Electrochemotherapy in pancreatic adenocarcinoma treatment: pre-clinical and clinical studies.

BACKGROUND: Pancreatic adenocarcinoma is currently one of the deadliest cancers with high mortality rate. This disease leads to an aggressive local invasion and early metastases, and is poorly responsive to treatment with chemotherapy or chemo-radiotherapy. Radical resection is still the only curative treatment for pancreatic cancer, but it is generally accepted that a multimodality strategy is necessary for its management. Therefore, new alternative therapies have been considered for local treatment. CONCLUSIONS: Chemotherapeutic resistance in pancreatic cancer is associated to a low penetration of drugs into tumour cells due to the presence of fibrotic stroma surrounding cells. In order to increase the uptake of chemotherapeutic drugs into tumour cells, electrochemotherapy can be used for treatment of pancreatic adenocarcinoma leading to an increased tumour response rate. This review will summarize the published papers reported in literature on the efficacy and safety of electrochemotherapy in pre-clinical and clinical studies on pancreatic cancer.

Salvage radiofrequency ablation for microwave ablation treated hepatocellular carcinoma complicated by gas gangrene: case report.

AIM: Gas gangrene (GG) is a rare severe infection with a very high mortality rate mainly caused by Clostridium species. It develops suddenly, often as a complication of abdominal surgery or liver transplantation. We report a case of GG of the liver occurred after percutaneous microwave (MW) ablation of an hepatocellular carcinoma (HCC) successfully treated with percutaneous Radiofrequency ablation (RFA). CASE PRESENTATION: A 76-year-old female patient was treated with MW ablation for a large HCC in the VIII segment; 2 days later she developed fever, weakness, abdominal swelling and was hospitalized with diagnosis of anaerobic liver abscess. Despite antibiotic therapy, the patient conditions worsened, and she was moved to the intensive care unit (ICU). Percutaneous drainage was attempted, but was unsuccessful. The surgeon and the anesthesiologist excluded any indication of surgical resection. We performed RFA of the GG by 3 cool-tip needles into the infected area. The procedure was well tolerated by the patient, who left the hospital for follow-up. CONCLUSION: Percutaneous RFA could be a valuable therapy of focal GG of the liver in patients refractory to antibiotics and when surgery and OLT are not feasible. A fast and early indication is needed in case of rapid worsening of the patient's conditions.

Is There Indication for the Use of Biological Mesh in Cancer Patients?

Up to 28% of all patients who undergo open surgery will develop a ventral hernia (VH) in the post-operative period. VH surgery is a debated topic in the literature, especially in oncological patients due to complex management. We searched in the surgical database of the Hepatobiliary Unit of the National Cancer Institute of Naples "G. Pascale Foundation" for all patients who underwent abdominal surgery for malignancy from January 2010 to December 2018. Our surgical approach and our choice of mesh for VH repair was planned case-by-case. We selected 57 patients that fulfilled our inclusion criteria, and we divided them into two groups: biological versus synthetic prosthesis. Anterior component separation was used in 31 patients (54.4%) vs. bridging procedure in 26 (45.6%). In 41 cases (71.9%), we used a biological mesh while a synthetic one was adopted in the remaining patients. Of our patients, 57% were male (33 male vs. 24 female) with a median age of 65 and a mean BMI of 30.8. We collected ventral hernia defects from 35 cm2 to 600 cm2 (mean 205.2 cm2); 30-day complications were present in 24 patients (42.1%), no 30-day mortality was reported, and 21 patients had a recurrence of pathology during study follow-up. This study confirms VH recurrence risk is not related with the type of mesh but is strongly related with BMI and type of surgery also in oncological patients.

Epigallocatechin-3-gallate in the prevention and treatment of hepatocellular carcinoma: experimental findings and translational perspectives.

