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Eleanna Makris,1 Lucy Hu,1 Graham B Jones,1,2 Justin M Wright1 1TRD Innovation Group, Novartis Pharmaceuticals, East Hanover, NJ 07936, USA; 2Clinical and Translational Science Institute, Tufts University Medical Center, Boston, MA 02111, USACorrespondence: Graham B Jones Email graham.jones@novartis.comIntroduction: Heart failure remains a substantive contributor to patient morbidity and mortality rates worldwide and represents a significant burden on the healthcare ecosystem. Faced with persistent physical symptoms and debilitating social consequences, patients follow complex treatment regimens and often have difficulty adhering to them.Purpose: In this manuscript, we review factors which contribute to low adherence rates and advance potential single- and multi-factor-based interventions. It is hoped that these observations can lead to improvements in managed care of this vulnerable population of patients.Methods: A narrative review of the primary literature was performed on contributing factors with primary focus on the period 2015– 2020 using available databases and search engines. Adherence pain points identified were mapped against a series of potential solutions which are presented.Results: Enhancement of treatment adherence relies on two approaches viz. single-factor and multi-factor solutions. Single factors identified include electronic reminders, enhanced health education, financial incentives, gamification strategies, community drivers, persona-based modeling, and burden relief of poly pharmacy. Multi-factor solutions combine two or more of the seven approaches offering the potential for flexible interventions tailored to the individual.Discussion and Conclusion: Heart failure patients with poor adherence have increased mortality, hospitalization needs, and healthcare costs. This review highlights current single-factor and multi-factor adherence methods. Against a backdrop of diversity of approaches, multi-factor solutions cast the widest net for positively influencing adherent behaviors. A key enabler lies in the development and leveraging of patient personas in the synthesis of successful intervention methods. Deployable solutions can also be envisioned in clinical trials where adherence tracking represents an essential component.Keywords: heart failure, cardiac disease, treatment adherence, intervention, connected health

Background: Smoking is the most important, preventable cause of premature death and this addiction can be regarded as a chronic, recurrent disease. The benefits of smoking cessation are unquestionable and all health care professionals should become more active in recommending it. Aim: To characterise the population seeking medical support for smoking cessation and to investigate the effectiveness of a smoking cessation programme performed, in the University Hospital of Larissa, for outpatients. Materials and Methods: Retrospective analysis of medical records of outpatients in follow-up between March 2004 and October 2007. Age, gender, level of education, smoking habits, compliance in pharmacological treatment, gain weight and abstinence and relapse rates were evaluated. Results: Were studied 376 smokers, 60% male with an average age of 46.9 years. Men, upper graduated smokers have higher cessation rates whereas, in heavy smokers with high degree of dependence was observed lower cessation rates. The continuous abstinence rate at 12 months was 38%, and among pharmacological treatment, varenicline resulted elevated rate of quit smoking. The rate of relapse was found in 39%.Conclusions: This study suggests that smoking cessation programmes may be highly effective in helping smoking withdrawal and should be a strongly recommended component of daily clinical practice. [ABSTRACT FROM AUTHOR]

Abstract Background The aim of the study was, despite the special characteristics of prisons, to identify the features which led prisoners who attended the Smoking Cessation Centre at the Kassavetia Detention Centre in Volos (region of Thessaly, in the central part of mainland Greece) to quit smoking. Methods Personal interviews with 204 male prisoners irrespective of smoking habitus over the period June 2008 to December 2010 were obtained. Information about medical history, history of tobacco use and addiction to narcotic use was obtained and imprisonment status was recorded. Pharmaceutical treatment (Varenicline) and counselling or only counselling were suggested as alternative strategies to them in order to help quit smoking. SPSS v15.0 software was employed, descriptive statistics were used, and a X2 independence test and Student’s t-test were performed. Results Of the sample examined, 75.5% (154) were smokers. They were mainly Greeks (51.5%), single (53.4%) and had not gratuated from a high school (secondary education level) (70.6%). 59.75% begun smoking early ( ≤14 years of age ) and 64.9% were highly addicted according to Fagerstrom Tolerance Questionnaire. 74% (114) of all smokers at the prison attended the Smoking Cessation Centre. Of them, 30.7% were able to quit smoking at 3 months but 1 year later there were 20.2% ex-smokers. The key characteristics of those who were able to be ex-smokers were a change in smoking habits (decreased) compared to when free (p = .001), previous attempts to quit (while incarcerated and in general) (p = .001), average dependence levels (p Conclusions Average dependence, a past free of addictive substance abuse and a better environment of daily living for certain prisoners (as far as the number of cellmates was concerned) had a catalytic impact on prisoners finally managed to quit smoking.

Accurately predicting the pairing order of bases in RNA molecules is essential for anticipating RNA secondary structures. Consequently, this task holds significant importance in unveiling previously unknown biological processes. The urgent need to comprehend RNA structures has been accentuated by the unprecedented impact of the widespread COVID-19 pandemic. This paper presents a framework, Knotify_V2.0, which makes use of syntactic pattern recognition techniques in order to predict RNA structures, with a specific emphasis on tackling the demanding task of predicting H-type pseudoknots that encompass bulges and hairpins. By leveraging the expressive capabilities of a Context-Free Grammar (CFG), the suggested framework integrates the inherent benefits of CFG and makes use of minimum free energy and maximum base pairing criteria. This integration enables the effective management of this inherently ambiguous task. The main contribution of Knotify_V2.0 compared to earlier versions lies in its capacity to identify additional motifs like bulges and hairpins within the internal loops of the pseudoknot. Notably, the proposed methodology, Knotify_V2.0, demonstrates superior accuracy in predicting core stems compared to state-of-the-art frameworks. Knotify_V2.0 exhibited exceptional performance by accurately identifying both core base pairing that form the ground truth pseudoknot in 70% of the examined sequences. Furthermore, Knotify_V2.0 narrowed the performance gap with Knotty, which had demonstrated better performance than Knotify and even surpassed it in Recall and F1-score metrics. Knotify_V2.0 achieved a higher count of true positives ( tp ) and a significantly lower count of false negatives ( fn ) compared to Knotify, highlighting improvements in Prediction and Recall metrics, respectively. Consequently, Knotify_V2.0 achieved a higher F1-score than any other platform. The source code and comprehensive implementation details of Knotify_V2.0 are publicly available on GitHub.

