Radical Resection in Entero-Pancreatic Neuroendocrine Tumors: Recurrence-Free Survival Rate and Definition of a Risk Score for Recurrence.

BACKGROUND: Surgery with radical intent is the only potentially curative option for entero-pancreatic neuroendocrine tumors (EP-NETs) but many patients develop recurrence even after many years. The subset of patients at high risk of disease recurrence has not been clearly defined to date. OBJECTIVE: The aim of this retrospective study was to define, in a series of completely resected EP-NETs, the recurrence-free survival (RFS) rate and a risk score for disease recurrence. PATIENTS AND METHODS: This was a multicenter retrospective analysis of sporadic pancreatic NETs (PanNETs) or small intestine NETs (SiNETs) [G1/G2] that underwent R0/R1 surgery (years 2000-2016) with at least a 24-month follow-up. Survival analysis was performed using the Kaplan-Meier method and risk factor analysis was performed using the Cox regression model. RESULTS: Overall, 441 patients (224 PanNETs and 217 SiNETs) were included, with a median Ki67 of 2% in tumor tissue and 8.2% stage IV disease. Median RFS was 101 months (5-year rate 67.9%). The derived prognostic score defined by multivariable analysis included prognostic parameters, such as TNM stage, lymph node ratio, margin status, and grading. The score distinguished three risk categories with a significantly different RFS (p < 0.01). CONCLUSIONS: Approximately 30% of patients with EP-NETs recurred within 5 years after radical surgery. Risk factors for recurrence were disease stage, lymph node ratio, margin status, and grading. The definition of risk categories may help in selecting patients who might benefit from adjuvant treatments and more intensive follow-up programs.

Prehospital triage of acute aortic syndrome using a machine learning algorithm.

BACKGROUND: Acute aortic syndrome (AAS) comprises a complex and potentially fatal group of conditions requiring emergency specialist management. The aim of this study was to build a prediction algorithm to assist prehospital triage of AAS. METHODS: Details of consecutive patients enrolled in a regional specialist aortic network were collected prospectively. Two prediction algorithms for AAS based on logistic regression and an ensemble machine learning method called SuperLearner (SL) were developed. Undertriage was defined as the proportion of patients with AAS not transported to the specialist aortic centre, and overtriage as the proportion of patients with alternative diagnoses but transported to the specialist aortic centre. RESULTS: Data for 976 hospital admissions between February 2010 and June 2017 were included; 609 (62·4 per cent) had AAS. Overtriage and undertriage rates were 52·3 and 16·1 per cent respectively. The population was divided into a training cohort (743 patients) and a validation cohort (233). The area under the receiver operating characteristic (ROC) curve values for the logistic regression score and the SL were 0·68 (95 per cent c.i. 0·64 to 0·72) and 0·87 (0·84 to 0·89) respectively (P < 0·001) in the training cohort, and 0·67 (0·60 to 0·74) and 0·73 (0·66 to 0·79) in the validation cohort (P = 0·038). The logistic regression score was associated with undertriage and overtriage rates of 33·7 (bootstrapped 95 per cent c.i. 29·3 to 38·3) and 7·2 (4·8 to 9·8) per cent respectively, whereas the SL yielded undertriage and overtriage rates of 1·0 (0·3 to 2·0) and 30·2 (25·8 to 34·8) per cent respectively. CONCLUSION: A machine learning prediction model performed well in discriminating AAS and could be clinically useful in prehospital triage of patients with suspected AAS.

