Alberto Benito

Phase I Trial of Intratumoral Injection of an Adenovirus Encoding Interleukin-12 for Advanced Digestive Tumors

PURPOSE To evaluate the feasibility and safety of intratumoral injection of an adenoviral vector encoding human interleukin-12 genes (Ad.IL-12) and secondarily, its biologic effect for the treatment of advanced digestive tumors. PATIENTS AND METHODS Ad.IL-12 was administered in doses ranging from 2.5 x 10(10) to 3 x 10(12) viral particles, to seven cohorts of patients with advanced pancreatic, colorectal, or primary liver malignancies. Patients were thoroughly assessed for toxicity, and antitumor response was evaluated by imaging techniques, tumor biopsy, and hypersensitivity skin tests. Patients with stable disease and no serious adverse reactions were allowed to receive up to 3 monthly doses of Ad.IL-12. RESULTS Twenty-one patients (nine with primary liver, five with colorectal, and seven with pancreatic cancers) received a total of 44 injections. Ad.IL-12 was well tolerated, and dose-limiting toxicity was not reached. Frequent but transient adverse reactions, including fever, malaise, sweating, and lymphopenia, seemed to be related to vector injection rather than to transgene expression. No cumulative toxicity was observed. In four of 10 assessable patients, a significant increase in tumor infiltration by effector immune cells was apparent. A partial objective remission of the injected tumor mass was observed in a patient with hepatocellular carcinoma. Stable disease was observed in 29% of patients, mainly those with primary liver cancer. CONCLUSION Intratumoral injection of up to 3 x 10(12) viral particles of Ad.IL-12 to patients with advanced digestive malignancies is a feasible and well-tolerated procedure that exerts only mild antitumor effects.

Intratumoral Injection of Dendritic Cells Engineered to Secrete Interleukin-12 by Recombinant Adenovirus in Patients With Metastatic Gastrointestinal Carcinomas

PURPOSE To evaluate the feasibility and safety of intratumoral injection of autologous dendritic cells (DCs) transfected with an adenovirus encoding interleukin-12 genes (AFIL-12) for patients with metastatic gastrointestinal carcinomas. Secondarily, we have evaluated biologic effects and antitumoral activity. PATIENTS AND METHODS Seventeen patients with metastatic pancreatic (n = 3), colorectal (n = 5), or primary liver (n = 9) malignancies entered the study. DCs were generated from CD14+ monocytes from leukapheresis, cultured and transfected with AFIL-12 before administration. Doses from 10 x 10(6) to 50 x 10(6) cells were escalated in three cohorts of patients. Patients received up to three doses at 21-day intervals. RESULTS Fifteen (88%) and 11 of 17 (65%) patients were assessable for toxicity and response, respectively. Intratumoral DC injections were mainly guided by ultrasound. Treatment was well tolerated. The most common side effects were lymphopenia, fever, and malaise. Interferon gamma and interleukin-6 serum concentrations were increased in 15 patients after each treatment, as well as peripheral blood natural killer activity in five patients. DC transfected with AFIL-12 stimulated a potent antibody response against adenoviral capsides. DC treatment induced a marked increase of infiltrating CD8+ T lymphocytes in three of 11 tumor biopsies analyzed. A partial response was observed in one patient with pancreatic carcinoma. Stable disease was observed in two patients and progression in eight patients, with two of the cases fast-progressing during treatment. CONCLUSION Intratumoral injection of DC transfected with an adenovirus encoding interleukin-12 to patients with metastatic gastrointestinal malignancies is feasible and well tolerated. Further studies are necessary to define and increase clinical efficacy.

