Rationale: Currently, for locoregionally advanced nasopharyngeal carcinoma (LA-NPC), there is no effective blood-based method to predict distant metastasis. We aimed to detect plasma protein profiles to identify biomarkers that could distinguish patients with NPC who are at high risk of posttreatment distant metastasis.Methods: A high-throughput antibody array was initially applied to detect 1000 proteins in pretreatment plasma from 16 matched LA-NPC patients with or without distant metastasis after radical treatment. Differentially expressed proteins were further examined using a low-throughput array to construct a plasma protein-based signature for distant metastasis (PSDM) in a cohort of 226 patients.Results: Fifty circulating proteins were differentially expressed between metastatic and non-metastatic patients and 18 were proven to be strongly correlated with distant metastasis-free survival (DMFS) in NPC. A PSDM signature consisting of five proteins  was established to assign patients with NPC into a high-risk group and a low-risk group. Patients in the high-risk group had shorter DMFS (P < 0.001), disease-free survival (DFS) (P < 0.001) and overall survival (OS) (P < 0.001). Moreover, the PSDM performed better than N stage and Epstein-Barr virus (EBV) DNA load at effectively identifying patients with NPC at high risk of metastasis. For patients in the high-risk group, induction chemotherapy significantly improved DMFS, DFS, and OS.Conclusions: The PSDM could be a useful liquid biopsy tool to effectively predict distant metastasis and the benefit of induction chemotherapy in patients with LA-NPC. Nasopharyngeal carcinoma (NPC), an aggressive head and neck cancer, is highly prevalent in east and southeast Asia, especially southern China Liquid biopsy is a convenient and non-invasive sampling method that can dynamically reflect the changes of circulating components related to tumor diagnosis and prognosis In the current study, we aimed to investigate whether circulating proteins could be used to determine the metastasis risk in patients with LA-NPC. Using antibody arrays, we compared the differential pretreatment plasma protein profiles between LA-NPC patients with or without posttreatment metastasis. Then, we developed a plasma protein-based signature for distant metastasis (PSDM) consisting of five markers, which showed improved efficacy compared with that of single proteins, N stage, and EBV DNA load to predict metastasis. Moreover, the PSDM classifier could identify patients who might benefit from induction chemotherapy.g for 10 minutes at 4 °C. The plasma was stored at -80 °C until analysis. No patients had received any anti-tumor therapy before blood sampling.We collected 228 plasma samples from pretreatment patients with non-metastatic stage III-IVa LA-NPC at Sun Yat-sen University Cancer Center  between July 2010 and December 2016. At the time of diagnosis, the blood was collected and centrifuged under anticoagulant conditions at 2330 × 2 cisplatin on weeks 1,4, and 7 of radiotherapy or 35-40 mg/m2 cisplatin weekly The 8th edition of the American Joint Committee on Cancer (AJCC) Staging Manual was used to pathologically diagnose and restage all the patients For the induction chemotherapy benefit analysis, propensity score matching was adopted to adjust for patient selection bias and to generate two clinicopathologically matched groups with or without Taxane-Platinum-5FU (TPF) IC. The propensity score was calculated based on host and tumor factors, including age, sex, T stage, N stage, EBV DNA levels, and radiotherapy methods using the caliper algorithm with 0.05 by “MatchIT” packages in the R software (version 3.6.1) This study was approved by the Institutional Ethical Review Boards of the Sun Yat-Sen University Cancer Center, and the written informed consent was obtained from all patients. The results of the present study are reported according to the Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK) criteria High-throughput plasma protein profiles were acquired at the non-metastatic phase of eight patients with LA-NPC, who developed posttreatment metastasis during follow-up, and eight matched patients with LA-NPC, who did not, using a Quantibody Human Kiloplex Proteomics Array  according to the manufacturer's instructions. A total of 1000 proteins were detected semiquantitatively, including those related to immunity or inflammation , angiogenesis, cell growth, apoptosis, and signal transduction.P value < 0.05.Each protein was analyzed in quadruplicate together with positive controls in the array, using a sandwich assay detection technique Next, the differentially expressed proteins without cross-reaction were measured using a low-throughput customized quantitative Quantibody Human Array in a larger population of 226 patients with LA-NPC. The standard proteins were assayed simultaneously in each array together with the samples using a sandwich-based procedure to generate standard curves. By comparing normalized signals from unknown samples to the standard curve, the protein concentration in the samples was determined, and then log2-transformed before being subjected to subsequent analyses. We filtered out the proteins with concentrations below the lower limit of detection of the quantitative array in more than 50% of samples.P values less than 0.05 in the model construction. We then chose overexpressed proteins and adopted a LASSO Cox regression method to select candidates for the PSDM using the “glmnet” package in R software. The LASSO algorithm is a popular machine learning method, which is broadly applied to the Cox proportional hazard regression models for survival analysis To construct the PSDM, we first performed univariate Cox analysis to select proteins that correlated with distant metastasis-free survival (DMFS). Given the aim to identify candidate proteins that are highly related to metastasis and that the strictness of multiple test correction might rule out some of these potential markers, we included protein candidates with unadjusted Our primary endpoint was DMFS, with disease-free survival (DFS) and overall survival (OS) as the secondary endpoints. DMFS was calculated from the first day of treatment to the date of first distant relapse or death from any cause, whichever occurred first. DFS was calculated from the first day of treatment to the date of the first relapse at any site or death from any cause, whichever occurred first. OS was calculated from the first day of treatment to the date of death from any cause. The Kaplan-Meier method and the log-rank test were used to estimate DMFS, DFS, and OS. Cox regression analyses were used to calculate the hazard ratios (HRs).2 test or Fisher's exact test were used to compare categorical variables. We used univariate Cox analysis to analyze the correlations between the clinical outcomes and factors such as the PSDM, age, sex, T stage, N stage, and EBV DNA load. The factors that correlated significantly with the outcomes were further tested with multivariate Cox regression analysis. The predictive efficiency with regard to metastasis was compared between the PSDM and single proteins, as well as between the PSDM and clinical factors, using time-dependent receiver operating characteristic (ROC) curves and time-dependent area under the curve (AUC) analysis. We also performed a subgroup analysis with the Kaplan-Meier method and log-rank test to evaluate whether the PSDM could distinguish patients with better outcomes from those with worse outcomes in the groups with different stages and EBV DNA levels. All statistical tests were two-sided and differences were deemed significant at a P value < 0.05. R software (version 3.6.1) was used to perform the statistical analyses.We assessed the differentially expressed proteins between the metastatic and nonmetastatic group with Student's t-test. The χWe included 228 pretreatment patients with non-metastatic LA-NPC in this study. For the high-throughput profiles, eight patients with posttreatment metastasis and eight patients without posttreatment metastasis were strictly matched by age, sex, TNM stage, EBV DNA levels, and treatment methods to rule out the potential influence of those factors on metastasis . We thenP < 0.05). These proteins showed strong classification properties in distinguishing the two groups .In the high-throughput proteomic array analysis, 50 proteins were found to be differentially expressed among 1000 proteins detected between 16 matched NPC patients with or without metastasis . Seventeen of them were upregulated and one was downregulated in patients with distant metastasis after treatment. Statistically, 15 of the 18 prognostic proteins were significantly and differentially expressed (P < 0.05). In addition, we also discovered that 13 proteins associated significantly with DFS, and 11 proteins correlated significantly with OS (P < 0.05). The cutoff value of each protein concentration that had the maximum sum of sensitivity and specificity to predict 5-year DMFS, based on the time-dependent ROC curve, was used to separate patients into low and high expression groups. The Kaplan-Meier curves of DMFS, DFS, and OS according to the low and high expression of these proteins in patients with NPC are provided in DMFS was the primary endpoint in the current study; therefore, we adopted univariate Cox regression analysis to identify DMFS-related proteins candidates for PSDM signature construction. The results showed that 18 candidates correlated significantly with DMFS , endothelial cell-specific molecule 1 (ESM-1), insulin receptor (INSR), matrix metalloproteinase 8 (MMP-8) and serpin family A member 5 (Serpin A5) . Patients in the high-risk group had a shorter 5-year DMFS  2.97-11.86, P < 0.001), 5-year DFS  and 5-year OS  than the low-risk group   for the PSDM, we classified 145 patients into the low-risk group and 81 patients into the high-risk group. Each of the five proteins in the PSDM signature was significantly upregulated in the high-risk group . However, in patients with EBV DNA burden < 2000 copies/ml, the Kaplan-Meier curves showed no significant association between the PSDM and any clinical outcome , DFS  and OS  in patients in the high-risk group but not in patients in the low-risk group  The five proteins that compose the PSDM have been reported to be associated with pathophysiological processes in cancers, especially in processes related to metastasis We also performed a stratification analysis to determine the prognostic value of the PSDM in patients with different EBV DNA loads. In the subgroup with high EBV DNA levels, our PSDM maintained outstanding efficacy to discriminate among patients with distinctly different outcomes; however, this was not true in the low EBV DNA subgroup. It has been noted that the EBV DNA load may reflect the potential metastasis risk in patients with NPC Accumulating evidence shows that induction chemotherapy could provide a survival benefit by improving distant control in NPC Our study was limited by the lack of patients with early-stage disease (TNM stage I-II); therefore, the PSDM might not be suitable or may need to be modified for early-stage patients. In addition, we also acknowledge that this study was limited by its retrospective and single-center nature. The current marker panel requires further validation by other methods, such as enzyme-linked immunosorbent assays (ELISA) and prospective evaluation in independent cohorts before its clinical application.In conclusion, we developed a plasma protein-based signature consisting of five proteins that performed much better than clinical indicators to predict the distant metastasis of NPC. Moreover, we showed that the PSDM classifier could identify patients who might benefit from TPF IC. Therefore, the PSDM, which is easily detected in peripheral blood, might be a useful liquid biopsy tool to classify patients with different metastatic risks and could lead to more individualized treatment of LA-NPC.Supplementary figures and tables.Click here for additional data file.