ANTECEDENTES: Los síndromes aórticos agudos (aortic acute syndromes, AAS) constituyen un grupo complejo y potencialmente letal de entidades que requieren un tratamiento especializado en emergencias. El objetivo de este estudio fue construir un algoritmo de predicción para ayudar a la selección prehospitalaria de los AAS. MÉTODOS: Se recogieron prospectivamente una serie de pacientes consecutivos inscritos en una red regional especializada en patología aórtica. Se desarrollaron dos algoritmos de predicción para AAS basados en una regresión logística y en un método de aprendizaje automático denominado Super Learner (SL). Undertriage (infra-selección) se definió como la proporción de pacientes con AAS no transportados al centro especializado en patología aórtica y el overtriage (sobre-selección) como la proporción de pacientes con diagnósticos alternativos al AAS pero transportados al centro especializado en patología aórtica. RESULTADOS: Se incluyeron los datos de 976 ingresos hospitalarios entre febrero de 2010 y junio de 2017, con 609 (62,4%) AAS. Las tasas de overtriage y undertriage fueron del 52,3% y del 16,1%, respectivamente. La población se dividió en una cohorte de entrenamiento (n = 743) y en una cohorte de validación (n = 233). El área bajo la curva ROC para la puntuación de regresión logística y el SL fueron de 0,68 (0,64, 0,72) y de 0,87 (0,84, 0,89), respectivamente (P < 0,001) en la cohorte de entrenamiento, y de 0,67 (0,60, 0,74) y de 0,73 (0,66, 0,79) en la cohorte de validación (P = 0,038). La puntuación de regresión logística se asoció con tasas de undertriage y overtriage de 33,7% (i.c. del 95% bootstrapped 29,3%, 38,3%) y de 7,2% (4,8%, 9,8%), respectivamente, mientras que el SL presentó tasas de undertriage y overtriage de 1,0% (0,3%, 2,0%) y de 30,2% (25,8%, 34,8%), respectivamente. CONCLUSIÓN: El modelo de predicción de aprendizaje automático funcionó bien para discriminar AAS y podría ser clínicamente útil en la selección prehospitalaria de pacientes con sospecha de síndrome aórtico agudo.

Meta-analysis of mortality in patients with high-risk intraductal papillary mucinous neoplasms under observation.

BACKGROUND: Although consensus guidelines suggest that patients with high-risk intraductal papillary mucinous neoplasms (IPMNs) should have surgery, a non-operative strategy is often selected in patients who are poor surgical candidates. The aim was to determine the risk of disease-related death from IPMN in patients with worrisome features or high-risk stigmata who were kept under observation. METHODS: A PubMed literature search was undertaken of articles published from August 1992 to June 2016 (updated October 2017). The methodology was developed from PRISMA and MOOSE checklists. Incidence proportions and rates of overall and IPMN-related deaths were calculated, with subgroup analyses for main-duct/mixed-type and branch-duct IPMNs. Quality of the studies, publication bias and heterogeneity were explored. RESULTS: Six studies reported data on overall mortality and eight described disease-specific mortality for 556 patients during follow-up ranging from 24·9 to 60·0 months. Pooled rates of overall and IPMN-related mortality were 30·9 (95 per cent c.i. 19·6 to 45·1) and 11·6 (6·0 to 21·2) per cent respectively. The pooled incidence rate for overall mortality was substantially higher than that for IPMN-related mortality: 78 (95 per cent c.i. 44 to 111) and 23 (9 to 37) per 1000 patient-years respectively. The pooled incidence rate for disease-specific mortality was considerably lower for branch-duct than for main-duct or mixed-type IPMNs: 5 (0 to 10) and 32 (12 to 52) per 1000 patient-years respectively. CONCLUSION: In patients unfit for surgery, IPMN-related mortality among patients with worrisome features and high-risk stigmata is low, and the risk of death from other causes much higher.

Assessment of the Central Effects of Natural Uranium via Behavioural Performances and the Cerebrospinal Fluid Metabolome.

Natural uranium (NU), a component of the earth's crust, is not only a heavy metal but also an alpha particle emitter, with chemical and radiological toxicity. Populations may therefore be chronically exposed to NU through drinking water and food. Since the central nervous system is known to be sensitive to pollutants during its development, we assessed the effects on the behaviour and the cerebrospinal fluid (CSF) metabolome of rats exposed for 9 months from birth to NU via lactation and drinking water (1.5, 10, or 40 mg·L(-1) for male rats and 40 mg·L(-1) for female rats). Medium-term memory decreased in comparison to controls in male rats exposed to 1.5, 10, or 40 mg·L(-1) NU. In male rats, spatial working memory and anxiety- and depressive-like behaviour were only altered by exposure to 40 mg·L(-1) NU and any significant effect was observed on locomotor activity. In female rats exposed to NU, only locomotor activity was significantly increased in comparison with controls. LC-MS metabolomics of CSF discriminated the fingerprints of the male and/or female NU-exposed and control groups. This study suggests that exposure to environmental doses of NU from development to adulthood can have an impact on rat brain function.

