS-DA) was applied to identify relevant proteins associated with achieving sDFR. Results No significant differences in clinical baseline characteristics were found between those achieving sDFR vs controls (p>0.05). PLS-DA identified 14 proteins of which 6/14 (n/N) were associated with a decreased chance of achieving sDFR. The protein considered most important (i.e. highest variable on importance (VIP) score) was chemokine (C-C motif) ligand 20 (CCL20, VIP 1.49). In total, 88 significantly enriched Gene Ontology (GO) terms were identified analysing the proteins; 5 terms, of which “positive regulation of leukocyte migration” (p≤3.41E-02) and “leukocyte chemotaxis” (p≤3.49E-03) were found in both proteomic and transcriptomic analyses. Significant transcript-protein correlations are shown in figure 1; the TIMP metallopeptidase inhibitor 1 (TIMP-1) protein showed the highest number (n=12) of correlations. Blue dots=transcripts, green triangles=proteins. Conclusions Several relevant proteins were found associated with achieving sDFR after treatment with TCZ. When performing pathway analyses, several enriched pathways within the protein biomarkers were also previously identified in the transcriptomic analyses, providing further insight into gene expression and translation of inflammatory proteins in early RA patients. Reference [1] Teitsma XM, Jacobs JWH, Mokry M, et al. Identification of differential co-expressed gene networks in early rheumatoid arthritis achieving sustained drug-free remission after treatment with a tocilizumab-based or methotrexate-based strategy. Arthritis Res Ther2017;19:170. Disclosure of Interest X. Teitsma: None declared, J. Jacobs Grant/research support from: The department of the author (JWGJ) who included patients in the U-Act-Early trial received reimbursements from Roche Nederland BV., A. Concepcion: None declared, A. Petho-Schramm Employee of: AP-S is an employee of F Hoffmann-La Roche, M. Borm Employee of: MEAB is an employee of Roche Nederland BV, J. van Laar Grant/research support from: JMvL received fees from Arthrogeen, MSD, Pfizer, Eli Lilly, and BMS and research grants from Astra Zeneca, Roche-Genentech., J. Bijlsma Grant/research support from: JWJB reported grants and fees from Roche, AbbVie, Bristol-Myers Squibb, Merck Sharp and Dohme, Pfizer, and UCB., F. Lafeber Grant/research support from: FPJL reports grants from Roche.

Background: For rheumatoid arthritis (RA) patients included in clinical trials, background treatment with glucocorticoids (GCs) is quite common (40–60%), but their potential contribution to efficacy and safety of the disease modifying anti-rheumatic drug (DMARD) tested in that trial has rarely been evaluated. Objectives: To establish whether a stable GC dose at baseline and during the study contributed to the efficacy and safety of TCZ monotherapy initiated in RA patients in 4 TCZ RCTs. In addition, to investigate the same issue in the comparator arms of these trials, in which adalimumab (ADA) or methotrexate (MTX) was initiated. Methods: Data from 4 randomized controlled double-blind trials (AMBITION, ACT-RAY, ADACTA and FUNCTION) with TCZ monotherapy arms was analysed in this post hoc analysis [1–4]. Study participants were MTX-naive, intolerant or had an inadequate response to conventional synthetic DMARDs (csDMARD-IR). Because of differences between the studies in region, and baseline RA duration and disease severity, analyses were done separately for each study. Stable GC dose at baseline was allowed and was to be continued unchanged during the first 24 weeks. Analyses of covariance (ANCOVA) of change from baseline to Week 24 in CDAI and DAS28 and logistic regression analyses at Week 24 for CDAI remission and ACR50 were performed. Repeated measures analyses using all visits up to week 24 were also done. Incidence rates of serious adverse events (SAEs) were assessed by GC use. Results: Baseline characteristics were mostly comparable between GC users and non-GC users in each treatment arm for each study. The adjusted differences (95% CIs) of CDAI change at week 24 between GC and non-GC users in TCZ arms of AMBITION, FUNCTION, ACT-RAY and ADACTA were -1.4 (-4.8, 2.1), 0.8 (-2.5, 4.1), 1.2 (-4.0, 6.3) and -4.2 (-9.7, 1.4), respectively (table 1). CDAI remission rates, ACR50 response rates and DAS28 score changes at 24 weeks neither were significantly different between GC users and non-GC users in the TCZ arms, nor in the MTX and ADA arms (table 1). Repeated measures analyses to week 24 showed no significant differences in DAS28 or CDAI. Statistically significant predictors for the various clinical outcomes included baseline CDAI, baseline DAS28, age, sex, RA duration and region. A numerically higher but not significantly different SAE rate was seen in the GC-arms of all four trials, compared to the non-GC-arms. Conclusions: No evidence was found that GC treatment at baseline and continued at a stable dose affects either clinical efficacy or safety over 24 weeks of TCZ, MTX, or ADA monotherapy initiated at baseline in RA clinical trials. References [1]Jones G, et al. Ann Rheum Dis2010;69:88–96. [2]Dougados M, et al. Ann Rheum Dis2013;72:43–50. [3]Gabay C, et al. Lancet2013;381:1541–50 [4]Burmester GR, et al. Ann Rheum Dis2017;76:1279–84. Disclosure of Interest: M. Safy Grant/research support from: Research grant from AZ, J. Jacobs: None declared, M. Edwardes Employee of: Everest Clinical Research, Canada, J. Pei Employee of: US Medical Affairs, Immunology, Genentech, Inc., M. De Hair: None declared, X. Teitsma: None declared, P. Welsing: None declared, M. Borm Employee of: employee of Roche Nederland BV., Y. Luder Employee of: 4 F Hoffmann-La Roche, Basel, Switzerland, J. Van Laar Consultant for: Arthrogen, MSD, Pfizer, Eli Lilly, and BMS and research grants from Astra Zeneca, Roche-Genentech., A. Petho-Schramm Employee of: F Hoffmann-La Roche, J. Bijlsma Consultant for: Grants and fees from Roche, AbbVie, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, and UCB