Isabella Reccia

Non-alcoholic fatty liver disease: A sign of systemic disease

Non-alcoholic fatty liver disease (NAFLD) is the most common form of liver disease and leading cause of cirrhosis in the United States and developed countries. NAFLD is closely associated with obesity, insulin resistance and metabolic syndrome, significantly contributing to the exacerbation of the latter. Although NAFLD represents the hepatic component of metabolic syndrome, it can also be found in patients prior to their presentation with other manifestations of the syndrome. The pathogenesis of NAFLD is complex and closely intertwined with insulin resistance and obesity. Several mechanisms are undoubtedly involved in its pathogenesis and progression. In this review, we bring together the current understanding of the pathogenesis that makes NAFLD a systemic disease.

Targeted Delivery of C/EBPα -saRNA by Pancreatic Ductal Adenocarcinoma-specific RNA Aptamers Inhibits Tumor Growth In Vivo

The 5-year survival rate for pancreatic ductal adenocarcinoma (PDAC) remains dismal despite current chemotherapeutic agents and inhibitors of molecular targets. As the incidence of PDAC constantly increases, more effective multidrug approaches must be made. Here, we report a novel method of delivering antitumorigenic therapy in PDAC by upregulating the transcriptional factor CCAAT/enhancer-binding protein-α (C/EBPα), recognized for its antiproliferative effects. Small activating RNA (saRNA) duplexes designed to increase C/EBPα expression were linked onto PDAC-specific 2′-Fluropyrimidine RNA aptamers (2′F-RNA) - P19 and P1 for construction of a cell type–specific delivery vehicle. Both P19- and P1-C/EBPα-saRNA conjugates increased expression of C/EBPα and significantly suppressed cell proliferation. Tail vein injection of the saRNA/aptamer conjugates in PANC-1 and in gemcitabine-resistant AsPC-1 mouse-xenografts led to reduced tumor size with no observed toxicity. To exploit the specificity of the P19/P1 aptamers for PDAC cells, we also assessed if conjugation with Cy3 would allow it to be used as a diagnostic tool on archival human pancreatic duodenectomy tissue sections. Scoring pattern from 72 patients suggested a positive correlation between high fluorescent signal in the high mortality patient groups. We propose a novel aptamer-based strategy for delivery of targeted molecular therapy in advanced PDAC where current modalities fail.

Aptamer-Drug Conjugates of Active Metabolites of Nucleoside Analogs and Cytotoxic Agents Inhibit Pancreatic Tumor Cell Growth

Aptamer-drug conjugates (ApDCs) have the potential to improve the therapeutic index of traditional chemotherapeutic agents due to their ability to deliver cytotoxic drugs specifically to cancer cells while sparing normal cells. This study reports on the conjugation of cytotoxic drugs to an aptamer previously described by our group, the pancreatic cancer RNA aptamer P19. To this end, P19 was incorporated with gemcitabine and 5-fluorouracil (5-FU), or conjugated to monomethyl auristatin E (MMAE) and derivative of maytansine 1 (DM1). The ApDCs P19-dFdCMP and P19-5FdUMP were shown to induce the phosphorylation of histone H2AX on Ser139 (γ-H2AX) and significantly inhibited cell proliferation by 51%–53% in PANC-1 and by 54%–34% in the gemcitabine-resistant pancreatic cancer cell line AsPC-1 (p ≤ 0.0001). P19-MMAE and P19-DM1 caused mitotic G2/M phase arrest and inhibited cell proliferation by up to 56% in a dose-dependent manner when compared to the control group (p ≤ 0.001). In addition, the cytotoxicity of P19-MMAE and P19-DM1 in normal cells and the control human breast cancer cell line MCF7 was minimal. These results suggest that this approach may be useful in decreasing cytotoxic side effects in non-tumoral tissue.

An uncommon presentation of metastatic melanoma: a case report.