Discharge policies concerning hospitalization after endoscopic pituitary tumor surgery are highly variable. A few studies support fast-track discharge; however, this is not commonplace. Our goal was to report the transition to and evaluate the feasibility, safety, clinical- and patient-reported outcomes and costs of fast-track care in pituitary surgery.N = 307).This observational study included 155 patients undergoing pituitary surgery between December 2016 and December 2018. Fast-track care consisted of planned discharge 2–3 days after surgery, followed by daily surveillance by a case manager. All outcomes were compared with patients not eligible for fast-track discharge. The total group (fast-track and non-fast-track) was compared with historic controls (p < 0.001), the total length of stay did not differ . Although the total group had more readmissions compared with historic controls , no life-threatening complications occurred after discharge. On average, clinical- and patient-reported outcomes improved over time, both in the fast-track and non-fast-track groups. The mean overall costs within 30 days after surgery did not differ between the total group € 9992 (SD € 4562) and historic controls € 9818 (SD € 3488) (p = 0.649).A total of 79/155 patients (51%) were considered eligible for fast-track discharge, of whom 69 (87%) were discharged within 3 days. The total group was discharged more often within 3 days compared with historic controls (49 vs. 20%, A stratified fast-track care trajectory with enhanced postoperative outpatient surveillance after pituitary tumor surgery is safe and feasible. As expected, costs of the fast-track were lower than the non-fast-track group, however we could not prove overall cost-effectiveness compared with the historic controls. Transsphenoidal surgery is the primary treatment option for most pituitary tumors –4 and ovN < 50) and the occurrence of water and electrolyte disturbances during the immediate postdischarge period, as well as patients’ experiences were not evaluated. Length of stay (LOS) is an important measure, however, it is insufficient by itself to measure success of the surgery and studies should encompass patient-relevant outcomes [In line with trends in general surgical care, fast-track care trajectories are applied in some centers that treat pituitary tumors. Common practice, however, is highly variable and many centers keep patients admitted for 5–8 days after uneventful surgery. The results from a limited number of studies support the concept that early discharge, e.g. discharge 2–3 days postoperatively, is feasible and safe –14. Howeoutcomes , 16. FurIn our tertiary referral center, part of the endoERN reference network, the general policy was to discharge patients 5 days after pituitary tumor surgery and we did not stratify patients on anticipated LOS. Through an innovation project we introduced a fast-track protocol with such a preoperative stratification and with daily outpatient monitoring after discharge. This predefined protocol was based on a literature-based risk evaluation . The aimThis prospective cohort study was performed among a consecutive group of pituitary tumor patients treated endoscopically between December 2016 and December 2018 in a tertiary reference center. There were two reference groups: the first consisted of all pituitary tumor patients operated in the same period but were not considered eligible for fast-track discharge; the second was a retrospective cohort consisting of patients treated endoscopically prior to the intervention between January 2010 and November 2016 (historic controls). The Ethical Committee of the Leiden University Medical Center approved the prospective part prior to the study (p16.091). Consent was obtained from each patient after full explanation of the purpose and nature of all procedures used. For the historic control group, the same ethical committee approved a waiver of medical ethical review (G19.011).All patients were diagnosed with a pituitary tumor and underwent endoscopic transsphenoidal resection between January 2010 and December 2018 at our tertiary referral center, the Leiden University Medical Center in the Netherlands. From December 2016 onwards, patients were preoperatively assessed for eligibility for fast-track discharge. The systematic assessments were based according to a literature-based clinical protocol during a weekly pituitary multidisciplinary team meeting. Predefined reasons for ineligibility for the fast-track group were: need for emergency surgery (e.g. apoplexy), Cushing’s disease (CD), giant adenoma, craniopharyngioma, living far from the hospital, inadequate support network, and/or cognitive deficits. Directly after surgery, re-evaluation of the eligibility for fast-track discharge as well as an estimation of complication risks was performed by the treating neurosurgeon. Discharge was based on clinical grounds and only when deemed safe by the treating physician. This was re-assessed on a daily basis after surgery. Patients in the historic control group received care as usual.Patients considered eligible for the fast-track care trajectory were instructed to actively participate in their own postoperative care by means of a standardized checklist which they had to report to the case manager on a daily basis after discharge. This checklist was composed to support patients to keep track of their fluid balance, weight, and relevant clinical signs and symptoms , CD, prolactinoma (PRL), TSH-producing adenoma, Rathke’s cleft cyst, or craniopharyngioma (Cranio). Pituitary function was defined as: (1) no deficits, (2) single hormone deficiency, (3) single hormone deficiency plus DI, (4) multiple hormone deficiencies, (5) multiple hormone deficiencies plus DI, and (6) DI alone. Visual functioning was defined as the presence of visual field deficits, or not. Prior treatments were described as: (1) no treatment, (2) prior medical (tumor) treatment, (3) prior surgery, and (4) prior radiotherapy.Primary outcomes were feasibility, safety, ability to predict postoperative complications, patient-reported experience, and costs. Patient-reported outcomes were secondary outcomes.Feasibility was defined as the proportion of patients allocated to the fast-track group, who were discharged 2–3 days after surgery and not readmitted within the fifth postoperative day (POD), which was often the date of discharge prior to the implementation of the protocol. Furthermore, adherence to the fast-track surveillance protocol was registered by means of the length of surveillance and the frequency and duration of fluid balance interventions.Safety was defined as the occurrence of a severe complication after discharge (Clavien–Dindo grade III or higher) . ComplicThe estimated risk of complications was evaluated immediately after surgery by the neurosurgeons to investigate whether this would help to differentiate between patients at risk of complications and those who were not. The likelihood of complications included transient DI, permanent DI, new onset of pituitary deficiencies, epistaxis, postoperative CSF leak, and intracranial hemorrhage. The likelihood of complications was dichotomized into not likely and possible, from which the sensitivity and specificity were calculated.A comprehensive set of PROMs was administered at baseline (preoperatively) and 6 weeks after surgery. Changes in PROMs were calculated as between group differences corrected for baseline. Disease bother was measured through the Leiden Bother and Needs Questionnaire-pituitary (LBNQ-pituitary) , which wPatient-reported experiences were measured 4 weeks after surgery among patients in the fast-track group by means of a self-designed questionnaire and included experience of delivered care, sense of safety at home during the first 3 days at home, as well as the period after (day 4 through day 7). This questionnaire also assessed the self-perceived patient empowerment on a five-point Likert scale  and the self-perceived optimal discharge date (range: −2 to +4 days).Costs were estimated from a healthcare perspective, at price level 2019. Hospital care included the initial admission (regardless of duration) and all subsequent hospital care up to 30 days after surgery . All healthcare use was assessed from patient records, except for outpatient clinic visits in the non-fast-track and historic cohort, which was set at two visits, unless hospitalization lasted for more than 30 days. Costs for surgery were derived from the Dutch Healthcare Authority , 29, andp < 0.05 (two-sided). Missing data on the validated questionnaires were handled by parcel summary imputation [All statistical analyses were performed with SPSS 25.0 software . Nominal variables are presented as frequencies with percentages, numerical variables as means and standard deviations (SD), or medians with interquartile ranges (IQR). Comparisons were made between the fast-track and non-fast-track groups, as well as between the historic group and the total group (fast-track and non-fast-track). Comparisons were performed through one-way ANOVA, Chi-square analyses, Fisher’s exact test, or general linear mixed models (GLM), where applicable. The sensitivity (Se) and specificity (Sp) were used to calculate the discriminative ability of the predictions, as approximated by ½(Se + Sp) . Longituputation .The historic control group comprised of all patients surgically treated between January 2010 and December 2016, including those with diagnoses that were not considered eligible for fast-track surgery. In an attempt to compare the fast-track group with representative patients from our historical cohort, all comparisons were repeated after exclusion of patients with CD, Cranio, giant adenomas, and acute apoplexy .Between December 2016 and December 2018, a total of 155 patients were surgically treated for a pituitary tumor. Patients had a mean age of 48.4 years (SD 16.9) and 54% were female. Most patients had an NFA (45%), followed by ACRO and PRL (both 16%), CD (14%), and other tumors (9%). Among the historic cohort, surgical treatment was performed among 307 patients, with a mean age of 51.5 years (SD 16.9). Of these, 53% were female and most patients