Jorge Quiroga

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.

Systemic and regional hemodynamics in patients with liver cirrhosis and ascites with and without functional renal failure

Systemic, femoral, and renal hemodynamics were evaluated in 7 control subjects and 20 cirrhotic patients with ascites, 14 of them without (group A) and 6 with (group B) functional renal failure. Hyperdynamic systemic circulation, increased plasma volume, and hyperreninism were present in groups A and B. These changes were more severe in group B, which showed, as compared with group A, lower total vascular resistances and mean arterial pressure together with increased cardiac index and plasma renin activity. Significant differences in regional hemodynamics were also observed between groups. In group A, femoral and renal fractions of cardiac output were respectively increased and reduced as compared with controls. By contrast, in group B, both fractions of cardiac output were reduced when compared either with controls or with group A. In the entire patient group there was a close direct correlation between femoral and renal fractions of cardiac output (r = 0.88; p less than 0.001) and both of them correlated independently with total vascular resistances (r = 0.79; p less than 0.001 in both cases). These results indicate that, in nonazotemic cirrhotics with ascites, vasodilatation in extrasplanchnic areas contributes to the genesis of the hyperdynamic circulation. The presence in group B of a reduced flow to extrasplanchnic territories, in association with an increase of the hyperdynamic circulatory status, suggests that exacerbation of splanchnic vasodilatation is involved in the development of the hepatorenal syndrome. Finally, in cirrhosis, the changes that occur in systemic hemodynamics appear to influence renal function and renal blood flow.

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)

De Novo neoplasia after liver transplantation: An analysis of risk factors and influence on survival

Immunosuppression increases the risk of posttransplant malignancy and it may increase posttransplant mortality. The finding of factors related to the development of posttransplant malignancy may serve as a guide to avoid those risk factors and to develop strategies of posttransplant surveillance. The incidence and risk factors of malignancy were studied in 187 consecutive liver transplant recipients surviving more than 3 months. None of the 12 patients surviving less than 3 months had de novo neoplasia. The impact of malignancy on survival was studied in a case‐control study. After a median follow‐up of 65 months, 49 patients developed 63 malignancies: 25 patients had 35 cutaneous neoplasias and 27 patients had 28 noncutaneous malignancies. The 5‐ and 10‐year actuarial rates of cutaneous neoplasia were 14 and 24% and the rates of noncutaneous neoplasia were 11 and 22%, respectively. Risk factors for the development of cutaneous malignancy were older age and Child‐Turcotte‐Pugh A status. Risk factors for the development of noncutaneous malignancy were older age, alcoholism, and smoking. Cutaneous neoplasia had no effect on survival, whereas patients with noncutaneous malignancy had a significant reduction of survival. The overall relative risk of cutaneous and noncutaneous neoplasia, as compared with the general population were 16.91 (95% confidence interval: 11.78‐23.51) and 3.23 (95% confidence interval: 2.15‐4.67), respectively. The relative risk of cancer‐related mortality (after excluding recurrent malignancy) was 2.93 (95% confidence interval: 1.56‐5.02). Multivariate analysis showed that noncutaneous malignancy was an independent risk factor for posttransplant mortality. In conclusion, liver transplant recipients have a higher risk of cancer‐related mortality than the general population. This increased risk is due to the development of noncutaneous neoplasia. Older age, alcoholism, and smoking increase the risk of de novo noncutaneous neoplasia. (Liver Transpl 2005;11:89–97.)

Liver cytoprotection by prostaglandins.

Abstract During the last decade intensive work on the relationships between the liver and the arachidonic acid cascade has greatly expanded our knowledge of this area of research. The liver has emerged as the major organ participating in the degradation and elimination of arachidonate products of systemic origin. The synthesis in the liver of arachidonate products derived from the cfyclooxygenase, lipoxygenase and cytochrome P450 system pathways has been demonstrated. The participation of leukotriene B4 and cysteinyl-leukotrienes as mediators of liver damage and the possible therapeutic usefulness of prostaglandins (PGs) in acute liver injury has attracted the interest of clinicians. This article reviews the essential features regarding the role of arachidonate metabolites in liver disease and specially focuses on the cytoprotective effects on the liver displayed by PGE2, PGE1, PGI2 and synthetic PG analogs in experimental models of liver damage induced by ischemia-reperfusion injury, carbon tetrachloride, bacterial lipopolysaccharide and viral hepatitis and on the possible mechanisms underlying liver cytoprotection in these experimental models. The therapeutic usefulness of PGs in clinical practice is critically analyzed on the basis of available evidence in patients with fulminant hepatic failure and primary graft nonfunction following liver transplantation.

Liver transplantation in patients with hepatocellular carcinoma across Milan criteria