The accurate "base pairing" in RNA molecules, which leads to the prediction of RNA secondary structures, is crucial in order to explain unknown biological operations. Recently, COVID-19, a widespread disease, has caused many deaths, affecting humanity in an unprecedented way. SARS-CoV-2, a single-stranded RNA virus, has shown the significance of analyzing these molecules and their structures. This paper aims to create a pioneering framework in the direction of predicting specific RNA structures, leveraging syntactic pattern recognition. The proposed framework, Knotify+, addresses the problem of predicting H-type pseudoknots, including bulges and internal loops, by featuring the power of context-free grammar (CFG). We combine the grammar's advantages with maximum base pairing and minimum free energy to tackle this ambiguous task in a performant way. Specifically, our proposed methodology, Knotify+, outperforms state-of-the-art frameworks with regards to its accuracy in core stems prediction. Additionally, it performs more accurately in small sequences and presents a comparable accuracy rate in larger ones, while it requires a smaller execution time compared to well-known platforms. The Knotify+ source code and implementation details are available as a public repository on GitHub.

Objective: To improve the prognostic accuracy of the eighth edition of AJCC staging system for pNETs with establishment and validation of a new staging system., Background: Validation of the updated eighth AJCC staging system for pNETs has been limited and controversial., Methods: Data from the SEER registry (1975-2016) (n = 3303) and a multi-institutional database (2000-2016) (n = 825) was used as development and validation cohorts, respectively. A mTNM was proposed by maintaining the eighth AJCC T and M definitions, and the recently proposed N status as N0 (no LNM), N1 (1-3 LNM), and N2 (≥4 LNM), but adopting a new stage classification., Results: The eighth TNM staging system failed to stratify patients with stage I versus IIA, stage IIB versus IIIA, and overall stage I versus II relative to long-term OS in both database. There was a monotonic decrement in survival based on the proposed mTNM staging classification among patients derived from both the SEER (5-year OS, stage I 87.0% vs stage II 80.3% vs stage III 72.9% vs stage IV 57.2%, all P < 0.001), and multi-institutional (5-year OS, stage I 97.6% vs stage II 82.7% vs stage III 78.4% vs stage IV 50.0%, all P < 0.05) datasets. On multivariable analysis, mTNM staging remained strongly associated with prognosis, as the hazard of death incrementally increased with each stage among patients in the 2 cohorts., Conclusion: A mTNM pNETs clinical staging system using N0, N1, N2 nodal categories was better at stratifying patients relative to long-term OS than the eighth AJCC staging., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Obtaining valuable clues for noncoding RNA (ribonucleic acid) subsequences remains a significant challenge, acknowledging that most of the human genome transcribes into noncoding RNA parts related to unknown biological operations. Capturing these clues relies on accurate "base pairing" prediction, also known as "RNA secondary structure prediction". As COVID-19 is considered a severe global threat, the single-stranded SARS-CoV-2 virus reveals the importance of establishing an efficient RNA analysis toolkit. This work aimed to contribute to that by introducing a novel system committed to predicting RNA secondary structure patterns (i.e., RNA's pseudoknots) that leverage syntactic pattern-recognition strategies. Having focused on the pseudoknot predictions, we formalized the secondary structure prediction of the RNA to be primarily a parsing and, secondly, an optimization problem. The proposed methodology addresses the problem of predicting pseudoknots of the first order (H-type). We introduce a context-free grammar (CFG) that affords enough expression power to recognize potential pseudoknot pattern. In addition, an alternative methodology of detecting possible pseudoknots is also implemented as well, using a brute-force algorithm. Any input sequence may highlight multiple potential folding patterns requiring a strict methodology to determine the single biologically realistic one. We conscripted a novel heuristic over the widely accepted notion of free-energy minimization to tackle such ambiguity in a performant way by utilizing each pattern's context to unveil the most prominent pseudoknot pattern. The overall process features polynomial-time complexity, while its parallel implementation enhances the end performance, as proportional to the deployed hardware. The proposed methodology does succeed in predicting the core stems of any RNA pseudoknot of the test dataset by performing a 76.4% recall ratio. The methodology achieved a F1-score equal to 0.774 and MCC equal 0.543 in discovering all the stems of an RNA sequence, outperforming the particular task. Measurements were taken using a dataset of 262 RNA sequences establishing a performance speed of 1.31, 3.45, and 7.76 compared to three well-known platforms. The implementation source code is publicly available under knotify github repo.

