Nuevas terapias target y vías moleculares clínicamente relevantes en carcinoma hepatocelular avanzado / New targeted therapies and molecular routes clinically relevant in advanced hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common tumors worldwide. Most cases occur in patients with chronic liver disease who are diagnosed at an advanced stage, and their prognosis is poor. Because HCC is resistant to conventional systemic therapies, molecular therapies have emerged and been established as the standard for advanced forms of the disease. Since the publication of phase III clinical studies on sorafenib, research has searched for new molecular targets. Thus, multiple clinical studies that inhibit relevant molecular pathways have been performed with numerous patients. Many of these trials have had unexpectedly negative results, not only due to patient complexity and the difficulty in evaluating a therapeutic response, quality of life and the survival rate but also because phase II clinical studies, without the selection of molecular targets, have continued on to poor results in phase III studies. This review article aims to evaluate different phase II and phase III clinical studies to understand the clinically relevant molecular pathways and to improve the future management of HCC patients.

El carcinoma hepatocelular (CHC) es uno de los tumores más comunes a nivel mundial. La mayoría de los casos ocurre en pacientes con enfermedad hepática crónica, quienes son diagnosticados en un estado avanzado con muy pobre pronóstico. Terapias moleculares orientadas al tratamiento del CHC han sido destacadas; estas pueden afectar la proliferación celular del tumor, diferenciación celular, angiogénesis, invasión y metástasis, entre otros procesos críticos al desarrollo del tumor. El estándar para el CHC avanzado es la terapia target usando Sorafenib, sin embargo, nuevas moléculas han sido testeadas en estudios fase III de primera línea, tales como sunitinib, brivanib, erlotinib y linifanib, sin superioridad sobre sorafenib. La investigación de nuevos tratamientos es un desafío para investigadores, hepatólogos y oncólogos. Las principales vías moleculares de CHC con relevancia en estudios clínicos fase II y III son: MAP-kinase (MAPK), PI3K/AKT/mTOR, (HGF)/c-Met, cromatina y regulación epigenética, mantenimiento de telómeros, Notch, Hedgehog, Hippo y vía señalizante Jak/STAT. Las terapias futuras en CHC pueden ser orientadas rutinariamente usando sólo objetivos adecuados para terapias moleculares y seleccionando subgrupos de pacientes sobre la base de la expresión de targets moleculares o basados en nuevas clasificaciones definidas por estudios genómicos.

Potencial herramienta en la personalización del tratamiento oncológico: Casos clínicos / In vitro cell response to chemotherapeutic agents, to personalize ovarian cancer treatment: Report of two cases

Our laboratory has implemented an in vitro assay to estimate the response to chemotherapy in ovarian cancer cells pertaining to individual patients. In two selected patients, we determined the correlation between an in vitro assay of cells from suspected ovarian cancer ascites, with the clinical chemotherapy response. Cancer cells isolated from peritoneal fluid with suspected ovarian cancer were tested for cytotoxicity with corresponding chemotherapy regimens. Circulating Cal25 levels and attending physician consultation determined clinical course and response to chemotherapy. The in vitro assay result correlated with Cal25 levels, progression free survival and attending physician evaluation. The assay predicted correctly the failure of two successive chemotherapy regimes in the first patient, while predicting a favorable clinical response in the second subject.

[Umbilical cord hematopoietic precursors transplantation. Report of five patients]. / Trasplante con precursores hematopoyéticos de cordón umbilical en adultos con neoplasias hematológicas en Chile: serie clínica.

Hematopoietic precursors transplantation is a therapeutic alternative for leukemia, some metabolic diseases and some immune deficiency syndromes. In its allogeneic variety leukemia eradication is based in the conditioning prior to transplantation and the allograñ effect against leukemia. Umbilical cord blood is an alternative source of hematopoietic precursors when there are no HLA compatible relatives available. Between 2003 and 2007 we have performed five umbilical cord blood transplant in adult patients in a University hospital. All patients had malignant diseases. Conditioning protocols were ablative in all except in one patient and in all, more than one unit of umbilical cord blood was used. Hematopoietic engraftment was confirmed in all patients and the main complications registered were infectious and associated to immunosuppression.

