Attitudes and beliefs of argentinian medical oncologists regarding palliative care referral / Actitudes y creencias de los médicos oncólogos argentinos sobre la derivación a cuidados paliativos

Abstract Introduction: Local evidence suggests insufficient access to palliative care (PC) for advanced cancer patients. The objective was to investigate the attitudes and beliefs of Argentinian medical oncologists regarding PC referral of their patients. Methods: All medical oncologists listed in the main national Clinical Oncology Associations (N = 831) were invited to participate in a telephone survey. Results: Fifty nine percent (N = 489) completed the survey. Most reported being informed about the scopes of PC (83%) and having accessible PC service/specialists (71%). However, 53% did not work collaboratively, and 55% exceptionally or never referred their patients. Oncologists who usually referred their patients did so mainly due to uncontrolled pain (67%) or absence of curative treatment (48%). Only 19% supported early-referral criteria. Those who exception ally referred their patients argued that PC was not meaningful/beneficial/a priority (78%) or that they preferred to handle the patient's problems by themselves (55%). End-of-life care (33%) and improvement in quality of life (32%) were stated as primary benefits of PC for cancer patients. Addressing psychological aspects was consid ered the least important item (2%). Having an accessible PC service (P = 0.002) and being well informed about PC (P = 0.008) were associated with frequent referral. Having ≤10 years or >30 years from graduation were associated with exceptional or no referral (P = 0.012 and 0.001, respectively). Discussion: Oncologists report awareness of the potential advantages of PC and have accessible PC services, but rarely refer patients. They mainly use late-referral criteria. Younger and older age are negatively associated with referral. More research is needed to improve the referral rate and timing of cancer patients to PC.

Resumen Introducción: La evidencia local sugiere un acceso insuficiente a los cuidados paliativos (CP) para los pacien tes con cáncer avanzado. El objetivo fue investigar las actitudes y creencias de médicos oncólogos argentinos respecto de la derivación de sus pacientes a CP. Métodos: Todos los médicos oncólogos registrados en las principales Asociaciones Nacionales de Oncología Clínica (N = 831) fueron invitados a participar en una encuesta telefónica. Resultados: El 59% (N = 489) completó la encuesta. La mayoría informó estar informado sobre los alcances de CP (83%) y tener especialistas/servicios de CP acce sibles (71%). Sin embargo, el 53% no trabajaba de forma colaborativa y el 55% excepcionalmente o nunca derivaba a sus pacientes. Los oncólogos que habi tualmente derivan a sus pacientes lo hacen principalmente por dolor no controlado (67%) o ausencia de trata miento curativo (48%). Solo el 19% mencionó criterios de derivación temprana. Aquellos que excepcionalmente derivan a sus pacientes argumentaron que los CP no era significativos, beneficiosos o prioritarios (78%) o que preferían manejar los problemas del paciente por sí mismos (55%). La atención al final de la vida (33 %) y la mejora de la calidad de vida (32 %) se señalaron como los principales beneficios de los CP para los pacientes con cáncer. El abordaje de los aspectos psicológicos fue el ítem menos señalado (2%). Tener un servicio de CP accesible (P= 0,002) y estar bien informado sobre CP (P = 0,008) se asociaron con la derivación frecuente. Tener ≤10 años o >30 años desde la graduación se asoció con una derivación excepcional o nula (P = 0,012 y 0,001, respectivamente). Discusión: Los oncólogos refieren conocer las ventajas potenciales de los CP y tienen servicios de CP accesibles, pero rara vez derivan pacientes. Utilizan principalmente criterios de derivación tardía. Las edades más jóvenes y mayores se asocian negativamente con la derivación. Se necesita más investigación para mejorar la tasa y momento de derivación de los pacientes con cáncer a CP.

Attitudes and beliefs of Argentinian medical oncologists regarding palliative care referral.