Objective: To determine the prognostic role of metastatic lymph node (LN) number and the minimal number of LNs for optimal staging of patients with pancreatic neuroendocrine tumors (pNETs)., Background: Prognosis relative to number of LN metastasis (LNM), and minimal number of LNs needed to evaluate for accurate staging, have been poorly defined for pNETs., Methods: Number of LNM and total number of LN evaluated (TNLE) were assessed relative to recurrence-free survival (RFS) and overall survival (OS) in a multi-institutional database. External validation was performed using Surveillance, Epidemiology and End Results (SEER) registry., Results: Among 854 patients who underwent resection, 233 (27.3%) had at least 1 LNM. Patients with 1, 2, or 3 LNM had a comparable worse RFS versus patients with no nodal metastasis (5-year RFS, 1 LNM 65.6%, 2 LNM 68.2%, 3 LNM 63.2% vs 0 LNM 82.6%; all P < 0.001). In contrast, patients with ≥4 LNM (proposed N2) had a worse RFS versus patients who either had 1 to 3 LNM (proposed N1) or node-negative disease (5-year RFS, ≥4 LNM 43.5% vs 1-3 LNM 66.3%, 0 LNM 82.6%; all P < 0.05) [C-statistics area under the curve (AUC) 0.650]. TNLE ≥8 had the highest discriminatory power relative to RFS (AUC 0.713) and OS (AUC 0.726) among patients who had 1 to 3 LNM, and patients who had ≥4 LNM in the multi-institutional and SEER database (n = 2764)., Conclusions: Regional lymphadenectomy of at least 8 lymph nodes was necessary to stage patients accurately. The proposed nodal staging of N0, N1, and N2 optimally staged patients., Competing Interests: The authors report no conflicts of interest, (Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Identifying patients at risk for early recurrence (ER) following resection for pancreatic neuroendocrine tumors (pNETs) might help to tailor adjuvant therapies and surveillance intensity in the post-operative setting., Methods: Patients undergoing surgical resection for pNETs between 1998-2018 were identified using a multi-institutional database. Using a minimum p -value approach, optimal cut-off value of recurrence-free survival (RFS) was determined based on the difference in post-recurrence survival (PRS). Risk factors for early recurrence were identified., Results: Among 807 patients who underwent curative-intent resection for pNETs, the optimal length of RFS to define ER was identified at 18 months (lowest p -value of 0.019). Median RFS was 11.0 months (95% 8.5-12.60) among ER patients ( n = 49) versus 41.0 months (95% CI: 35.0-45.9) among non-ER patients ( n = 77). Median PRS was worse among ER patients compared with non-ER patients (42.6 months vs. 81.5 months, p = 0.04). On multivariable analysis, tumor size (OR: 1.20, 95% CI: 1.05-1.37, p = 0.007) and positive lymph nodes (OR: 4.69, 95% CI: 1.41-15.58, p = 0.01) were independently associated with ER., Conclusion: An evidence-based cut-off value for ER after surgery for pNET was defined at 18 months. These data emphasized the importance of close follow-up in the first two years after surgery.

Background: Pancreatoduodenectomy (PD) or distal pancreatectomy (DP) are common procedures for patients with a pancreatic neuroendocrine tumor (pNET). Nevertheless, certain patients may benefit from a pancreas-preserving resection such as enucleation (EN). The aim of this study was to define the indications and differences in long-term outcomes among patients undergoing EN and PD/DP., Methods: Patients undergoing resection of a pNET between 1992 and 2016 were identified. Indications and outcomes were evaluated, and propensity score matching (PSM) analysis was performed to compare long-term outcomes between patients who underwent EN versus PD/DP., Results: Among 1034 patients, 143 (13.8%) underwent EN, 304 (29.4%) PD, and 587 (56.8%) DP. Indications for EN were small size (1.5 cm, IQR:1.0-1.9), functional tumors (58.0%) that were mainly insulinomas (51.7%). After PSM (n = 109 per group), incidence of postoperative pancreatic fistula (POPF) grade B/C was higher after EN (24.5%) compared with PD/DP (14.0%) (p = 0.049). Median recurrence-free survival (RFS) was comparable among patients who underwent EN (47 months, 95% CI:23-71) versus PD/DP (37 months, 95% CI: 33-47, p = 0.480)., Conclusion: Comparable long-term outcomes were noted among patients who underwent EN versus PD/DP for pNET. The incidence of clinically significant POPF was higher after EN., (Copyright © 2020 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: The adoption of spleen-preserving distal pancreatectomy (SPDP) for malignant disease such as pancreatic neuroendocrine tumors (pNETs) has been controversial. The objective of the current study was to assess the impact of SPDP on outcomes of patients with pNETs., Methods: Patients undergoing a distal pancreatectomy for pNET between 2002 and 2016 were identified in the US Neuroendocrine Tumor Study Group database. Propensity score matching (PSM) was used to compare short- and long-term outcomes of patients undergoing SPDP versus distal pancreatectomy with splenectomy (DPS)., Results: Among 621 patients, 103 patients (16.6%) underwent an SPDP. Patients who underwent SPDP were more likely to have lower BMI (median, 27.5 [IQR 24.0-31.2] vs. 28.7 [IQR 25.7-33.6]; p = 0.005) and have undergone minimally invasive surgery (n = 56, 54.4% vs. n = 185, 35.7%; p < 0.001). After PSM, while the median total number of lymph nodes examined among patients who underwent an SPDP was lower compared with DPS (3 [IQR 1-8] vs. 9 [5-13]; p < 0.001), 5-year overall survival (OS) and recurrence-free survival (RFS) were comparable (OS: 96.8 vs. 92.0%, log-rank p = 0.21, RFS: 91.1 vs. 84.7%, log-rank p = 0.93). In addition, patients undergoing SPDP had less intraoperative blood loss (median, 100 mL [IQR 10-250] vs. 150 mL [IQR 100-400]; p = 0.001), lower incidence of serious complications (n = 13, 12.8% vs. n = 28, 27.5%; p = 0.014), and shorter length of stay (median: 5 days [IQR 4-7] vs. 6 days [IQR 5-13]; p = 0.049) compared with patients undergoing DPS., Conclusion: SPDP for pNET was associated with acceptable perioperative and long-term outcomes that were comparable to DPS. SPDP should be considered for patients with pNET., (© 2020 S. Karger AG, Basel.)