Modulation of PKM alternative splicing by PTBP1 promotes gemcitabine resistance in pancreatic cancer cells.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and incurable disease. Poor prognosis is due to multiple reasons, including acquisition of resistance to gemcitabine, the first-line chemotherapeutic approach. Thus, there is a strong need for novel therapies, targeting more directly the molecular aberrations of this disease. We found that chronic exposure of PDAC cells to gemcitabine selected a subpopulation of cells that are drug-resistant (DR-PDAC cells). Importantly, alternative splicing (AS) of the pyruvate kinase gene (PKM) was differentially modulated in DR-PDAC cells, resulting in promotion of the cancer-related PKM2 isoform, whose high expression also correlated with shorter recurrence-free survival in PDAC patients. Switching PKM splicing by antisense oligonucleotides to favor the alternative PKM1 variant rescued sensitivity of DR-PDAC cells to gemcitabine and cisplatin, suggesting that PKM2 expression is required to withstand drug-induced genotoxic stress. Mechanistically, upregulation of the polypyrimidine-tract binding protein (PTBP1), a key modulator of PKM splicing, correlated with PKM2 expression in DR-PDAC cell lines. PTBP1 was recruited more efficiently to PKM pre-mRNA in DR- than in parental PDAC cells. Accordingly, knockdown of PTBP1 in DR-PDAC cells reduced its recruitment to the PKM pre-mRNA, promoted splicing of the PKM1 variant and abolished drug resistance. Thus, chronic exposure to gemcitabine leads to upregulation of PTBP1 and modulation of PKM AS in PDAC cells, conferring resistance to the drug. These findings point to PKM2 and PTBP1 as new potential therapeutic targets to improve response of PDAC to chemotherapy.

Application of clinical indexes in ulcerative colitis patients in regular follow-up visit: correlation with endoscopic 'mucosal healing' and implication for management. Preliminary results.

OBJECTIVE: Ulcerative Colitis (UC) is a chronic inflammatory disease of the colon of unknown etiology. Several clinical indexes have been proposed for UC disease activity evaluation, but none have been properly validated. Moreover, the reference parameter for the scores and their prognostic value is not clear. Mucosal healing has been recently proposed as an important end-point. Aim of the present study was to evaluate the correlation of four clinical indexes with objective diagnostic tools for UC evaluation, the discriminative ability in identifying patients with endoscopic mucosal healing, and to analyze the possible prognostic indication for disease course in 1 year of follow-up. PATIENTS AND METHODS: We analyzed data of 75 patients recorded in regular follow-up visit in IBD clinic at S. Andrea Hospital, Rome, between 2007-2011. We recorded clinical data and lab tests at the time of the visit, and endoscopic/histological reports performed within 1 month. Clinical indexes (Seo' activity index, Simple Clinical Colitis Activity Index, partial Mayo score and Endoscopic-Clinical Correlation Index) were calculated and correlation to endoscopic and histologic activity, and to C-reactive protein increment, was assessed by mean of Spearman's rank correlation. Discriminative ability of the indexes for patients with and without endoscopic mucosal healing was tested by calculation of area under ROC curve (AUC). Patients with low and high clinical scores were compared for number of flares and increment of therapy during 1 year of follow-up. RESULTS: Clinical indexes had a good correlation with endoscopic activity (mean r = 0.73 ± 0.06), a fair correlation with CRP-increment (mean r = 0.55 ± 0.01) and a poor one with histologic activity (mean r = 0.35 ± 0.01). The discriminatory ability of the indexes for endoscopic mucosal healing was good for all the indexes (mean AUC = 0.87 ± 0.05). Patients with high clinical score had more flares and required more frequently increase of therapy at 1 year of follow up compared with patients with low score. CONCLUSIONS: Clinical indexes have a good correlation with endoscopic activity and can discriminate patients with and without mucosal healing. Patients with low and high score have different risk of disease flare and of need to increase therapy at 1 year. Clinical indexes may represent a useful tool for disease assessment in clinical practice in UC outpatients with mild-moderate disease.

Glioblastoma multiforme and hepatitis B: do the right thing(s).