Trasplante con precursores hematopoyéticos de cordón umbilical en adultos con neoplasias hematológicas en Chile: Serie clínica / Umbilical cord hematopoietic precursors transplantation: Report of five patients

Hematopoietic precursors transplantation is a therapeutic alternative for leukemia, some metabolic diseases and some immune deficiency syndromes. In its allogeneic variety leukemia eradication is based in the conditioning prior to transplantation and the allograñ effect against leukemia. Umbilical cord blood is an alternative source of hematopoietic precursors when there are no HLA compatible relatives available. Between 2003 and 2007 we have performed five umbilical cord blood transplant in adult patients in a University hospital. All patients had malignant diseases. Conditioning protocols were ablative in all except in one patient and in all, more than one unit of umbilical cord blood was used. Hematopoietic engraftment was confirmed in all patients and the main complications registered were infectious and associated to immunosuppression.

[Etiology of febrile neutropenia episodes among cancer patients from Hospital Clinico Universidad Catolica, Santiago-Chile]. / Etiología de episodios de neutropenia febril en pacientes adultos con cáncer hematológico y de órganos sólidos en el Hospital Clínico Universidad Católica, Santiago-Chile.

INTRODUCTION: The surveillance of febrile neutropenia (FN) episodes in every center allows adapt the antibiotic therapy guidelines to local epidemiology. AIM: To characterize clinical features and compare the FN etiology between hematological cancer (HC) and solid organ cancer (SOC) in our center. PATIENTS AND METHODS: Surveillance study in adult patients with FN admitted to Hospital Clinico Universidad Católica, in Santiago, Chile, from January 2004 to August 2007. RESULTS: 154 FN episodes corresponding to 87 patients were included. Mean age: 47 +/- 6 years-old; 71% had HC and 29% SOC. A clinical and/or microbiologically documented infection was recognized in 76%. Gastrointestinal 31.5%, upper respiratory 30.3% and lower respiratory 16.9% were the more frequent clinical focus. In 30.5% blood culture resulted positive: gram negative rods 51%, gram positive cocci 41% and yeasts 8%; being Escherichia coli 22%, S. coagulase negative (SCoN) 20% and Klebsiella pneumoniae 12% most frequent bacteria; 22.2% Enterobacteriaceae were ESBL producers and 55.6% 5CoN were methicillin resistant. In 18.3% of FN episodes the etiology was not established. Highest mortality was observed in episodes with microbiologically documented infection (14.5% vs 1.3%, p < 0.005). A clinical observed focus and positive blood cultures were more frequently obtamed among HC than SOC associated episodes: 37.3% vs 13.6%; (p < 0.01) and 67.2% vs 50%; (p = 0.045), respectively. CONCLUSIONS: The etiological profile of FN in our center and the necessity to continue the surveillance was described. Future studies are needed regarding risk factors of invasive infection that have worst prognosis.

[Invasive fungal disease in hemato-oncological and hematopoietic stem cell transplantation patients from Hospital Clinico Universidad Católica, Santiago-Chile using revised EORTC/MSG diagnostic criteria]. / Enfermedad fúngica invasora en pacientes hemato-oncológicos y receptores de trasplante de precursores hematopoyéticos bajo la perspectiva de los criterios diagnósticos EORTC/MSG.

INTRODUCTION: Invasive fungal disease (IFD) is a severe complication occurring mostly in haematooncological (H-O) patients and hematopoietic stem cell transplant (HSCT) receptors. Our aim was to describe the IFD occurring in our H-O and HSCT patients according to the EORTC/MSG revised criteria. PATIENTS AND METHODS: IFD surveillance was performed in adult patients of the Hospital Clínico Universidad Catolica, Santiago, Chile, from January 2004 to January 2008. RESULTS: A total of 41 IFD episodes were identified in 39 patients; mean age was 46.6 +/- 9.9 years, and 87.8% and 12.2% occurred in H-O and HCTS patients respectively. 15/41(36.6%) episodes were proven, 36.6% probable and 11/41 (26.8%) possible. In 26 (63.4%) episodes aspergillosis was diagnosed (20 pulmonary, 3 sinus, 1 laryngeal and 1 case with pulmonary and cerebral involvement). In 7 patients (17.1%) candidiasis was diagnosed, 5 with a proven bloodstream infection and 2 with possible hepatosplenic candidiasis; mucormyeosis was diagnosed in 4 (9.8%) Fusarium infection was demonstrated in 2 patients (4.9%), and Mucor and Aspergillus pulmonary coinfection and Alternaria sp rhino-sinusitis in one patient each. The frequency of IFD among febrile neutropenic patients was 26.2% and 6.4% in H-O and HSCT receptors respectively. The overall mortality was 36%. CONCLUSIONS: Aspergillosis is the most common IFD infection among H-O patients and HSCT receptors in our center. Candidiasis followed although only in H-O patients most probably because of routine use of antifungal prophylaxis in HSCT recipients. Continuous surveillance is required to develop local guidelines and to evaluate antifungal strategies in different clinical scenarios.