Background: Pancreatic neuroendocrine tumors (PNETs) are often indolent; however, identifying patients at risk for rapidly progressing variants is critical, particularly for those with small tumors who may be candidates for expectant management. Specific growth rate (SGR) has been predictive of survival in other malignancies but has not been examined in PNETs., Methods: A retrospective cohort study of adult patients who underwent PNET resection from 2000 to 2016 was performed utilizing the multi-institutional United States Neuroendocrine Study Group database. Patients with ≥ 2 preoperative cross-sectional imaging studies at least 30 days apart were included in our analysis (N = 288). Patients were grouped as "high SGR" or "low SGR." Demographic and clinical factors were compared between the groups. Kaplan-Meier and log-rank analysis were used for survival analysis. Cox proportional hazard analysis was used to assess the impact of various clinical factors on overall survival (OS)., Results: High SGR was associated with higher T stage at resection, shorter doubling time, and elevated HbA1c (all P ≤ 0.01). Patients with high SGR had significantly decreased 5-year OS (63 vs 80%, P = 0.01) and disease-specific survival (72 vs 91%, P = 0.03) compared to those with low SGR. In patients with small (≤ 2 cm) tumors (N = 106), high SGR predicted lower 5-year OS (79 vs 96%, P = 0.01). On multivariate analysis, high SGR was independently associated with worse OS (hazard ratio 2.67, 95% confidence interval 1.05-6.84, P = 0.04)., Conclusion: High SGR is associated with worse survival in PNET patients. Evaluating PNET SGR may enhance clinical decision-making, particularly when weighing expectant management versus surgery in patients with small tumors.

Background: Appendiceal neuroendocrine tumors (A-NETs) are rare neoplasms of the GI tract. They are typically managed according to tumor size; however, the impact of surgical strategy on the short- and long-term outcomes is unknown., Methods: All patients who underwent resection of A-NET at 8 institutions from 2000 to 2016 were analyzed retrospectively. Patient clinicopathologic features and outcomes were stratified according to resection type., Results: Of 61 patients identified with A-NET, mean age of presentation was 44.7 ± 16.0 years and patients were predominantly Caucasian (77%) and female (56%). Mean tumor size was 1.2 ± 1.3 cm with a median of 0.8 cm. Thirty-one patients (51%) underwent appendectomy and 30 (49%) underwent colonic resection. The appendectomy group had more T1 tumors (87% vs 42%, p < 0.01) than the colon resection group. Of patients in the colon resection group, 27% had positive lymph nodes and 3% had M1 disease. R0 resections were achieved in 90% of appendectomy patients and 97% of colon resection patients. Complications occurred with a higher frequency in the colon resection group (30%) compared with those in the appendectomy group (6%, p = 0.02). The colon resection group also had a longer length of stay, higher average blood loss, and longer average OR time. Median RFS and OS were similar between groups., Conclusion: A-NET RFS and OS are equivalent regardless of surgical strategy. Formal colon resection is associated with increased length of stay, OR time, higher blood loss, and more complications. Further study is warranted to identify patients that are likely to benefit from more aggressive surgery.

Background: To investigate the feasibility of Tumor Burden Score (TBS) to predict tumor recurrence following curative-intent resection of non-functional pancreatic neuroendocrine tumors (NF-pNETs)., Method: The TBS cut-off values were determined by a statistical tool, X-tile. The influence of TBS on recurrence-free survival (RFS) was examined., Results: Among 842 NF-pNETs patients, there was an incremental worsening of RFS as the TBS increased (5-year RFS, low, medium, and high TBS: 92.0%, 73.3%, and 59.3%, respectively; P < 0.001). TBS (AUC 0.74) out-performed both maximum tumor size (AUC 0.65) and number of tumors (AUC 0.5) to predict RFS (TBS vs. maximum tumor size, p = 0.05; TBS vs. number of tumors, p < 0.01). The impact of margin (low TBS: R0 80.4% vs. R1 71.9%, p = 0.01 vs. medium TBS: R0 55.8% vs. R1 37.5%, p = 0.67 vs. high TBS: R0 31.9% vs. R1 12.0%, p = 0.11) and nodal (5-year RFS, low TBS: N0 94.9% vs. N1 68.4%, p < 0.01 vs. medium TBS: N0 81.8% vs. N1 55.4%, p < 0.01 vs. high TBS: N0 58.0% vs. N1 54.2%, p = 0.15) status on 5-year RFS outcomes disappeared among patients who had higher TBS., Conclusions: TBS was strongly associated with risk of recurrence and outperformed both tumor size and number alone., (Copyright © 2019 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: The role of routine lymphadenectomy in the surgical treatment of pancreatic neuroendocrine tumors (pNET) remains poorly defined. The objective of the current study was to investigate trends in the number of lymph nodes (LN) evaluated for pNET treatment at a nationwide level., Methods: Patients undergoing surgery for pNET between 2000 and 2016 were identified in the U.S. Neuroendocrine Tumor Study Group (US-NETSG) database as well as the Surveillance, Epidemiology, and End Results (SEER) database. The number of LNs examined was evaluated over time., Results: The median number of evaluated LNs increased roughly fourfold over the study period (US-NETSG, 2000: 3 LNs vs. 2016: 13 LNs; SEER, 2000: 3 LNs vs. 2016: 11 LNs, both p < 0.001). While no difference in 5-year OS and RFS was noted among patients who had 1-3 lymph node metastases (LNM) vs. ≥ 4 LNM between 2000-2007 (OS 73.5% vs. 69.9%, p = 0.12; RFS: 64.9% vs. 40.1%, p = 0.39), patients who underwent resection and LN evaluation during the period 2008-2016 had an incrementally worse survival if the patient had node negative disease, 1-3 LNM and ≥ 4 LNM (OS 86.8% vs. 82.7% vs. 74.9%, p < 0.001; RFS: 86.3% vs. 64.7% vs. 50.4%, p < 0.001). On multivariable analysis, a more recent year of diagnosis, pancreatic head tumor location, and tumor size > 2 cm were associated with 12 or more LNs evaluated in both US-NETSG and SEER databases., Conclusion: The number of LNs examined nearly quadrupled over the last decade. The increased number of LNs examined suggested a growing adoption of the AJCC staging manual recommendations regarding LN evaluation in the treatment of pNET.