Hepatocellular carcinoma (HCC), a primary liver malignancy, is one of the deadliest cancers worldwide. Despite orthotopic liver transplantation and hepatic resection representing the principal lines of treatment for this pathology, only a minority of patients can be resected owing to cirrhosis or late diagnosis. Keeping in mind the end goal of conquering these challenges, new alternative approaches have been proposed. Accumulating evidence has demonstrated that epigallocatechin-3-gallate (EGCG), the principal catechin of green tea with multiple biological properties, is able to modulate different molecular mechanisms underlying HCC, mainly through its antioxidant activity. In this article, we revise these findings reported in the literature, in order to highlight the potential roles of EGCG in the treatment of HCC. The CAMARADES criteria were applied for quality assessment of animal studies, and a narrative synthesis performed. New bits of information available for translational perspectives into clinical practice are addressed.

Dissecting the roles of thymoquinone on the prevention and the treatment of hepatocellular carcinoma: an overview on the current state of knowledge.

Thymoquinone (TQ) is the principal active monomer isolated from the seed of the medicinal plant Nigella sativa. This compound has antitumor effects against various types of cancer including hepatocellular carcinoma (HCC), mainly due to its anti-inflammatory and anti-oxidant properties. Several pre-clinical studies showed that TQ, through the modulation of different molecular pathways, is able to induce anti-apoptotic and anti-proliferative effects in HCC, without signs of toxicity. Moreover, it has been suggested that TQ has hepatoprotective effects by enhancing the tolerability and effectivity of neoadjuvant therapy prior to liver surgery, although the underlying mechanisms are not completely understood. Based on these findings, is assumable that TQ could represent a valuable therapeutic option for patients suffering from HCC. In this review, we summarize the potential roles of TQ in the prevention and treatment of HCC, by revising the preclinical studies and by highlighting the potential applications of TQ as a therapeutic choice for HCC treatment into clinical practices.

Irreversible electroporation of locally advanced solid pseudopapillary carcinoma of the pancreas: A case report.

INTRODUCTION: Solid pseudopapillary Carcinoma (SPC) is a rare pancreatic Tumor with variable, usually low, malignancy potential. Howewer, several SPC are associated with aggressive behavior, local vascular infiltration, organ invasion, distant metastasis, and can be unresectable. Irreversible Electroporation (IRE) is an emerging non-thermal ablation technique for the treatment of locally advanced pancreatic carcinoma. We report the results of four year disease-free follow-up in a case of locally advanced unresectable SPC treated with IRE. PRESENTATION OF CASE: A 24-year female patient with SPC of the pancreas underwent IRE during laparotomy under general anesthesia with intubation. Computed Tomography (CT) showed complete tumor thrombosis of splenic vein, encasement of celiac artery and mesenteric vein. Six insertions of 3-4 electrodes per insertion were performed. One month-CT-control showed shrinkage of the tumor. 6 months-post-treatment imaging showed complete regression of the mass, patent Splenic/mesenteric veins, absence of local recurrence or distant metastasis. Post treatment CTs at 12-18-24-30-36-42-48 months follow-up confirmed absence of local or distant recurrence. DISCUSSION: Surgery is the first choice curative treatment of SPC. Howewer aggressive surgery (duodeno-pancreasectomy) in unresectable cases, may have a high risk of recurrences, morbidities and death, and bring concerns about endocrine and exocrine insufficiency in a young patient. In these cases, IRE could be a safe and effective alternative treatment and could realize, in selected cases, the condition for a radical surgery, and a bridge to R-0 resection. CONCLUSIONS: IRE could represent an effective alternative therapy to surgery in local advanced, unresectable SPC.

Electrochemotherapy of cholangiocellular carcinoma at hepatic hilum: A feasibility study.