Enfermedad fúngica invasora en pacientes hemato-oncológicos y receptores de trasplante de precursores hematopoyéticos bajo la perspectiva de los criterios diagnósticos EORTC/MSG / Invasive fungal disease in hemato-oncological and hematopoietic stem cell transplantation patients from Hospital Clinico Universidad Católica, Santiago-Chile using revised EORTC/MSG diagnostic criteria

Introduction: Invasive fungal disease (IFD) is a severe complication occurring mostly in haemato-oncological (H-O) patients and hematopoietic stem cell transplant (HSCT) receptors. Our aim was to describe the IFD occurring in our H-O and HSCT patients according to the EORTC/MSG revised criteria. Patients and Methods: IFD surveillance was performed in adult patients of the Hospital Clínico Universidad Católica, Santiago, Chile, from January 2004 to January 2008. Results: A total of 41 IFD episodes were identified in 39 patients; mean age was 46.6 ± 9.9 years, and 87.8 percent and 12.2 percent occurred in H-O and HCTS patients respectively. 15/41(36.6 percent) episodes were proven, 36.6 percent probable and 11/41 (26.8 percent) possible. In 26 (63.4 percent) episodes aspergillosis was diagnosed (20 pulmonary, 3 sinus, 1 laryngeal and 1 case with pulmonary and cerebral involvement). In 7 patients (17.1 percent) candidiasis was diagnosed, 5 with a proven bloodstream infection and 2 with possible hepatosplenic candidiasis; mucormyeosis was diagnosed in 4 (9.8 percent) Fusarium infection was demonstrated in 2 patients (4.9 percent), and Mucor and Aspergillus pulmonary coinfection and Alternaría sp rhino-sinusitis in one patient each. The frequency of IFD among febrile neutropenic patients was 26.2 percent and 6.4 percent in H-O and HSCT receptors respectively. The overall mortality was 36 percent. Conclusions: Aspergillosis is the most common IFD infection among H-O patients and HSCT receptors in our center. Candidiasis followed although only in H-O patients most probably because of routine use of antifungal prophylaxis in HSCT recipients. Continuous surveillance is required to develop local guidelines and to evaluate antifungal strategies in different clinical scenarios.

Introducción: La enfermedad fúngica invasora (EFI) es una complicación grave en pacientes hemato-oncológicos (H-O) y receptores de trasplante de precursores hematopoyéticos (TPH). Objetivo: Describir las EFI diagnosticadas en pacientes adultos H-O y receptores de TPH de nuestro centro, bajo los criterios diagnósticos revisados de EORTC/MSG. Pacientes y Métodos: Estudio de vigilancia de EFI en pacientes adultos del Hospital Clínico de la Pontificia Universidad Católica de Chile entre enero 2004 y enero 2008. Resultados: Se identificaron 41 episodios de EFI, correspondientes a 39 pacientes: 46,6 ± 9,9 años, 87,8 por ciento H-Oy 12,2 por ciento TPH. Se documentaron 15/41 (36,6 por ciento) EFI demostrada, 36,6 por ciento probable y 11/41 (26,8 por ciento) posible. En 26/41 (63,4 por cientoo) se diagnosticó aspergilosis (20 pulmonar, 3 rinosinusal, 1 laríngeo y un caso cerebral-pulmonar). En 7/41 (17,1 por ciento) se diagnosticó candidiasis, 5 candidemias y 2 candidiasis hepato-esplénica posibles; 4/41 (9,8 por cientoo) correspondió a mucormicosis demostrada (2 rinosinusal, 1 oral y 1 pulmonar); en 2/41 (4,9 por cientoo) fusariosis; 1/41(2,4 por ciento)) coinfección pulmonar por mucoral y Aspergillus sp y 1 caso de rinosinusitis por Alternaría sp. La frecuencia de EFI entre pacientes H-O con neutropenia febril fue 26,2 por ciento) y 6,4 por ciento) en los receptores de TPH. La mortalidad global fue de 36 por ciento). Conclusiones: Aspergilosis es la EFI más frecuente en H-O y receptores de TPH de nuestro centro. Candidiasis es la segunda EFI en frecuencia; sin embargo, no se documentó entre los pacientes receptores de TPH, lo que puede relacionarse al uso de antifúngicos profilácticos en este grupo. Es necesaria la vigilancia continua para desarrollar guías clínicas locales y evaluar estrategias de uso de antifúngicos en distintos escenarios clínicos.