also had an NFA (45%), followed by CD (17%), ACRO (16%), PRL (10%), and other tumors (12%)  and three of these patients (4%) needed to be readmitted within POD5. Among the patients eligible for fast-track discharge that required a stay of more than 3 days (range 4–17 days), one was readmitted within the fifth POD. In addition, among patients not considered eligible at preoperative counseling, 7 (9%) were successfully discharged after 2–3 days after surgery . In comparison, in the historic cohort, only 61 patients (20%) were discharged 2–3 days after surgery .Of the 155 patients, 79 patients (51%) were preoperatively considered eligible for fast-track discharge. Of these, 69 patients (87%) were discharged 2–3 days after surgery as planned , emergency surgery , and due to various comorbidities   and a postoperative CSF leak in three patients (4%). The three most frequent reasons for a priori non-eligibility were CD  Figs. .Fig. 1FlN = 8), fluctuating fluid balance/uncontrolled DI (N = 9), persisting physical complaints (N = 2), and a previous readmission (N = 2). During follow-up, 24 patients received a fluid restriction, which started on average 7.3 days (SD 1.1) after surgery and lasted for a mean of 4.6 days (SD 2.4)  Fig. . All butp < 0.001), however the overall LOS of the total group was not significantly lower compared with the historic cohort   Table .Table 2SN = 6, 43%) and did not differ with the non-fast-track group, among which 14 (18%) were readmitted (p = 0.747). Patients readmitted among the non-fast-track group were readmitted on average 13.2 days (6.2 SD) after surgery and also most frequently due to delayed hyponatremia . In the historic cohort group, there were significantly fewer readmissions compared with the total group . In the total group, the reason for readmission was most frequently due to delayed hyponatremia  , in particular not in the period between fast-track discharge and “regular” discharge. However, two patients 2.5%) were readmitted for the surgical treatment of an epistaxis late after fast-track discharge . In the fast-track discharge group, a total of 13 patients (16%) were readmitted after discharge, on average 8.5 days (SD 6.0) after surgery. This was most frequently due to delayed hyponatremia . The mean overall sense of safety at home during the first 3 days after discharge was 6.7 , which was not statistically different between patients who were not readmitted compared with those who were . After the initial period at home (3 days), the mean overall sense of safety improved to a mean of 7.7 , which was significantly lower among patients readmitted compared with those who were not . Over half of the patients (54%) perceived themselves as very/completely empowered, which did not differ between both groups (p = 1.00). Nearly 40% of patients (N = 23/58), however, would have preferred to stay admitted one or more days longer, which was significantly higher among readmitted patients (p = 0.02) , which was significantly lower among patients readmitted after discharge compared with those who were not readmitted . There was no significant difference in costs between the total group  and the historic cohort  (Table The mean costs of perioperative treatment were € 8652 (SD € 1748) for patients in the fast-track group, which was significantly lower compared with patients in the non-fast-track group , but higher occurrence of transient DI . The costs in the fast-track group were significantly lower than in the selected historic control group  (Supplementary Table Excluding patients with diagnoses not considered eligible for fast-track from the historic control group yielded a selection of 213 patients. Both groups (fast-track and selected historic cohort) were grossly comparable  in the fast-track discharge, as well as the non-fast-track discharge group (18%) compared with historical controls (10%). Since this was mainly due to SIADH and the protocol was directed to detect patients at risk at an early stage, it is likely that we were more aware of diagnosing and treating this complication at an early stage. Importantly, no life-threatening complications occurred in the home setting. So, we conclude that the high readmission rate most likely reflects the intense attention to postoperative complications combined with our low threshold for readmittance. Results shown in this study provide useful information that will facilitate better expectation management, improve water and electrolyte imbalance protocols, decrease the occurrence of delayed hyponatremia, and subsequent readmissions.Even though there are more centers that discharge patients at POD2 or even sooner, the feasibility and safety has only been scarcely evaluated –14. In tOne of the main reasons to initiate this fast-track protocol was the impression that our patients thought that postoperative hospitalization was only for complication surveillance, not for actual needed care. An unanticipated result is the lower than expected overall sense of safety at home during the first 3 days as perceived by patients discharged early after surgery. Control data of experienced safety in the first days after discharge are not available for pituitary surgery, so we do not know if this is uncommon or not. Furthermore, the majority of our patients indicated afterwards that they were content with the day of discharge. Based on obtained patients’ experiences, we doubt whether further shortening the admission period, albeit commonplace in some centers, would be desired by patients. Patients who were readmitted reported a lower perceived safety at home, which might be explained in part by the fact that patients who experience adverse events after discharge often have lower evaluations of care . So, patThere are several recent publications regarding standardized fluid restrictions in the short-term postoperative phase –39. BeneThe size, comprehensiveness, and prospective nature are the main strengths of this study. Previous studies had smaller sample sizes (up to 47 patients) compared with our study. By comparing results from the fast-track group with the non-fast-track group, as well as with the historic cohort group, we have provided more accurate reference data from which we drew our conclusions regarding the outcomes of our fast-track protocol. Ideally, we would have performed a randomized controlled trial or a cluster randomized trial, however due to the rarity of the disease, the heterogeneity of the population, and the odds of contamination of the non-surveillance group, these methods were deemed not feasible .Also, by presenting and comparing the results of these three groups we have attempted to provide insight into the possible occurrence of selection bias. The differences in terms of costs appear to be small, but promising, if only those patients from the historic cohort are considered that meet eligibility criteria for fast-track. Nevertheless, results of the sensitivity analysis should be interpreted with caution, since it is unknown what direction the results of the historic cohort would go towards when the selection of patients would have been performed like that of the fast-track group. We potentially introduced recall bias, which was introduced by asking patients to recollect their initial sense of safety several weeks after discharge instead of on the actual date itself.Another limitation of this study is the standardization of costs for the retrospective and non-fast-track group. This might have resulted in lower overall costs for these groups of patients and future research should focus more on the cost aspect of the intervention. Preferably this should be done through a time-driven-activity-based-costing approach, which is advocated within the model of value-based healthcare . Also, fDischarging selected patients 2–3 days after transsphenoidal surgery through a well-defined fast-track care trajectory appears feasible and safe. Although the overall costs of the fast-track group were lower compared with the non-fast-track group, the overall costs between the total group and the historic group did not differ, while a specialized case manager provided prolonged daily monitoring. Since the prediction of complications remains difficult and readmissions do occur, monitoring is needed also after uneventful surgery. With this approach we did not encounter any life-threatening situations by expediting the date of discharge in a large group of patients. Additional patient education and expectation management are needed to improve the reassurance about the safety of early discharge.Supplementary Table 1Supplementary Table 2Supplementary Table 3Supplementary Table 4Supplementary Table 5