INTRODUCTION: Local evidence suggests insufficient access to palliative care (PC) for advanced cancer patients. The objective was to investigate the attitudes and beliefs of Argentinian medical oncologists regarding PC referral of their patients. METHODS: All medical oncologists listed in the main national Clinical Oncology Associations (N = 831) were invited to participate in a telephone survey. RESULTS: Fifty nine percent (N = 489) completed the survey. Most reported being informed about the scopes of PC (83%) and having accessible PC service/specialists (71%). However, 53% did not work collaboratively, and 55% exceptionally or never referred their patients. Oncologists who usually referred their patients did so mainly due to uncontrolled pain (67%) or absence of curative treatment (48%). Only 19% supported early-referral criteria. Those who exceptionally referred their patients argued that PC was not meaningful/beneficial/a priority (78%) or that they preferred to handle the patient's problems by themselves (55%). End-of-life care (33%) and improvement in quality of life (32%) were stated as primary benefits of PC for cancer patients. Addressing psychological aspects was considered the least important item (2%). Having an accessible PC service (P = 0.002) and being well informed about PC (P = 0.008) were associated with frequent referral. Having =10 years or >30 years from graduation were associated with exceptional or no referral (P = 0.012 and 0.001, respectively). DISCUSSION: Oncologists report awareness of the potential advantages of PC and have accessible PC services, but rarely refer patients. They mainly use late-referral criteria. Younger and older age are negatively associated with referral. More research is needed to improve the referral rate and timing of cancer patients to PC.

Introducción: La evidencia local sugiere un acceso insuficiente a los cuidados paliativos (CP) para los pacientes con cáncer avanzado. El objetivo fue investigar las actitudes y creencias de médicos oncólogos argentinos respecto de la derivación de sus pacientes a CP. Métodos: Todos los médicos oncólogos registrados en las principales Asociaciones Nacionales de Oncología Clínica (N = 831) fueron invitados a participar en una encuesta telefónica. Resultados: El 59% (N = 489) completó la encuesta. La mayoría informó estar informado sobre los alcances de CP (83%) y tener especialistas/servicios de CP acce sibles (71%). Sin embargo, el 53% no trabajaba de forma colaborativa y el 55% excepcionalmente o nunca derivaba a sus pacientes. Los oncólogos que habitualmente derivan a sus pacientes lo hacen principalmente por dolor no controlado (67%) o ausencia de tratamiento curativo (48%). Solo el 19% mencionó criterios de derivación temprana. Aquellos que excepcionalmente derivan a sus pacientes argumentaron que los CP no era significativos, beneficiosos o prioritarios (78%) o que preferían manejar los problemas del paciente por sí mismos (55%). La atención al final de la vida (33 %) y la mejora de la calidad de vida (32 %) se señalaron como los principales beneficios de los CP para los pacientes con cáncer. El abordaje de los aspectos psicológicos fue el ítem menos señalado (2%). Tener un servicio de CP accesible (P= 0,002) y estar bien informado sobre CP (P = 0,008) se asociaron con la derivación frecuente. Tener =10 años o >30 años desde la graduación se asoció con una derivación excepcional o nula (P = 0,012 y 0,001, respectivamente). Discusión: Los oncólogos refieren conocer las ventajas potenciales de los CP y tienen servicios de CP accesibles, pero rara vez derivan pacientes. Utilizan principalmente criterios de derivación tardía. Las edades más jóvenes y mayores se asocian negativamente con la derivación. Se necesita más investigación para mejorar la tasa y momento de derivación de los pacientes con cáncer a CP.

First-line methadone for cancer pain: titration time analysis.

BACKGROUND: Methadone is a low-cost, strong opioid that is increasingly used as a first-line treatment for pain in palliative care (PC). Its long and unpredictable half-life and slow elimination phase can make titration challenging. Evidence for titration modalities is scarce. OBJECTIVE: To describe the titration phase of the treatment with low-dose first-line methadone and the use of methadone for breakthrough pain. METHODS: Prospective study with strong opioid-naïve patients with moderate to severe cancer pain followed at a tertiary PC unit in Argentina. Starting methadone dose was 2.5-5 mg/day every 8, 12, or 24 h. Titration allowed daily dose increases from day 1, and prescription of oral methadone 2.5 mg every 2 h with a maximum of 3 rescue doses/day for breakthrough pain. Pain control, methadone stabilization dose, and adverse effects, among other variables, were daily assessed over the first 7 days (T0-T7). RESULTS: Sixty-two patients were included. Initial median (IQR) methadone dose was 5 (2.5) mg/day. Pain intensity decreased from a median (IQR) of 8 (2.3) at T0 to 4 (2.3) at T1 and remained ≤ 4 until T7 (all p < 0.0001 compared to T0). Similar results were obtained through the categorical and tolerability scales for pain. Fifty patients (81%) reached pain control, 66% in the first 48 h. Methadone daily doses at T2 and T7 were higher than that at T0: 7.5 (3) and 6.7 (5.5) versus 5 (2.5), respectively (all p < 0.05). The opioid escalation index at T7 was 1.7%. The median (IQR) number of rescues, stabilization dose, and time for stabilization was 0 (1), 5(4.5) mg, and 3(2) days, respectively. Two patients were discontinued due to delirium. All other side effects were mild. CONCLUSIONS: First-line, low-dose methadone using rescue methadone resulted in a pronounced and rapid decrease in pain, with minimal need for titration and for breakthrough doses, and no evidence of accumulation or sedation by the end of the week.