AbstractMetastases to the spleen are rare and are generally part of a multi-visceral metastatic disease. The most common sources of splenic metastases include breast, lung and colorectal malignancies as well as melanoma and ovarian carcinoma. Solitary splenic metastasis is very uncommon.We present a case of a 44-year-old man who presented at our department for gallstones symptoms. He had a past medical history of neck cutaneous melanoma (T3bN0M0—Stage IIb). He had not attended follow-up schedule for personal reasons. However, abdominal ultrasound revealed the presence of a solitary solid lesion in the spleen. Preoperative workup was completed with CT scan that confirmed the presence of a large splenic lesion with subcapsular fluid collection, also compatible with a post-traumatic lesion.Preoperative findings could not exclude malignancy and patient was therefore submitted to surgery. At laparoscopy, a condition of peritoneal melanosis was present. Splenectomy was carried out. Histological report confirmed the peritoneal melanosis and the diagnosis of metastatic spleen lesion from melanoma. Patient was observed, but died of metastatic disease 14 months after surgery.Splenic metastases are uncommon. Isolated metastases from melanoma are rare and could be found several months after primary diagnosis of melanoma. Surgery remains the most effective treatment, especially for metachronous disease, offering the best chance of long-term survival. Prognosis remains poor, as metachronous disease is indicative of aggressive widespread of the disease.

The Role of Normothermic Perfusion in Liver Transplantation (TRaNsIT Study): A Systematic Review of Preliminary Studies

Introduction The success of liver transplantation has been limited by the unavailability of suitable donor livers. The current organ preservation technique, i.e., static cold storage (SCS), is not suitable for marginal organs. Alternatively, normothermic machine perfusion (NMP) promises to recreate the physiological environment and hence holds promise for the better organ preservation. The objective of this systematic review is to provide an overview of the safety, benefits, and insight into the other potential useful parameters of NMP in the liver preservation. Material and Methods We searched the current literature following registration in the International Prospective Register of Systematic Reviews (PROSPERO) with registration number CRD42018086034 for prospective trials comparing the role of NMP device to SCS in liver transplant by searching the PubMed, EMBASE, Cochrane, BIOSIS, Crossref, and Scopus databases and clinical trial registry. Results The literature search identified five prospective clinical trials (four being early phase single institutional and single randomized multi-institutional) comparing 187 donor livers on NMP device to 273 donor livers on SCS. The primary outcome of interest was to assess the safety and graft survival at day 30 after transplant following NMP of the donor liver. Secondary outcomes included were early allograft dysfunction (EAD) in the first seven days; serum measures of liver functions as bilirubin, aspartate aminotransferase (AST), alanine amino transferase (ALT), alkaline phosphatase (ALP), and international normalized ratio (INR) on days 1–7; major complications as defined by a Clavien-Dindo score ≥ 3; and patient and graft survival and biliary complications at six months. The peaked median AST level between days 1 and 7 in the five trials was 417–1252 U/L (range 84–15009 U/L) while on NMP and 839–1474 U/L (range 153–8786 U/L) in SCS group. The median bilirubin level on day 7 ranged within 25–79 µmol/L (range 8–344 µmol/l) and 30–47.53 µmol/l (range 9–340 µmol/l) in NMP and SCS groups, respectively. A single case of PNF was reported in NMP group in the randomized trial while none of the other preliminary studies reported any in either group. There was intertrial variability in EAD which ranged within 15–56% in NMP group while being within 23–37% in SCS group. Biliary complications observed in NMP group ranged from 0 to 20%. Single device malfunction was reported in randomized controlled trial leading to renouncement of transplant while none of the other trials reported any machine failure, although two user related device errors inadvertent were reported. Conclusion This review outlines that NMP not only demonstrated safety and efficacy but also provided the favourable environment of organ preservation, repair, and viability assessment to donor liver prior to the transplantation with low rate of posttransplantation complication as PNF, EAD, and biliary complication; however further studies are needed to broaden our horizon.

