A simple clinical score to promote and enhance ferroportin disease screening.

BACKGROUND & AIMS: Ferroportin disease is a rare genetic iron overload disorder which may be underdiagnosed, with recent data suggesting it occurs at a higher prevalence than suspected. Costs and the lack of defined criteria to prompt genetic testing preclude large-scale molecular screening. Hence, we aimed to develop a readily available scoring system to promote and enhance ferroportin disease screening. METHODS: Our derivation cohort included probands tested for ferroportin disease from 2008 to 2016 in our rare disease network. Data were prospectively recorded. Univariate and multivariate logistic regression were used to determine significant criteria, and odds ratios were used to build a weighted score. A cut-off value was defined using a ROC curve with a predefined aim of 90% sensitivity. An independent cohort was used for cross validation. RESULTS: Our derivation cohort included 1,306 patients. Mean age was 55±14 years, ferritin 1,351±1,357 µg/L, and liver iron concentration (LIC) 166±77 µmol/g. Pathogenic variants (n = 32) were identified in 71 patients. In multivariate analysis: female sex, younger age, higher ferritin, higher LIC and the absence of hypertension or diabetes were significantly associated with the diagnosis of ferroportin disease (AUROC in whole derivation cohort 0.83 [0.78-0.88]). The weighted score was based on sex, age, the presence of hypertension or diabetes, ferritin level and LIC. An AUROC of 0.83 (0.77-0.88) was obtained in the derivation cohort without missing values. Using 9.5 as a cut-off, sensitivity was 93.6 (91.7-98.3) %, specificity 49.5 (45.5-53.6) %, positive likelihood ratio 1.8 (1.6-2.0) and negative likelihood ratio 0.17 (0.04-0.37). CONCLUSION: We describe a readily available score with simple criteria and good diagnostic performance that could be used to screen patients for ferroportin disease in routine clinical practice. LAY SUMMARY: Increased iron burden associated with metabolic syndrome is a very common condition. Ferroportin disease is a dominant genetic iron overload disorder whose prevalence is higher than initially thought. They can be difficult to distinguish from each other, but the limited availability of genetic testing and the lack of definitive guidelines prevent adequate screening. We herein describe a simple and definitive clinical score to help clinicians decide whether to perform genetic testing.

Doxorubicin-loaded nanoparticles for patients with advanced hepatocellular carcinoma after sorafenib treatment failure (RELIVE): a phase 3 randomised controlled trial.

BACKGROUND: Cytotoxic chemotherapy is generally ineffective in patients with hepatocellular carcinoma. We assessed the intravenous perfusion of doxorubicin-loaded nanoparticles in patients with hepatocellular carcinoma in whom previous sorafenib therapy had failed. METHODS: We did a multicentre, open-label, randomised, controlled phase 3 trial at 70 sites in 11 countries. Patients with hepatocellular carcinoma with one or more previous systemic therapies, including sorafenib, were randomly assigned to receive 30 mg/m2 doxorubicin-loaded nanoparticles (30 mg/m2 group), 20 mg/m2 doxorubicin-loaded nanoparticles (20 mg/m2 group), or standard care using a computer-generated randomisation list prepared by the funder and stratified by geographic region. Patients in the experimental groups received perfusion of the drug every 4 weeks and those in the control group received any systemic anticancer therapy (except sorafenib) as per investigator decision. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in the population of patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT01655693. FINDINGS: Between June 15, 2012, and Jan 27, 2017, 541 patients were screened, of whom 144 were excluded and 397 were randomly assigned to one of the groups (133 to the 30 mg/m2 group; 130 to the 20 mg/m2 group; and 134 to the control group). Median follow-up was 22·7 months (IQR 11·2-34·9). After pooling the doxorubicin groups for the efficacy analysis, median overall survival was 9·1 months (95% CI 8·1-10·4) in the pooled doxorubicin-loaded nanoparticles group and 9·0 months (7·1-11·8) in the control group (HR 1·00 [95% CI 0·78-1·28], two-sided p=0·99). 227 (94%) of 242 patients who received doxorubicin-loaded nanoparticles and 100 (75%) of 134 patients in the control group had at least one treatment-emergent adverse event. The most common drug-related grade 3 or 4 treatment-emergent adverse events were neutropenia (25 [10%] of 242 treated with doxorubicin-loaded nanoparticles and eight [6%] of 134 in the control group), asthenia (six [2%] and four [3%]), and thrombocytopenia (three [1%] and ten [7%]). Six (2%) patients treated with doxorubicin-loaded nanoparticles and one (1%) of those in the control group were deemed by investigators to have had a drug-related death. Serious adverse events occurred in 74 (31%) patients who received doxorubicin-loaded nanoparticles and 48 (36%) in the control group. INTERPRETATION: Doxorubicin-loaded nanoparticles did not improve overall survival for patients with hepatocellular carcinoma in whom previous sorafenib treatment had failed. FUNDING: Onxeo.

