Non-hypervascular hepatobiliary phase hypointense lesions detected in patients with hepatocellular carcinoma: a post hoc analysis of SORAMIC trial to identify risk factors for progression.

OBJECTIVES: To identify clinical and imaging parameters associated with progression of non-hypervascular hepatobiliary phase hypointense lesions during follow-up in patients who received treatment for hepatocellular carcinoma. METHODS: A total of 67 patients with 106 lesions were identified after screening 538 patients who underwent gadoxetic acid-enhanced MRI within the SORAMIC trial. All patients were allocated to the trial treatment according to the trial scheme, and 61 of 67 patients received systemic treatment with sorafenib (either alone or combined with locoregional therapies) during the trial period. Follow-up images after treatment according to trial scheme were reviewed for subsequent hypervascularization or > 1 cm size increase. The correlation between progression and several imaging and clinical parameters was assessed using univariable and multivariable analyses. RESULTS: On a median 178 (range, 48-1072) days follow-up period, progression was encountered in 18 (16.9%) lesions in 12 (17.9%) patients. In univariable analysis size > 12.6 mm (p = 0.070), ECOG-PS (p = 0.025), hypointensity at T1-weighted imaging (p = 0.028), hyperintensity at T2-weighted imaging (p < 0.001), hyperintensity at DWI images (p = 0.007), and cirrhosis (p = 0.065) were correlated with progression during follow-up. Hyperintensity at T2 images (p = 0.011) was an independent risk factor for progression in multivariable analysis, as well as cirrhosis (p = 0.033) and ECOG-PS (p = 0.030). CONCLUSIONS: Non-hypervascular hepatobiliary phase hypointense lesions are associated with subsequent progression after treatment in patients with HCC. T2 hyperintensity, diffusion restriction, cirrhosis, and higher ECOG-PS could identify lesions with increased risk. These factors should be considered for further diagnostic evaluation or treatment of such lesions. KEY POINTS: • Non-hypervascular hepatobiliary phase hypointense lesions have considerable risk of progression in patients with hepatocellular carcinoma receiving treatment. • T2 hyperintensity, cirrhosis, ECOG-PS, and hyperintensity at DWI are associated with increased risk of progression. • Non-hypervascular hepatobiliary phase hypointense lesions should be considered in the decision-making process of locoregional therapies, especially in the presence of these risk factors.

Ultrasound examination, MRI, or ROMA for discriminating between inconclusive adnexal masses as determined by IOTA Simple Rules: a prospective study.

OBJECTIVE: To determine the best second-step approach for discriminating benign from malignant adnexal masses classified as inconclusive by International Ovarian Tumour Analysis Simple Rules (IOTA-SR). METHODS: Single-center prospective study comprising a consecutive series of patients diagnosed as having an adnexal mass classified as inconclusive according to IOTA-SR. All women underwent Risk of Ovarian Malignancy Algorithm (ROMA) analysis, MRI interpreted by a radiologist, and ultrasound examination by a gynecological sonologist. Cases were clinically managed according to the result of the ultrasound expert examination by either serial follow-up for at least 1 year or surgery. Reference standard was histology (patient was submitted to surgery if any of the tests was suspicious) or follow-up (masses with no signs of malignancy after 12 months were considered benign). Diagnostic performance of all three approaches was calculated and compared. Direct cost analysis of the test used was also performed. RESULTS: Eighty-two adnexal masses in 80 women (median age 47.6 years, range 16 to 73 years) were included. Seventeen patients (17 masses) were managed expectantly (none had diagnosis of ovarian cancer after at least 12 months of follow-up) and 63 patients (65 masses) underwent surgery and tumor removal (40 benign and 25 malignant tumors). Sensitivity and specificity for ultrasound, MRI, and ROMA were 96% and 93%, 100% and 81%, and 24% and 93%, respectively. The specificity of ultrasound was better than that for MRI (p=0.021), and the sensitivity of ultrasound was better than that for ROMA (p<0.001), sensitivity was better for MRI than for ROMA (p<0.001) and the specificity of ROMA was better than that for MRI (p<0.001). Ultrasound evaluation was the most effective and least costly method as compared with MRI and ROMA. CONCLUSION: In this study, ultrasound examination was the best second-step approach in inconclusive adnexal masses as determined by IOTA-SR, but the findings require confirmation in multicenter prospective trials.