Although binge drinking peaks at age 21 to 25 years, there is limited research on the effects of serious games in this population, as well as on the process by which playing serious games impacts alcohol-related outcomes. Designed with both health behavioral theory and game theory, One Shot is an online serious game that aims to prevent binge drinking.This study utilized a conceptual model for serious video game processes. Using One Shot, the model assessed the following process stages: (1) Alcohol Use Disorders Identification Test-Concise (AUDIT-C); (2) in-game factors of game time and risky alcohol decisions; (3) game enjoyment; and (4) postgame outcomes of intention to drink less and drinking refusal self-efficacy.In a one-group pretest-posttest quasi-experimental design, a sample (N=550) of young adults (age 21-25 years) who reported recent binge drinking played the One Shot game. Intention to drink less and drinking refusal self-efficacy were measured at pregame and postgame, with their effects lagged in statistical analysis. Participants were presented with various scenarios in the game that pertained to risky alcohol decisions, which, along with game time, were unobtrusively recorded by the server. A structural equation model (SEM) was used to test the conceptual model, with assessments made to determine if enjoyment mediated the effects of game time and risky alcohol decisions on the 2 postgame alcohol-related outcomes.P<.001) mediated the effects of game time and risky alcohol decision on intention to drink less and drinking refusal self-efficacy.A well-fitting SEM demonstrated support for the multistep model, with AUDIT-C predicting risky alcohol decisions (β=.30). Risky alcohol decisions (β=−.22) and game time (β=.18) predicted enjoyment, which, in turn, predicted intention to drink less (β=.21) and drinking refusal self-efficacy (β=.16). Enjoyment significantly (The results support a conceptual model in which staggered individual and in-game factors influence alcohol-related outcomes. Enjoyment is important for participants’ intentions to drink less and beliefs that they can refuse alcohol. Although it is well recognized that alcohol use is a leading risk factor for morbidity and mortality, recent estimates indicate that it accounts for a larger percentage of global deaths than previously recognized, with 10% of deaths among 15 to 49-year-old individuals attributed to alcohol -4. BingeWhile there are several serious games on substance use, few are exclusively focused on alcohol, with nearly all such games targeting adolescents and college students ,11-13. RThere are very few studies specific to adults of legal drinking age  in the United States. Though understudied, young adults  represent an important population for alcohol-prevention gaming because excessive alcohol consumption peaks at the end of or even after college, with binge drinking levels at a high for women at age 22 years and for men at age 23 years . These pThe aim of this study was to explain how individual characteristics and in-game factors of a serious game can influence drinking-related outcomes for young adults aged 21 to 25 years. To study the underlying mechanisms, we build a multistep model that entails individual factors, in-game factors, and postgame alcohol outcomes. Below, we describe our serious video game and its theoretical basis. Then, we articulate expectations related to our conceptual model.This study’s serious game “One Shot” is an online single-player game designed by a physician  specializing in alcohol addiction among young adults. Single-player games can be particularly adept at imparting new skills and knowledge . One ShoThe design of One Shot utilizes both game theory and health behavioral theory given that the combination of both theoretical approaches elicits the strongest health outcomes . In termIn terms of health behavioral theory, protection motivation theory (PMT) has the following 2 core concepts: perceived threat and coping. It suggests people are likely to take action to avert a severe threat if they are provided with coping strategies . In the In addition, given that previous research has demonstrated that social norms influence alcohol consumption ,23, One Our conceptual model for serious video game processes is depicted in The first set of factors in our conceptual model is the individual characteristics of the game player. Prior research has implemented health predispositions as an individual factor . For exaThe second main stage in our conceptual model entails in-game factors specific to the One Shot serious game. In Pertinent to this stage in the model, research indicates that video game players behave in a virtual environment similarly to how they behave in the real world . Thus, wUnclear, however, is the effect of hazardous drinking on time spent playing the game. The first research question (RQ1) is as follows: What is the effect of AUDIT-C on game time?The second substage of in-game factors  entails Despite the suggested importance of enjoyment, few serious games specific to alcohol prevention account for the role of enjoyment in influencing related game outcomes. In our conceptual model, the in-game factors of game time and risky alcohol decisions predict game enjoyment. Previous research found that in-game experiences are associated with enjoyment . AdditioNext, we considered the effects of risky alcohol decisions. In the One Shot game, players who make more risky alcohol decisions are more extensively exposed to game scenarios that lead to the game’s severe consequences . These severe consequences serve as fear appeals, which elicit an unpleasant emotional state that arises from a threat , and in The third stage in our conceptual model  entails We consider the effects of enjoyment on both of these outcomes. Enjoyment of a game underpins the entertainment media experience, such that attaining game enjoyment is necessary for substantive effects, most notably learning outcomes . PreviouGiven the multistage aspect of our conceptual model for serious video game processes , we alsoThis study utilized a one-group pretest-posttest quasi-experimental design , which hThere were the following 4 demographics: age, education, ethnicity (W=1), and gender (M=1). Education was measured on a 7-point scale from less than high school graduate (1) to doctoral degree (7) and recoded to represent years of study. Other variables were AUDIT-C, game time, risky alcohol decisions, enjoyment, intention to drink less, and drinking refusal self-efficacy. AUDIT-C was assessed at pregame, whereas enjoyment was assessed at postgame. Intention to drink less and drinking refusal self-efficacy were assessed at pregame and postgame.r=0.54, P<.001). Intention to drink less was measured with one item on a 5-point scale (with responses from 0-4), involving whether participants planned to moderate their alcohol use in the future [With scores ranging from 0 to 12, AUDIT-C entails 3 survey items that help identify people who are hazardous drinkers or have active alcohol-use disorders . Game tie future . Drinkine future . For exat tests comparing pregame and postgame means of the dependent variables, were used for variables in their pretransformation form. Posttransformation variables were used for the structural equation model (SEM), which was implemented using the maximum likelihood method of estimation and covariance structure analysis. SEM is a technique for confirming a specified model of multivariate relationships [Stata 16 (Stata Corp) was used for statistical analysis. No outliers were identified. Square root transformations were conducted for skewed-right variables . Square transformations were implemented for skewed-left variables . Descriptive statistics, as well as ionships . Entailiionships  as folloExogeneous control variables included age, education, ethnicity (W=1), and gender (M=1), as well as the pregame measures of intention to drink less and drinking refusal self-efficacy. Endogenous variables included AUDIT-C, game time, risky alcohol decisions, and enjoyment, as well as postgame measures of intention to drink less and drinking refusal self-efficacy. Paths were drawn from exogenous variables to endogenous variables and among endogenous variables, as depicted in In the SEM, enjoyment, risky alcohol decisions, and pregame and postgame drinking refusal self-efficacy were instituted as latent variables, while the other variables were observed. In the first step of the SEM approach, confirmatory factor analysis (CFA) was conducted to test the unidimensionality of the latent variables on pregame and postgame drinking refusal self-efficacy. Second, a structural model was tested to assess relationships among the latent and observed variables. Mediation was assessed with the product of coefficients approach .549=−2.97, P=.003). Similar tests were run on the 7 pregame and postgame manifest indicators of drinking refusal self-efficacy, which was instituted as a latent variable in the SEM. In the following 5 cases, the item means were higher at postgame than at pregame  item 3, t549=−5.29, P<.001; (3) item 4, t549=−5.89, P<.001; (4) item 5, t549=−8.11, P<.001; and (5) item 6, t549=−2.65, P=.008. In the other 2 cases, the item means did not vary significantly from pregame to postgame  itepostgame  as follo269=312.61, P<.001). According to modification indices, 2 additional covariance paths were added between latent variable indicators. The retested CFA had good model fit . This latent variable structure, with factor loadings on the 2 factors, was used in the structural model, which was calculated next. The tested SEM had good model fit . The Bentler-Raykov squared multiple correlation coefficients were as follows: AUDIT-C, 5.58%; game time, 2.01%; risky alcohol decisions, 11.53%; enjoyment, 17.22%; postgame intention to drink less, 40.57%; and postgame drinking refusal self-efficacy, 70.35%.CFA included the latent structures for pregame and postgame drinking refusal self-efficacy. The initial CFA included covariance paths between pregame and postgame drinking refusal self-efficacy and between each pregame manifest indicator and its analogous postgame manifest indicator. The tested CFA had decent model fit , which suggests over-time stability in measurement. The positive effect of AUDIT-C on risky alcohol decisions was significant , supporting H1. In terms of RQ1, the effect of AUDIT-C on game time was not significant (β=−.03). The positive effect of game time on enjoyment was significant , supporting H2. The negative effect of risky alcohol decisions on game enjoyment was significant , supporting H3. The positive effect of enjoyment on postgame intention to drink less was significant , supporting H4. The positive effect of game enjoyment on postgame drinking refusal self-efficacy was significant , supporting H5.The effects of variables are depicted in P<.001) [P<.001) [P<.001) [P<.001) [H6 and H7 entail mediation paths. The significant role of enjoyment in mediating the effect of game time on intention to drink less was documented, with a product of coefficients of 13.28 (P<.001) . Similar[P<.001) . These f[P<.001) . Similar[P<.001) . These fOur conceptual process model depicts how a serious game for alcohol prevention influences changes in alcohol-related outcomes. With our sample of young adults aged 21 to 25 years, which is an understudied yet at-risk group for binge drinking, the analysis suggested improvements from pregame to postgame in intention to drink less, as well as in 5 of the 7 manifest indicators of drinking refusal self-efficacy. The SEM approach supports the multistep conceptual model, moving from individual factors to 2 staggered substages of in-game