Milan criteria are the most frequently used limits for liver transplantation (LT) in patients with hepatocellular carcinoma (HCC), but our previous experience with expanded criteria showed encouraging results. The aim of this study was to investigate whether our expanded Clinica Universitaria de Navarra (CUN) criteria (1 nodule up to 6 cm or 2–3 nodules up to 5 cm each) could be used to select patients with HCC for LT. Eighty‐five patients with HCC fulfilling CUN criteria were included as candidates for LT. Survival of transplanted HCC patients was compared with survival of patients without HCC (n = 180). After the exclusion of 2 patients with tumor seeding of the chest wall due to pre‐LT tumor biopsy, survival and recurrence rates were compared according to tumor staging. Twenty‐six out of 85 (30%) patients exceeded Milan criteria. Twelve patients had tumor progression on the waiting list. Patients exceeding Milan criteria had a higher dropout rate due to tumoral progression. One‐, 3‐, 5‐, 7‐, and 10‐year survival rates of the 73 transplanted HCC patients were 86%, 74%, 70%, 61%, and 50%, respectively. Survival of patients with HCC was significantly lower than that of patients without HCC, but by multivariate analysis, HCC was not associated with lower survival. Tumor recurrence and survival rates were similar for patients fulfilling Milan and CUN criteria. Pathological staging showed 55 patients within Milan criteria, 7 patients exceeding them but within CUN criteria, and 9 patients exceeding CUN criteria. Tumor recurrence rates were 2/55 (4%), 0/7 (0%), and 4/9 (44%) in each of these groups, respectively. In conclusion, following CUN criteria could increase the number of HCC patients who could benefit from LT, without worsening the results. Because of the short number of patients in this series, these data need external validation. Liver Transpl 14:272–278, 2008.

Liver Transplant Recipients Older Than 60 Years Have Lower Survival and Higher Incidence of Malignancy

Older age is not considered a contraindication for liver transplantation, but age‐related morbidity may be a cause of mortality. Survival and the incidence of the main post‐transplant complications were assessed in 111 adult liver transplant recipients. They were divided in two groups according to their age (patients younger than 60 years, n=54; patients older than 60 years, n=57) and both groups were compared. Older patients were more frequently transplanted for hepatitis C (p= 0.03) and hepatocellular carcinoma (p= 0.05) and their liver disease was less advanced (Child‐Pugh and MELD scores were significantly lower; p=0.004 and p=0.05, respectively). After transplantation, older patients had a significantly lower survival (p=0.02). Higher age was independently associated with mortality (hazard ratio for each 10‐year increase: 2.1; 95% confidence interval: 1.1‐ 4.0; p=0.02). The incidence of de novo neoplasia and nonskin neoplasia were higher in older patients (p=0.02 and p =0.007, respectively). Malignancy was the cause of death in one patient younger than 60 years and in 12 patients older than 60 years (p =0.002). In multivariate analysis, a higher age and smoking were independently associated with a higher risk of dying of de novo neoplasia. In conclusion, older liver transplant recipients have a significantly lower survival than younger patients. Malignancy is responsible for this decreased survival.

The Role of Thrombopoietin in the Thrombocytopenia of Patients with Liver Cirrhosis

OBJECTIVES:Thrombocytopenia is a common disorder among cirrhotics that has been traditionally explained by splenic platelet pooling and destruction. Thrombopoietin (TPO), the main stimuli for thrombopoiesis is produced primarily in the liver and degraded by circulating platelets, but its role in the thrombocytopenia of liver cirrhosis is not well understood. The main goal of this study is to clarify the role of TPO in the pathogenesis of thrombocytopenia in cirrhosis.METHODS:The relation among TPO, platelet count, spleen size, portal hypertension, and liver function was studied in 33 cirrhotic patients before and after either partial splenic embolization or liver transplantation.RESULTS:Cirrhotics with thrombocytopenia had lower serum TPO levels than healthy controls (median values (interquartile range: ICR) were 120.7 (42.0–191.6) vs 756.4 (527.0–965.1) pg/mL, respectively; p < 0.001). Among cirrhotics with thrombocytopenia, serum TPO was related to spleen size (ρ=−0.387, p= 0.046), but not to platelet count as occurs physiologically. After partial splenic embolization, TPO and platelet count increased significantly and the physiological relation between TPO and platelet count was restored (ρ=−0.665, p= 0.026). Similar results were observed after liver transplantation.CONCLUSIONS:Our results suggest that besides impaired production in the failing liver, an increased TPO degradation by platelets sequestered in the congested spleen may contribute to thrombocytopenia in cirrhotic patients.

Response to radioembolization with yttrium-90 resin microspheres may allow surgical treatment with curative intent and prolonged survival in previously unresectable hepatocellular carcinoma

BACKGROUND Occasionally, patients with hepatocellular carcinoma (HCC) who receive radioembolization with palliative intent are downstaged for radical treatments. The aim of this study was to describe and analyze the overall survival (OS) in these patients compared with patients of the same baseline stage (UNOS T3), who were not eligible for radical treatment after radioembolization. METHODS Between September 2003 and August 2010, 118 patients with HCC received radioembolization with yttrium-90 ((90)Y) resin microspheres. Of these, 21 patients with UNOS T3 stage were retrospectively identified and included in this analysis. RESULTS In total, 6 of 21 patients were downstaged and treated radically between 2 and 35 months post-radioembolization. Three patients were resected, 2 received liver transplantation and 1 was ablated and then resected. Patients treated radically were significantly younger (62 vs. 73 years, p = 0.006) and had higher tumor volume (583 mL vs. 137 mL, p = 0.001) than patients who did not achieve radical treatment. There were no differences between the groups in number of lesions, BCLC stage, previous cirrhosis, activity administered per tumor volume, or median levels of alpha-fetoprotein or total bilirubin. Across the whole series, the median OS was 27.0 months (95% CI 5.0-48.9), varying significantly between those treated radically (OS not reached after a median follow-up of 41.5 months since radical therapy) and those who received palliative treatment only (22.0 months; 95% CI 15.0-30.9). CONCLUSIONS Radical therapy following tumor downstaging with radioembolization provides the possibility of long-term survival in a select subgroup (UNOS T3 stage) with otherwise limited options.