Safety and efficacy of intra-arterial hepatic chemotherapy with doxorubicin-loaded nanoparticles in hepatocellular carcinoma.

BACKGROUND: Doxorubicin Transdrug (DT), a nanoformulation of doxorubicin, was demonstrated to overcome the chemoresistance of hepatocellular carcinoma (HCC) in preclinical models. Its efficacy and safety were thus investigated in phase I and randomised phase II trials in unresectable HCC. PATIENTS AND METHODS: Phase I was a single dose of DT through the hepatic intra-arterial (HIA) route, dose-escalating 3+3 trial, evaluating five-dose levels from 10 to 40 mg/m2 with maximal tolerated dose (MTD) as primary endpoint. The multicentre phase II trial randomly assigned (2:1 ratio) patients to receive either 30 mg/m2 of DT through HIA route every 4 weeks for up to three courses or best standard of care (BSC). Progression-free survival (PFS) rate at 3 months was the primary endpoint. Overall survival (OS) and disease control rate (DCR) were secondary endpoints. RESULTS: In phase I, haematological and respiratory limited toxicities were reported at 35 and 40 mg/m2, giving MTD at 30 mg/m2. Partial response rate was 10%, and stable disease 70%. Phase II was discontinued due to three severe acute respiratory distress events in the DT group while 17 patients had received 30 mg/m2 DT and 11 BSC. At 3 months, PFS was 64% (95% CI 31 to 89) vs 75% (95% CI 35 to 97), and DCR 35% vs 27% in DT and BSC, respectively (p=NS). Median OS was 32.6 months (95% CI 8.2 to 34.1) in DT group and 15 months (95% CI 8.0 to 18.8) in BSC group (p<0.05). CONCLUSION: DT increased OS in unresectable HCC but induced severe respiratory distress. Efficacy data deserve further investigation using a safer dosing and schedule regimen. TRIAL REGISTRATION NUMBER: EUDRACT 2006-004088-77; Results.

Salvage Versus Primary Liver Transplantation for Early Hepatocellular Carcinoma: Do Both Strategies Yield Similar Outcomes?

BACKGROUND DATA: In compensated cirrhotics with early hepatocellular carcinoma (HCC-cirr), upfront liver resection (LR) and salvage liver transplantation (SLT) in case of recurrence may have outcomes comparable to primary LT (PLT). OBJECTIVE: An intention-to-treat (ITT) analysis comparing PLT and SLT strategies. METHODS: Of 130 HCC-cirr patients who underwent upfront LR (group LR), 90 (69%) recurred, 31 could undergo SLT (group SLT). During the same period, 366 patients were listed for LT (group LLT); 26 dropped-out (7.1%), 340 finally underwent PLT (group PLT). We compared survival between groups LR and LLT, LR and PLT, and PLT and SLT. RESULTS: Feasibility of SLT strategy was 34% (31/90). In an ITT analysis, group LLT had better 5-yr/10-yr overall survival (OS) compared with group LR (68%/58% vs. 58%/35%; P = 0.008). Similarly, 5-yr/10-yr OS and disease-free survival (DFS) were better in group PLT versus group LR (OS 73%/63% vs. 58%/35%, P = 0.0007; DFS 69%/61% vs. 27%/21%, P < 0.0001). Upfront resection and microvascular tumor invasion were poor prognostic factors for both OS and DFS, presence of satellite tumor nodules additionally predicted worse DFS. Group SLT had similar postoperative and long-term outcomes compared with group PLT (starting from time of LT) (OS 54%/54% vs. 73%/63%, P = 0.35; DFS 48%/48% vs. 69%/61%, P = 0.18, respectively). CONCLUSIONS: In initially transplantable HCC-cirr patients, ITT survival was better in group PLT compared with group LR. SLT was feasible in only a third of patients who recurred after LR. Post SLT, short and long-term outcomes were comparable with PLT. Better patient selection for the "resection first" approach and early detection of recurrence may improve outcomes of the SLT strategy.

