A 1-year follow-up study on checkpoint inhibitor-induced colitis: results from a European consortium.

BACKGROUND: Data regarding the clinical outcome of patients with immune checkpoint inhibitor (ICI)-induced colitis are scant. We aimed to describe the 12-month clinical outcome of patients with ICI-induced colitis. MATERIALS AND METHODS: This was a retrospective, European, multicentre study. Endoscopy/histology-proven ICI-induced colitis patients were enrolled. The 12-month clinical remission rate, defined as a Common Terminology Criteria for Adverse Events diarrhoea grade of 0-1, and the correlates of 12-month remission were assessed. RESULTS: Ninety-six patients [male:female ratio 1.5:1; median age 65 years, interquartile range (IQR) 55.5-71.5 years] were included. Lung cancer (41, 42.7%) and melanoma (30, 31.2%) were the most common cancers. ICI-related gastrointestinal symptoms occurred at a median time of 4 months (IQR 2-7 months). An inflammatory bowel disease (IBD)-like pattern was present in 74 patients (77.1%) [35 (47.3%) ulcerative colitis (UC)-like, 11 (14.9%) Crohn's disease (CD)-like, 28 (37.8%) IBD-like unclassified], while microscopic colitis was present in 19 patients (19.8%). As a first line, systemic steroids were the most prescribed drugs (65, 67.7%). The 12-month clinical remission rate was 47.7 per 100 person-years [95% confidence interval (CI) 33.5-67.8). ICI was discontinued due to colitis in 66 patients (79.5%). A CD-like pattern was associated with remission failure (hazard ratio 3.84, 95% CI 1.16-12.69). Having histopathological signs of microscopic colitis (P = 0.049) and microscopic versus UC-/CD-like colitis (P = 0.014) were associated with a better outcome. Discontinuing the ICI was not related to the 12-month remission (P = 0.483). Four patients (3.1%) died from ICI-induced colitis. CONCLUSIONS: Patients with IBD-like colitis may need an early and more aggressive treatment. Future studies should focus on how to improve long-term clinical outcomes.

MPFL reconstruction and tibial tuberosity transposition in patients with patellar instability: May it troubleshots also trochlear dysplasia?

PURPOSE: This study aimed to highlight short- and medium-term outcomes of combined medial patello-femoral ligament (MPFL) reconstruction and anterior tibial tuberosity (ATT) transposition surgery in patients with recurrent patellar instability and different degrees of trochlear dysplasia. METHODS: Between January 2014 and May 2019, 25 patients with patellar instability underwent a surgical procedure combining the lowering/transposition of the ATT and the MPFL reconstruction. Each patient were preoperative assessed by Kujala score, International Knee Documentation Committee (IKDC), Tegner activity level scale. The assessment of instability predisposing factors was carried out with patellar height, tibial tuberosity-trochlear groove (TT-TG) distance, trochlear dysplasia, sulcus angle, patellar tilt and MPFL injuries. Functional outcomes were evaluated with Kujala, IKDC and Tegner scores at 3, 6 and 12 months after surgery. RESULTS: The average age of the patients was 20 years (range 13-43 years). Pre- operative Caton-Deschamps index was pathological in 10 (40%). Sulcus angle was elevated in 13 patients (52%) and TT-TG distance was irregular in 17 patients (68%). Trochlear dysplasia was present in 13 patients (9 type A, 3 type B, 1 type C according to Dejour's Classification). No re-dislocation occurred during the follow-up. There was a significant increase in the Kujala, IKDC and Lysholm scores after 3, 6 and 12 months, and the results were compared for the different follow-up times and patient's trochlear dysplasia degree. CONCLUSION: This prospective observational longitudinal study identified good clinical outcomes in patients who underwent MPFL reconstruction and ATT transposition for patellar instability. Finally, the different risk factors for patellar instability examined, particularly the presence of trochlear dysplasia, did not significantly influence the final functional results, which range from good to excellent without re-dislocation episodes.