This study compared pedestrian behaviors in five countries (Estonia, Greece, Kosovo, Russia, and Turkey) and investigated the relationships between these behaviors and values in each country. The study participants were 131 pedestrians for Estonia, 249 for Greece, 112 for Kosovo, 176 for Russia, and 145 for Turkey. The principal component analyses revealed that the four-factor structure of the Pedestrian Behavior Scale (PBS) was highly consistent across the five countries. ANCOVA results revealed significant differences between countries on the PBS items and scale scores. Specifically, Greek and Turkish participants reported transgressive pedestrian behaviors more frequently than Estonian, Kosovar, and Russian pedestrians while Kosovar participants reported transgressive pedestrian behaviors less frequently than Estonian pedestrians. In addition, Turkish and Russian pedestrians reported lapses and aggressive behaviors more frequently than Estonian, Greek, and Kosovar pedestrians. Finally, Turkish and Estonian pedestrians reported positive behaviors more frequently than Kosovar pedestrians. Unexpectedly, the regression analyses showed that values have varying effects on pedestrian behavior in the five countries. That is, context or country may determine the effect of values on pedestrian behaviors. The results are discussed in relation to the previous literature., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: To define recurrence patterns and time course, as well as risk factors associated with recurrence following curative resection of pNETs., Method: Patients who underwent curative-intent resection for pNET between 1997 and 2016 were identified from the US Neuroendocrine Tumor Study Group. Data on baseline and tumor-specific characteristics, overall survival (OS), timing and first-site of recurrence, predictors and recurrence management were analyzed., Results: Among 1020 patients, 154 (15.1%) patients developed recurrence. Among patients who experienced recurrence, 76 (49.4%) had liver-only recurrence, while 35 (22.7%) had pancreas-only recurrence. The proportion of liver-only recurrence increased from 54.3% within one-year after surgery to 61.5% from four-to-six years after surgery; whereas the proportion of pancreas-only recurrence decreased from 26.1% to 7.7% over these time periods. While liver-only recurrence was associated with tumor characteristics, pancreas-only recurrence was only associated with surgical margin status. Patients undergoing curative resection of recurrence had comparable OS with patients who had no recurrence (median OS, pancreas-only recurrence, 133.9 months; liver-only recurrence, not attained; no recurrence, 143.0 months, p = 0.499) CONCLUSIONS: Different recurrence patterns and timing course, as well as risk factors suggest biological heterogeneity of pNET recurrence. A personalized approach to postoperative surveillance and treatment of recurrence disease should be considered., (Copyright © 2019 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: In a changing health care environment where patient outcomes will be more closely scrutinized, the ability to predict surgical complications is becoming increasingly important. The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) online risk calculator is a popular tool to predict surgical risk. This paper aims to assess the applicability of the ACS NSQIP calculator to patients undergoing surgery for pancreatic neuroendocrine tumors (PNETs)., Methods: Using the US Neuroendocrine Tumor Study Group (USNET-SG), 890 patients who underwent pancreatic procedures between 1/1/2000-12/31/2016 were evaluated. Predicted and actual outcomes were compared using C-statistics and Brier scores., Results: The most commonly performed procedure was distal pancreatectomy, followed by standard and pylorus-preserving pancreaticoduodenectomy. For the entire group of patients studied, C-statistics were highest for discharge destination (0.79) and cardiac complications (0.71), and less than 0.7 for all other complications. The Brier scores for surgical site infection (0.1441) and discharge to nursing/rehabilitation facility (0.0279) were below the Brier score cut-off, while the rest were equal to or above and therefore not useful for interpretation., Conclusion: This work indicates that the ACS NSQIP risk calculator is a valuable tool that should be used with caution and in coordination with clinical assessment for PNET clinical decision-making.

Background: Single institution reports demonstrate variable safety profiles when liver-directed therapy with Yttrium-90 (Y-90) is followed by hepatectomy. We hypothesized that in well-selected patients, hepatectomy after Y90 is feasible and safe., Methods: Nine institutions contributed data for patients undergoing Y90 followed by hepatectomy (2008-2017). Clinicopathologic and perioperative data were analyzed, with 90-day morbidity and mortality as primary endpoints., Results: Forty-seven patients were included. Median age was 59 (20-75) and 62% were male. Malignancies treated included hepatocellular cancer (n = 14; 30%), colorectal cancer (n = 11; 23%), cholangiocarcinoma (n = 8; 17%), neuroendocrine (n = 8; 17%) and other tumors (n = 6). The distribution of Y-90 treatment was: right (n = 30; 64%), bilobar (n = 14; 30%), and left (n = 3; 6%). Median future liver remnant (FLR) following Y90 was 44% (30-78). Resections were primarily right (n = 16; 34%) and extended right (n = 14; 30%) hepatectomies. The median time to resection from Y90 was 196 days (13-947). The 90-day complication rate was 43% and mortality was 2%. Risk factors for Clavien-Dindo Grade>3 complications included: number of Y-90-treated lobes (OR 4.5; 95% CI1.14-17.7; p = 0.03), extent of surgery (p = 0.04) and operative time (p = 0.009)., Conclusions: These data demonstrate that hepatectomy following Y-90 is safe in well-selected populations. This multi-disciplinary treatment paradigm should be more widely studied, and potentially adopted, for patients with inadequate FLR., (Copyright © 2019 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: To determine short- and long-term oncologic outcomes after minimally invasive distal pancreatectomy (MIDP) with open distal pancreatectomy (ODP) for the treatment of pancreatic neuroendocrine tumor (pNET)., Methods: The data of the patients who underwent curative MIDP or ODP for pNET between 2000 and 2016 were collected from a multi-institutional database. Propensity score matching (PSM) was used to generate 1:1 matched patients with MIDP and ODP., Results: A total of 576 patients undergoing curative DP for pNET were included. Two hundred and fourteen (37.2%) patients underwent MIDP, whereas 362 (62.8%) underwent ODP. MIDP was increasingly performed over time (2000-2004: 9.3% vs 2013-2016: 54.8%; P < 0.01). In the matched cohort (n = 141 in each group), patients who underwent MIDP had less blood loss (median, 100 vs 200 mL, P < 0.001), lower incidence of Clavien-Dindo ≥ III complications (12.1% vs 24.8%, P = 0.026), and a shorter hospital stay versus ODP (median, 4 versus 7 days, P = 0.026). Patients who underwent MIDP had a lower incidence of recurrence (5-year cumulative recurrence, 10.1% vs 31.1%, P < 0.001), yet equivalent overall survival (OS) rate (5-year OS, 92.1% vs 90.9%, P = 0.550) compared with patients who underwent OPD., Conclusion: Patients undergoing MIDP over ODP in the treatment of pNET had comparable oncologic surgical metrics, as well as similar long-term OS., (© 2019 Wiley Periodicals, Inc.)