The journey of radiofrequency-assisted liver resection

Please cite this article in press as: I. Reccia doi.org/10.1016/j.suronc.2018.01.004 Due to its high propensity for significant bleeding, the liver has historically been considered a treacherous organ on which to carry out surgery. The first patient reported to have undergone liver resection by Dr A Lius in Italy in 1886 died 6 hours postoperatively due to bleeding. In 1957, Claude Couinaud, a French surgeonwhowas also a dedicated liver anatomist, named the liver segments in a concentric way from segment 1 to segment 8 based on central Paris arrondissements [1]. Whether this is true or just an appealing myth, Couinaud was the first one to describe the segmental anatomy of the liver and introduced the concept of modern liver surgery based on the functional and surgical anatomy of the liver [2]. Only a few decades later, the “anatomical approach” for liver resection was translated into practice by Henri Bismuth, when he applied the knowledge of liver segmental anatomy to the liver resection technique to avoid complications, in particular uncontrolled hemorrhage, when performing non-anatomical liver resection [3]. The parenchymal transection phase of liver resection has always been a critical step. Several techniques to reduce intraoperative bleeding and liver-related complications have been developed, including inflow control (Pringles maneuver) [4], Makuuchis intermittent hemihepatic inflow occlusion [5] and other selective inflow clamping techniques [6], Glissonean pedicle approach [7], Belghitis technique for hepatic vein occlusion [8], total vascular exclusion [9], and the use of low central venous pressure during surgery [10]. After Bismuth, anatomical liver resection gained popularity in view of better outcomes, reduced blood loss and benefits of liver parenchyma preservation. Subsequently, with improvement in intraoperative ultrasound and surgical technique, segmental and subsegmental resections became the gold standard for liver resection, particularly for hepatocellular carcinoma [11e13]. For colorectal cancer liver metastases, the introduction of more effective chemotherapeutic agents, the expansion of criteria for resectability, the introduction of volume augmentation techniques (portal vein embolization, two-stage hepatectomies), the combination of resection with ablation, and the use of neoadjuvant chemotherapy to decrease tumour volume have all contributed to a significant increase in the number of patients with secondary liver tumors undergoing surgery [14]. In these patients, non-anatomical, parenchymal-sparing resection is now considered a comparable technique to anatomical resection with achievement of similar oncological outcomes [15]. Energy-based devices generate mechanic or electric energy to allow transection of the liver parenchyma and/or sealing of blood vessels and bile ducts during liver resection [16]. Different devices have been developed but no consensus exits in regards to standard

Radiofrequency assisted pancreaticoduodenectomy for palliative surgical resection of locally advanced pancreatic adenocarcinoma

Background Despite careful patient selection and preoperative investigations curative resection rate (R0) in pancreaticoduodenectomy ranges from 15% to 87%. Here we describe a new palliative approach for pancreaticoduodenectomy using a radiofrequency energy device to ablate tumor in situ in patients undergoing R1/R2 resections for locally advanced pancreatic ductal adenocarcinoma where vascular reconstruction was not feasible. Results There was neither postoperative mortality nor significant morbidity. Each time the ablation lasted less than 15 minutes. Following radiofrequency ablation it was observed that the tumor remnant attached to the vessel had shrunk significantly. In four patients this allowed easier separation and dissection of the ablated tumor from the adherent vessel leading to R1 resection. In the other two patients, the ablated tumor did not separate from vessel due to true tumor invasion and patients had an R2 resection. The ablated remnant part of the tumor was left in situ. Conclusion Whenever pancreaticoduodenectomy with R0 resection cannot be achieved, this new palliative procedure could be considered in order to facilitate resection and enable maximum destruction in remnant tumors. Method Six patients with suspected tumor infiltration and where vascular reconstruction was not warranted underwent radiofrequency-assisted pancreaticoduodenectomy for locally advanced pancreatic ductal adenocarcinoma. Radiofrequency was applied across the tumor vertically 5–10 mm from the edge of the mesenteric and portal veins. Following ablation, the duodenum and the head of pancreas were removed after knife excision along the ablated line. The remaining ablated tissue was left in situ attached to the vessel.