A snapshot of the immunogenicity, efficacy and safety of a full course of BNT162b2 anti-SARS-CoV-2 vaccine in cancer patients treated with PD-1/PD-L1 inhibitors: a longitudinal cohort study.

BACKGROUND: Very few cancer patients were enrolled in coronavirus disease-2019 vaccine studies. In order to address this gap of knowledge, real-world studies are mandatory. The aim of this study was to assess both humoral and cellular response after a messenger RNA vaccination schedule. PATIENTS AND METHODS: Eighty-eight consecutive cancer patients treated with programmed cell death protein 1/programmed death-ligand 1 inhibitors were enrolled from the beginning of the vaccination campaign for frail patients. Blood samples for humoral and cell-mediated immune response evaluation were obtained before vaccination (T0), before the second administration (T1) and 21 days after the second dose (T2). The primary endpoint was the evaluation of the percentage of participants showing a significant increase in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cells, measured by an enzyme-linked immunospot assay, after the second dose of BNT162b2 vaccine. The proportion of patients who reached the primary endpoint is computed together with its exact binomial 95% confidence interval. RESULTS: In SARS-CoV-2-naïve subjects, spike-specific T-cell response was almost undetectable at T0 [median 0.0 interferon-γ (IFN-γ) spot forming units (SFU)/million peripheral blood mononuclear cell (PBMC) interquartile range (IQR) 0-7.5] and significantly increased at T1 and T2 (median 15.0 IFN-γ SFU/million PBMC, 25th-75th 0-40 versus 90 IFN-γ SFU/million PBMC, 25th-75th 32.5-224, respectively) (P < 0.001). Focusing on naïve and experienced SARS-CoV-2 subjects, no differences were reported both in terms of CD4- and CD8-specific T-cell response, suggesting that BNT162b2 is able to elicit both adaptive responses after complete vaccination schedule, regardless of previous SARS-CoV-2 exposure. The level of SARS-CoV-2 neutralizing antibodies was low at T1 in SARS-CoV-2-naïve subjects [median 1 : 5 (IQR 1 : 5-1 : 20)] but reached a significantly higher median of 1 : 80 (25th-75th 1 : 20-1 : 160) at T2 (P < 0.0001). Moreover, no COVID-19 cases were documented throughout the period of study. CONCLUSIONS: Our data have demonstrated that the administration of a full course of BNT162b2 vaccine elicited a sustained immune response against SARS-CoV-2 regardless of the type of cancer and/or the type of immune checkpoint inhibitors.

Quality of life and psychopathology in candidates to bariatric surgery: relationship with BMI class.

PURPOSE: This cross-sectional study aimed at comparing the quality of life (Qol), the prevalence of psychiatric diagnosis and pharmacological treatment in 104 candidates to bariatric surgery according to the degree of obesity (class 2 vs. class ≥ 3 obesity). METHODS: All surgical candidates underwent a detailed psychiatric interview based on DSM-5 criteria, including sociodemographic, clinical, psychological and psychiatric data. Participants completed the Binge Eating Scale (BES) and the 12-Item Short Form Health Survey (SF-12). RESULTS: Overall, bariatric candidates reported a significant impairment in the physical (PCS 38.8 [95% CI 36.2-41.5]) and mental (MCS 42.2 [95% CI 40.4-43.9]) components of Qol compared to population norms (p < 0.001 for both). Subjects with class 2 obesity scored significantly lower in the MCS compared to those with class 3 (38.7 (8.1) vs. 43.6 (8.4), p = 0.008). No other statistically significant differences were found between the two groups in terms of sociodemographic and clinical variables. CONCLUSION: These data support the usefulness of Qol assessment in bariatric candidates as a sensible screening parameter, especially in patients with lower BMI, in whom MCS could identify the need for early psychosocial intervention. LEVEL OF EVIDENCE: Level III, case-control analytic study.