OBJECTIVE: Hepatitis B virus (HBV) reactivation is a well-known complication related to immunosuppression. Clinical manifestations of HBV relapse range from self-limiting anicteric hepatitis to acute hepatic failure. Temozolomide (TMZ) is an alkylating agent used for the treatment of glioblastoma multiforme (GBM), the most common and deadliest of malignant primary brain tumors. CASE REPORT: We report the case of a 52-year old man with a history of serological positivity for hepatitis B surface antigen (HBsAg) who was diagnosed with GBM. Since the tumor was multifocal and thus inoperable, the patient received radiotherapy with concomitant TMZ and corticosteroids, without a prophylactic therapy for HBV infection. Acute hepatitis developed five months later the beginning of anticancer therapy. We started antiviral entecavir, which led to a decrease of HBV-DNA titer to 20 IU/ml, allowing the prosecution of the TMZ therapy. CONCLUSIONS: Up to now only four other cases of HBV relapse during TMZ therapy have been reported in literature. These cases underline the need of HBV screening and antiviral prophylaxis before starting TMZ administration.

Prevalence and risk factors of extrapancreatic malignancies in a large cohort of patients with intraductal papillary mucinous neoplasm (IPMN) of the pancreas.

BACKGROUND: The objectives of this study are to estimate prevalence and incidence of extrapancreatic malignancies (EPMs) among intraductal papillary mucinous neoplasms (IPMNs) of the pancreas, and to identify risk factors for their occurrence. PATIENTS AND METHODS: We conducted multicentric cohort study in Italy from January 2010 to January 2011 including 390 IPMN cases. EPMs were grouped as previous, synchronous (both prevalent) and metachronous (incident). We calculated the observed/expected (O/E) ratio of prevalent EPMs, and compared the distribution of demographic, medical history and lifestyle habits. RESULTS: Ninety-seven EPMs were diagnosed in 92 patients (23.6%), among them 78 (80.4%) were previous, 14 (14.4%) were synchronous and 5 (5.2%) were metachronous. O/E ratios for prevalent EPMs were significantly increased for colorectal carcinoma (2.26; CI 95% 1.17-3.96), renal cell carcinoma (6.00; CI 95% 2.74-11.39) and thyroid carcinoma (5.56; CI 95% 1.80-12.96). Increased age, heavy cigarette smoking, alcohol consumption and first-degree family history of gastric cancer are significant risk factors for EPMs, while first-degree family history of colorectal carcinoma was borderline. CONCLUSION: We report an increased prevalence of EPMs in Italian patients with IPMN, especially for colorectal carcinoma, renal cell and thyroid cancers. A systematic surveillance of IPMN cases for such cancer types would be advised.

Endoscopic snare papillectomy: a possible radical treatment for a subgroup of T1 ampullary adenocarcinomas.

Pancreaticoduodenectomy is the standard care for invasive ampullary adenocarcinomas. However, endoscopic snare papillectomy (ESP) might play a curative role in very selected patients. We studied a series of 15 patients with T1 ampullary adenocarcinoma who were treated by ESP alone and followed up for a mean of 29.6 ± 21.9 months (range 8 - 81 months). ESP was curative for eight patients (57.1 %). No tumor-related death was observed in patients with a cancer infiltration depth of ≤ 4 mm. According to this preliminary experience, we suggest that this measurable variable threshold should be considered as a possible basis for future large-scale studies.

Gemcitabine triggers a pro-survival response in pancreatic cancer cells through activation of the MNK2/eIF4E pathway.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive neoplastic disease. Gemcitabine, the currently used chemotherapeutic drug for PDAC, elicits only minor benefits, because of the development of escape pathways leading to chemoresistance. Herein, we aimed at investigating the involvement of the mitogen activating protein kinase interacting kinase (MNK)/eIF4E pathway in the acquired drug resistance of PDAC cells. Screening of a cohort of PDAC patients by immunohistochemistry showed that eIF4E phosphorylation correlated with disease grade, early onset of disease and worse prognosis. In PDAC cell lines, chemotherapeutic drugs induced MNK-dependent phosphorylation of eIF4E. Importantly, pharmacological inhibition of MNK activity synergistically enhanced the cytostatic effect of gemcitabine, by promoting apoptosis. RNA interference (RNAi) experiments indicated that MNK2 is mainly responsible for eIF4E phosphorylation and gemcitabine resistance in PDAC cells. Furthermore, we found that gemcitabine induced the expression of the oncogenic splicing factor SRSF1 and splicing of MNK2b, a splice variant that overrides upstream regulatory pathways and confers increased resistance to the drug. Silencing of SRSF1 by RNAi abolished this splicing event and recapitulated the effects of MNK pharmacological or genetic inhibition on eIF4E phosphorylation and apoptosis in gemcitabine-treated cells. Our results highlight a novel pro-survival pathway triggered by gemcitabine in PDAC cells, which leads to MNK2-dependent phosphorylation of eIF4E, suggesting that the MNK/eIF4E pathway represents an escape route utilized by PDAC cells to withstand chemotherapeutic treatments.