Etiología de episodios de neutropenia febril en pacientes adultos con cáncer hematológico y de órganos sólidos en el Hospital Clínico Universidad Católica, Santiago-Chile / Etiology of febrile neutropenia episodes among cancer patients from Hospital Clinico Universidad Catolica, Santiago-Chile

Introduction: The surveillance of febrile neutropenia (FN) episodes in every center allows adapt the antibiotic therapy guidelines to local epidemiology. Aim: To characterize clinical features and compare the FN etiology between hematological cáncer (HC) and solid organ cancer (SOC) in our center. Patients and Methods: Surveillance study in adult patients with FN admitted to Hospital Clinico Universidad Católica, in Santiago, Chile, from January 2004 to August 2007. Results: 154 FN episodes corresponding to 87 patients were included. Mean age: 47 ± 6 years-old; 71 percent had HC and 29 percent SOC. A clinical and/or microbiologically documented infection was recognized in 76 percent. Gastrointestinal 31.5 percent, upper respiratory 30.3 percent and lower respiratory 16.9 percent were the more frequent clinical focus. In 30.5 percent blood culture resulted positive: gram negative rods 51 percent, gram positive cocci 41 percent and yeasts 8 percent; being Escherichia coli 22 percent, S. coagulase negative (SCoN) 20 percent and Klebsiella pneumoniae 12 percent most frequent bacteria; 22.2 percent Enterobacteriaceae were ESBL producers and 55.6 percent 5CoN were methicillin resistant. In 18.3 percent of FN episodes the etiology was not established. Highest mortality was observed in episodes with microbiologically documented infection (14.5 percent vs 1.3 percent, p < 0.005). A clinical observed focus and positive blood cultures were more frequently obtamed among HC than SOC associated episodes: 37.3 percent vs 13.6 percent; (p < 0.01) and 67.2 percent vs 50 percent; (p = 0.045), respectively. Conclusions: The etiological profile of FN in our center and the necessity to continue the surveillance was described. Future studies are needed regarding risk factors of invasive infection that have worst prognosis.

Introducción: La vigilancia de la etiología de los episodios de neutropenia febril (NF) en cada centro permite adaptar guías de antibioterapia a la epidemiología local. Objetivo: Caracterizar y comparar la etiología de la NF en pacientes con cáncer hematológico (CH) y de órganos sólidos (COS). Pacientes y Métodos: Estudio de vigilancia de NF de pacientes adultos en el Hospital Clínico Universidad Católica, en Santiago, Chile, entre enero 2004 y agosto 2007. Resultados: 154 episodios de NF correspondientes a 87 pacientes: 47 ± 6 años; 71 por ciento CH y 29 por ciento COS. Se documentó infección clínica y/o microbiológicamente en 76 por cientoo. Más frecuente fueron: foco gastrointestinal 31,5 por ciento, respiratorio alto 30,3 por cientoo y respiratorio bajo 16,9 por cientoo. En 30,5 por cientoo hubo hemocultivos positivos: bacilos gramne-gativos en 51 por ciento, cocáceas grampositivas en 41 por ciento, levaduras en 8 por cientoo; predominando: Escherichia coli 22 por cientoo, Staphylococcus coagulasa negativa (SCoN) 20 por cientoo y Klebsiella pneumoniae 12 por ciento; 22,2 por cientoo de las entero-bacterias eran productoras de (3-lactamasa de espectro expandido y 55,6 por cientoo >SCoN meticilina resistentes. En 18,3 por cientoo de los episodios no se identificó causa de fiebre. Hubo mayor mortalidad en episodios con documentación microbiológica (14,5 por ciento vs 1,3 por ciento, p < 0,005). En los pacientes con CH fue más frecuente obtener hemocultivos positivos (37,3 por cientoo vs 13,6 por ciento; p < 0,01) e identificar foco clínico (67,2 por ciento vs 50 por ciento; p = 0,045). Conclusiones: Se establece el perfil etiológico de las NF en nuestro centro y la necesidad de mantener vigilancia. En futuros estudios será necesario evaluar factores de riesgo de pacientes con infecciones invasores que tendrían peor pronóstico.