Perspectives of the International Society for Cell & Gene Therapy Gastrointestinal Scientific Committee on the Intravenous Use of Mesenchymal Stromal Cells in Inflammatory Bowel Disease (PeMeGi).

Inflammatory bowel disease (IBD), namely, Crohn's disease and ulcerative colitis, remains a grievous and recalcitrant problem incurring significant human and health care costs, even in consideration of the growing incidence. Initial goals of care aimed to achieve the induction and maintenance of clinical remission. The advent of novel treat-to-target approaches using patient stratification, early introduction of immunosuppressants and rapid escalation to biologics or early use of combination therapy has refocused the goals of care toward the achievement of mucosal healing. This is in an attempt to preserve intestinal function, decrease hospitalization and surgery rates and improve the quality of life of affected patients. Cellular therapeutics for the treatment of IBD offers an unprecedented opportunity to change the current paradigm from single-targeted to systems-targeted therapy, trying to dampen the whole inflammatory cascade instead of a only molecule. Therefore, as we move forward, the importance of designing informative and possibly adaptive trial designs, standardizing methodologies, harmonizing goals of therapy and evaluating methods cannot be underemphasized. In this article, we review the current literature on the application of mesenchymal stromal cells for the treatment of IBD in an effort to establish a consensus on designing efficient and consistent clinical trials for the intravenous use of this cellular therapy in IBD.

The Presence of HLA-A Bw4-80I KIR Ligands Could Predict "Difficult-to-Treat" Psoriasis and Poor Response to Etanercept.

BACKGROUND: Psoriasis is an immune-mediated dermatosis with a wide genetic predisposition. The immunogenetic background, specifically interactions between human leukocyte antigen (HLA) class I ligands and killer-cell immunoglobulin-like receptor (KIRs), have functional significance in modulating natural killer (NK) cells and can influence susceptibility and response to biological therapy. OBJECTIVE: The main aim of this study was to correlate HLA-A and -B KIR ligands with response to biological therapy in patients with psoriasis. METHODS: HLA-A and -B polymorphisms were determined in 48 patients (35 males and 13 females), with a mean of 22 years of disease (range 8-55). All patients were treated with biological therapy (adalimumab, etanercept, infliximab, or ustekinumab) for at least 6 months. RESULTS: This study identifies, with statistical significance, the presence of at least one ligand HLA-A Bw4-80I in the "poor-responder" population (patients who needed two or more biologics) compared with the "responder" population (patients with good response after a single biological drug) (47.62 vs. 11.11%; p = 0.006) as well as in "non-responders to etanercept" compared with "responders to etanercept" (52.63 vs. 5%; p = 0.001). CONCLUSION: Our preliminary results suggest that at least one ligand HLA-A Bw4-80I could be associated with "difficult-to-treat" psoriasis and that this ligand may reduce the probability of response to etanercept, producing more tumor necrosis factor (TNF)-α and neutralizing NK activity through a predominance of activating KIR. The ab initio identification of genetic markers of response to biologic therapy could improve the efficacy and economic impact of these agents.

Multimodal Approach of Pulmonary Artery Intimal Sarcoma: A Single-Institution Experience.

INTRODUCTION: Pulmonary artery sarcoma (PAS) is a rare tumor, whose therapeutic approach is mainly based on surgery, either pneumonectomy or pulmonary endarterectomy (PEA). The prognosis reported in published series is very poor, with survival of 1.5 months without any kind of treatment. PATIENTS AND METHODS: From January 2010 to January 2016, 1027 patients were referred to our hospital for symptoms of acute or chronic pulmonary thromboembolic disease. Twelve patients having a confirmed diagnosis of PAS underwent PEA. Median age was 64.5 years. Most patients had a long history of symptoms, having a median time of 7.5 months from onset of symptoms to surgery. RESULTS: Following PEA and cardiopulmonary rehabilitation, 10 patients received conventional chemotherapy with doxorubicin and ifosfamide, starting at a median of 42 days from surgery. Four patients also received radiotherapy. Four patients have died due to disease progression, while 7 are still alive, with 5 being disease-free at 4-55+ months from diagnosis. CONCLUSIONS: In patients with PAS, a multimodal approach including PEA, CT, and RT is feasible but it should be evaluated individually, according to the tumor extension and the patient's clinical condition. Apart from improving quality of life mainly by reducing or delaying symptoms due to PH, it may improve life expectancy.