Background: Gastric carcinoids are rare neuroendocrine tumors of the gastrointestinal tract. They are typically managed according to their etiology. However, there is little known about the impact of surgical strategy on the long-term outcomes of these patients., Methods: All patients who underwent resection of gastric carcinoids at 8 institutions from 2000 to 2016 were analyzed retrospectively. Tumors were stratified according to subtype (I, II, III, IV) and resection type (local resection, LR or formal gastrectomy, FG). Clinicopathological parameters, recurrence-free (RFS) and overall survival (OS) were compared between groups., Results: Of 79 patients identified with gastric carcinoids, 34 had type I lesions associated with atrophic gastritis, 4 had type II lesions associated with a gastrinoma, 37 had type III sporadic lesions, and 4 had type IV poorly-differentiated lesions. The mean age of presentation was 56 years in predominantly Caucasian (77%) and female (63%) patients. Mean tumor size was 2.4 cm and multifocal tumors were found in 24 (30%) of patients with the majority occurring in those with type I tumors. Lymph node positive tumors were seen in 15 (19%) patients and 7 (8%) had M1 disease; both most often in type IV followed by type III tumors. R0 resection was achieved in 56 (71%) patients while 15 (19%) had R1 resections and 6 (8%) R2 resections. Patients with type I and III tumors were equally likely to have a LR (50% and 43% respectively) compared to FG while those with type II and IV all had FG with one exception. Type IV tumors had the poorest RFS and OS while Type II tumors had the most favorable RFS and OS (p < 0.04 and p < 0.0004, respectively). While there was no difference in RFS in those patients undergoing FG versus LR, OS was worse in the FG group (p < 0.017). This trend persisted when type II and type IV groups were excluded (p < 0.045)., Conclusion: Gastric carcinoid treatment should be tailored to tumor type, as biologic behavior rather than resection technique is the more important factor contributing to long-term outcomes., (Copyright © 2018. Published by Elsevier Inc.)