factors to postgame alcohol outcomes. In a practical sense, the effects on intention to drink less and drinking refusal self-efficacy are important given their likelihood of predicting subsequent decreases in alcohol consumption behavior ,36. Of tConsistent with game theory, the extent that game players enjoyed One Shot elicited increases from pregame to postgame in their intention to drink less and drinking refusal self-efficacy. Notably, enjoyment mediated the effects of the following 2 in-game factors: game time and risky alcohol decisions. Thus, instead of these in-game factors having direct effects on alcohol outcomes, their documented influence was indirect, as mediated by enjoyment. These indirect effects are suggestive of the complex processes by which an alcohol-prevention serious game functions, with the concept of enjoyment at its core, which is consistent with media entertainment theory that posits that enjoyment is central to learning-related outcomes for entertainment media in general and serious games in particular .These results on the mediating role of enjoyment suggest the need to integrate entertainment content, components, and appeals in serious game design and development as a means to foster learning and behavioral outcomes related to health. The combination of behavioral theory and game theory is needed to elicit desired health-related outcomes . The desIt is also important to consider the role of AUDIT-C in the process. Participants with higher scores on AUDIT-C selected more in-game risky alcohol decisions, which is emblematic of how in-game decisions mirror real-world behaviors. In turn, participants who made more risky decisions enjoyed the game less. In terms of the overall process, participants with higher levels of AUDIT-C enjoyed the game less and, via the indirect pathway, had lower levels of intention to drink less and drinking refusal self-efficacy. That achieving positive health outcomes is impeded in this manner for our sample’s most hazardous drinkers  may relate to message discrepancy , which iWe consider 4 main limitations here. First, while we assessed game time and risky alcohol decisions, there may be other in-game factors at play, including presence, flow, and engagement, which should be considered in future research. Second, our conceptual model included only one individual characteristic, AUDIT-C. Future research may want to use the full AUDIT because it has greater specificity in identifying hazardous drinking. Another individual factor that should be considered in future research is impulsivity, which is a well-recognized risk factor for both the initiation and continuation of alcohol misuse . Third, Using the serious video game One Shot, we built and tested a multistep model for serious video game processes. The confirmation of research hypotheses suggests that serious video games can influence the alcohol consumption outcomes of young adults aged 21 to 25 years, which is an understudied at-risk group. Enjoyment is at the core of the documented processes, serving as an essential step in explaining how alcohol-related outcomes result from individuals’ differential hazardous drinking levels and in-game decisions. This integral role of enjoyment has theoretical implications for researchers of serious video games and practical implications for game designers and developers.


Small-intestinal neuroendocrine tumors (SI-NETs) are the most prevalent small bowel neoplasms with an increasing frequency. In the multimodal management of SI-NETs, surgery plays a key role, either in curative intent, even if R0 resection is feasible in only 20% of patients due to advanced stage at diagnosis, or palliative intent. Surgeons must be informed about the specific surgical management of SI-NETs according to their hormonal secretion, their usual dissemination at the time of diagnosis and the need for bowel-preserving surgery to avoid short bowel syndrome. The aim of this paper is to review the surgical indications and techniques, and perioperative and postoperative management of SI-NETs. Small-intestinal neuroendocrine tumors (SI-NETs) are the most prevalent small bowel neoplasms . SI-NETsIn the multimodal management of SI-NETs, surgery plays a key role, either in curative intent, even if R0 resection is feasible in only 20% of patients due to advanced stage at diagnosis, or palliative intent ,15. The Preoperative imaging in SI-NETs is time- and cost-consuming, requiring both morphological and metabolic imaging. Imaging work-up aims to map and stage the disease with a view to scheduling treatment even if tumor burden is often underestimated in all imaging modalities ,17.Morphological imaging provides anatomical information, such as the exact size and location of lesions. Morphological imaging techniques like contrast-enhanced computed tomography (CT) scans and magnetic resonance imaging (MRI) are routinely used in first line for either diagnosis, staging or follow-up .68Gallium (68Ga-PET)-labeled somatostatin analogues . 68Ga-PET is now preferred, because of its considerably better yield for well-differentiated neuroendocrine tumor (NET) imaging [68Ga-PET [68Ga-PET for the preoperative evaluation in SI-NETs when 68Ga-PET is not available. The third one is 18F-2-fluorodeoxyglucose (FDG-PET) which mainly has a prognostic value high FDG uptake which is correlated with worse survival even in well-differentiated NETs such as SI-NETs. The results of FDG-PET and SSTRI can be combined to perform metabolic grading [Functional imaging provides whole-body imaging which facilitates the diagnosis of abdominal and extra-abdominal lesions. Functional imaging may also evaluate tumor aggressiveness and related therapeutic possibilities (for peptide-radionuclide receptor therapy (PRRT)). Three functional imaging techniques can be used in SI-NETs. The first one is SomatoSTatin Receptor Imaging (SSTRI) which has diagnostic value, a prognostic value high uptake is correlated with better survival and a theranostic value high uptake is correlated with PRRT efficacy ,19. SSTR imaging . The sec68Ga-PET ,22,23. F grading ,25,26. MPrimary SI-NETs may be non-visualized on imaging  and only suspected in cases of typical MLNM with retractile mesenteritis or in cases of neuroendocrine liver metastases with high levels of urinary 5-hydroxyindoleacetic acid (5-HIAA) and in the absence of pulmonary or pancreatic tumors on a CT scan. Additional non-invasive techniques may improve the rate of primary tumor detection, such as CT or magnetic resonance (MR) enteroclysis, and capsule endoscopy. However, these additional imaging procedures seem useless for the preoperative work-up, as none of them can replace manual bowel palpation at the time of the surgery ,27,28.For MLNM, the challenge is not the identification of the lesion but the assessment of its resectability. Surgeons should not consider the MLNM complex to be inextricable and, conversely, should not indicate a laparotomy for an inextricable lesion . For a pDetection of liver metastases on metabolic imaging is not sufficient before liver surgery. Liver MRI, which is more effective than a CT scan for the detection of liver metastases , is usuaAs defined by the preoperative assessment, liver metastases can be classified into three groups: one metastasis of any size (type I); one metastasis accompanied by smaller lesions in both lobes (type II); and disseminated metastatic spread with both liver lobes always involved (type III) .68Ga-PET seem able to detect them with an accuracy of 100% as cited in small published case series [In SI-NETs, carcinomatosis and ovarian metastases are respectively found in 20% and 4% of patients . As in oe series ,36. To dThe perioperative period must be exploited to prepare the patient for surgery, either by specific preparation for SI-NET surgery or by general preparation for oncological abdominal surgery. Specific preparation includes the diagnosis and management of carcinoid syndrome, and of carcinoid heart disease, and the prevention and treatment of carcinoid crisis. The general preparation includes immunonutritional support, optimization of the patient’s comorbidities, and correction of bad behavior (smoking cessation). The general preparation is not detailed in this review.Carcinoid syndrome is characterized by episodic facial flushing (60–85%), diarrhea (60–80%), abdominal cramps, hypotension, and intermittent bronchial wheezing . The preThe diagnosis of carcinoid syndrome is confirmed by the dosage of 5-HIAA, a metabolite of serotonin, the main mediator of carcinoid syndrome with a sensitivity of up to 100% and specificity of 85% to 90% . The uriChromogranin A is not recommended for the preoperative work-up, but most research teams measure it because it is often used for the follow-up.Upon evidence or suspicion of carcinoid syndrome, antisecretory therapy with somatostatin analogues must be initiated before any invasive procedure in SI-NET patients . There aCarcinoid heart disease is the most feared complication of carcinoid syndrome. It is characterized by a fibrotic degeneration of the valves, particularly affecting the right heart chambers—isolated tricuspid valve regurgitation in up to 90% of cases—leading to a deterioration of the right ventricular function ,44,45. CThe diagnosis of carcinoid heart disease is established by a transthoracic echocardiography carried out by an expert in carcinoid heart disease for SI-NETs. As most patients are initially asymptomatic, the European Neuroendocrine Tumor Society (ENETS) recommends a transthoracic echocardiography in patients with elevated urinary 5-HIAA levels regardless of the presence of carcinoid syndrome . A urinaIt has been shown that cardiac neurohormone N-terminal pro-brain natriuretic peptide (NT-pro-BNP) has both diagnostic significance with a sensitivity of 92% and a specificity of 91% for a cut-off level of 260 pg/mL (31 pmol/L) and prognostic significance for carcinoid heart disease ,48. A maIf carcinoid heart disease is diagnosed, cardiological management must be carried out before any oncological surgery . CardiolCarcinoid crisis seems to be the continuation of carcinoid syndrome even if its physiopathology remains largely