Global Performance Status Score: A New Tool to Assess Physical Performance in Kidney Transplant Patients.

BACKGROUND: Information on physical performance in renal transplantation is limited because of the shortage of specifically designed evaluation instruments. Therefore, we elaborated and validated the Global Performance Status (GloPerSta) score to provide a new and comprehensive tool, exploring the different components of physical performance in kidney transplant patients. METHODS: We elaborated the GloPerSta score on the basis of the data obtained from a cross-sectional study, in which we evaluated the physical performance of a cohort of kidney transplant patients. The results of these analyses were weighted to describe the different contribution of any single test, via the generation of a structural equation model, resulting in the definition of the GloPerSta. Then, to internally validate this score, we studied its correlation with clinical parameters and quality of life (evaluated as KDQOL-SF, Kidney Disease Quality of Life-Short Form) in the same patient population. RESULTS: We enrolled 132 patients in whom the functional tests revealed a great heterogeneity. GloPerSta allowed the stratification of the patients in 3 different physical performance categories (low: score 0-11; medium: 12-22; high: 23-33). Internal validation showed that GloPerSta was directly and significantly correlated with the quality of life and allograft function, independent of the time from transplantation. CONCLUSIONS: The GloPerSta is a reliable tool to assess physical performance in a kidney transplant population. Its application might be of help in identifying patients needing intensive and personalized rehabilitation programs.

In irritable bowel syndrome, postprandial abdominal distention is associated with a reduction of intestinal tone.

BACKGROUND: The pathophysiology of abdominal distention in irritable bowel syndrome (IBS) is still a matter of debate, but the relationship between modifications of intestinal tone and abdominal volume has never been analyzed. METHODS: Eighty-four patients affected by IBS and reporting moderate to severe abdominal distention were enrolled. Thirty-nine presented abdominal distention immediately after and forty-five presented abdominal distention independently of meal intake. Twenty healthy volunteers (HV), comparable for gender and age, were also enrolled. All the subjects underwent fasting and postprandial recto-sigmoid volume monitoring with barostat and abdominal girth measurement to evaluate abdominal distention. KEY RESULTS: In comparison with HV (75±13 mL) and with patients with meal-unrelated abdominal distention (135±56 mL), in the subgroup of patients with severe meal-related abdominal distention recto-sigmoid tone response to the meal was significantly reduced (mean increase of balloon volume 184±89 mL; P<.001), paralleling abdominal girth increase and occurring immediately after test meal intake. Meal-induced abdominal girth modification was significantly correlated with meal-related modification of recto-sigmoid tone (r=.71) and abdominal symptoms. CONCLUSIONS: In patients with IBS suffering from severe postprandial abdominal distention, a postprandial reduction of intestinal tone is associated with this bothersome symptom. Further studies are needed to evaluate whether drugs acting on the modification of intestinal tone could be useful in the treatment of these patients.

Kidney Intragraft Homing of De Novo Donor-Specific HLA Antibodies Is an Essential Step of Antibody-Mediated Damage but Not Per Se Predictive of Graft Loss.