Gene activation of CEBPA using saRNA: preclinical studies of the first in human saRNA drug candidate for liver cancer

Liver diseases are a growing epidemic worldwide. If unresolved, liver fibrosis develops and can lead to cirrhosis and clinical decompensation. Around 5% of cirrhotic liver diseased patients develop hepatocellular carcinoma (HCC), which in its advanced stages has limited therapeutic options and negative survival outcomes. CEPBA is a master regulator of hepatic function where its expression is known to be suppressed in many forms of liver disease including HCC. Injection of MTL-CEBPA, a small activating RNA oligonucleotide therapy (CEBPA-51) formulated in liposomal nanoparticles (NOV340- SMARTICLES) upregulates hepatic CEBPA expression. Here we show how MTL-CEBPA therapy promotes disease reversal in rodent models of cirrhosis, fibrosis, hepatosteatosis, and significantly reduces tumor burden in cirrhotic HCC. Restoration of liver function markers were observed in a carbon-tetrachloride-induced rat model of fibrosis following 2 weeks of MTL-CEBPA therapy. At 14 weeks, animals showed reduction in ascites and enhanced survival rates. MTL-CEBPA reversed changes associated with hepatosteatosis in non-alcoholic methionine and cholic-deficient diet-induced steaotic liver disease. In diethylnitrosamine induced cirrhotic HCC rats, MTL-CEBPA treatment led to a significant reduction in tumor burden. The data included here and the rapid adoption of MTL-CEBPA into a Phase 1 study may lead to new therapeutic oligonucleotides for undruggable diseases.

Systemic meta-analysis assessing the short term applicability of early conversion to mammalian target of rapamycin inhibitors in kidney transplant

AIM To consolidate the present evidence of effectiveness in renal functioning and graft survival following early introduction of mammalian target of rapamycin (mTOR) inhibitors with or without calcineurin inhibitors (CNIs) in renal transplant recipients. METHODS We analysed the current literature following PROSPERO approval describing the role of immunosuppressive agent, mTOR inhibitors as an alternative to CNI within six months of renal transplant by searching the PubMed, EMBASE, Cochrane, Crossref, and Scopus using MeSH terms. RESULTS Six articles of early withdrawal of CNI and introduction of mTOR-inhibitors within six months of renal transplantation were sought. Glomerular filtration rate (GFR) and serum creatinine were significantly better in mTOR inhibitor group with equivalent survival at 12 mo, even though Biopsy Proven Acute rejection was significantly higher in mTOR-inhibitor group. CONCLUSION The evidence reviewed in this meta-analysis suggests that early introduction mTOR-inhibitors substantial CNI minimization. The mTOR inhibitors such as everolimus and sirolimus, due to their complementary mechanism of action and favourable nephrotoxicity profile; better glomerular filtration, lower serum creatinine with equivalent survival. Having said that, due to the higher rejection rate, may influence the use of these regimens to patients with moderate to high immunological risk patients.

Radiofrequency-assisted liver resection: Technique and results

BACKGROUND Radiofrequency (RF)-assisted liver resection allows non-anatomical liver resection with reduced blood loss and offers the opportunity for a combination of resection and ablation. However, there are still concerns with regard to postoperative complications related to this technique. In the present study, we discuss the technical aspects of RF-assisted liver resections and analyse the rate of perioperative complications, focusing on post-hepatectomy liver failure (PLF), bile leak and abscess, and mortality. METHODS Between 2001 and 2015, 857 consecutive open and laparoscopic elective RF-assisted liver resections for benign and malignant liver tumours were reviewed retrospectively to assess perioperative outcomes. RESULTS Median intraoperative blood loss was 130 mL, with 9.8% of patients requiring blood transfusion. Intra-abdominal collections requiring percutaneous drainage developed in 8.7% of all patients, while bile leak at resection margin developed in 2.8% of the cases. Major liver resection was performed in 34% of patients and the incidence of PLF was 1.5% with one directly related mortality (0.1%). CONCLUSION RF-assisted liver resection has evolved into a feasible and safe technique of liver resection with an acceptable incidence of perioperative morbidity and a low incidence of PLF and related mortality.