AIM: We evaluated feasibility, safety and efficacy of Electrochemotherapy (ECT) in a prospective series of patients with unresectable Perihilar-Cholangiocarcinoma (PHCCA). PATIENTS AND METHODS: Five patients with PHCCA underwent ECT. Three patients underwent percutaneous ECT of a single PHCCA nodule. One patient underwent resection of a nodule in the IV segment and intraoperative ECT of a large PHCCA in the VIII segment. Another patient underwent percutaneous ECT of a large PHCCA recurrence after left lobectomy and RF ablation of a synchronous metastasis in the VI segment. ECT was performed under US guidance. Efficacy was evaluated by contrast-enhanced multiple-detector-computed-tomography (MDCT) 4 weeks after treatment. Follow-up entailed MDCT every 6 months thereafter. RESULTS: No major complication occurred. Follow-up ranges from 10 to 30 months. Four weeks post-treatment CT showed complete response in 3 cases. These patients are still alive, and follow-up CT controls demonstrated no local or distant intrahepatic recurrences and no biliary duct dilation in 2 cases and local recurrence at 18 months follow-up control in 1 patient. In the remaining 2 cases, 4-weeks-post-treatment CT showed incomplete response (>90%). In these patients follow-up CT demonstrated local progression of the disease at 6 months. One of them had bilateral external biliary drainages and died because of tumor progression at 16-months-follow-up. The other patient, died at 10 months follow-up for cardiovascular failure not related to the hepatobiliary disease. CONCLUSIONS: ECT is feasible, safe and effective therapy to improve prognosis and quality of life of patients with unresectable PHCCA.

Surgical crossectomy and saphenic trunk sclerotherapy. Preliminary results of a combined approach to the treatment of saphenous vein varices.

AIM: Here our proposal of a new approach to the incontinent saphenous-femoral junction (SFJ) based on the combination of surgery and sclerotherapy for treatment of incontinent varices. It is a two-step procedure with a surgical ligation and transection of SFJ followed by a sclerosis of saphenous trunk and extra-fascial tributaries. MATERIALS AND METHODS: From January to December 2017, 95 patients (63 females and 32 males) with a mean age of 56.43 ± 6.07 years for a total of 121 limbs were treated with the SHSC approach. Under local anesthesia, after surgical selective hemodynamic crossectomy and a retrograde cannulation of the saphenous trunk by means of 8-10 ch nelaton-like catheter, 0.5-1% polydocanol foam, obtained with Tessari's technique, is injected into the vein. During injection, the catheter must be progressively withdrawn, so that the entire vein comes in contact with the foam. RESULTS: 121 limbs have been treated with the above technique. A complete obliteration of the saphenous trunk was observed after 116 (95.86%) treatments in the immediate postoperative time. With regard to collateral veins sclerosis, 99 (81.81%) complete obliterations were observed. 28 (23.14%) collateral varices had to be refined by sclerotherapy. DISCUSSION: SHSC associates the execution of a selective hemodynamic crossectomy with an intraoperative foam sclerotherapy for the treatment of the saphenous trunk and collateral varicose veins. SHSC, compared to classical US-guided foam sclerotherapy seems to be safer, with fewer risks of pulmonary and / or cerebral embolic complications. SHSC prevents blood wash out which could destabilize the consolidation of the saphenous trunk sclerosis. CONCLUSIONS: SHSC can be considered an effective treatment of varicose veins, simple to perform, minimally invasive and well tolerated KEY WORDS: Crossectomy, Saphenous vein, Sclerotherapy, SFJ.

The risk of venous thromboembolism in patients with cirrhosis. A systematic review and meta-analysis.

Some studies suggest that patients with cirrhosis have an increased risk of deep venous thrombosis (DVT) and pulmonary embolism (PE). Unfortunately, available data on this association are contrasting. It was the objective of this study to perform a systematic review and meta-analysis of literature to evaluate the risk of venous thromboembolism (VTE) associated with cirrhosis. Studies reporting on VTE risk associated with cirrhosis were systematically searched in the PubMed, Web of Science, Scopus and EMBASE databases. Eleven studies (15 data-sets) showed a significantly increased VTE risk in 695,012 cirrhotic patients as compared with 1,494,660 non-cirrhotic controls (OR: 1.703; 95 %CI: 1.333, 2.175; P<0.0001). These results were confirmed when specifically considering the risk of DVT (7 studies, OR: 2.038; 95 %CI: 1.817, 2.285; P<0.0001) and the risk of PE (5 studies, OR: 1.655; 95 %CI: 1.042, 2.630; p=0.033). The increased VTE risk associated with cirrhosis was consistently confirmed when analysing nine studies reporting adjusted risk estimates (OR: 1.493; 95 %CI: 1.266, 1.762; p<0.0001), and after excluding studies specifically enrolling populations exposed to transient risk factors for VTE (OR: 1.689; 95 %CI: 1.321, 2.160; p<0.0001). Meta-regression models suggested that male gender may significantly impact on the risk of VTE associated with cirrhosis. Results of our meta-analysis suggest that cirrhotic subjects may exhibit an increased risk of VTE. This should be considered to plan specific prevention strategies in this clinical setting.