unknown . CarcinoEven if octreotide is the treatment of choice for carcinoid crisis according to its efficacy in carcinoid syndrome, data on its value for both managing and preventing the crisis are still scarce and conflicting ,54,55,56Surgical treatment is a cornerstone of SI-NET multimodal management and may be curative when a complete R0 resection is obtained. However, a R0 resection is feasible in only 20% of cases due to the usual advanced stage at diagnosis .Surgery is the gold standard for curative treatment of SI-NETs. The main rules for SI-NET surgery are the resection of all the primary tumors, associated with a systematic lymphadenectomy, while focusing on the preservation of the small bowel ,15. ShorExploration is the first surgical step, as up to 60–70% of the disease is missed on preoperative imaging ,57,58. TManual palpation of the entire small bowel maximizes the detection of multiple synchronous tumors, missed in more than 60% of patients on preoperative imaging ,60. HoweThe liver surface should also be examined, as half of the number of liver metastases are undetected on preoperative imaging . UltrasoLymphadenectomy is the second surgical step and should be performed before the bowel resection. The remnant vascularized intestine after mesentery dissection will guide the extent of bowel resection for vascular purposes . Lymphad68Ga-PET if fewer than 8 lymph nodes have been resected [Retrospective registry analyses have suggested that at least 8 (or possibly 12) removed lymph nodes are needed to improve overall survival ,8,9. Morresected . This isThe upper limit of lymphadenectomy is less consensual. In the absence of a retro-pancreatic target on preoperative imaging, lymphadenectomy is usually conducted along the trunk of the superior mesenteric vessels below the pancreas. However, Pasquer et al. reported the presence of lymph node skip metastases  and suggested that a systematic lymph node dissection up to the retro-pancreatic area should be realized . NeverthMost patients with SI-NETs (nearly 80%) present nonspecific symptoms mainly related to the local effect of MLNM than to the primary tumor ,5,66. AmNearly 50% of patients with SI-NETs present liver metastases at diagnosis . When feEach candidate for radical destruction should be discussed at a multidisciplinary meeting. ENETS guidelines recommend considering radical destruction if it can be achieved with an acceptable predicted morbidity <30% and mortality rate <5% . SelectiRadical treatment of liver metastases could be more palliative than curative: even if radical liver treatment is achieved, recurrence is the rule when the follow-up is long enough  34,73,7,773,74. Regarding their relatively low aggressive behavior, SI-NET liver metastases can be an accepted indication for liver transplantation for selected patients with unresectable liver disease, without any other organ involvement and with pre-transplant curative resection of all extrahepatic lesions; but the patient selection criteria remain vague superior mesenteric artery .Recent publications reported a five-year overall and disease-free survival after liver transplantation respectively between 47% and 71% and 31% and 57% . Those dPeritoneal carcinomatosis affects approximately 20% of patients with SI-NET . PeritonPerioperative scores are commonly used to evaluate the extent and the resectability of peritoneal carcinomatosis. Among the available scores, the Peritoneal Carcinomatosis Index (PCI) is the most frequently used even if it has not yet been validated in SI-NETs. A PCI score >20 may lead to a failure of radical resection ,87. To cIf the indication for complete resection of the peritoneal disease is admitted, the added value of hyperthermic intraperitoneal chemotherapy (HIPEC) remains unknown. The largest published experience of HIPEC in SI-NETs was published by Elias et al. . Elias ePalliative strategy in SI-NET patients aims to relieve symptoms and delay a fatal outcome which is mainly due to liver failure from liver metastases and otherwise bowel complications. Cytoreductive surgery is part of the multimodal palliative strategy even if its position and its benefits have not been unequivocally proven by randomized control trials.Resection of symptomatic local disease (nearly 80% of cases) is recommended in order to relieve symptoms in the setting of unresectable liver metastases ,68,88. HArguments supporting resection in this context are: (i) the prevention of local complications, (ii) the control of locoregional disease to focus on hepatic treatment, and (iii) the improvement of overall survival rate. A recent meta-analysis favored asymptomatic local disease resection with a better five-year survival rate in the resected vs. the non-resected group , and this resection seemed to be safe  . In spitThésaurus National de Cancérologie Digestive (TNCD)) recommend local disease resection in cases of asymptomatic localized tumor and unresectable liver metastases, but not the National Comprehensive Cancer Network guidelines [Most academic guidelines , North American Neuroendocrine Tumor Society (NANETS), idelines ,69,91,92MLNM plus fibrosis can be unresectable when they surround the origin of the mesenteric vessels (LN stage IV). Symptoms related to these bulky MLNM vary among patients, including absence of symptoms, chronic mesenteric ischemia, and bowel obstruction. Patients, who are asymptomatic, with the development of a collateral circulation avoiding mesenteric ischemia, are treated medically. If they are symptomatic, the optimal strategy in order to relieve symptoms is aggressive surgery—radical or partial debulking surgery  preserviIn a few patients, debulking surgery cannot be performed or it does not relieve symptoms, especially ischemic ones. In such cases, the insertion of a self-expandable stent in the superior mesenteric vein (more easily compressed than the artery) at the level of the mass, inserted through the portal vein, has been undertaken in a small number of patients with uncertain results ,95.In patients with unresectable liver metastases, palliative surgery and/or thermal ablation are just part of the multimodal strategy including arterial embolization, chemoembolization, PRRT, and liver transplantation. Despite the absence of evidence through randomized control trials, palliative liver surgery may be proposed to decrease local or hormonal symptoms, and possibly to improve survival rates. It has been supported that 90%, or more recently >70%, of the metastatic liver burden should be resected in order to obtain clinical benefit ,94,95,96Laparotomy is traditionally the approach of choice, because it allows an optimal exploration of the entire abdominal cavity including small bowel palpation and vascular control at the origin of the superior mesenteric vessels . For theIn palliative intent, the laparoscopic approach seems to be advantageous for the resection of the local disease in patients with unresectable liver metastases.In SI-NET patients, the prevalence of gallstone disease ranges between 36% and 63%, and the five-year cumulative risk of having cholecystectomy or a biliary drainage is nearly 20%, which is considerably higher than in the general population ,100,101.Cholecystectomy at the time of the SI-NET surgery is recommended by NANETS and ENETS guidelines if long-term somatostatin analogue treatment is anticipated ,15. ThisDownsizing SI-NET lesions is an attractive concept, to make a non-resectable tumor resectable or to facilitate the resection of a borderline lesion (LN stage III or IV and type II or III liver metastases). Unfortunately, neoadjuvant treatments are lacking in SI-NETs as they are poorly chemo-sensitive (either with cytotoxic or targeted chemotherapy) and as somatostatin analogues may increase survival but do not shrink the tumor. Regarding PRRT, the NETTER-1 trial reported a partial response according to RECIST in 18% of SI-NET patients with well differentiated G1/G2 advanced tumors, progressing on long-acting octreotide . So far,Several studies have reported a long-term recurrence rate of around 50% after curative R0 surgery for SI-NET without distant metastases .68Ga-DOTA PET/CT compared with OctreoScan, and MRI compared with CT scan for liver lesions). As described above, chromogranin A reflects tumor burden and may be used to assess the speed of tumor growth. Some series have shown that elevated chromogranin A levels can be observed months to years before the evidence of radiographic recurrence, suggesting its usefulness for the early detection of tumor relapse after successful curative resection [After surgery in curative intent, the ENETS consensus guidelines and French guidelines recommend performing conventional imaging (CT or MRI with diffusion-weighted imaging), functional imaging (using the previous positive scintigraphic technique), and chromogranin A and 5-HIAA level measurements at regular intervals: from 3–6 months initially, then every 6–12 months over the following five years, then every 12–24 months over the following ten years, and finally every five years ,107. Excesection . Twenty-In the case of unresected liver metastases, CT or MRI and biochemical follow-up should be performed at three months, then every 3–6 months for two years, and finally every 6–12 months in cases of stable disease ,107.After curative surgery for SI-NETs, there is no proven role for adjuvant systemic therapy .Somatostatin analogues are indicated for their antiproliferative efficacy as first-line therapy in cases of slowly progressive well-differentiated metastatic SI-NETs, or for antisecretory purposes in cases of persistent secreting syndrome or refractory diarrhea through inhibition of gastrointestinal secretions ,42. Theyp < 0.00001) compared to high-dose octreotide in patients with SI-NETs progressing radiographically on somatostatin analogue therapy) [Regarding PRRT, in the NETTER-1 trial, PRRT improved progression-free survival by 79% (therapy) . To dateNo adjuvant chemotherapy is indicated after curative surgery for SI-NETs.SI-NET surgery presents specific challenges but offers the opportunity to provide significant improvements in both quality of life and survival in SI-NET patients.