[Interconsultation on palliative care for patients with cancer in a general hospital. Features and opportunity]. / Interconsultas de cuidados paliativos para pacientes con cáncer en un hospital general. Características y oportunidad.

The international recommendations point to the early integration of palliative care (PC) in cancer through simultaneous care and training of primary teams. The PC Unit of the Hospital General de Agudos E. Tornú conducts interconsultations for hospitalized patients in the hospital and provides training to the treatment teams. The profile of the interconsultations carried out could provide important information about the characteristics of the PC intervention within the institution. The objective of this study was to retrospectively analyze the first-time interconsultations of cancer patients carried out over 2 years, focusing on temporality, identification of problems by the treating team and the PC interconsultation team, the promptness of response and the prognostic capacity of the latter. In the period, 168 interconsultations were carried out. Most patients had advanced disease, poor performance status, no possibility of oncological treatment and recent diagnosis. In approximately 25% of the cases, evidence of early intervention and participation of the pc team in decision making was found. The opportunity of PC intervention is discussed and areas needing improvement are indicated, such as the identification of non-physical symptoms and prognosis, to be considered in future care and educational activities.

Las recomendaciones internacionales apuntan a la integración temprana de cuidados paliativos (CP) en cáncer a través de la atención simultánea y del entrenamiento de los equipos primarios. La Unidad de CP del Hospital General de Agudos E. Tornú realiza interconsultas para pacientes internados en el hospital y brinda capacitación a los equipos tratantes. El perfil de las interconsultas realizadas podría brindar información importante sobre las características de la intervención de CP dentro de la institución. El objetivo de este estudio fue analizar retrospectivamente las interconsultas de primera vez de pacientes con cáncer realizadas a lo largo de 2 años, con foco en la temporalidad, la identificación de problemas por parte del equipo tratante y del equipo de interconsulta de CP, y la prontitud de respuesta y capacidad pronóstica de este último. La población atendida en interconsulta (168 casos) estuvo constituida principalmente por pacientes con enfermedad avanzada, deterioro del estado general, sin posibilidad de tratamiento oncológico y diagnóstico reciente. En aproximadamente 25% de los casos se encontraron indicios de intervención temprana y participación del equipo de CP en la toma de decisiones. Se discute la oportunidad de la intervención de CP y se señalan áreas con necesidad de mejora, como la identificación de síntomas no físicos y el pronóstico, a ser tenidas cuenta en las futuras actividades asistenciales y educativas.

[Frequency and determinants of the delay in the diagnosis of cancer in children, in Argentina]. / Frecuencia y determinantes del retraso en el diagnóstico de cáncer infantil en Argentina.

In Argentina, mortality from childhood cancer is higher than in more developed countries, with late diagnosis being one of the possible causes. Our objective was to determine the frequency of barriers to diagnosis faced by families assisted by a Non-Governmental Organization, and some associated demographic, institutional and medical factors. A retrospective observational and quantitative analysis of the diagnosis pathway of children with cancer assisted by the N.D. Flexer Foundation, Argentina, between 1/1/2011 and 12/31/2015 was carried out. The primary outcome was the presence of barriers to diagnosis. It was considered that there was a barrier when there were consultations without diagnostic suspicion, family delay, institutional delay, self-derivation and/or more than 30 days between the onset of symptoms and diagnosis. The frequency of barriers within each category was contrasted by the y2 test. A multivariate logistic regression was used to examine its association with relevant variables. Among the 1818 families included, 63.5% faced delays/ barriers to diagnosis. Negative modulators were diagnosis at age younger than 1-year, renal tumor and first attention at a public hospital of the City of Buenos Aires or a provincial capital hospital (all p < 0.0001). Positive modulators were the diagnosis of bone tumor (p = 0.009) and first attention at a primary healthcare center (p< 0.0001) or private doctor's office (p = 0.001). The main non-biological factor associated with the possibility of facing barriers to diagnosis was the type of first contact-health institution.