Prognostic value of baseline imaging and clinical features in patients with advanced hepatocellular carcinoma.

AIMS: To investigate the prognostic value of baseline imaging features for overall survival (OS) and liver decompensation (LD) in patients with hepatocellular carcinoma (HCC). DESIGN: Patients with advanced HCC from the SORAMIC trial were evaluated in this post hoc analysis. Several radiological imaging features were collected from baseline computed tomography (CT) and magnetic resonance imaging (MRI) imaging, besides clinical values. The prognostic value of these features for OS and LD (grade 2 bilirubin increase) was quantified with univariate Cox proportional hazard models and multivariate Least Absolute Shrinkage and Selection Operator (LASSO) regression. RESULTS: Three hundred and seventy-six patients were included in this study. The treatment arm was not correlated with OS. LASSO showed satellite lesions, atypical HCC, peritumoral arterial enhancement, larger tumour size, higher albumin-bilirubin (ALBI) score, liver-spleen ratio <1.5, ascites, pleural effusion and higher bilirubin values were predictors of worse OS, and higher relative liver enhancement, smooth margin and capsule were associated with better OS. LASSO analysis for LD showed satellite lesions, peritumoral hypointensity in hepatobiliary phase, high ALBI score, higher bilirubin values and ascites were predictors of LD, while randomisation to sorafenib arm was associated with lower LD. CONCLUSIONS: Imaging features showing aggressive tumour biology and poor liver function, in addition to clinical parameters, can serve as imaging biomarkers for OS and LD in patients receiving sorafenib and selective internal radiation therapy for HCC.

Full Laparoscopic Vascular Reconstruction for Portal Tumoral Invasion During a Right Hepatectomy Using the Caudal Approach.

BACKGROUND: Laparoscopic liver surgery has progressively evolved. Consequently, liver procedures are increasingly performed laparoscopically, particularly in experienced centers. However, vascular resection and reconstruction still are considered a limitation for laparoscopy1 due to the risk of bleeding and the technical difficulty. METHODS: A 72-year-old woman with a history of colorectal cancer had a 10 cm metastasis diagnosed in the right hemiliver with tumoral invasion of the right portal branch and tumor thrombus advancing to the portal confluence. After adjuvant chemotherapy and with stable disease, surgical resection was planned.2,3 Tips to avoid portal stenosis were carefully followed. RESULTS: The operation was performed with a fully laparoscopic procedure. To minimize manipulation, an in situ right hepatectomy was performed.4 The right hepatic artery was dissected and ligated. The liver transection was guided with a caudal approach of the middle hepatic vein.5 The right biliary duct was then divided, achieving an excellent exposure of the portal bifurcation. The main and left portal trunks were occluded with vascular clamps, and the right portal vein was sharply divided with scissors. The stump was sutured to minimize backflow bleeding and to cover the tumor thrombus. Then, the portal opening was transversally sutured with a 5/0 running suture. The clamps were released, and the authors observed no bleeding and an adequate caliber with no stenosis. The procedure was completed in the standard fashion. The postoperative course was uneventful, and the woman was discharged on postoperative day 3. No early or late complications were observed.6 CONCLUSIONS: In selected cases, patients who require vascular resection and reconstruction during hepatectomies can benefit from the advantages of a laparoscopic approach.

Correlation of liver enhancement in gadoxetic acid-enhanced MRI with liver functions: a multicenter-multivendor analysis of hepatocellular carcinoma patients from SORAMIC trial.