Percutaneous electrochemotherapy in the treatment of portal vein tumor thrombosis at hepatic hilum in patients with hepatocellular carcinoma in cirrhosis: A feasibility study.

AIM: To treated with electrochemotherapy (ECT) a prospective case series of patients with liver cirrhosis and Vp3-Vp4- portal vein tumor thrombus (PVTT) from hepatocellular carcinoma (HCC), in order to evaluate the feasibility, safety and efficacy of this new non thermal ablative technique in those patients. METHODS: Six patients (5 males and 1 female), aged 61-85 years (mean age, 70 years), four in Child-Pugh A and two in Child-Pugh B class, entered our study series. All patients were studied with three-phase computed tomography (CT), contrast enhanced ultrasound (CEUS) and ultrasound-guided percutaneous biopsy of the thrombus before ECT. All patients underwent ECT treatment (Cliniporator Vitae®, IGEA SpA, Carpi, Modena, Italy) of Vp3-Vp4 PVTT in a single session. At the end of the procedure a post-treatment biopsy of the thrombus was performed. Scheduled follow-up in all patients entailed: CEUS within 24 h after treatment; triphasic contrast-enhanced CT and CEUS at 3 mo after treatment and every six months thereafter. RESULTS: Post-treatment CEUS showed complete absence of enhancement of the treated thrombus in all cases. Post-treatment biopsy showed apoptosis and necrosis of tumor cells in all cases. The follow-up ranged from 9 to 20 mo (median, 14 mo). In 2 patients, the follow-up CT and CEUS demonstrated complete patency of the treated portal vein. Other 3 patients showed a persistent avascular non-tumoral shrinked thrombus at CEUS and CT during follow-up. No local recurrence was observed at follow-up CT and CEUS in 5/6 patients. One patient was lost to follow-up because of death from gastrointestinal hemorrage 5 wk after ECT. CONCLUSION: In patients with cirrhosis, ECT seems effective and safe for curative treatment of Vp3-Vp4 PVTT from HCC.

The risk of venous thromboembolism in patients with hepatitis C. A systematic review and meta-analysis.

Some studies suggest that patients with hepatitis C virus (HCV) infection have an increased risk of deep venous thrombosis (DVT) and pulmonary embolism (PE). Unfortunately, available data on this association are contrasting. A systematic review and meta-analysis of literature studies was performed to evaluate the risk of venous thromboembolism (VTE) associated with HCV. Studies reporting on VTE risk associated with HCV were systematically searched in the PubMed, Web of Science, Scopus and EMBASE databases. Six studies (10 data-sets) showed a significantly increased VTE risk in 100,364 HCV patients as compared with 8,471,176 uninfected controls (odds ratio [OR]: 1.900; 95 % confidence interval [CI]: 1.406, 2.570; p<0.0001). These results were confirmed when specifically considering the risk of DVT (6 studies, OR: 1.918; 95 %CI: 1.351, 2.723; p<0.0001), whereas a trend towards an increased risk of PE was documented in HCV patients (4 studies, OR: 1.811; 95 %CI: 0.895, 3.663; p=0.099). The increased VTE risk associated with HCV infection was consistently confirmed when analysing four studies reporting adjusted risk estimates (OR: 1.876; 95 %CI: 1.326, 2.654; P<0.0001), and after excluding studies specifically enrolling populations exposed to transient risk factors for VTE (4 studies, OR: 1.493; 95 %CI: 1.167, 1.910; p=0.001). Meta-regression models suggested that age and male gender may significantly impact on the risk of VTE associated with HCV-positivity. Results of our meta-analysis suggest that HCV-infected subjects may exhibit an increased risk of VTE. However, further high quality studies are needed to extend and confirm our findings.