Impact of clinically evident portal hypertension on the course of hepatocellular carcinoma in patients listed for liver transplantation.

UNLABELLED: Liver transplantation (LT) is the best curative treatment for early hepatocellular carcinoma (HCC) in patients with cirrhosis. However, the current shortage of organs causes prolonged waiting times and poorer intention-to-treat (ITT) survival (i.e., after listing) owing to tumor progression and dropout. Portal hypertension (PH) is a recognized risk factor of HCC development in patients with cirrhosis and its recurrence after resection. The aim of this study was to evaluate the potential impact of PHT on the results of LT on an ITT basis. Patients with cirrhosis listed for LT for HCC were included and their outcomes after listing were compared according to the presence or absence of PH defined as presence of esophageal varices or ascites or low platelet count and splenomegaly. Among 243 consecutively listed patients, 70% were affected by PH, which was associated with a significantly higher risk of tumor progression (38% vs. 22%; P = 0.017) and a higher risk of dropout (22% vs. 8%; P = 0.01). Transarterial chemoembolization (TACE) was similarly applied to the two groups (60% vs. 67%; P = 0.325). An absence of TACE was the only other independent risk factor of dropout owing to tumor progression. Under an ITT analysis, PH reduced overall survival (OS), but there was no difference in OS and time to recurrence post-LT. The only pathological feature that could potentially explain this observation was the lower complete response to TACE in the PHT group (12% vs. 36%; P = 0.001). CONCLUSION: PH should be regarded as a major risk factor of dropout owing to tumor progression and should be taken into consideration when managing patients with HCC who are waiting for LT.

Resection or transplantation for early hepatocellular carcinoma in a cirrhotic liver: does size define the best oncological strategy?

BACKGROUND: Resection and liver transplantation (LT) are the only curative options for hepatocellular carcinoma in cirrhotic patients (HCC-cirr). OBJECTIVE: We tried to define the best primary intention-to-treat strategy in patients undergoing either resection or LT for early single HCC-cirr (≤5 cm). METHODS: From 1990 to 2010, 198 patients with early HCC-cirr underwent either resection (group R, n = 97) or LT (group T, n = 101) as the primary procedure. Our policy was to prioritize Childs A patients with peripheral lesions for resection rather than LT. Patient and tumor characteristics, and outcomes (recurrence-free survival [RFS] and overall survival [OS]), were studied. RESULTS: A longer diagnosis-to-surgery interval, more Child Pugh B/C patients, and more tumor nodules (on histopathological examination) were found in group T patients. The postoperative mortality (4.1% vs 3.0%, P = 0.72) and rate of major complications (19.1% vs 24.7%, P = 0.35) were similar in groups R and T, respectively, whereas tumor recurrence was higher in group R (62% vs 10% in group T, P < 0.0001). The 5-year OS (75% vs 52%, P = 0.0008) and RFS (72% vs 20%, P < 0.0001) were better in group T; similarly, more patients were disease free at last follow-up (27% vs 62%, P < 0.0001). Resection as the surgical procedure, tumor diameter 3 cm or more on histology, and microvascular tumor invasion were poor prognostic factors for OS and RFS. Including dropout patients from LT list in the analysis, the outcomes in group T were still better (70% and 61% vs 51% and 36% at 5 and 10 years, P = 0.01). CONCLUSIONS: On an intention-to-treat basis, LT is associated with the best survival outcomes in patients with early HCC-cirr. Resection may achieve comparable OS in patients with single HCC-cirr of size smaller than 3 cm; however, the RFS still remains lower than that in patients of group T. This study could serve as a guide for HCC-cirr patients who are candidates for either resection or LT.

[Biliary lithiasis]. / Lithiase biliaire.