OBJECTIVES: To evaluate the correlation between liver enhancement on hepatobiliary phase and liver function parameters in a multicenter, multivendor study. METHODS: A total of 359 patients who underwent gadoxetic acid-enhanced MRI using a standardized protocol with various scanners within a prospective multicenter phase II trial (SORAMIC) were evaluated. The correlation between liver enhancement on hepatobiliary phase normalized to the spleen (liver-to-spleen ratio, LSR) and biochemical laboratory parameters, clinical findings related to liver functions, liver function grading systems (Child-Pugh and Albumin-Bilirubin [ALBI]), and scanner characteristics were analyzed using uni- and multivariate analyses. RESULTS: There was a significant positive correlation between LSR and albumin (rho = 0.193; p < 0.001), platelet counts (rho = 0.148; p = 0.004), and sodium (rho = 0.161; p = 0.002); and a negative correlation between LSR and total bilirubin (rho = -0.215; p < 0.001) and AST (rho = -0.191; p < 0.001). Multivariate analysis confirmed independent significance for each of albumin (p = 0.022), total bilirubin (p = 0.045), AST (p = 0.031), platelet counts (p = 0.012), and sodium (p = 0.006). The presence of ascites (1.47 vs. 1.69, p < 0.001) and varices (1.55 vs. 1.69, p = 0.006) was related to significantly lower LSR. Similarly, patients with ALBI grade 1 had significantly higher LSR than patients with grade 2 (1.74 ± 0.447 vs. 1.56 ± 0.408, p < 0.001); and Child-Pugh A patients had a significantly higher LSR than Child-Pugh B (1.67 ± 0.44 vs. 1.49 ± 0.33, p = 0.021). Also, LSR was negatively correlated with MELD-Na scores (rho = -0.137; p = 0.013). However, one scanner brand was significantly associated with lower LSR (p < 0.001). CONCLUSIONS: The liver enhancement on the hepatobiliary phase of gadoxetic acid-enhanced MRI is correlated with biomarkers of liver functions in a multicenter cohort. However, this correlation shows variations between scanner brands. KEY POINTS: • The correlation between liver enhancement on the hepatobiliary phase of gadoxetic acid-enhanced MRI and liver function is consistent in a multicenter-multivendor cohort. • Signal intensity-based indices (liver-to-spleen ratio) can be used as an imaging biomarker of liver function. • However, absolute values might change between vendors.

Pure laparoscopic major liver resection after yttrium90 radioembolization: a case-matched series analysis of feasibility and outcomes.

BACKGROUND: Liver surgery after radioembolization (RE) entails highly demanding and challenging procedures due to the frequent combination of large tumors, severe RE-related adhesions, and the necessity of conducting major hepatectomies. Laparoscopic liver resection (LLR) and its associated advantages could provide benefits, as yet unreported, to these patients. The current study evaluated feasibility, morbidity, mortality, and survival outcomes for major laparoscopic liver resection after radioembolization. MATERIAL AND METHODS: In this retrospective, single-center study patients diagnosed with hepatocellular carcinoma, intrahepatic cholangiocarcinoma or metastases from colorectal cancer undergoing major laparoscopic hepatectomy after RE were identified from institutional databases. They were matched (1:2) on several pre-operative characteristics to a group of patients that underwent major LLR for the same malignancies during the same period but without previous RE. RESULTS: From March 2011 to November 2020, 9 patients underwent a major LLR after RE. No differences were observed in intraoperative blood loss (50 vs. 150 ml; p = 0.621), operative time (478 vs. 407 min; p = 0.135) or pedicle clamping time (90.5 vs 74 min; p = 0.133) between the post-RE LLR and the matched group. Similarly, no differences were observed on hospital stay (median 3 vs. 4 days; p = 0.300), Clavien-Dindo ≥ III complications (2 vs. 1 cases; p = 0.250), specific liver morbidity (1 vs. 1 case p = 1.000), or 90 day mortality (0 vs. 0; p = 1.000). CONCLUSION: The laparoscopic approach for post radioembolization patients may be a feasible and safe procedure with excellent surgical and oncological outcomes and meets the current standards for laparoscopic liver resections. Further studies with larger series are needed to confirm the results herein presented.