Prognostic factors and prevention of radioembolization‐induced liver disease

Radioembolization (RE)‐induced liver disease (REILD) has been defined as jaundice and ascites appearing 1 to 2 months after RE in the absence of tumor progression or bile duct occlusion. Our aims were to study the incidence of REILD in a large cohort of patients and the impact of a series of changes introduced in the processes of treatment design, activity calculation, and the routine use of ursodeoxycholic acid and low‐dose steroids (modified protocol). Between 2003 and 2011, 260 patients with liver tumors treated by RE were studied (standard protocol: 75, modified protocol: 185). REILD appeared only in patients with cirrhosis or in noncirrhosis patients exposed to systemic chemotherapy prior to RE. Globally, the incidence of REILD was reduced in the modified protocol group from 22.7% to 5.4% and the incidence of severe REILD from 13.3% to 2.2% (P < 0.0001). Treatment efficacy was not jeopardized since 3‐month disease control rates were virtually identical in both groups (66.7% and 67.2%, P = 0.93). Exposure to chemotherapy in the 2‐month period following RE and being treated by the standard protocol were independent predictors of REILD among noncirrhosis patients. In cirrhosis, the presence of a small liver (total volume <1.5 L), an abnormal bilirubin (>1.2 mg/dL), and treatment in a selective fashion were independently associated with REILD. Conclusion: REILD is an uncommon but relevant complication that appears when liver tissue primed by cirrhosis or prior and subsequent chemotherapy is exposed to the radiation delivered by radioactive microspheres. We designed a comprehensive treatment protocol that reduces the frequency and the severity of REILD. (HEPATOLOGY 2013)

Transjugular Intrahepatic Portosystemic Shunt (TIPS) in the Treatment of Venous Symptomatic Chronic Portal Thrombosis in Non-cirrhotic Patients

AbstractPurpose: To present a series of cases of non-cirrhotic patients with symptomatic massive portal thrombosis treated by percutaneous techniques. All patients underwent a TIPS procedure in order to maintain the patency of the portal vein by facilitating the outflow. Methods: A total of six patients were treated for thrombosis of the main portal vein (6/6); the main right and left branches (3/6) and the splenic vein (5/6) and superior mesenteric vein (6/6). Two patients had a pancreatic malignancy; one patient with an orthotopic liver transplant had been surgically treated for a pancreatic carcinoma. Two patients had idiopathic thrombocytosis, and in the remaining patient no cause for the portal thrombosis was identified. During the initial procedure in each patient one or more approaches were tried: transhepatic (5/6), transileocolic (1/6), trans-splenic (1/6) or transjugular (1/6). In all cases the procedure was completed with a TIPS with either ultrasound guidance (3/6), “gun-shot” technique (2/6) or fluoroscopic guidance (1/6). Results: No complications were observed during the procedures. One patient had a repeat episode of variceal bleeding at 30 months, one patient remained asymptomatic and was lost to follow-up at 24 months, two patients were successfully treated surgically (cephalic duodenopancreatectomy) and are alive at 4 and 36 months. One patient remains asymptomatic (without new episodes of abdominal pain) at 16 months of follow-up. One patient died because of tumor progession at 10 months. Conclusion: Percutaneous techniques for portal recanalization are an interesting alternative even in non-acute thrombosis. Once flow has been restored in the portal vein TIPS may be necessary to obtain an adequate outflow, hence facilitating and maintaining the portal flow.

Prothrombin Fragment 1+2 Is Associated With Carotid Intima-Media Thickness in Subjects Free of Clinical Cardiovascular Disease