No treatment is recommended for silent gallstones. The diagnosis of acute cholecystitis is based on clinical and biological signs and on abdominal sonography. Early laparoscopic cholecystectomy is the treatment of choice, except in case of severe (grade III) cholecystitis where a percutaneous cholecystostomy associated with antibiotic therapy is recommended. The diagnostic accuracy of abdominal sonography for the diagnosis of common bile duct stones is poor. A second-line MR cholangiopancreatography or an endoscopic sonography is often needed to confirm the diagnosis. The treatment of acute cholangitis is based on both antibiotic therapy and biliary drainage. Results of the treatment of common bile duct stone with either laparoscopic surgery or with the combined endoscopic sphincterotomy plus laparoscopic cholecystectomy are comparable when performed by well-trained practitionners. The choice of the method should be based on the locally available treatment.

Prediction of drainage effectiveness during endoscopic stenting of malignant hilar strictures: the role of liver volume assessment.

BACKGROUND: The optimal endoscopic approach to the drainage of malignant hilar strictures remains controversial, especially with regard to the extent of desirable drainage and unilateral or bilateral stenting. OBJECTIVE: To identify useful criteria for predicting successful endoscopic drainage. DESIGN AND SETTING: Retrospective 2-center study in the greater Paris area in France. PATIENTS: A total of 107 patients who had undergone endoscopic stenting for hilar tumors Bismuth type II, III, or IV and a set of contemporaneous cross-sectional imaging data available. INTERVENTIONS: The relative volumetry of the 3 main hepatic sectors (left, right anterior, and right posterior) was assessed on CT scans. The liver volume drained was estimated and classified into 1 of 3 classes: less than 30%, 30% to 50%, and more than 50% of the total liver volume. MAIN OUTCOME MEASUREMENTS: The primary outcome was effective drainage, defined as a decrease in the bilirubin level of more than 50% at 30 days after drainage. Secondary outcomes were early cholangitis rate and survival. RESULTS: The main factor associated with drainage effectiveness was a liver volume drained of more than 50% (odds ratio 4.5, P = .001), especially in Bismuth III strictures. Intubating an atrophic sector (<30%) was useless and increased the risk of cholangitis (odds ratio 3.04, P = .01). A drainage > 50% was associated with a longer median survival (119 vs 59 days, P = .005). LIMITATIONS: Heterogeneous population and volume assessment methodology to improve in further prospective studies. CONCLUSION: Draining more than 50% of the liver volume, which frequently requires bilateral stent placement, seems to be an important predictor of drainage effectiveness in malignant, especially Bismuth III, hilar strictures. A pre-ERCP assessment of hepatic volume distribution on cross-sectional imaging may optimize endoscopic procedures.

Hepatocellular carcinoma and occupation in men: a case-control study.

OBJECTIVE: The principal objective of this work was to evaluate the association between the risk of hepatocellular carcinoma (HCC) and various occupations. METHODS: This case-control study, conducted during 2000 to 2003 in four French hospitals, included 125 men younger than 75 years with incident HCC and 142 men as control subjects. RESULTS: An association with HCC was observed for machinery fitters and machine assemblers (odds ratio [OR] = 4.4 [1.0-19.0], eight exposed cases and three exposed controls). A higher percentage of cases than controls were metal machinists (OR = 2.2 [0.8-5.8], 14 exposed cases and 10 exposed controls), although the difference was not statistically significant. These associations were strongest for subjects with duration of employment greater than 20 years. CONCLUSIONS: Our findings suggest an association between metal machining jobs and hepatocellular carcinoma, although we cannot rule out the possibility that it was observed by chance.

Multiple peritoneal calcifying fibrous tumors revealed by ischemic colitis.

We report the case of a 41-year-old man presenting with multiple calcifying fibrous tumor (CFT) revealed by ischemic colitis. Peritoneal nodular lesions involved omental, mesenteric, mesorectal, and mesocolic serosal surfaces. Histologically, nodules were composed of dense bundles of collagen, calcifications, and lymphoplasmacytic infiltrate. These findings were diagnostic of CFTs, a rare and often asymptomatic benign fibrous process. Multiple peritoneal CFTs are very uncommon and usually occur in women. Calcifying fibrous tumors are usually cured by surgical excision. The differential diagnosis and histogenesis of this entity are discussed.

[Duodenal duplication revealed by acute pancreatitis: endoscopic treatment]. / Duplication duodénale révélée par une pancréatite aiguë: traitement endoscopique.