To assess whether preoperative versus intraoperative insertion of an intra-aortic balloon pump is associated with lower 30-day mortality or reduced length of hospital stay among patients who had an intra-aortic balloon pump inserted for cardiac surgery.This was an observational study of patients who had an intra-aortic balloon pump inserted in the preoperative or intraoperative period of cardiac surgery in our department between 2000 and 2012. We assessed the association between preoperative versus intraoperative insertion of an intra-aortic balloon pump and 30-day mortality in a multivariable logistic regression analysis, including preoperative New York Heart Association class, postoperative atrial fibrillation, reoperation, postoperative creatinine and isolated coronary bypass grafting as cofactors. We used a multivariate linear model to assess whether a preoperative versus intraoperative intra-aortic balloon pump was associated with length of postoperative hospital stay, adjusting for reoperation, isolated coronary bypass grafting, heart valve surgery, sex, age, cardiopulmonary bypass time, aortic cross-clamp time, preoperative patients’ status  and preoperative myocardial infarction.Overall, 7,540 consecutive patients underwent open heart surgery in our department, and an intra-aortic balloon pump was inserted pre- or intraoperatively in 322 (4.2%) patients. The mean age was 67 ± 10.2 years old, the 30-day mortality was 12.7%, and the median length of hospital stay was 9 days (7 - 13). Preoperative versus intraoperative intra-aortic balloon pump insertion did not affect the incidence of 30-day mortality  and length of postoperative hospital stay .Preoperative insertion of an intra-aortic balloon pump was not associated with a lower 30-day mortality or reduced length of postoperative hospital stay compared to intraoperative insertion. Intra-aortic balloon pump (IABP) is widely used as a mechanical circulatory support device to prevent and treat low cardiac output syndrome in patients with unstable ischemic heart disease, acute coronary syndrome, heart failure and those who underwent cardiac surgery. Perioperative IABP insertion may improve cardiac output by 10 - 30%, particularly in patients with preoperative low left ventricular ejection fraction (LVEF) and low cardiac output syndrome who are undergoing heart operations.-3 In addition, IABP is indicated in high risk patients with LVEF < 30%, significant left main disease (LMD) with hemodynamic consequences (hemodynamic instability) and acute or chronic heart failure, and patients having difficulty weaning from cardiopulmonary bypass (CPB) during cardiac surgery operations difficulty.,4The effectiveness of an IABP lies on its ability to reduce the oxygen demand of the myocardium while facilitating an increase in myocardial oxygen supply. This is achieved through a series of hemodynamic effects, which include increased diastolic pressure and decreased afterload.versus intraoperative insertion of IABP is associated with a lower 30-day mortality or smaller length of hospital stay among patients who had IABP inserted in the pre- or intraoperative periods of cardiac surgery.In this study, we evaluated the risk factors associated with outcomes after IABP insertion in patients who underwent open heart surgery. Our primary aim was to assess whether pre- Between 2000 and 2012 7,540 consecutive patients underwent open heart surgery in our department, and IABP was inserted preoperatively and intraoperatively in 322 (4.2%) patients . All preThis study was an observational study including 322 cardiac surgery patients who received IABP (preoperative and intraoperative). Furthermore, this study was approved by the hospital’s institutional ethics committee.The follow-up was performed in the outpatient clinic, and the first follow-up was 30 days after discharge. The second follow-up was 6 months after the first follow-up date and after one visit/year. When the patients were discharged and did not visit the outpatient clinic, then the 30-day mortality incidence was recorded after telephone contact with the patient . In addition, in our study, the median follow-up of patients was 10 (1 - 49) months.In this study, we included patients who underwent the entire spectrum of heart operations in our department (excluding off pump coronary bypass grafting (CABG)): isolated CABG, CABG with left descending artery endarterectomy, heart valve replacement, aortic root replacement , ascending aorta replacement and combined heart operations.2, systolic pressure (SP) < 80mmHg, mean arterial pressure < 50mmHg, intraoperative transesophageal echocardiography of the LVEF < 20 - 25% and severe metabolic acidosis despite the maximal vasoactive/inotropic support .The indications for IABP insertion  were: cardiac index < 2.2L/min/mIn addition, for analysis purposes, the patients were divided into two groups:a) Preoperative: in the operating room before patient intubation or in the cardiology intensive care unit (ICU) or catheterization laboratory.b) Intraoperative: in the operating room after patient intubation and any time before the patient was transferred from the operating room to the ICU.Continuous variables are presented as the mean values ± standard deviation or medians (interquartile range) for non-normally distributed variables. The categorical variables are presented as the absolute values (count) and percentages. Normality of the continuous variables was tested using the Kolmogorov-Smirnov criterion or graphically assessed through P-P plots.Differences in continuous variables between groups of patients according to the time of insertion of IABP  episode at the end of the 10-year follow-up) were evaluated through independent samples Student’s t-test or the nonparametric Mann-Whitney test and chi-squared test for nominal variables.Subsequently, logistic regression analysis was applied to evaluate the association between baseline predictors and the likelihood of developing 30-day mortality and in-hospital mortality (dependent outcome) after adjusting for various confounders. The primary endpoints were 30-day mortality and survival rate, while secondary endpoints were in-hospital mortality and in-hospital stay. The effect size  was reported as the estimated odds ratios (OR) and the corresponding 95% confidence intervals (95%CI). A multivariable linear regression analysis was used to predict the length of in-hospital stay based on the preoperative and intraoperative factors. In addition, Cox proportional-hazards models were used to examine the association between variables of interest and the main endpoints of the study under survival settings. Associations are presented as hazard ratios (HR) with 95%CI. Log rank tests and Nelson-Aalen curves for the cumulative hazard of death across the follow-up were also implemented in the survival analysis. In addition, a competing risk regression analysis was performed to assess the association of baseline predictors with the specific outcome of fatal cardiogenic shock based on Fine-Gray’s proportional subhazard model. In detail, death from cardiogenic shock was flagged as the outcome of interest, while other causes of death (sepsis or multiple organ failure) were set as competing risks. Cumulative incidence curves estimated the probability of this type of death in the setting where other competing risks are acknowledged to exist. Multivariable regression  models were built under Collett’s approach: all significant univariate (p < 0.05) predictors of death were initially entered in a fully adjusted model and subsequently selected through forward and backward selection loops. Certain variables of biological interest  were included in the final multivariable models. Goodness of fit for logistic regression models was evaluated by the Hosmer-Lemeshow test.Statistical analysis was performed by STATA package, version 11.1 . Statistical significance was set at p < 0.05. To avoid overfitting in the final multivariable regression models, a ratio of 5 - 10 events per covariate was retained in all analyses.Of the 322 patients who received IABP, 79.8% were male, with an average age of 67 ± 10.2 years old. Among the patients with dyspnea, most (65.5%) were graded as class I according to a New York Heart Association (NYHA) classification, while most patients (41.3%) with angina were graded as class I according to a Canadian Cardiovascular Society Classification (CCSC). In addition, 40.7% of the patients had a recent (< 90 days) preoperative ACS, and 19.9% suffered from LMD > 50%. The mean preoperative creatinine value was 1.3mg/dL. Furthermore, preoperative LVEF was classified into 3 categories . The demographic characteristics and preoperative data of the study population are shown in The perioperative details are presented in The postoperative details and follow-up data, including the cause of death, are presented in Preoperative IABP insertion was recorded in 28 patients - elective operations with preoperative LVEF < 25% and ischemic heart disease in 18 patients, emergency operations with ACS and cardiogenic shock in 3 patients, emergency operations after unable percutaneous coronary intervention (PCI) in catheterization laboratory with ACS and hemodynamic instability in two patients, emergency operations for mechanical complications due to ACS in two patients , emergency operation with left main thrombosis and hemodynamic instability in one patient, emergency operation after unable PCI in catheterization laboratory without ACS and hemodynamic instability in 1 patient