En Argentina, la mortalidad por cáncer infantil es mayor que en países más desarrollados, siendo el diagnóstico tardío una de las posibles causas. Nuestro objetivo fue determinar la frecuencia de obstáculos al diagnóstico enfrentados por las familias de niños con cáncer asistidas por un Organismo No Gubernamental, y algunos factores demográficos, institucionales y médicos asociados. Se realizó un análisis retrospectivo observacional y cuantitativo del recorrido diagnóstico de los niños con cáncer asistidos por la Fundación N.D. Flexer, Argentina, entre el 1/1/2011 y el 31/12/2015. El resultado primario fue la presencia de obstáculos para acceder al diagnóstico. Se consideró que existió un obstáculo cuando tuvieron lugar consultas no orientativas, demora familiar, demora institucional, autoderivación y/o más de 30 días entre la aparición de síntomas y el diagnóstico. La frecuencia dentro de cada categoría se contrastó mediante la prueba de y2. La influencia de distintas variables se evaluó mediante una regresión logística multivariada. De 1818 familias incluidas, 63.5% enfrentaron algún tipo de obstáculos. Resultaron moduladores negativos el diagnóstico antes del año, de tumor renal y la concurrencia a un hospital público de la Ciudad de Buenos Aires o de capital provincial como centro de primer contacto (todos p < 0.0001). Resultaron moduladores positivos el diagnóstico de tumor óseo (p = 0.009) y los centros de atención primaria (p < 0.0001) y consultorios particulares (p = 0.001) como centros de primer contacto. El principal factor no biológico asociado a la frecuencia de obstáculos al diagnóstico de cáncer infantil fue el tipo de centro de primer contacto.

Interconsultas de cuidados paliativos para pacientes con cáncer en un hospital general: Características y oportunidad / Interconsultation on palliative care for patients with cancer in a general hospital. Features and opportunity

Las recomendaciones internacionales apuntan a la integración temprana de cuidados paliativos (CP) en cáncer a través de la atención simultánea y del entrenamiento de los equipos primarios. La Unidad de CP del Hospital General de Agudos E. Tornú realiza interconsultas para pacientes internados en el hospital y brinda capacitación a los equipos tratantes. El perfil de las interconsultas realizadas podría brindar información importante sobre las características de la intervención de CP dentro de la institución. El objetivo de este estudio fue analizar retrospectivamente las interconsultas de primera vez de pacientes con cáncer realizadas a lo largo de 2 años, con foco en la temporalidad, la identificación de problemas por parte del equipo tratante y del equipo de interconsulta de CP, y la prontitud de respuesta y capacidad pronóstica de este último. La población atendida en interconsulta (168 casos) estuvo constituida principalmente por pacientes con enfermedad avanzada, deterioro del estado general, sin posibilidad de tratamiento oncológico y diagnóstico reciente. En aproximadamente 25% de los casos se encontraron indicios de intervención temprana y participación del equipo de CP en la toma de decisiones. Se discute la oportunidad de la intervención de CP y se señalan áreas con necesidad de mejora, como la identificación de síntomas no físicos y el pronóstico, a ser tenidas cuenta en las futuras actividades asistenciales y educativas.

The international recommendations point to the early integration of palliative care (PC) in cancer through simultaneous care and training of primary teams. The PC Unit of the Hospital General de Agudos E. Tornú conducts interconsultations for hospitalized patients in the hospital and provides training to the treatment teams. The profile of the interconsultations carried out could provide important information about the characteristics of the PC intervention within the institution. The objective of this study was to retrospectively analyze the first-time interconsultations of cancer patients carried out over 2 years, focusing on temporality, identification of problems by the treating team and the PC interconsultation team, the promptness of response and the prognostic capacity of the latter. In the period, 168 interconsultations were carried out. Most patients had advanced disease, poor performance status, no possibility of oncological treatment and recent diagnosis. In approximately 25% of the cases, evidence of early intervention and participation of the pc team in decision making was found. The opportunity of PC intervention is discussed and areas needing improvement are indicated, such as the identification of non-physical symptoms and prognosis, to be considered in future care and educational activities.