Background and Purpose— Thrombin, a central enzyme in the clotting cascade, plays a role not only in thrombosis but also in the progression of atherosclerosis. We studied the relationship between prothrombin fragment 1+2 (F1+2), a specific marker of thrombin generation in vivo, and carotid intima-media thickness (IMT), an index of subclinical atherosclerosis. Methods— We examined 181 asymptomatic middle-aged subjects (mean age 55.6 years, 76.7% men) free of overt clinical atherosclerotic disease. F1+2 was measured by enzyme-linked immunosorbent assay and IMT by duplex ultrasonography of carotid artery. Multiple linear regression analysis was used to assess the relationship between the 2 parameters. Results— Compared with individuals in the lowest tertile of F1+2, those in the upper tertile (>0.55 nmol/L) showed significantly higher IMT (P <0.01). In correlation analysis, a positive relationship was found between plasma F1+2 and carotid IMT. F1+2 also correlated positively with cholesterol (P <0.008) and low-density lipoprotein cholesterol (P <0.005), but not with blood pressure or body mass index. In the multivariate analysis, the association of F1+2 with carotid IMT remained significant (P <0.001) after adjustment for age, sex, body mass index, systolic blood pressure, cholesterol, diabetes, and smoking. Conclusions— In a population sample of adults without clinically overt atherosclerotic disease, the plasma levels of F1+2 were significantly associated with carotid IMT, suggesting a relationship between thrombin generation and the development atherosclerosis.

Totally laparoscopic Roux-en-Y duct-to-mucosa pancreaticojejunostomy after middle pancreatectomy: a consecutive nine-case series at a single institution.

Objective:To present the results of a series of laparoscopic middle pancreatectomies with roux-en-Y duct-to-mucosa pancreaticojejunostomy. Summary of Background Data:Middle pancreatectomy makes it possible to preserve pancreatic parenchyma in the resection of lesions that traditionally have been treated by distal splenopancreatectomy or cephalic duodenopancreatectomy. The laparoscopic approach could minimize the invasiveness of the procedure and enhance the benefits of middle pancreatectomy. Methods:From March 2005 to October 2007, 9 consecutive patients with benign or low malignant potential lesions in the pancreatic neck or body underwent surgery. Laparoscopic middle pancreatectomy with a roux-en-Y duct-to-mucosa pancreaticojejunostomy was planned on all of them. In the first 2 patients, the pancreas was transected by endostapler; in the last 7, the staple line was reinforced with absorbable polymer membrane. Results:The intervention was concluded laparoscopically in every case except 1 (laparoscopic-assisted) in which pancreaticojejunostomy was performed by means of minilaparotomy. Mortality was 0% and perioperative morbidity was 33%, (fistula of the cephalic stump in the first 2 patients (22%)). The pancreaticojejunostomy fistula rate was 0%. The median postoperative hospital stay was 5 days (range, 3–41). In the last 7 patients, in which pancreas was transected with staple line reinforcement material there were no stump fistulas; morbidity decreased to 14% and the median hospital stay was 4 days (range, 3–30). Conclusions:Laparoscopic middle pancreatectomy is feasible and safe. Duct-to-mucosa pancreaticojejunostomy can be performed safely using this approach. The method of pancreatic transection seems to be decisive in the incidence of cephalic stump fistulas.

Transjugular intrahepatic portosystemic shunt (TIPS): current status and future possibilities.

AbstractSince the insertion of the first TIPS in 1989 much has been learned about this therapeutic procedure. It has an established role for the treatment of some complications of portal hypertension: prevention of recurrent variceal bleeding and rescue of patients with acute uncontrollable variceal bleeding. In addition TIPS is useful for Budd-Chiari syndrome, refractory ascites and hepatorenal syndrome, although its specific role in these indications remains to be definitively established. However, the decrease in sinusoidal blood flow induced by TIPS can lead to the patient developing hepatic encephalopathy and liver failure in some cases. Therefore, TIPS should be used with caution in patients with very poor liver function. From a technical point of view, successful placement of TIPS is achieved in more than 98% of cases by experienced groups. At present, evaluation of TIPS dysfunction based on morphology probably leads to an overdiagnosis of this complication since most of these cases are not associated with clinical manifestations (recurrent bleeding or refractory ascites). The major disadvantage of TIPS remains its poor long-term patency requiring a mandatory surveillance program. The indicator for shunt function/malfunction should be the portosystemic pressure gradient, which is best assessed by intravascular measurements. Shunt obstructions may be prevented or reduced by the use of stent-grafts in the future.

Totally laparoscopic right-lobe hepatectomy for adult living donor liver transplantation: useful strategies to enhance safety.