Comparison of phenotypes and outcomes following resection of incidental versus symptomatic pancreatic neuroendocrine tumors.

BACKGROUND AND AIM: fifty to 70 percent of pancreatic neuroendocrine tumors are diagnosed incidentally. The objective of this study was to compare the phenotype and oncological outcomes of incidental versus symptomatic pancreatic neuroendocrine tumors. METHODS: a retrospective study was performed, identifying all incidental and symptomatic tumors resected between 2000 and 2019. Baseline characteristics, symptoms, operative variables and pathological stage were all recorded. Patterns of recurrence and overall and disease-free survival were analyzed in both groups. RESULTS: fifty-one incidental and 45 symptomatic pancreatic tumor resections were performed. Symptomatic tumors were more frequent in females (29 vs 17; p = 0.005) and younger patients (median years; 50 vs 58; p = 0.012) and were detected at a more advanced stage (p = 0.027). There were no differences in location and most resections (n = 49; 51 %) were performed laparoscopically. There were no operative mortalities and 17 (17.7 %) severe complications (≥ IIIb on the Clavien-Dindo classification) were recorded with no differences between the two groups. With a median follow-up of 64.4 months (range 13.5-90), overall survival at five and ten years was 89.7 % and 72.8 % for the non-incidental tumors and 80.9 % and 54.6 % for the incidental tumors (p = ns), respectively. Disease-free survival in both groups (excluding M1a) was 71.2 % and 47.5 %, and 93.7 % and 78.1 %, respectively (p = ns). CONCLUSIONS: symptomatic tumors are more frequent in females and present at more advanced pathological stages. There were no significant differences in overall and disease-free survival between the two groups. Resection of incidental tumors ≥ 1.5-2 cm seems advisable, although each case should be assessed on an individual basis.

Incidental lesions of the pancreas. A clinicopathological study of 100 cases surgically treated.

OBJECTIVE: the objective of the present study was to analyze the characteristics of resected incidental lesions of the pancreas. MATERIAL AND METHODS: a retrospective study was performed of pancreatectomies due to incidentalomas between 1995 and 2018. RESULTS: one hundred pancreatectomies were performed due to incidental lesions; 64 (64%) were solid and 36 (36%) were cystic lesions. The cytological analysis agreed with the diagnosis in 67/71 (88.7%) cases. Thirty-six tumors were cystic, 48 were neuroendocrine and 16 were adenocarcinomas. Disease-free survival for patients with cystic, neuroendocrine tumors and adenocarcinomas was 100%, 79% and 57.7% (p < 0.04). CONCLUSION: pancreatic incidentalomas have a heterogeneous phenotype and should be treated in experienced centers.

Ultrasound/Elastography techniques, lipidomic and blood markers compared to Magnetic Resonance Imaging in non-alcoholic fatty liver disease adults.

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) may progress to steatohepatitis, cirrhosis and complicated hepatocellular carcinoma with defined differential symptoms and manifestations. OBJECTIVE: To evaluate the fatty liver status by several validated approaches and to compare imaging techniques, lipidomic and routine blood markers with magnetic resonance imaging in adults subjects with non-alcoholic fatty liver disease. MATERIALS AND METHODS: A total of 127 overweight/obese with NAFLD, were parallelly assessed by Magnetic Resonance Imaging (MRI), ultrasonography, transient elastography and a validated metabolomic designed test to diagnose NAFLD in this cross-sectional study. Body composition (DXA), hepatic related biochemical measurements as well as the Fatty Liver Index (FLI) were evaluated. This study was registered as FLiO: Fatty Liver in Obesity study; NCT03183193. RESULTS: The subjects with more severe liver disease were found to have worse metabolic parameters. Positive associations between MRI with inflammatory and insulin biomarkers were found. A linear regression model including ALT, RBP4 and HOMA-IR was able to explain 40.9% of the variability in fat content by MRI. In ROC analyses a combination panel formed of ALT, HOMA-IR and RBP4 followed by ultrasonography, ALT and metabolomic test showed the major predictive ability (77.3%, 74.6%, 74.3% and 71.1%, respectively) for liver fat content. CONCLUSIONS: A panel combination including routine blood markers linked to insulin resistance showed highest associations with MRI considered as a gold standard for determining liver fat content. This combination of tests can facilitate the diagnosis of early stages of non-alcoholic liver disease thereby avoiding other invasive and expensive methods.

