Josu Sola

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.

Gastroduodenal Injury After Radioembolization of Hepatic Tumors

BACKGROUND:Radioembolization is a new tool for the treatment of hepatic tumors that consists in the injection of biocompatible microspheres carrying radioisotopes into the hepatic artery or its branches.METHODS:We have performed radioembolization in 78 patients with hepatic tumors using resin-based microspheres loaded with yttrium-90. All patients were previously evaluated to minimize the risk of hazardous irradiation to nontarget organs and to obtain the data needed for dose calculation.RESULTS:We report a complication found in three cases (3.8%) that consists of abdominal pain resulting from gastroduodenal lesions and that had a chronic, insidious course. Microscopically, microspheres were detected in the specimens obtained from all affected gastric areas. Since these gastroduodenal lesions do not appear when nonradiating microspheres are injected in animals, lesions are likely to be due to radiation and not to an ischemic effect of vascular occlusion by spheres.CONCLUSIONS:We believe that a pretreatment evaluation that includes a more thorough scrutiny of the hepatic vascularization in search of small collaterals connecting to the gastroduodenal tract can help prevent this awkward complication.

Impact of Perineural and Lymphovascular Invasion on Oncological Outcomes in Rectal Cancer Treated with Neoadjuvant Chemoradiotherapy and Surgery

The prognostic significance of perineural and/or lymphovascular invasion (PLVI) and its relationship with tumor regression grade (TRG) in patients with locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiotherapy (CRT) and surgery. A total of 324 patients with LARC were treated with CRT and operated on between January 1992 and June 2007. Tumors were graded using a quantitative 5-grade TRG classification and the presence of PLVI was histologically studied. At a median follow-up of 79.0 months (range 3–250 months), a total of 80 patients (24.7 %) relapsed. The observed 5- and 10-year overall survival (OS) was 83.2 and 74.9 %, respectively. The 5- and 10-year disease-free survival (DFS) was 75.1 and 71.4 %, respectively. A significant correlation was found between the TRG and survival (log rank, p < 0.001). The 10-year OS was 32.7 % for grade 1, 63.8 % for grade 2, 75.0 % for grade 3, 90.4 % for grade 3+, and 96.0 %,for grade 4. The 10-year DFS was 31.8 % for grade 1, 58.6 % for grade 2, 70.4 % for grade 3, 88.4 % for grade 3+, and 97.1 % for grade 4. In patients with PLVI, the TRG had no impact on survival. When excluding patients with PLVI, the TRG was an independent prognostic factor for OS and DFS. The presence of PLVI is a more powerful prognostic factor than TRG in LARC patients treated with neoadjuvant CRT followed by surgery. PLVI denotes an aggressive phenotype, suggesting that these patients may benefit from adjuvant systemic therapy.BackgroundThe prognostic significance of perineural and/or lymphovascular invasion (PLVI) and its relationship with tumor regression grade (TRG) in patients with locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiotherapy (CRT) and surgery.MethodsA total of 324 patients with LARC were treated with CRT and operated on between January 1992 and June 2007. Tumors were graded using a quantitative 5-grade TRG classification and the presence of PLVI was histologically studied.ResultsAt a median follow-up of 79.0 months (range 3–250 months), a total of 80 patients (24.7 %) relapsed. The observed 5- and 10-year overall survival (OS) was 83.2 and 74.9 %, respectively. The 5- and 10-year disease-free survival (DFS) was 75.1 and 71.4 %, respectively. A significant correlation was found between the TRG and survival (log rank, p < 0.001). The 10-year OS was 32.7 % for grade 1, 63.8 % for grade 2, 75.0 % for grade 3, 90.4 % for grade 3+, and 96.0 %,for grade 4. The 10-year DFS was 31.8 % for grade 1, 58.6 % for grade 2, 70.4 % for grade 3, 88.4 % for grade 3+, and 97.1 % for grade 4. In patients with PLVI, the TRG had no impact on survival. When excluding patients with PLVI, the TRG was an independent prognostic factor for OS and DFS.ConclusionsThe presence of PLVI is a more powerful prognostic factor than TRG in LARC patients treated with neoadjuvant CRT followed by surgery. PLVI denotes an aggressive phenotype, suggesting that these patients may benefit from adjuvant systemic therapy.

Patterns of Response After Preoperative Intensity-Modulated Radiation Therapy and Capecitabine/Oxaliplatin in Rectal Cancer: Is There Still a Place for Ecoendoscopic Ultrasound?