Donor-specific HLA antibody (DSA)-mediated graft injury is the major cause of kidney loss. Among DSA characteristics, graft homing has been suggested as an indicator of severe tissue damage. We analyzed the role of de novo DSA (dnDSA) graft homing on kidney transplantation outcome. Graft biopsy specimens and parallel sera from 48 nonsensitized pediatric kidney recipients were analyzed. Serum samples and eluates from graft biopsy specimens were tested for the presence of dnDSAs with flow bead technology. Intragraft dnDSAs (gDSAs) were never detected in the absence of serum dnDSAs (sDSAs), whereas in the presence of sDSAs, gDSAs were demonstrated in 72% of biopsy specimens. A significantly higher homing capability was expressed by class II sDSAs endowed with high mean fluorescence intensity and C3d- and/or C1q-fixing properties. In patients with available sequential biopsy specimens, we detected gDSAs before the appearance of antibody-mediated rejection. In sDSA-positive patients, gDSA positivity did not allow stratification for antibody-mediated graft lesions and graft loss. However, a consistent detection of skewed unique DSA specificities was observed over time within the graft, likely responsible for the damage. Our results indicate that gDSAs could represent an instrumental tool to identify, among sDSAs, clinically relevant antibody specificities requiring monitoring and possibly guiding patient management.

The possible role of burden of therapy on the risk of myeloma extramedullary spread.

Extramedullary relapse (EMR) represents a poor prognostic marker in the course of multiple myeloma (MM). We reviewed data from 329 patients, diagnosed between 2000 and 2010, without extramedullary disease at onset to explore possible risk factors for EMR. The median overall survival of our study cohort was 6.4 years. The risk of EMR was 28 % with a median time from diagnosis to first EMR of 2.2 years (0.2-9.1 years). Patients with soft tissue masses located in extra-osseous organs (EMR-S) showed the worst outcome, compared to those with tumor masses arising from adjacent bone (EMR-B) (median OS 1.6 vs 2.4 years, p = 0.006). In addition, patients with EMR-S showed a significant trend for further development of extramedullary masses in a very short time (3.7 vs 5.7 months for EMR-B, p = 0.043). Multivariate analysis failed to identify any clinically presenting features predictive for EMR. The occurrence of EMR was higher in patients with more complex treatment history, defined on the basis of longer treatment duration (≥6 vs <6 months) and on elevated number of treatment lines administered (>2 vs ≤2 lines) (HR = 4.5, p < 0.001 and HR = 9.0, p < 0.001, respectively, when one or both factors are present).In conclusion, increasing burden of treatment might be a possible risk factor for EMR. MM patients with multiple relapses should be comprehensively investigated including, when possible, a whole-body-targeted radiologic technique to accurately detect EMR. Treatment choice should take into account the very poor outcome for patients with soft tissue involvement.

Use of herbal remedies by multiple sclerosis patients: a nation-wide survey in Italy.

Though recent progress in multiple sclerosis (MS) treatment is remarkable, numerous unmet needs remain to be addressed often inducing patients to look for complementary and alternative medicines (CAM), especially herbal remedies (HR). HR use, scarcely investigated in MS, may cause adverse reactions (AR) and interfere with conventional treatment. We performed a survey aimed at evaluating use and attitudes towards HR and factor associated to HR use. Other CAM use and attitudes have been investigated as well. Multiple-choice questionnaires were distributed to MS out patients attending 14 Italian referral Centers. Multivariable logistic regression was used to identify HR use determinants. Present/past HR use for either MS or other diseases was reported in 35.6 % of 2419 cases (95 % CI 36.0-40.0 %). CAM use was reported in 42.5 % of cases. Independent predictors of HR use were represented by higher education, geographic area, dissatisfaction with conventional treatment of diseases other than MS and benefit perception from CAM use. Both HR and CAM use were not always disclosed to the healthcare professional. In conclusion, HR and other CAM appear to be popular among MS patients. The involvement of the healthcare professionals appears to be scarce with potential risk of AR or interference with conventional treatments.

Acquisition of C3d-Binding Activity by De Novo Donor-Specific HLA Antibodies Correlates With Graft Loss in Nonsensitized Pediatric Kidney Recipients.