Systematic review of resection of primary midgut carcinoid tumour in patients with unresectable liver metastases.

BACKGROUND: Surgery for small intestinal neuroendocrine tumours (SI-NETs) is limited by metastatic disease in most patients. However, resection of the primary lesion alone has been advocated in patients with unresectable liver metastases. The present systematic review investigated the value of surgical resection of the primary lesion in patients with unresectable metastatic disease. METHODS: MEDLINE was searched for studies reporting the outcome of patients with SI-NETs and unresectable liver metastases where there was an explicit comparison between resection of the primary lesion alone and no resection. The primary outcome was overall survival. Secondary outcomes were progression-free survival, treatment-related mortality and relief of symptoms. RESULTS: Meta-analysis was not possible, but six studies were analysed qualitatively to highlight useful information. Possible confounders in these studies were the inclusion of patients with other primary tumour sites, unknown primary tumour or non-metastatic disease. Bearing in mind these limitations, there was a clear trend towards longer survival in patients who underwent surgical resection in all studies; their median overall survival ranged from 75 to 139 months compared with 50-88 months in patients who did not have resection. The difference between the two groups was statistically significant in three studies. Data on symptomatic improvement were scarce and did not suggest a clear benefit of surgery. Surgery-related mortality seemed low. CONCLUSION: Available data suggest a possible benefit of resection of the primary lesion in patients with unresectable liver metastases, but the studies have several limitations and the results should therefore be considered with caution.

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.

Fasting glucose and treatment outcome in breast and colorectal cancer patients treated with targeted agents: results from a historic cohort.

BACKGROUND: We investigated pretreatment fasting glucose as a predictor of patients' important outcomes in breast and colorectal cancers undergoing targeted therapies. PATIENTS AND METHODS: In a historic cohort of 202 breast and 218 colorectal cancers treated with targeted agents from 1998 to 2009, we used the Kaplan-Meier method and the log-rank test to estimate survival through tertiles of fasting glucose and the Cox proportional hazards model for multivariate analysis stratified by primary site of cancer and including gender, age and body mass index. RESULTS: The median follow-up was 20 months (1-128). At 60 months, 65% of patients in the lowest tertile of fasting glucose did not experiment disease progression compared with 34% in the highest tertile (P=0.001). Seventy-six percent of females in the lowest tertile showed no progression compared with 49% in the top tertiles (P=0.015). In multivariate analysis, fasting glucose was a significant predictor of time to disease progression only in breast cancer patients in the first tertile compared with the third (P=0.017). CONCLUSIONS: We found evidence of a predictive role of pretreatment fasting glucose in the development of resistance in breast cancer patients treated with targeted agents. Prospective studies are warranted to confirm our findings.

Development of type I gastric carcinoid in patients with chronic atrophic gastritis.

BACKGROUND: Long-term observational studies assessing the incidence of type I gastric carcinoid (typeIGC) in patients with chronic atrophic gastritis are few. AIM: To evaluate the occurrence of typeIGC at diagnosis and during follow-up and to identify patient features associated with the presence of typeIGC in a cohort of chronic atrophic gastritis patients. METHODS: Three hundred and sixty-seven chronic atrophic gastritis patients [245 women, age 54 (18-79) years] underwent regular follow-up by gastroscopy. The incidence of typeIGC was determined in chronic atrophic gastritis patients with at least 2 years of follow-up (n = 214). Baseline clinical and histological features were analysed as factors associated with the presence of typeIGC by univariate analysis. RESULTS: Type I gastric carcinoid was diagnosed in nine (2.4%) patients at the moment when chronic atrophic gastritis was diagnosed. After 1463 person-years, six patients developed typeIGC with an annual incidence rate (person-year) of 0.4%. Patients with typeIGC had significantly higher levels of gastrin, chromogranin A and more frequently the presence of body polyps and ECL-dysplasia compared with chronic atrophic gastritis patients without typeIGC. CONCLUSIONS: This cohort study shows that typeIGC is a rare complication in patients with chronic atrophic gastritis, and the presence of body polyps and ECL-dysplasia at gastroscopic/histologic evaluation is strongly associated with the presence of typeIGC.