The overriding concern in living donor liver transplantation is donor safety. A totally laparoscopic right hepatectomy without middle hepatic vein for adult living donor liver transplantation is presented. The surgical procedure is described in detail, focusing on relevant technical aspects to enhance donor safety, specifically the hanging maneuver and dynamic fluoroscopy‐controlled bile duct division.

Promising Prospects for 44Sc-/47Sc-Based Theragnostics: Application of 47Sc for Radionuclide Tumor Therapy in Mice

In recent years, 47Sc has attracted attention because of its favorable decay characteristics (half-life, 3.35 d; average energy, 162 keV; Eγ, 159 keV) for therapeutic application and for SPECT imaging. The aim of the present study was to investigate the suitability of 47Sc for radionuclide therapy in a preclinical setting. For this purpose a novel DOTA-folate conjugate (cm10) with an albumin-binding entity was used. Methods: 47Sc was produced via the 46Ca(n,γ)47Ca→β−47Sc nuclear reaction at the high-flux reactor at the Institut Laue-Langevin. Separation of the 47Sc from the target material was performed by a semi-automated process using extraction chromatography and cation exchange chromatography. 47Sc-labeled cm10 was tested on folate receptor–positive KB tumor cells in vitro. Biodistribution and SPECT imaging experiments were performed in KB tumor–bearing mice. Radionuclide therapy was conducted with two groups of mice, which received either 47Sc-cm10 (10 MBq) or only saline. Tumor growth and survival time were compared between the two groups of mice. Results: Irradiation of 46Ca resulted in approximately 1.8 GBq of 47Ca, which subsequently decayed to 47Sc. Separation of 47Sc from 47Ca was obtained with 80% yield in only 10 min. The 47Sc was then available in a small volume (∼500 μL) of an ammonium acetate/HCl (pH 4.5) solution suitable for direct radiolabeling. 47Sc-cm10 was prepared with a radiochemical yield of more than 96% at a specific activity of up to 13 MBq/nmol. In vitro 47Sc-cm10 showed folate receptor–specific binding and uptake into KB tumor cells. In vivo SPECT/CT images allowed the visualization of accumulated radioactivity in KB tumors and in the kidneys. The therapy study showed a significantly delayed tumor growth in mice, which received 47Sc-cm10 (10 MBq, 10 Gy) resulting in a more than 50% increase in survival time, compared with untreated control mice. Conclusion: With this study, we demonstrated the suitability of using 47Sc for therapeutic purposes. On the basis of our recent results obtained with 44Sc-folate, the present work confirms the applicability of 44Sc/47Sc as an excellent matched pair of nuclides for PET imaging and radionuclide therapy.

Interventional therapeutic techniques in Budd-Chiari syndrome

PurposeTo analyze the results obtained with percutaneous therapeutic procedures in patients with Budd-Chiari syndrome (BCHS).MethodsBetween August 1991 and April 1993, seven patients with BCHS were treated in our hospital. Three presented with a congenital web; in another three cases the hepatic veins and/or the inferior vena cava (IVC) were compromised after major hepatic surgery; one patient presented with a severe stenosis of the intrahepatic IVC due to hepatomegaly.ResultsOne of the patients with congenital web has required several new dilatations due to restenosis; one patient required a transjugular intrahepatic portosystemic shunt procedure while awaiting a liver transplantation. The two postsurgical patients with stenosed hepatic veins did not require any new procedure after the placement of metallic endoprostheses. However, the patient with liver transplantation presented IVC restenosis after balloon angioplasty that required the deployment of metallic endoprostheses. In the patient with hepatomegaly a self-expandable prosthesis was placed in the intrahepatic portion of the IVC before (4 months) a liver transplantation.ConclusionInterventional therapeutic techniques offer a wide variety of possibilities for the treatment of patients with BCHS. For IVC stenoses, the results obtained with balloon angioplasty are at least as good as those obtained with surgery.