Combined inhibition of IL-1, IL-33 and IL-36 signalling by targeting IL1RAP ameliorates skin and lung fibrosis in preclinical models of systemic sclerosis.

BACKGROUND: The interleukin (IL)-1 receptor accessory protein (IL1RAP) is an essential coreceptor required for signalling through the IL-1, IL-33 and IL-36 receptors. Here, we investigate the antifibrotic potential of the combined inhibition of these cytokines by an anti-IL1RAP antibody to provide a scientific background for clinical development in systemic sclerosis (SSc). METHODS: The expression of IL1RAP-associated signalling molecules was determined by data mining of publicly available RNA sequencing (RNAseq) data as well as by imaging mass cytometry. The efficacy of therapeutic dosing of anti-IL1RAP antibodies was determined in three complementary mouse models: sclerodermatous chronic graft-versus-host disease (cGvHD), bleomycin-induced dermal fibrosis model and topoisomerase-I (topo)-induced fibrosis. RESULTS: SSc skin showed upregulation of IL1RAP and IL1RAP-related signalling molecules on mRNA and protein level compared with normal skin. IL-1, IL-33 and IL-36 all regulate distinct gene sets related to different pathophysiological processes in SSc. The responses of human fibroblasts and endothelial cells to IL-1, IL-33 and IL-36 were completely blocked by treatment with an anti-IL1RAP antibody in vitro. Moreover, anti-IL1RAP antibody treatment reduced dermal and pulmonary fibrosis in cGvHD-induced, bleomycin-induced and topoisomerase-induced fibrosis. Importantly, RNAseq analyses revealed effects of IL1RAP inhibition on multiple processes related to inflammation and fibrosis that are also deregulated in human SSc skin. CONCLUSION: This study provides the first evidence for the therapeutic benefits of targeting IL1RAP in SSc. Our findings have high translational potential as the anti-IL1RAP antibody CAN10 has recently entered a phase one clinical trial.

An Attempt to Build a National Prospective Electronic Database for Pancreaticoduodenectomies in Romania - Preliminary Results of the First Year Enrollment.

Introduction: National databases for pancreaticoduodenectomies (PD) have contributed to better postoperative outcomes after such complex surgical procedure because the multicentre collection of data allowed more reliable analyses with quality assessment and further improvement of technical issues and perioperative management. The current practice and outcomes after PD are poorly known in Romania because there was no national database for these patients. Thus, in 2016 a national-intent electronic registry for PD was proposed for all Romanian surgical centers. The study aims to present the preliminary results of this national-intent registry for PD after one-year enrollment. Patients Methods: The database was started on October 1st, 2016. Data were prospectively collected with an electronic online form including 102 items for each patient. The registry was opened to all the Departments of Surgery from Romania performing PD, with no restriction. Results: During the first year of enrollment were collected the data of 181 patients with PD performed by 24 surgeons from four surgical centers. The age of patients was 64 years (28 - 81 years), with slightly male predominance (61.3%). Computed tomography was the main preoperative imaging investigation (84.5%). All the PDs were performed by an open approach. The Whipple technique was used in 53% of patients, and a venous resection was required in 14.3% of cases. A posterior approach PD was considered in 16.6% of patients. The stomach was used to treat the distal remnant pancreas in 50.1% of patients. The operative time was 285 min (110 - 615 min), and the estimated blood loss was 400 ml (80 - 3000 ml). The overall morbidity rate was 55.8%, with severe (i.e., grade III-IV Dindo-Clavien) morbidity rate of 10%, and 3.9% in-hospital mortality rate. The overall pancreatic fistula, delayed gastric emptying and hemorrhage rates were 19.9%, 39.8% and 15.5%. Periampullary malignancies were the main indications for PD (78.9%), with pancreatic cancer on the top (48%). Conclusions: To build a prospective electronic online database for PD in Romania appears to be a feasible project and a useful tool to know the current practice and outcomes after PD in our country. However, improvements are still required to encourage a larger number of surgical centers to introduce the data of patients with PD.