Cystic tumors of the pancreas. An update of the surgical experience in a single institution.

BACKGROUND: the aim of the present study was to analyze the clinicopathological features of patients undergoing pancreatic surgical resections due to cystic neoplasms of the pancreas. MATERIAL AND METHODS: demographic data, form of presentation, radiologic images and location of the tumors within the pancreas were analyzed. Data was also collected on the type of surgery (open/laparoscopic), postoperative complications and their severity and oncologic outcomes. RESULTS: eighty-two pancreatic resections were performed. The mean age of patients was 57 years and 49 (59%) were female. Forty-one tumors (50%) were incidental and the most frequent symptoms in the group of symptomatic patients were abdominal pain (63.4%) and weight loss (36.5%). Thirty-two tumors (39%) were located in the tail of the pancreas, 25 (30.5%) in the head and 20 (24.4%) in the body. Thirty-nine (47.5%) distal pancreatectomies, 16 central, ten duodenal pancreatectomies and one enucleation were performed; 40 (48.5%) were carried out laparoscopically. Mean hospital stay was ten days and eight patients (7%) experienced severe complications, one was a pancreatic fistula. Sixty-six tumors (80.5%) were recorded as non-invasive and 16 (19.5%) as invasive: seven intraductal mucinous papillary tumors, one cystic mucinous tumor, four solid pseudopapillary tumors and four cystic neuroendocrine tumors. There was a median follow-up of 64 months; disease-free survival at five and ten years was 97.4% in the patients with non-invasive tumors and 84.6% and 70.5% in the invasive tumors group (p < 0.01). CONCLUSIONS: fifty percent of cystic neoplasms of the pancreas are incidental. Two phenotypes exist, invasive and non-invasive.

Intraductal papillary mucinous neoplasm (IPMN) of the pancreas: clinicopathological features and long-term outcomes following a pancreatectomy.

OBJECTIVE: the objective of this study was to analyze the anatomical and clinical features and long-term oncologic outcomes of 25 patients that underwent surgery due to intraductal papillary mucinous neoplasm of the pancreas. MATERIAL AND METHODS: patients undergoing surgery for intraductal papillary mucinous neoplasm of the pancreas were identified from a prospective database of pancreatic resections. Demographic data, symptoms, type of surgery and type of lesion (branch type, main duct or mixed) were recorded. The lesions were classified into invasive (high grade dysplasia and carcinoma) and noninvasive (low- or intermediate-grade dysplasia). Postoperative complications were analyzed as well as the pattern of recurrence and disease-free survival at five and ten years. RESULTS: the most common symptoms in the 25 patients (14 males and eleven females) were abdominal pain and weight loss. Eight (32%) cases were diagnosed incidentally. Twelve (48%) of the lesions were of the branch type, three affected the main duct and ten (40%) were mixed. Twelve cephalic duodenopancreatectomies and seven total pancreatectomies were performed; three were central; two, distal; and one, enucleation. Seven cases (32%) had an invasive phenotype. Three patients had locoregional and distant recurrence at six, 16 and 46 months after surgery with a median follow-up of 7.7 years. Disease-free survival at five and ten years for the noninvasive type was 94% and 57% for invasive phenotypes (p < 0.05). CONCLUSIONS: intraductal papillary mucinous neoplasm is a heterogeneous entity with well differentiated phenotypes, which requires a tailored strategy and treatment, as established in the current consensus guidelines due to its malignant potential.

Arterial spin labeling MRI is able to detect early hemodynamic changes in diabetic nephropathy.