Background: The impact of margin status on resection of primary pancreatic neuroendocrine tumors has been poorly defined. The objectives of the present study were to determine the impact of margin status on long-term survival of patients with pancreatic neuroendocrine tumors after curative resection and evaluate the impact of reresection to obtain a microscopically negative margin., Methods: Patients who underwent curative-intent resection for pancreatic neuroendocrine tumors between 2000 and 2016 were identified at 8 hepatobiliary centers. Overall and recurrence-free survival were analyzed relative to surgical margin status using univariable and multivariable analyses., Results: Among 1,020 patients, 866 (84.9%) had an R0 (>1 mm margin) resection, whereas 154 (15.1%) had an R1 (≤1 mm margin) resection. R1 resection was associated with a worse recurrence-free survival (10-year recurrence-free survival, R1 47.3% vs R0 62.8%, hazard ratio 1.8, 95% confidence interval 1.2-2.7, P = .002); residual tumor at either the transection margin (R1t) or the mobilization margin (R1m) was associated with increased recurrence versus R0 (R1t versus R0: hazard ratio 1.8, 95% confidence interval 1.0-3.0, P = .033; R1m versus R0: hazard ratio 1.3, 95% confidence interval 1.0-1.7, P = .060). In contrast, margin status was not associated with overall survival (10-year overall survival, R1 71.1% vs R0 71.8%, P = .392). Intraoperatively, 539 (53.6%) patients had frozen section evaluation of the surgical margin; 49 (9.1%) patients had a positive margin on frozen section analysis; 38 of the 49 patients (77.6%) had reresection, and a final R0 (secondary R0) margin was achieved in 30 patients (78.9%). Extending resection to achieve an R0 status remained associated with worse overall survival (hazard ratio 3.1, 95% confidence interval 1.6-6.2, P = .001) and recurrence-free survival (hazard ratio 2.6, 95% confidence interval 1.4-5.0, P = .004) compared with primary R0 resection. On multivariable analyses, tumor-specific factors, such as cellular differentiation, perineural invasion, Ki-67 index, and major vascular invasion, rather than surgical margin, were associated with long-term outcomes., Conclusion: Margin status was not associated with long-term survival. The reresection of an initially positive surgical margin to achieve a negative margin did not improve the outcome of patients with pancreatic neuroendocrine tumors. Parenchymal-sparing pancreatic procedures for pancreatic neuroendocrine tumors may be appropriate when feasible., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: The incidence, clinical characteristics, and long-term outcomes of patients with gastroenteropancreatic neuroendrocrine tumors and carcinoid syndrome undergoing operative resection have not been well characterized., Methods: Patients undergoing resection of primary or metastatic gastroenteropancreatic neuroendrocrine tumors between 2000 and 2016 were identified from an 8-institution collaborative database. Clinicopathologic and postoperative characteristics as well as overall survival and disease-free survival were compared among patients with and without carcinoid syndrome., Results: Among 2,182 patients who underwent resection, 139 (6.4%) had preoperative carcinoid syndrome. Patients with carcinoid syndrome were more likely to have midgut primary tumors (44.6% vs 21.4%, P < .001), lymph node metastasis (63.4% vs 44.3%, P < .001), and metastatic disease (62.8% vs 26.7%, P < .001). There was no difference in tumor differentiation, grade, or Ki67 status. Perioperative carcinoid crisis was rare (1.6% vs 0%, P < .01), and the presence of preoperative carcinoid syndrome was not associated with postoperative morbidity (38.8% vs 45.5%, P = .129). Substantial symptom improvement was reported in 59.5% of patients who underwent curative-intent resection, but occurred in only 22.7% who underwent debulking. Despite an association on univariate analysis (P = .04), carcinoid syndrome was not independently associated with disease-free survival after controlling for confounding factors (hazard ratio 0.97, 95% confidence interval 0.64-1.45). Preoperative carcinoid syndrome was not associated with overall survival on univariate or multivariate analysis., Conclusion: Among patients undergoing operative resection of gastroenteropancreatic neuroendrocrine tumors, the prevalence of preoperative carcinoid syndrome was low. Although operative intervention with resection or especially debulking in patients with carcinoid syndrome was disappointing and often failed to improve symptoms, after controlling for markers of tumor burden, carcinoid syndrome was not independently associated with worse disease-free survival or overall survival., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Importance: Little information is available regarding the minimum number of lymph nodes needed to accurately stage patients when performing a mesenteric lymphadenectomy for small-bowel neuroendocrine tumors., Objectives: To determine the prognostic role of lymph node positivity and the ideal number of lymph nodes for accurately staging patients with small-bowel neuroendocrine tumors., Design, Setting, and Participants: This case series from the US Neuroendocrine Tumor Study Group, a collaboration among 8 US-based, academic tertiary care referral centers, obtained demographic, perioperative, and pathologic data from the group's database, Social Security Death Index, and publicly available obituaries. All patients in these institutions with small-bowel neuroendocrine tumors who underwent curative-intent surgical resection of a primary tumor between January 1, 2000, and December 31, 2015, were included (n = 199). Patients with duodenal or ampullary tumors, other nonneuroendocrine concurrent malignant neoplasms, mortality of fewer than 30 days after the surgical procedure, and distant metastatic disease were excluded. Data analysis was conducted from September 1, 2017, to December 1, 2017., Main Outcomes and Measures: Primary study outcome was recurrence-free survival. Hypothesis was generated after data collection and data entry into the US Neuroendocrine Tumor Study Group database., Results: Of the 199 patients included, 112 (56.3%) were male and 87 (43.7%) female with a mean (SD) age of 60.3 (12.5) years and a mean (SD) body mass index of 29.5 (6.0). One hundred fifty-four patients (77.4%) had lymph node-positive disease. No difference in 3-year recurrence-free survival was found between patients with lymph node-positive and lymph node-negative disease. Patients with 4 positive lymph nodes had a worse 3-year recurrence-free survival compared with those with 1 to 3 or 0 positive lymph nodes (81.6% vs 91.4% vs 92.1%; P = .01). When examining patients with fewer than 8 resected lymph nodes, no difference in 3-year recurrence-free survival was observed among patients with 4 or more, 1 to 3, or 0 positive lymph nodes (100% vs 93.8% vs 91.7%; P = .87). Retrieval of 8 or more lymph nodes, however, accurately discriminated patients with 4 or more, 1 to 3, or 0 positive lymph nodes (3-year recurrence-free survival: 79.9% vs 89.6% vs 92.9%; P = .05)., Conclusions and Relevance: The findings from this study suggest that, for patients undergoing curative-intent resection of small-bowel neuroendocrine tumors, accurate lymph node staging requires a minimum of 8 lymph nodes for examination, and 4 or more positive lymph nodes are associated with decreased 3-year recurrence-free survival compared with 1 to 3 or 0 positive lymph nodes; a thorough regional lymphadenectomy may be critical for accurate staging and management of this disease.

Introduction: Patients with metastatic neuroendocrine tumor (NET) often have an indolent disease course yet the outcomes for patients with metastatic NET undergoing surgery for non-hormonal (NH) symptoms of GI obstruction, bleeding, or pain is not known., Methods: We identified patients with metastatic gastroenteropancreatic NET who underwent resection from 2000 to 2016 at 8 academic institutions who participated in the US Neuroendocrine Tumor Study Group., Results: Of 581 patients with metastatic NET to liver (61.3%), lymph nodes (24.1%), lung (2.1%), and bone (2.5%), 332 (57.1%) presented with NH symptoms of pain (n = 223, 67.4%), GI bleeding (n = 54, 16.3%), GI obstruction (n = 49, 14.8%), and biliary obstruction (n = 22, 6.7%). Most patients were undergoing their first operation (85.4%) within 4 weeks of diagnosis. The median overall survival was 110.4 months, and operative intent predicted survival (p < 0.001) with 66.3% undergoing curative resection. Removal of all metastatic disease was associated with the longest median survival (112.5 months) compared to debulking (89.2 months), or palliative resection (50.0 months; p < 0.001). The 1-, 3-, and 12-month mortality was 3.0%, 4.5%, and 9.0%, respectively. Factors associated with 1-year mortality included palliative operations (OR 6.54, p = 0.006), foregut NET (5.62, p = 0.042), major complication (4.91, p = 0.001), and high tumor grade (11.2, p < 0.001). The conditional survival for patients who lived past 1 year was 119 months., Conclusions: Patients with metastatic NET and NH symptoms that necessitate surgery have long-term survival, and goals of care should focus on both oncologic and quality of life impact. Surgical intervention remains a critical component of multidisciplinary care of symptomatic patients.