Frecuencia y determinantes del retraso en el diagnóstico de cáncer infantil en Argentina / Frequency and determinants of the delay in the diagnosis of cancer in children, in Argentina

En Argentina, la mortalidad por cáncer infantil es mayor que en países más desarrollados, siendo el diagnóstico tardío una de las posibles causas. Nuestro objetivo fue determinar la frecuencia de obstáculos al diagnóstico enfrentados por las familias de niños con cáncer asistidas por un Organismo No Gubernamental, y algunos factores demográficos, institucionales y médicos asociados. Se realizó un análisis retrospectivo observacional y cuantitativo del recorrido diagnóstico de los niños con cáncer asistidos por la Fundación N.D. Flexer, Argentina, entre el 1/1/2011 y el 31/12/2015. El resultado primario fue la presencia de obstáculos para acceder al diagnóstico. Se consideró que existió un obstáculo cuando tuvieron lugar consultas no orientativas, demora familiar, demora institucional, autoderivación y/o más de 30 días entre la aparición de síntomas y el diagnóstico. La frecuencia dentro de cada categoría se contrastó mediante la prueba de χ2. La influencia de distintas variables se evaluó mediante una regresión logística multivariada. De 1818 familias incluidas, 63.5% enfrentaron algún tipo de obstáculos. Resultaron moduladores negativos el diagnóstico antes del año, de tumor renal y la concurrencia a un hospital público de la Ciudad de Buenos Aires o de capital provincial como centro de primer contacto (todos p < 0.0001). Resultaron moduladores positivos el diagnóstico de tumor óseo (p = 0.009) y los centros de atención primaria (p < 0.0001) y consultorios particulares (p = 0.001) como centros de primer contacto. El principal factor no biológico asociado a la frecuencia de obstáculos al diagnóstico de cáncer infantil fue el tipo de centro de primer contacto.

In Argentina, mortality from childhood cancer is higher than in more developed countries, with late diagnosis being one of the possible causes. Our objective was to determine the frequency of barriers to diagnosis faced by families assisted by a Non-Governmental Organization, and some associated demographic, institutional and medical factors. A retrospective observational and quantitative analysis of the diagnosis pathway of children with cancer assisted by the N.D. Flexer Foundation, Argentina, between 1/1/2011 and 12/31/2015 was carried out. The primary outcome was the presence of barriers to diagnosis. It was considered that there was a barrier when there were consultations without diagnostic suspicion, family delay, institutional delay, self-derivation and/ or more than 30 days between the onset of symptoms and diagnosis. The frequency of barriers within each category was contrasted by the χ2 test. A multivariate logistic regression was used to examine its association with relevant variables. Among the 1818 families included, 63.5% faced delays/ barriers to diagnosis. Negative modulators were diagnosis at age younger than 1-year, renal tumor and first attention at a public hospital of the City of Buenos Aires or a provincial capital hospital (all p < 0.0001). Positive modulators were the diagnosis of bone tumor (p = 0.009) and first attention at a primary healthcare center (p< 0.0001) or private doctor's office (p= 0.001). The main non-biological factor associated with the possibility of facing barriers to diagnosis was the type of first contact-health institution.

B cells inhibit the antitumor immunity against an established murine fibrosarcoma.

Despite the classic role of B cells in favoring the immune response, an inhibitory action of B lymphocytes in tumor immunity has emerged in certain studies. In methylcolanthrene-induced murine fibrosarcoma (MCC), the loss of immunogenicity and the establishment of tolerance are paralleled by systemic immune suppression and the appearance of B+IL-10+ cells in tumor-draining lymph nodes. The present study aimed to assess the role of the B+IL-10+ cell population in the immune evasion and tolerance induced by MCC through the depletion of B cells in mice at various times of tumor progression: Prior to or subsequent to tumor implantation. Tumor growth and immunological parameters were evaluated. B cell depletion prior to tumor inoculum enhanced tumor growth, initiating the onset of the tumor-induced systemic immune response; however, an increase in the T regulatory cells (Tregs) at the tumor-draining lymph node could account for tumor exacerbation. B cell depletion once the tumor was established resulted in decreased tumor growth and a delayed onset of tolerance. Additionally, B cell absence exacerbated T cell dependent-tumor rejection, reduced Tregs and increased cytotoxic CD8+ T cells. In vitro analysis showed a direct effect of B cells upon T cell proliferation. In conclusion, B cell depletion exerts opposite effects when performed prior to or subsequent to tumor implantation. In this initially immunogenic tumor, B cell absence would delay the establishment of immunological tolerance probably by unmasking a pre-existing antitumor response. The present findings elucidate the convenience of modulating B cells in the development of future and more effective immunotherapies against cancer.