PURPOSE: To investigate whether arterial spin labeling (ASL) MRI could detect renal hemodynamic impairment in diabetes mellitus (DM) along different stages of chronic kidney disease (CKD). MATERIALS AND METHODS: Three Tesla (3T) ASL-MRI was performed to evaluate renal blood flow (RBF) in 91 subjects (46 healthy volunteers and 45 type 2 diabetic patients). Patients were classified according to their estimated glomerular filtration rate (eGFR) as group I (eGFR > 60 mL/min/1.73 m2 ), group II (60 ≥ eGFR>30 mL/min/1.73 m2 ), or group III (eGFR ≤ 30 mL/min/1.73 m2 ), to determine differences depending on renal function. Studies were performed at 3T using a 12-channel flexible body array combined with the spine array coil as receiver. RESULTS: A 28% reduction in cortical RBF was seen in diabetics in comparison with healthy controls (185.79 [54.60] versus 258.83 [37.96] mL/min/100 g, P < 3 × 10-6 ). Differences were also seen between controls and diabetic patients despite normal eGFR and absence of overt albuminuria (RBF [mL/min/100 g]: controls=258.83 [37.96], group I=208.89 [58.83], P = 0.0018; eGFR [mL/min/1.73 m2 ]: controls = 95.50 [12.60], group I = 82.00 [20.76], P > 0.05; albumin-creatinine ratio [mg/g]: controls = 3.50 [4.45], group I = 17.50 [21.20], P > 0.05). A marked decrease in RBF was noted a long with progression of diabetic nephropathy (DN) through the five stages of CKD (χ2 = 43.58; P = 1.85 × 10-9 ). Strong correlation (r = 0.62; P = 4 × 10-10 ) was obtained between RBF and GFR estimated by cystatin C. CONCLUSION: ASL-MRI is able to quantify early renal perfusion impairment in DM, as well as changes according to different CKD stages of DN. In addition, we demonstrated a correlation of RBF quantified by ASL and GFR estimated by cystatin C. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2017;46:1810-1817.

Short- and long-term outcomes of laparoscopic organ-sparing resection in pancreatic neuroendocrine tumors: a single-center experience.

BACKGROUND: Laparoscopic organ-sparing pancreatectomy (LOSP) is an ideal therapeutic option in selected cases of pancreatic neuroendocrine tumors (PNETs). Nevertheless, given the low frequency of PNETs, there is scarce evidence regarding short and particularly long-term outcomes of LOSP in this clinical setting. METHODS: All patients with PNETs who underwent surgery (under a LOSP policy) were retrospectively reviewed from a prospective database maintained at our center. Preoperative characteristics, operative data, pathological features and postoperative outcomes were analyzed. RESULTS: Between December 2003 and December 2015, 36 patients with PNETs underwent laparoscopic resections. Ten were functional tumors, 26 non-functional and 16 were "incidental" cases. The following procedures were performed: one enucleation, eight central pancreatectomies (LCP), one resection of the uncinate process and 26 distal pancreatectomies (DP) (15 of them laparoscopic vessels-preserving). There were no conversions to open surgery, and no drains were routinely left. Mean operative time was 288 min (SD 99). Hospital stay was 6 days. Eighteen patients (50%) experienced some complication of which most were mild (Clavien-Dindo I/II). Three postoperative bleedings occurred: two grade B/one grade C; two required laparoscopic reoperation. Thirteen (36.1%) patients developed peripancreatic fluid collections: two were symptomatic and were managed with transgastric drainage (one presented post-puncture abscesification requiring surgical drainage and splenectomy). Four patients (11%)-one DP and three LCP-developed new-onset pancreatogenic diabetes mellitus (NODM) in the long term. According to the European Neuroendocrine Tumor Society, 19 cases were stage I, seven IIA, two IIIA, one IIIB and seven stage IV. Over a mean follow-up of 51 months, two patients died, one due to recurrence of the tumor and another due to cirrhosis. CONCLUSIONS: The existing different surgical options must be individually considered according to the location and particular characteristics of every tumor. Results from this single-center study document the effectiveness of LOSP in selected cases of PNETs.