Background: The risk of recurrence after resection of non-metastatic gastro-entero-pancreatic neuroendocrine tumors (GEP-NET) is poorly defined. We developed/validated a nomogram to predict risk of recurrence after curative-intent resection., Methods: A training set to develop the nomogram and test set for validation were identified. The predictive ability of the nomogram was assessed using c-indices., Results: Among 1477 patients, 673 (46%) were included in the training set and 804 (54%) in y the test set. On multivariable analysis, Ki-67, tumor size, nodal status, and invasion of adjacent organs were independent predictors of DFS. The risk of death increased by 8% for each percentage increase in the Ki-67 index (HR 1.08, 95% CI, 1.05-1.10; P < 0.001). GEP-NET invading adjacent organs had a HR of 1.65 (95% CI, 1.03-2.65; P = 0.038), similar to tumors ≥3 cm (HR 1.67, 95% CI, 1.11-2.51; P = 0.014). Patients with 1-3 positive nodes and patients with >3 positive nodes had a HR of 1.81 (95% CI, 1.12-2.87; P = 0.014) and 2.51 (95% CI, 1.50-4.24; P < 0.001), respectively. The nomogram demonstrated good ability to predict risk of recurrence (c-index: training set, 0.739; test set, 0.718)., Conclusion: The nomogram was able to predict the risk of recurrence and can be easily applied in the clinical setting., (© 2018 Wiley Periodicals, Inc.)

Objective: The focus of tissue engineering of neocartilage has traditionally been on enhancing extracellular matrix and thus biomechanical properties. Emphasis has been placed on the enhancement of collagen type and quantity, and, concomitantly, tensile properties. The objective of this study was to improve crosslinking of the collagen network by testing the hypothesis that hypoxia could promote pyridinoline (PYR) crosslinks and, thus, improve neocartilage's tensile properties., Methods: Chondrocyte expression of lysyl oxidase (LOX), an enzyme responsible for the formation of collagen PYR crosslinks, was first assessed pre- and post- hypoxia application. Then, the mechanical properties of self-assembled neocartilage constructs were measured, after 4 weeks of culture, for groups exposed to 4% O2 at different initiation times and durations, i.e., during the 1st and 3rd weeks, 3rd and 4th weeks, 4th week only, continuously after cell seeding, or never., Results: Results showed that LOX gene expression was upregulated ∼20-fold in chondrocytes in response to hypoxia. Hypoxia applied during the 3rd and 4th weeks significantly increased PYR crosslinks without affecting collagen content. Excitingly, neocartilage tensile properties were increased ∼2-fold. It should be noted that these properties exhibited a distinct temporal dependence to hypoxia exposure, since upregulation of these properties was due to hypoxia applied only during the 3rd and 4th weeks., Conclusion: These data elucidate the role of hypoxia-mediated upregulation of LOX and subsequent increases in PYR crosslinks in engineered cartilage. These results hold promise toward applying hypoxia at precise time points to promote tensile integrity and direct construct maturation., (Copyright © 2013 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Introduction: The aim of the current study is the identification of clinical phenotypes of patients visiting a specialized smoking cessation center and the determination of smoking cessation rate for each phenotype, 1 year after the initial evaluation., Methods: Seven hundred eighty-three smokers who visited the outpatient clinic were included in the study. Demographic data, smoking habits, tobacco dependence and comorbidities were recorded. Smoking cessation rates and carbon monoxide levels were determined 1 year after the initial evaluation., Results: The overall smoking cessation rate 1 year after the initial evaluation was 32.3%. Four distinct phenotypes were identified. The first one included mainly young women with low tobacco dependence and allergic profile. The second and the third ones included mainly men with high tobacco dependence, without comorbidities, treated with varenicline and bupropione SR, respectively. The fourth one included mainly older men with high tobacco dependence and smoking related comorbidities. Smoking cessation rates for each phenotype were 33.8, 39.4, 23.3, and 24.6%, respectively., Conclusion: Patients visiting a specialized smoking cessation center can be categorized in different phenotypes. Phenotyping may lead to a more personalized approach concerning smoking cessation., (Copyright © 2013 Elsevier Inc. All rights reserved.)

In this study a description of a new approach, for the generation of multi-block structured computational grids on patient-specific bifurcation geometries is presented. The structured grid generation technique is applied to data obtained by medical imaging examination, resulting in a surface conforming, high quality, multi-block structured grid of the branching geometry. As a case study application a patient specific abdominal aorta bifurcation is selected. For the evaluation of the grid produced by the novel method, a grid convergence study and a comparison between the grid produced by the method and unstructured grids produced by commercial meshing software are carried out., (Copyright © 2011 IPEM. Published by Elsevier Ltd. All rights reserved.)

This study presents the generation of a multi-block structured grid on a real abdominal aortic aneurysm (AAA) acquired from Digital Imaging and Communication in Medicine (DICOM) data. With the use of a computed tomography exam (or medical images in standard DICOM format), the shape of a human organ is extracted and a structured computational grid is created. The structured grid generation is done by utilising Floater's and Gopalsamy et al.'s algorithm. The proposed methodology is applied to the AAA case, but it may also be applied to other human organs, enabling the scientist to develop an advanced patient-specific model. More importantly, the proposed methodology provides a precise reconstruction of the human organs, which is required in an AAA, where small variations in the geometry may alter the flow field, the stresses exerted on the walls and finally the rupture risk of the aneurysm.