Role of the haemodynamic mapping in varicose vein surgery of lower limbs.

AIM: To demonstrate the importance of preoperative ultrasound haemodynamic mapping of venous system in surgery of varicose veins. MATERIALS AND METHODS: Doppler ultrasound evaluation of haemodynamic features of lower limb venous system according to Franceschi's subdivision. DISCUSSION: The importance of Doppler mapping in varicose veins surgery shows a similarity with the Plebographic classification of venous system developed by W. Hach. The study also reassesses the role of varicectomy in the surgery of varicose veins. CONCLUSIONS: Preoperative Doppler ultrasound mapping is essential to avoid accident and prevent recurrence of varicose veins. KEY WORDS: Doppler US, Surgery, Great Saphenous Vein, Varicose Veins, Stripping.

The risk of coronary artery disease and cerebrovascular disease in patients with hepatitis C: A systematic review and meta-analysis.

BACKGROUND/OBJECTIVES: Some studies suggest that patients with hepatitis C virus (HCV) infection have an increased risk of coronary artery disease (CAD) and cerebrovascular disease. Unfortunately, available data on this association are widely variable. We have performed a systematic review and meta-analysis of literature to evaluate the risk of cardio-cerebrovascular disease (CCD) associated with HCV. METHODS: Studies reporting on CCD risk associated with HCV were systematically searched in the PubMed, Web of Science, Scopus and EMBASE databases. RESULTS: Twenty-seven studies (34 data-sets) showed a significantly increased CCD risk in 297,613 HCV patients as compared with 557,814 uninfected controls (OR: 1.428; 95% CI: 1.214, 1.681). These results were confirmed when separately considering the risk of CAD (20 studies, OR: 1.382; 95% CI: 1.103, 1.732) and of cerebrovascular disease (13 studies, OR: 1.485; 95% CI: 1.079, 2.044). Similar results were confirmed when analyzing 21 studies reporting adjusted risk estimates (OR: 1.448; 95% CI: 1.218, 1.722) and when, after excluding studies defining CAD as positive angiographic or electrocardiographic evidence, we specifically included the 17 studies reporting on acute CCD-related events (OR: 1.357; 95% CI: 1.103, 1.670). Moreover, 4 studies evaluating CCD-related deaths showed a higher risk in HCV patients than controls (OR: 1.772; 95% CI: 1.448, 2.168; P<0.0001). Meta-regression models suggested a direct association between prevalence of cirrhosis and difference in CCD risk between HCV patients and controls. CONCLUSIONS: Results of our large meta-analysis suggest that HCV-infected subjects experience an increased risk of CCD. This should be considered to plan specific cardiovascular prevention strategies in this clinical setting.

Cardiovascular risk markers in patients with primary aldosteronism: A systematic review and meta-analysis of literature studies.

BACKGROUND/OBJECTIVES: Several studies reported an increased cardiovascular (CV) morbidity and mortality in patients with primary aldosteronism (PA). We performed a meta-analysis on the impact of PA on major markers of CV risk. METHODS: Studies on the relationship between PA and common carotid artery intima-media thickness (CCA-IMT), prevalence of carotid plaques, flow-mediated dilation (FMD), nitrate-mediated dilation (NMD), pulse-wave velocity (PWV), augmentation index (AIx), and ankle-brachial index (ABI) were systematically searched in the PubMed, Web of Science, Scopus and EMBASE databases. RESULTS: 12 case-control studies (445 cases, 472 controls) were included. Compared to subjects with essential hypertension (EH), PA patients showed a higher CCA-IMT (MD: 0.12 mm; 95% CI: 0.09, 0.16; P<0.00001), and a higher aortic-PWV (272 cases and 240 controls, MD: 1.39 m/s; 95% CI: 0.90, 1.87; P<0.00001). In contrast, non-significant differences were found in AIx and AIx normalized to a heart rate of 75 beats per minute (AIx@75). When compared to normotensive subjects, PA patients showed significantly higher CCA-IMT (MD: 0.16 mm; 95% CI: 0.05, 0.27; P=0.004), aortic-PWV (MD: 3.74 m/s; 95% CI: 3.43, 4.05; P<0.00001), AIx@75 (MD: 8.59%; 95% CI: 0.69, 16.50; P=0.03), and a significantly lower FMD (MD: -2.52%; 95% CI: -3.64, -1.40; P<0.0001). Sensitivity and subgroup analyses substantially confirmed our results. Metaregression models showed that male gender, diabetes, and smoking habit impact on the observed results. CONCLUSIONS: PA appears significantly associated with markers of subclinical atherosclerosis and CV risk. These findings could help establish more specific CV prevention strategies in this clinical setting.