Recombinant AAV Integration Is Not Associated With Hepatic Genotoxicity in Nonhuman Primates and Patients.

Recombinant adeno-associated viral vectors (rAAV) currently constitute a real therapeutic strategy for the sustained correction of diverse genetic conditions. Though a wealth of preclinical and clinical studies have been conducted with rAAV, the oncogenic potential of these vectors is still controversial, particularly when considering liver-directed gene therapy. Few preclinical studies and the recent discovery of incomplete wild-type AAV2 genomes integrated in human hepatocellular carcinoma biopsies have raised concerns on rAAV safety. In the present study, we have characterized the integration of both complete and partial rAAV2/5 genomes in nonhuman primate tissues and clinical liver biopsies from a trial aimed to treat acute intermittent porphyria. We applied a new multiplex linear amplification-mediated polymerase chain reaction (PCR) assay capable of detecting integration events that are originated throughout the rAAV genome. The integration rate was low both in nonhuman primates and patient's samples. Importantly, no integration clusters or events were found in genes previously reported to link rAAV integration with hepatocellular carcinoma development, thus showing the absence of genotoxicity of a systemically administered rAAV2/5 in a large animal model and in the clinical context.

Agenesis of the dorsal pancreas associated with mucinous cysts and chronic calcific non-alcoholic pancreatitis.

Agenesis of the dorsal pancreas is a rare malformation. Since 1911 and until 2008, 107 cases have been reported. Herein we report a new case on agenesis of the dorsal pancreas associated with mucinous is and chronic calcific non-alcoholic pancreatitis.

Cystic pancreatic neuroendocrine tumors (cPNETs): a systematic review and meta-analysis of case series.

Cystic pancreatic neuroendocrine tumors represent 13% of all neuroendocrine tumors. The aim of this study is to analyze the phenotype and biologic behavior of resected cystic neuroendocrine tumors. A systematic review and meta-analysis were conducted until September 2016 using a search in Medline, Scopus, and EMBASE with the terms "cystic pancreatic endocrine neoplasm", "cystic islets tumors" and "cystic islets neoplasms". From the 795 citations recovered 80 studies reporting on 431 patients were selected. 87.1% (n = 387) were sporadic tumors and 10.3% (n = 40) corresponded to multiple endocrine neoplasia endocrine type 1. Were diagnosed incidentally 44.6% (n = 135). Cytology was found to have a sensitivity of 78.5%. Were non-functional tumors 85% (n = 338), and among the functional tumors, insulinoma was the most frequent. According to the European Neuroendocrine Tumor Society staging, 87.8% were limited to the pancreas (I-IIb), and 12.2% were advanced (III-IV). Disease-free survival at 5 years in stages (I-IIIa) and (IIIb-IV) was 91.5% and 54.2%, respectively; and was significantly lower (p = 0.0001) in functional tumors. In patients with multiple endocrine neoplasia there was a higher incidence of functional (62.5%) and multifocal (28.1%) tumors. Disease-free survival at 5 and 10 years was 60%. Cystic pancreatic neuroendocrine tumors exhibit phenotypical characteristics which are different to those of solid neuroendocrine tumors.

Index lesion characterization by (11)C-Choline PET/CT and Apparent Diffusion Coefficient parameters at 3 Tesla MRI in primary prostate carcinoma.