and preoperative cardiac arrest in the operating room in one patient.When the study population was divided into two subgroups based on the time of insertion of IABP, the patients with intraoperative treatment with IABP were classified in the more severe class of angina (CCSC IV) and were more likely to be treated with an emergency surgery . In addiInterestingly, preoperative insertion of IABP was favorably associated with in-hospital stay (p = 0.02). In addition, a multivariable linear regression analysis was used to calculate the possible effect of the time of IABP insertion on the length of in-hospital stay. After adjusting for reoperation, isolated CABG, heart valve surgery, combined operation, sex, age, CPB time, ACC time, preoperative patients’ status, LVEF and preoperative myocardial infarction (MI), the time of IABP insertion did not predict the length of in-hospital stay .After univariable logistic regression analysis and among variables of interest, sex (p = 0.006), NYHA class (p < 0.001), postop creatinine (p = 0.004), postop maximum troponin level (p = 0.004), heart valve surgery (p = 0.012), modified Bentall operation (p = 0.016), redo surgery (p < 0.001), ACC (p = 0.006), postop atrial fibrillation (p < 0.001) and isolated CABG instead of combined operation (p < 0.001) correlated with the 30-day mortality, while age (p =0.066), preop ACS (p = 0.052) and LMD (p = 0.055) were not associated with 30-day mortality. After multi-adjustment, only NYHA class, postoperative atrial fibrillation, redo surgery, postoperative creatinine and isolated CABG determined the 30-day mortality, while the time of IABP insertion did not affect the incidence of 30-day mortality . Preoperversus combined surgery)  and the ACC time .When deaths from cardiogenic shock (n = 24) were assessed individually, only 3 parameters determined the incidence of this outcome, independently of age and sex: NYHA class , type of surgery . Time of insertion of IABP was not associated with the survival outcome in our study   .Upon completing risk regression analysis, only the performance of isolated CABG instead of combined surgery  and NYHA class   predicte-10 Intra-aortic balloon pump placement is an additional risk factor in already critically ill cardiac surgery patients. Malperfusion syndrome, limb ischemia, cerebrovascular accidents due to peripheral vascular disease, descending and abdominal aorta calcification and IABP malposition or displacement are the most common complications after IABP insertion.In recent years, many circulatory support devices have been proposed for hemodynamic support in critically ill patients in cardiology, ICU and cardiac surgery departments. Currently, extracorporeal membrane oxygenation (ECMO), percutaneous mechanical circulatory support, left ventricular assist devices, biventricular assist devices and IABP are the most common devices for circulatory support, particularly in cardiogenic shock due acute or chronic heart disease. On the other hand, many serious and fatal complications are observed during and after placement of these devices. Intra-aortic balloon pump compared to other devices has advantages because of its placement, checking of the correct position and easier management. For these reasons, IABP can be implemented in hospitals and departments without cardiac surgery support. In addition, IABP remains a useful device in critically ill cardiac surgery patients with perioperative low cardiac output syndrome who undergo elective or emergency cardiac surgery operations. The mortality rate in cardiac surgery patients who have received IABP is high, ranging from 10 - 40%, and it is affected by decision making with regard to which patients should be placed on IABP and when, with minimum adverse effects on patient outcomes .The most discussed issues with regard to IABP in cardiac surgery remain the time of insertion , age of cardiac surgery patients and type of heart operation.-9 Our study had comparable results with these studies, and we concluded that preoperative IABP insertion decreased in-hospital stay (p = 0.028) in our study population but did not influence in-hospital mortality (p = 0.374). Poirier et al. analyzed 46,067 patients and concluded that the preoperative insertion of IABP presented a decrease of in-hospital mortality and ICU stay, while its intraoperative and postoperative use was not clearly associated with clinical benefits.,6Another recent review  by Deppe et al. supports the beneficial effect of preoperative IABP insertion in high risk patients before CABG, with decreased risk of mortality, myocardial infarction, renal failure, hospital and ICU stay.In 2010, a study with 7,440 patients concluded that in-hospital and risk-adjusted mortality were lower when IABP was used before (10%) than during (16%) or after (29%) the cardiac surgery.This was also supported by another study in the same year, which showed that patients with cardiogenic shock complicating acute myocardial infarction who underwent PCI assisted by IABP had a more favorable in-hospital outcome and lower in-hospital mortality than patients who received IABP after PCI.However, a study with 173 patients published in 2013 suggested that postoperative IABP use is more promising, showing that the cumulative 30-day mortality was 44% in the group with preoperative IABP of patients and 37% in the postoperative IABP group. In contrast to the aforementioned studies, a recent study in 2014 concluded that IABP treatment commenced before or after PCI was not an independent predictor of mortality. On the other hand, cardiac surgery patients are different than patients who undergo PCI; in cardiac surgery, we have prognostic scores in our armamentarium for worse outcomes  and the Society of Thoracic Surgeons (STS) score. Perhaps preoperative IABP insertion should be considered as a predictive factor in the Euroscore II or STS score for evaluating the possible benefits of preoperative IABP placement in critically ill patients.As seen from many recent studies, preoperative IABP insertion has many benefits with regard to in-hospital mortality and postoperative adverse cardiac events.,13 More specifically, a study in 2016 with 522 patients found that age above 70 years was an independent risk factor for mortality within 30 days. In addition, in 2015, another working group of 572 patients concluded that patients older than 65 years undergoing IABP support had higher in-hospital mortality rates in comparison to younger patients.In the same direction, two studies in 2015 and 2016 included advanced age as one of the most important predictors of in-hospital mortality and adverse long term prognosis.,16Finally, a study with 134 elderly patients showed that patients > 80 years had higher mortality rates than those < 80 years after IABP placement. After multivariate analysis in our study, we showed that age of the patients was a risk factor for survival after IABP insertion (p = 0.009). Of note, the number of older patients with comorbidities undergoing cardiac surgery operations has increased in recent years, and this directly affects outcomes of patients who have received IABP.Another major risk factor that seems to be associated with 30-day and in-hospital mortality of patients with IABP is the age of the patient. Most studies have already found that older patients have higher mortality rates. These incidents are not surprising because the number of older patients is growing, and they have more coexisting diseases , which affect outcomes of critically ill patients, particularly cardiac surgery patients (independent of the need for IABP-support). In 2010, another study with 136 patients requiring an IABP concluded that the “operation-specific” mortality was higher in the heart valve surgery population. More specifically, the mortality rates were 21.2%, 50% and 64.3% among those who had isolated CABG, CABG and valve surgery and isolated valve surgery, respectively. In our study, after multiadjusted logistic regression analysis, we found that isolated CABG was a risk factor for 30-day mortality (p = 0.001), and it was possible that most of these patients underwent an emergency CABG operation.Currently, little data have been published about the types of cardiac operations (with IABP placement) as risk factors for 30-day and in-hospital mortality. In our study, we compared the mortality rates between isolated CABG, combined or valve replacement surgical procedures. In 2016, a study with 522 patients suggested that CABG combined with valve surgery should be identified as an independent risk factor for 30-day mortality. Among those who had that type of surgery, 47.5% died within 30 days; among those who did not have such a procedure, the mortality rate was 26.3%.This study included a small number of patients from a single department. Furthermore, the number of patients who received IABP preoperatively (compared with intraoperative) was too small to make safe conclusions. Long-term follow-up is required to demonstrate the potential benefits of preoperative or intraoperative IABP insertion in cardiac surgery patients who are already at high preoperative and intraoperative risk.Overall, 30-day mortality is substantial in patients needing intra-aortic balloon pump insertion in the pre- or intraoperative periods of cardiac surgery. Preoperative insertion of an intra-aortic balloon pump was not associated with lower 30-day mortality or lower length of postoperative hospital stay compared to intraoperative insertion after adjusting for potential confounders.