Diagnosis, morphopathological profile and treatment of mucinous cystadenoma of the pancreas - a single center experience.

AIM: Pancreatic mucinous cystadenoma (MCA) occurs almost exclusively in perimenopausal women and represents between 10% and 45% of cystic neoplasm of the pancreas, being considered a premalignant lesion. MATERIALS AND METHODS: From 1983 to 2017, 31 patients underwent surgery for MCA of the pancreas in our Center. The median age was 47 years (range 17-81 years). All data were obtained retrospectively. RESULTS: The female∕male gender ratio was 14.5∕1. Most of the patients (90.3%) were symptomatic. The most common clinical manifestation was non-specific abdominal pain (58.06%), followed by fatigue and vomiting. The median cyst size was 7 cm, with a range between 2 cm and 15 cm. There were 35 procedures in 31 patients (in four patients the resection was preceded by a drainage procedure). From the 28 resections, most of them (89.28%) were performed by an open approach; a minimal invasive approach was used in three patients (robotic - two; laparoscopic - one). Most of the resections (82.14%) were distal pancreatectomies. In all cases, the final diagnosis was based on histological examination that revealed columnar epithelium and ovarian-type stroma. Postoperative complications occurred in 10 (34.48%) patients. Postoperative mortality was 3.44% (one patient) by septic shock secondary to acute postoperative pancreatitis. CONCLUSIONS: MCAs represent a rare pancreatic pathology with challenging diagnostic and therapeutic implications. Multi-detector computed tomography (MDCT) scan, endoscopic ultrasound (EUS) and magnetic resonance imaging (MRI)∕magnetic resonance cholangiopancreatography (MRCP) are useful in the differential diagnosis with other pancreatic fluid collections and treatment. Oncological surgical resections are recommended. Histopathological examination establishes the final diagnosis. The most common postoperative complication is pancreatic fistula.

The Romanian National Program for Liver Transplantation - 852 Procedures in 815 Patients over 17 Years (2000-2017): A Continuous Evolution to Success.

Background: Liver transplantation (LT) has become an established treatment for end-stage liver disease, with more than 20.000 procedures yearly worldwide. The aim of this study was to analyze the results of Romanian National Program of LT. Methods: Between April 2000 and April 2017, 817 pts received 852 LTs in Romania. Male/female ratio was 487/330, while adult/pediatric ratio was 753/64, with a mean age of 46 years (median 50 yrs; range 7 months - 68 yrs). Main LT indications were HBV cirrhosis (230 pts; 28.2%), HCC (173 pts; 21.2%), and HCV cirrhosis (137 pts; 16.8%). Waiting time and indications for LT, patient and donor demographics, graft features, surgical procedures, and short and long-term outcomes were analyzed. Results: DDLT was performed in 682 pts (83.9%): whole LT in 662 pts (81%), split LT in 16 pts (2.3%), reduced LT in 2 pts (0.2%), and domino LT in 1 pts (0.1%). LDLT was performed in 135 pts (16.5%): right hemiliver in 93 pts (11.4%), left lateral section in 28 pts (3.4%), left hemiliver in 8 pts (1%), left hemiliver with segment 1 in 4 pts (0.5%), and dual graft LDLT in 2 pts (0.2%). Overall major morbidity rate was 31.4% (268 pts), while perioperative mortality was 7.9% (65 pts). Retransplantation rate was 4.3% (35 pts): 27 whole LTs, 3 reduced LTs, 3 split LTs, and 2 LDLT. Long-term overall 1-, 3-, and 5-year estimated survival rates for patients were 87.9%, 81.5%, and 79.1%, respectively. One-, 3-, and 5-year overall mortality on waiting list also decreased significantly over time from 31.4%, 54.1% and 63.5%, to 4.4%, 13.9% and 23.6%, respectively. Conclusions: The Romanian National program for liver transplantation addresses all causes of acute and chronic liver failure or liver tumors in adults and children, using all surgical techniques, with good long-term outcome. The program constantly evolved over time, leading to decreased mortality rate on the waiting list.