Alloantibody-mediated graft injury is a major cause of kidney dysfunction and loss. The complement-binding ability of de novo donor-specific antibodies (dnDSAs) has been suggested as a prognostic tool to stratify patients for clinical risk. In this study, we analyzed posttransplant kinetics of complement-fixing dnDSAs and their role in antibody-mediated rejection development and graft loss. A total of 114 pediatric nonsensitized recipients of first kidney allograft were periodically monitored for dnDSAs using flow bead assays, followed by C3d and C1q assay in case of positivity. Overall, 39 patients developed dnDSAs, which were C1q(+) and C3d(+) in 25 and nine patients, respectively. At follow-up, progressive acquisition over time of dnDSA C1q and C3d binding ability, within the same antigenic specificity, was observed, paralleled by an increase in mean fluorescence intensity that correlated with clinical outcome. C3d-fixing dnDSAs were better fit to stratify graft loss risk when the different dnDSA categories were evaluated in combined models because the 10-year graft survival probability was lower in patients with C3d-binding dnDSA than in those without dnDSAs or with C1q(+) /C3d(-) or non-complement-binding dnDSAs (40% vs. 94%, 100%, and 100%, respectively). Based on the kinetics profile, we favor dnDSA removal or modulation at first confirmed positivity, with treatment intensification guided by dnDSA biological characteristics.

Prevalence of Whipple's disease in north-western Italy.

Whipple's disease (WD) is a rare systemic infection due, in genetically susceptible individuals, to Tropheryma whipplei, a heterogeneous Gram-positive actinobacteria. Although it has already been recognised that WD affects mainly middle-aged Caucasian men, the prevalence of WD is virtually unknown. The annual incidence of WD in the general population is said to be less than 1 per 1,000,000, but scientific evidence for these figures is still lacking. On the basis of the number of patients recorded with a diagnosis of Whipple's disease in the regional registers for rare diseases of Lombardia, Liguria and Piemonte-Valle d'Aosta regions, we studied the prevalence of WD in the north-western part of Italy. Forty-six patients with Whipple's disease were recorded in these regions (13 females; mean age at diagnosis 52.1 ± 11.1 years). Since 16,130,725 inhabitants live in these four regions, prevalence of WD in the general population is 3/10(6) and almost 30% of the patients are females. WD is certainly a rare disease but it also affects women in a considerable proportion of cases.

Grading the neuroendocrine tumors of the lung: an evidence-based proposal.

Lung neuroendocrine tumors are catalogued in four categories by the World Health Organization (WHO 2004) classification. Its reproducibility and prognostic efficacy was disputed. The WHO 2010 classification of digestive neuroendocrine neoplasms is based on Ki67 proliferation assessment and proved prognostically effective. This study aims at comparing these two classifications and at defining a prognostic grading system for lung neuroendocrine tumors. The study included 399 patients who underwent surgery and with at least 1 year follow-up between 1989 and 2011. Data on 21 variables were collected, and performance of grading systems and their components was compared by Cox regression and multivariable analyses. All statistical tests were two-sided. At Cox analysis, WHO 2004 stratified patients into three major groups with statistically significant survival difference (typical carcinoid vs atypical carcinoid (AC), P=0.021; AC vs large-cell/small-cell lung neuroendocrine carcinomas, P<0.001). Optimal discrimination in three groups was observed by Ki67% (Ki67% cutoffs: G1 <4, G2 4-<25, G3 ≥25; G1 vs G2, P=0.021; and G2 vs G3, P≤0.001), mitotic count (G1 ≤2, G2 >2-47, G3 >47; G1 vs G2, P≤0.001; and G2 vs G3, P≤0.001), and presence of necrosis (G1 absent, G2 <10% of sample, G3 >10% of sample; G1 vs G2, P≤0.001; and G2 vs G3, P≤0.001) at uni and multivariable analyses. The combination of these three variables resulted in a simple and effective grading system. A three-tiers grading system based on Ki67 index, mitotic count, and necrosis with cutoffs specifically generated for lung neuroendocrine tumors is prognostically effective and accurate.