BACKGROUND: Index lesion characterization is important in the evaluation of primary prostate carcinoma (PPC). The aim of this study was to analyze the contribution of (11) C-Choline PET/CT and the Apparent Diffusion Coefficient maps (ADC) in detecting the Index Lesion and clinically significant tumors in PPC. METHODS: Twenty-one untreated patients with biopsy-proven PPC and candidates for radical prostatectomy (RP) were prospectively evaluated by means of Ultra-High Definition PET/CT and 3T MRI, which included T2-weighted imaging (T2WI) and ADC maps obtained from diffusion weighted imaging (DWI). Independent experts analyzed all the images separately and were unaware of the pathological data. In each case, the Index lesion was defined as the largest tumor measured on histopathology (Index H). In addition, the largest lesion observed on MRI (Index MRI) and the highest avid (11) C-Choline uptake lesion (Index PET) were obtained. The Gleason scores (GS) of the tumors were determined. PET/CT and ADC map quantitative parameters were also calculated. Measures of correlation among imaging parameters as well as the sensitivity (S), specificity (Sp), negative and positive predictive values (NPV and PPV) for tumor detection were analyzed. All data was validated with the pathological study. RESULTS: In the morphological study, 139 foci of carcinoma were identified, 47 of which corresponded to clinically significant tumors (>0.5 cm(3)). The remaining foci presented a maximum diameter (dmax ) of 0.1 cm ± SD 0.75 and were not classified as clinically significant. Thirty-two tumors presented a GS (3 + 3), nine GS (3 + 4), and six GS (4 + 3). A total of 21 Index H (dmax = 1.37 cm SD ± 0.61) were identified. The S, Sp, NPV, and PPV for tumor detection with PET were 100%, 70%, 83%, 100%, and for MRI were 46%, 100%, 100%, 54%, respectively. Both Index PET and Index MRI were complementary and identified 95% of the Index H when quantitative criteria were used. CONCLUSION: In spite of the fact that PET imaging has higher tumor sensitivity than MRI, (11) C-Choline PET and ADC maps have complementary roles in the evaluation of Index Lesion in PPC. Index PET and Index MRI could be complementary targets in the therapeutic planning of PPC.

Phase I open label liver-directed gene therapy clinical trial for acute intermittent porphyria.

BACKGROUND & AIMS: Acute intermittent porphyria (AIP) results from porphobilinogen deaminase (PBGD) haploinsufficiency, which leads to hepatic over-production of the neurotoxic heme precursors porphobilinogen (PBG) and delta-aminolevulinic acid (ALA) and the occurrence of neurovisceral attacks. Severe AIP is a devastating disease that can only be corrected by liver transplantation. Gene therapy represents a promising curative option. The objective of this study was to investigate the safety of a recombinant adeno-associated vector expressing PBGD (rAAV2/5-PBGD) administered for the first time in humans for the treatment of AIP. METHODS: In this phase I, open label, dose-escalation, multicenter clinical trial, four cohorts of 2 patients each received a single intravenous injection of the vector ranging from 5×10(11) to 1.8×10(13) genome copies/kg. Adverse events and changes in urinary PBG and ALA and in the clinical course of the disease were periodically evaluated prior and after treatment. Viral shedding, immune response against the vector and vector persistence in the liver were investigated. RESULTS: Treatment was safe in all cases. All patients developed anti-AAV5 neutralizing antibodies but no cellular responses against AAV5 or PBGD were observed. There was a trend towards a reduction of hospitalizations and heme treatments, although ALA and PBG levels remained unchanged. Vector genomes and transgene expression could be detected in the liver one year after therapy. CONCLUSIONS: rAAV2/5-PBGD administration is safe but AIP metabolic correction was not achieved at the doses tested in this trial. Notwithstanding, the treatment had a positive impact in clinical outcomes in most patients. LAY SUMMARY: Studies in an acute intermittent porphyria (AIP) animal model have shown that gene delivery of PBGD to hepatocytes using an adeno-associated virus vector (rAAV2/5-PBG) prevent mice from suffering porphyria acute attacks. In this phase I, open label, dose-escalation, multicenter clinical trial we show that the administration of rAAV2/5-PBGD to patients with severe AIP is safe but metabolic correction was not achieved at the doses tested; the treatment, however, had a positive but heterogeneous impact on clinical outcomes among treated patients and 2 out of 8 patients have stopped hematin treatment. CLINICAL TRIAL NUMBER: The observational phase was registered at Clinicaltrial.gov as NCT 02076763. The interventional phase study was registered at EudraCT as n° 2011-005590-23 and at Clinicaltrial.gov as NCT02082860.