Hereditary Spherocytosis - Diagnosis, Surgical Treatment and Outcomes. A Literature Review.

Hereditary spherocytosis (HS) is a disease affecting the red blood cells membrane and belongs to the congenital hemolytic anemias. The clinical spectrum ranges from asymptomatic patients to severe forms requiring transfusions in early childhood. The diagnosis can be based on the physical examination, complete red blood cell count, reticulocytes count, medical history and specific tests, preferentially the EMA test (eosin-5-maleimide binding) test and AGLT (Acidified Glycerol Lysis Time). Splenectomy is considered the standard surgical treatment in moderate and severe forms of hereditary spherocytosis. Total splenectomy exposes the patient to a life - long risk of potentially lethal infections and thus, its usage was reconsidered. Because of this reason, a feasible alternative is the partial splenectomy. The use of partial splenectomy aims to retain splenic immunologic function, while at the same time to decrease the rate of hemolysis. The long - term outcomes of patients with total or subtotal splenectomy for congenital hemolytic anemia, still remain unclear, but the majority of the studies showed a qualitative resolution of anemia and reduction of transfusion rate. Despite the well known advantages of conservative surgery, the optimal choice of treatment and outcomes should be confirmed with the patient.

Fibrolamellar hepatocellular carcinoma with ovarian metastasis - an unusual presentation.

AIM: Fibrolamellar carcinoma (FLC) has been considered a distinct clinical entity vs. hepatocellular carcinoma, with respect to its epidemiology, etiology, and prognosis. CASE PRESENTATION: We describe the unusual case of a 23-year-old female patient with FLC and ovarian (Krukenberg) and peritoneal metastases, clinically mimicking an ovarian carcinoma. Multiple recurrences occurred despite initial R0 resection and chemotherapy, requiring surgical treatment. The patient survived five years and died from generalized disease. DISCUSSION: The particularities of our case are discussed by comparison with the other two similar cases and other date from the literature. CONCLUSIONS: To our knowledge, the ovarian involvement encountered in our case is the third case published in literature, being explained by the superficial location of the liver tumor.

Biliary complications after liver transplantation--523 consecutive cases in two centers.

BACKGROUND/AIMS: Despite various surgical techniques, biliary tract complications (BC) remain a major source of morbidity after liver transplantation (LT). METHODOLOGY: Between April 2000 and November 2008, 523 LTs in 487 recipients (36 re transplantations) were performed as follows: 402 whole deceased donor graft LTs, and 121 partial liver transplantation: 75 living donor liver transplantation, 42 split liver transplantation, and 4 reduced size liver transplantation. RESULTS: Mean follow-up period was 935 days (range 1-3174), 1, 3 and 5-year survival rates were 78.7% 74.2% and 74.2%, respectively. One hundred twenty seven patients--from 487 (26%), developed (after 135 LT) 150 singular BC (in total were 181 BC). Sixty four (of 85) bile leaks (75.29%) were early BC, while 53 (of 63) stenosis (84.1%) were late BC. BC does not influenced significantly patients and graft survival (p > 0.6). From 102 deaths, 8 were due to BC (1.6%) and in only 14 (2.67%) graft loss of 523 LT BC had the main role. Multiple ducts, multiple biliary anastomosis and RYHJ determine BC if compared to a single duct graft. Moreover, ductoplasty, graft type and HAT were independent risk factors. CONCLUSION: Biliary complications are common after LT but are rarely an isolated cause of death.

Domino liver transplantation using a graft from a donor with familial hypercholesterolemia: seven-yr follow-up.