Hepatocellular carcinoma and liver metastases: clinical data on a new dual-lumen catheter kit for surgical sealant infusion to prevent perihepatic bleeding and dissemination of cancer cells following biopsy and loco-regional treatments.

BACKGROUND: RFA is a safe and effective procedure for treating unresectable primary or secondary liver malignancies, but it is not without complications. The most common reported complications include abdominal hemorrhage, bile leakage, biloma formation, hepatic abscesses, and neoplastic seeding. The aim of this study is to evaluate the feasibility of percutaneous use of surgical sealant with a new coaxial bilumen catheter, to prevent the perihepatic bleeding and dissemination of cancer cells through the needle-electrode (neoplastic seeding) or along the needle track. METHODS: We designed a novel dual-lumen catheter to facilitate the optimal application of fibrin sealant after diagnostic and therapeutic percutaneous procedures. Percutaneous RFA has been performed using mask ventilation or neuroleptanalgesia. The main aims of this study, after the ablation procedure, in the treatment of unresectable liver cancer were to prevent major adverse events: a) the perihepatic bleeding; b) dissemination of cancer cells through the needle-electrode and or needle track. RESULTS: A total of 181 patients were evaluated for this study at National Cancer Institute of Naples from January 2012 to January 2014. The association of blood loss (≤1 g/dl; ≥1 g/dl) with age, gender, histological diagnosis were analyzed. No statistical significance was observed between bleeding and age (p = 0.840), gender (p = 0.607) and histological diagnosis (p = 0,571), respectively. CONCLUSIONS: This study demonstrated that fibrin sealant or other surgical sealant injection, after any locoregional procedure such as biopsy or ablation, could make adverse events even more rare.

Inhibitory effect of (-)-epigallocatechin-3-gallate and bleomycin on human pancreatic cancer MiaPaca-2 cell growth.

BACKGROUND: Human pancreatic cancer is currently one of the deadliest cancers with high mortality rate. It has been previously shown that (-)-epigallocatechin-3-gallate (EGCG), the most abundant catechin found in green tea, has showed suppressive effects on human pancreatic cancer cells. Bleomycin, (BLM), an anti-cancer chemotherapeutic drug that induces DNA damage, has antitumor effects by induction of apoptosis in several cancer cell lines and also in pancreatic cancer cells. The present study investigated for the first time, the inhibitory effect of EGCG and BLM on pancreatic cancer cell growth. METHODS: Using the pancreatic cancer cell lines MIA PaCa-2 cells the efficacy and synergism of EGCG and BLM were evaluated by in vitro tests. Inhibition of cell proliferation was determined by MTT assay. Mitochondrial depolarization was performed with JC-1 probe. Viability and apoptosis were determined by Flow Cytometry with annexin V, propidium iodide staining and DNA fragmentation assay. RESULTS: Cell proliferation assay revealed significant additive inhibitory effects with combination of EGCG and BLM at 72 h in a dose dependent manner. The combination of EGCG and BLM induced cell cycle S-phase arrest and mitochondrial depolarization. Viability, apoptosis and DNA fragmentation assay indicated that the combination of EGCG and bleomycin potentiated apoptosis. CONCLUSIONS: Our results indicate that EGCG and BLM have additive anti-proliferative effects in vitro by induction of apoptosis of MIA PaCa-2 cells. This combination could represent a new strategy with potential advantages for treatment of pancreatic cancer. To date, this is the first report published of the inhibitory effect of EGCG and BLM on human pancreatic cancer MIA Paca-2 cell growth.