PURPOSE The main goals of preoperative chemoradiotherapy (CHRT) in rectal cancer are to achieve pathological response and to ensure tumor control with functional surgery when possible. Assessment of the concordance between clinical and pathological responses is necessary to make decisions regarding alternative conservative procedures. The present study evaluates the patterns of response after a preoperative CHRT regimen, and the value of endoscopic ultrasound (EUS) in assessing response. METHODS AND MATERIALS A total of 51 EUS-staged T3 to T4 and/or N0 to N+ rectal cancer patients received preoperative CHRT (intensity-modulated radiation therapy and capecitabine/oxaliplatin (XELOX) followed by radical resection. Clinical response was assesed by EUS. Rates of pathological tumor regression grade (TRG) and lymph node (LN) involvement were determined in the surgical specimen. Clinical and pathological responses were compared, and the accuracy of EUS in assessing response was calculated. RESULTS Twenty-four patients (45%) achieved a major pathological response (complete or >95% pathological response (TRG 3+/4)). Sensitivity, specificity, negative predictive value, and positive predictive value of EUS in predicting pathological T response after preoperative CHRT were 77.8%, 37.5%, 60%, and 58%, respectively. The EUS sensitivity, specificity, negative predictive value, and positive predictive value for nodal staging were 44%, 88%, 88%, and 44%, respectively. Furthermore, EUS after CHRT accurately predicted the absence of LN involvement in 7 of 7 patients (100%) with major pathological response of the primary tumor. CONCLUSION Preoperative IMRT with concomitant XELOX induces favorable rates of major pathological response. EUS has a limited ability to predict primary tumor response after preoperative CHRT, but it is useful for accurately determining LN status. EUS may have a potential value in identifying patients with a very low risk of LN involvement in association with a good pathological response as potential candidates for conservative local surgical protocols.

In Vivo Assessment of a New Method of Pulsatile Perfusion Based on a Centrifugal Pump

The aim of this study was to assess platelet dysfunction and damage to organs after extracorporeal circulation using a pump based on a new method that adds a pulsatile flow to the continuous flow provided by a centrifugal pump. The continuous component of the total flow (2-3 L/min) is created by a Bio-Pump centrifugal pump, while the pulsatile component is created by the pulsating of an inner membrane pneumatically controlled by an intra-aortic counterpulsation balloon console (systolic volume of 37.5 mL in an asynchronous way with a frequency of 60 bpm). Six pigs were subjected to a partial cardiopulmonary bypass lasting 180 min and were sacrificed 60 min after extracorporeal circulation was suspended. The hematological study included the measurement of hematocrit, hemoglobin, leukocytes, and platelet function. The new pump did not significantly alter either platelet count or platelet function. In contrast, hematocrit and hemoglobin were significantly reduced during extracorporeal circulation (approximately 5% P = 0.011, and 2 g/dL P = 0.01, respectively). The leukocyte count during extracorporeal circulation showed a tendency to decrease, but this was not significant. In general, the short-term use of the new pump (4 h) did not cause any serious morphological damage to the heart, lung, kidney, or liver. The results suggest that the hemodynamic performance of the new pump is similar to a conventional centrifugal pump and could therefore be appropriate for use in extracorporeal circulation.

Secuelas tras inyección ilegal de silicona líquida como técnica de aumento mamario: presentación de 2 casos

Resumen La utilizacion de silicona liquida con el fin de aumentar el volumen mamario tuvo una amplia difusion en la decada de los anos sesenta del siglo pasado, pero a finales de esta, tras la publicacion de numerosos estudios que describian la aparicion de un gran numero de complicaciones locales, asi como la migracion a distancia de pequenas cantidades de silicona, su practica se abandono. Su empleo dificulta posteriormente el diagnostico temprano del cancer de mama, por lo que este grupo de pacientes no debe incluirse en los programas habituales de cribado, sino que han de seguir controles periodicos y exhaustivos. En este contexto, la resonancia magnetica es la mejor prueba de imagen para la deteccion temprana de procesos malignos mamarios. La presencia de complicaciones locales, la sospecha de una lesion maligna o el deseo de la paciente por evitar ambas situaciones son indicacion de la mastectomia subcutanea.

Preoperative angiogenesis and clotting/fibrinolysis circulating factors correlate with tumor stage, p21 and c-myc in colorectal cancer

3699 Background: Activation of clotting and fibrinolysis systems occurs during tumor angiogenesis. Due to this process, increased circulating vascular endothelial growth factor (VEGF), von Willebrand factor (vWf), plasmingen activator inhibitor 1 (PAI-1), D-dimer (DD) and fibrinogen levels are observed, showing endothelial proliferation and fibrin clots formation and degradation. In addition, all these factors may correlate with cancer stage and molecular findings related to prognosis. The aim of this study was to correlate VEGF, vWf, PAI-1, DD and fibrinogen levels in stages I to III colorectal cancer (CRC) patients undergoing curative surgery with tumor stage (T and N), and over-expression of p21, p53, Ki67 and c-myc. Methods: 32 CRC patients, stages I to III, were enrolled in the study. Blood samples were taken the day before surgery and stored until further processing. Serum VEGF and plasma vWf, DD and fibrinogen were measured using commercial ELISA kits. Tumor specimens were collected, analyzed and s...