A 46-yr-old female with hepatocellular carcinoma and severe hepatitis B-related liver cirrhosis received a domino liver graft from a 25-yr-old female with homozygous familial hypercholesterolemia (HFHC) in September 2001. Hypercholesterolemia occurred in the graft recipient within one yr after transplantation and was partially controlled by atorvastatin. Three yr after transplantation, an autologous CD34(+) cell transplantation was performed in order to better control the hypercholesterolemia. Only preliminary results of this domino liver transplantation (DLT) were published in 2003, without a long-term analysis of the hypercholesterolemic effects in recipient. Subsequent to DLT, the average plasma cholesterol level in the domino donor rapidly normalized and seven yr after had a value of 182 mg/dL. After seven-yr follow-up, the domino recipient has no hepatocarcinoma recurrence. Moreover, no signs of cardiovascular or atherosclerotic lesions were noted despite an elevated plasma cholesterol level (339 mg/dL after seven yr of follow-up) resistant to drug therapy and stem cell autotransplantation. In conclusion, DLT using a liver graft from a patient with HFHC provides a viable option for marginal recipients.

Multimodal treatment of hepatocellular carcinoma: an eastern European experience.

BACKGROUND/AIMS: The aim of the present study was to evaluate the outcomes of a multimodal treatment approach of hepatocellular carcinoma (HCC) in a tertiary hepatobiliary specialty center. METHODOLOGY: A total of 294 consecutive patients treated for HCC were retrospectively analyzed. Two hundred sixteen patients (73.4%) were men and 78 (26.6%) were women. Liver resection (LR) was performed in 201 patients (68.4%), liver transplantation (LT) in 19 patients (6.5%), radiofrequency ablation (RFA) in 74 patients (25.1%), and 56 (19%) patients received adjuvant systemic chemotherapy. RESULTS: The median follow-up was 15.7 mo (range 0.1-90.3). Five-year overall survival and recurrence rates were 28% and 26.8%, respectively. Serum AFP > 43.8ng/ml (p = 0.005), BCLC C/D (p = 0.006) and JIS 3/4/5 classifications (p = 0.02) were independent negative prognostic factors for overall survival, while JIS 3/4/5 (p = 0.01) and BCLC C/D (p = 0.01) classifications, tumors larger than 6.5cm (p = 0.001) and RFA (p = 0.02) were independent predictors for recurrence. CONCLUSIONS: The current treatment of HCC should be multimodal, and therapeutic modalities and their combinations should be tailored to each patient. LT represents the best therapeutic option for patients with HCC in the setting of cirrhosis. Resection remains a good option in cirrhotic patients, while RFA is a safe and effective procedure for small tumors.

Costs and efficacy of "on demand" low-dose immunoprophylaxis in HBV transplanted patients: experience in the Romanian program of liver transplantation.

BACKGROUND: HBV in liver transplant (LT) patients is associated with good outcomes and the challenges are primarily focused around optimizing prophylactic regimens with hepatitis B immune globulin (HBIG) and minimizing related costs. AIM: To identify recurrence rates in patients transplanted for HBV or HBV+HDV infection in whom a combined "on demand" low-dose HBIG was used, maintaining low anti-HBs titres (not below 50 IU/L). METHODS: Medical records of 42 patients transplanted for HBV or HBV+HDV induced cirrhosis between April 2000 and September 2007 at Fundeni Clinical Institute were analyzed. Patients received immunoprophylaxis with lamivudine and HBIG (10,000 IU within anhepatic phase and daily within the first postoperative week, followed by 2,500 IU on demand). HBV recurrence rates and survival during follow-up were evaluated using the Kaplan Meier method. RESULTS: HBV recurrence rate was 4.8% after a median of 1.8 years. Three year patient survival rate was 70%. None of the patients died due to liver failure related to HBV recurrence. Using our "on demand" low-dose administration of HBIG, the total mean cost for HBIG and lamivudine for patient per month of survival was 598.3 Eur. The projected monthly cost for the "ideal" schedule/patient was 2,017 Eur. CONCLUSION: Individualization of immunoprophylaxis after LT for HBV related disease according to the lowest protective anti-HBs titers in combination with lamivudine is probably the best approach for non-replicative pre-LT patients in terms of costs and efficacy.