Effects on survival of loop diuretic dosing in ambulatory patients with chronic heart failure using a propensity score analysis.

OBJECTIVE: To ascertain whether increasing doses of orally administered furosemide are associated with impaired survival in outpatients with chronic heart failure (CHF) and left ventricular (LV) systolic dysfunction. METHODS: Transthoracic echo-Doppler examination was carried out at baseline in 813 consecutive CHF outpatients with LV ejection fraction ≤ 45%. The total daily dose of furosemide was assessed for each patient. Chronic kidney disease (CKD) was defined by a glomerular filtration rate < 60 ml/min/1.73 m(2). The end-point was all-cause mortality. To control the prognostic effect of furosemide for the propensity of using high doses of the drug, the Cox model was stratified by the propensity score, itself computed from a multivariable logistic model. Mean follow up was 44 months. RESULTS: After stratification for the propensity score, the risk of death increased linearly across quartiles of furosemide dose (HR 1.38, 95% CI 1.14-1.68, p < 0.001). A daily dose of 50 mg was identified as the best threshold value to predict a high risk of death within 3 years with an area under the ROC curve of 0.68 (95% CI 0.64-0.72). Increasing doses of furosemide were associated with an increased risk of death regardless of LV filling pattern, CKD and background therapy with ACE-inhibitors or beta-blockers. CONCLUSIONS: In outpatients with CHF, after stratification for the propensity score, the risk of death increased linearly across quartiles of furosemide daily dose. A threshold furosemide dose of 50 mg was related with the worse outcome.

TNM staging of neoplasms of the endocrine pancreas: results from a large international cohort study.

BACKGROUND: Both the European Neuroendocrine Tumor Society (ENETS) and the International Union for Cancer Control/American Joint Cancer Committee/World Health Organization (UICC/AJCC/WHO) have proposed TNM staging systems for pancreatic neuroendocrine neoplasms. This study aims to identify the most accurate and useful TNM system for pancreatic neuroendocrine neoplasms. METHODS: The study included 1072 patients who had undergone previous surgery for their cancer and for which at least 2 years of follow-up from 1990 to 2007 was available. Data on 28 variables were collected, and the performance of the two TNM staging systems was compared by Cox regression analysis and multivariable analyses. All statistical tests were two-sided. RESULTS: Differences in distribution of sex and age were observed for the ENETS TNM staging system. At Cox regression analysis, only the ENETS TNM staging system perfectly allocated patients into four statistically significantly different and equally populated risk groups (with stage I as the reference; stage II hazard ratio [HR] of death = 16.23, 95% confidence interval [CI] = 2.14 to 123, P = .007; stage III HR of death = 51.81, 95% CI = 7.11 to 377, P < .001; and stage IV HR of death = 160, 95% CI = 22.30 to 1143, P < .001). However, the UICC/AJCC/WHO 2010 TNM staging system compressed the disease into three differently populated classes, with most patients in stage I, and with the patients being equally distributed into stages II-III (statistically similar) and IV (with stage I as the reference; stage II HR of death = 9.57, 95% CI = 4.62 to 19.88, P < .001; stage III HR of death = 9.32, 95% CI = 3.69 to 23.53, P = .94; and stage IV HR of death = 30.84, 95% CI = 15.62 to 60.87, P < .001). Multivariable modeling indicated curative surgery, TNM staging, and grading were effective predictors of death, and grading was the second most effective independent predictor of survival in the absence of staging information. Though both TNM staging systems were independent predictors of survival, the UICC/AJCC/WHO 2010 TNM stages showed very large 95% confidence intervals for each stage, indicating an inaccurate predictive ability. CONCLUSION: Our data suggest the ENETS TNM staging system is superior to the UICC/AJCC/WHO 2010 TNM staging system and supports its use in clinical practice.