We report the case of a 17 year old man who presented with several episodes of acute pancreatitis due to a duodenal duplication. This was successfully treated by an incision by sphincterotome during interventional duodenoscopy. The patient is symptom free without recurrence 20 months after endoscopic treatment.

[Pancreatic intraductal tubular carcinoma: a sub-group of intraductal papillary-mucinous tumors or a distinct entity? A case report and review of the literature]. / Carcinome tubuleux intracanalaire pancréatique: sous-groupe ou entité distincte des tumeurs intracanalaires papillaires mucineuses? A propos d'un cas et revue de la littérature.

We report the case of a 67-year-old man presenting with an isolated 3 cm mass of the pancreatic tail revealed by weight loss. Distal pancreatectomy and splenectomy were performed. Microscopically, the tumor filled the main pancreatic duct, extending into the smaller ducts and was associated with a minor adenocarcinomatous invasive component. The intraductal tumor showed a cribriform pattern, atypical cells without mucus and a MUC1+, MUC2-, MUC5AC- phenotype, all characteristics of intraductal tubular carcinoma, a new entity described by Japanese authors. The differential diagnosis and its relationship with intraductal papillary-mucinous tumors are discussed.

[Post-cholecystectomy amputation neuroma of the common bile duct with obstructive jaundice]. / Sténose post-opératoire de la voie biliaire principale due à un névrome d'amputation post-cholécystectomie.

Amputation neuroma of the common bile duct after surgery is a rare and mostly asymptomatic lesion. A 60-year old patient presented with obstructive jaundice three months after a cholecystectomy for symptomatic gallstones. Imaging investigations showed common extrahepatic bile duct stenosis. Surgical resection of the stricture with biliodigestive anastomosis was performed. Histological examination of the surgical specimen revealed an amputation neuroma. Despite its rarity, amputation neuroma of the common bile duct should be considered in patients with post-cholecystectomy syndrome following liver or extrahepatic bile duct surgical procedures.

[A probable case of alveolar echinococcosis in Normandy, France]. / Un cas probable d'échinococcose alvéolaire en Normandie.

Echinococcus multilocularis induced liver infection was diagnosed in a Moroccan patient. Diagnosis was based on CT scan results and Western Blot test. Contamination probably occurred in France, in the Cherbourg area where the patient travelled frequently and ate wild berries. This case and other recently reported cases outside the usual endemic areas (Besançon and the Massif Central) suggest that the Echinococcus multilocularis epidemic has moved towards the west of France. French gastroenterologists should be aware of this parasitic disease.

Endoscopic treatment of cholangiocarcinoma and carcinoma of the duodenal papilla by intraductal high-intensity US: Results of a pilot study.

BACKGROUND: Local and infiltrative extension make some biliary carcinomas accessible to nonoperative intraductal destruction. This study assessed the clinical feasibility and short-term results of local tumor destruction with an intraductal high-intensity US probe during ERCP. METHODS: The probe is a flexible catheter with an 8 x 2.8 mm US transducer and a lumen for a guidewire. Ten patients (6 women, 4 men; mean age 74.8 years) were treated with this device. Lesions treated included carcinoma of the papilla (3), bile duct cholangiocarcinoma (2), Bismuth grade I and II hilar cholangiocarcinomas (4), and intrahepatic cystadenocarcinoma (1). Two patients underwent US therapy before surgery. Treatment was performed during standard ERCP: the probe was inserted through the malignant stricture and US therapy was applied over 360 degrees under fluoroscopic control. RESULTS: No serious adverse effects were observed; right upper abdominal pain developed in one patient for 12 hours. In one patient, histopathologic assessment of the resected tumor revealed extensive coagulation necrosis with inflammation up to 10 mm in depth surrounding the bile duct lumen. In the other operated patient, biopsy specimens from the treated portion of the bile duct were negative for malignancy. There was complete regression of cholangiocarcinoma of the bile duct in our patient, allowing for permanent stent removal (follow-up 30 months). A partial response was noted in 4 other patients and no response in 3 patients. CONCLUSIONS: This new method of intraductal tumor destruction by high-intensity US during ERCP is feasible and can induce objectively measurable tumor necrosis. Long-term follow-up will determine whether this method is curative in some cases and if it can reduce the need for biliary stent placement.