[Cytokeratin 20 as a marker of tumor progression or dissemination in patients with colorectal cancer]. / Detección de micrometástasis por RT-PCR de citokeratina 20 y su correlación con la sobrevida global en pacientes portadores de cáncer colorrectal.

BACKGROUND: Colorectal cancer relapses or metastasizes in 30% of cases. Cytokeratin 20 is present in 95% of colorectal tumors and their metastases and could be used as a marker to detect tumor cells. AIM: To assess the usefulness and prognostic value of peripheral blood and bone marrow cytokeratin 20 determinations in patients with colorectal cancer. MATERIAL AND METHODS: Blood and bone marrow samples were obtained from 56 patients with colorectal cancer aged 26 to 77 years (31 females) before surgical procedure. They were followed for a mean of 22 months (range 2.9 to 72 months) after surgery. Blood and bone marrow from 45 patients without cancer and 35 healthy subjects were used as negative controls. Messenger RNA expression of cytokeratin 20 was studied by real time and nested polymerase chain reaction. RESULTS: Cytokeratin 20 was detected in 6% of controls and 41% of patients. There was no relation between cytokeratin 20 expression and age, gender, overall survival, tumor relapse, progression, localization or stage. CONCLUSIONS: Cytokeratin 20 determination is not useful as a marker of tumor progression or dissemination in patients with colorectal cancer.

Detección de micrometástasis por RT-PCR de citokeratina 20 y su correlación con la sobrevida global en pacientes portadores de cáncer colorrectal / Cytokeratin 20 as a marker of tumor progression or dissemination in patients with colorectal cancer

Background: Colorectal cancer relapses or metastasizes in 30 percent of cases. Cytokeratin 20 is present in 95 percent of colorectal tumors and their metastases and could be used as a marker to detect tumor cells. Aim: To assess the usefulness and prognostic value of peripheral blood and bone marrow cytokeratin 20 determinations in patients with colorectal cancer. Material and methods: Blood and bone marrow samples were obtained from 56 patients with colorectal cancer aged 26 to 77 years (31 females) before surgical procedure. They were followed for a mean of 22 months (range 2.9 to 72 months) after surgery. Blood and bone marrow from 45 patients without cancer and 35 healthy subjects were used as negative controls. Messenger RNA expression of cytokeratin 20 was studied by real time and nested polymerase chain reaction. Results: Cytokeratin 20 was detected in 6 percent of controls and 41 percent of patients. There was no relation between cytokeratin 20 expression and age, gender, overall survival, tumor relapse, progression, localization or stage. Conclusions: Cytokeratin 20 determination is not useful as a marker of tumor progression or dissemination in patients with colorectal cancer.

Efecto de un inhibidor tirosina kinasa (imatinib) en pacientes con tumores estromales gastrointestinales metastásicos: Experiencia preliminar / Treatment of metastatic gastrointestinal stromal tumors with Imatinib: Report of four cases

Gastrointestinal stromal tumors (GIST) have mutations of the tyrosine kinase receptor. When they are localized, the treatment of choice is surgical excision, but advanced tumors have a limited response to chemo or radiotherapy. Imatinib (STI571 or Glivec®) is a selective inhibitor or tyrosine kinase proteins that has been used successfully in the treatment of advanced GIST. We report four patients (two women) with a metastatic GIST that were treated with Imatinib 400 mg day and followed for 40 months. The disease tumor stabilized in three patients and in one it had an initial reduction and progressed at the end of follow up. Therefore Imatinib can be a therapeutic alternative in patients with metastatic GIST.

[Treatment of metastatic gastrointestinal stromal tumors with Imatinib: report of four cases]. / Efecto de un inhibidor tirosina kinasa (Imatinib) en pacientes con tumores estromales gastrointestinales metastásicos: experiencia preliminar.

Gastrointestinal stromal tumors (GIST) have mutations of the tyrosine kinase receptor. When they are localized, the treatment of choice is surgical excision, but advanced tumors have a limited response to chemo or radiotherapy. Imatinib (STI571 or Glivec) is a selective inhibitor or tyrosine kinase proteins that has been used successfully in the treatment of advanced GIST. We report four patients (two women) with a metastatic GIST that were treated with Imatinib 400 mg day and followed for 40 months. The disease tumor stabilized in three patients and in one it had an initial reduction and progressed at the end of follow up. Therefore Imatinib can be a therapeutic alternative in patients with metastatic GIST.