Methadone as first-line opioid treatment for cancer pain in a developing country palliative care unit.

PURPOSE: The use of methadone for cancer pain is limited by the need of expertise and close titration due to variable half-life. Yet, it is a helpful palliative strategy in low-resources countries given its long-acting effect at low cost and worth additional study. Our aim was to describe the prescription and outcomes of methadone as a first-line treatment for cancer pain in a tertiary palliative care unit (PCU) in Argentina. METHODS: Retrospective review of medical records of patients with moderate to severe cancer pain seen at the PCU in 1-year period, who initiated strong opioids at the first consultation. Data collected during the first month of treatment included disease and pain characteristics, initial and final opioid type and dose and need for opioid rotation. RESULTS: Methadone was the most frequent opioid both at the initial and last assessment (71 and 66 % of the prescriptions). In all, treatment with strong opioids provided considerable decrease in pain intensity (p < 0.001) with low and stable opioid dose. Median and interquartile range (IR) of oral morphine equivalent daily dose (OMEDD) was 26 (16-32) and 39 (32-55) mg for initial and final assessments, respectively (p = 0.3). In patients initiated with methadone, the median (IR) daily methadone dose was 5 (4-6) mg at first and 7.5 (6-10) mg at final assessment, and the median (IR) index of opioid escalation was 0 (0-4) mg; (p < 0.05). Patients on methadone underwent less percentage of opioid rotation (15 versus 50 %; p < 0.001) and longer time to rotation (20.6 ± 4.4 versus 9.0 ± 2.7 days; p < 0.001) than patients on other opioids. CONCLUSIONS: Results indicate the preference of methadone as first-line strong opioid treatment in a PCU, providing good pain relief at low doses with low need for rotation. Several considerations about the costs of strong opioids in the region are given.

Meta-tyrosine. A powerful anti-metastatic factor with undetectable toxic-side effects.

Concomitant tumor resistance (CR) is a phenomenon in which a tumor-bearing host is resistant to the growth of secondary tumor implants and metastasis. While former studies have indicated that T-cell dependent processes mediate CR in hosts bearing immunogenic small tumors, the most universal manifestation of CR induced by immunogenic and non-immunogenic large tumors had been associated with an antitumor serum factor that remained an enigma for many years. In a recent paper, we identified that elusive factor(s) as an equi-molar mixture of meta-tyrosine and ortho-tyrosine, two isomers of tyrosine that are not present in normal proteins and that proved to be responsible for 90% and 10%, respectively, of the total serum anti-tumor activity. In this work, we have extended our previous findings demonstrating that a periodic intravenous administration of meta-tyrosine induced a dramatic reduction of lung and hepatic metastases generated in mice bearing two different metastatic murine tumors and decreased the rate of death from 100% up to 25% in tumor-excised mice that already exhibited established metastases at the time of surgery. These anti-metastatic effects were achieved even at very low concentrations and without displaying any detectable toxic-side effects, suggesting that the use of meta-tyrosine may help to develop new and less harmful means of managing malignant diseases, especially those aimed to control the growth of metastases that is the most serious problem in cancer pathology.

Meta-tyrosine: A powerful anti-metastatic factor with undetectable toxic-side effects

Concomitant tumor resistance (CR) is a phenomenon in which a tumor-bearing host is resistant to the growth of secondary tumor implants and metastasis. While former studies have indicated that T-cell dependent processes mediate CR in hosts bearing immunogenic small tumors, the most universal manifestation of CR induced by immunogenic and non-immunogenic large tumors had been associated with an antitumor serum factor that remained an enigma for many years. In a recent paper, we identified that elusive factor(s) as an equi-molar mixture of meta-tyrosine and ortho-tyrosine, two isomers of tyrosine that are not present in normal proteins and that proved to be responsible for 90% and 10%, respectively, of the total serum anti-tumor activity. In this work, we have extended our previous findings demonstrating that a periodic intravenous administration of meta-tyrosine induced a dramatic reduction of lung and hepatic metastases generated in mice bearing two different metastatic murine tumors and decreased the rate of death from 100% up to 25% in tumor-excised mice that already exhibited established metastases at the time of surgery. These anti-metastatic effects were achieved even at very low concentrations and without displaying any detectable toxic-side effects, suggesting that the use of meta-tyrosine may help to develop new and less harmful means of managing malignant diseases, especially those aimed to control the growth of metastases that is the most serious problem in cancer pathology.

La resistencia concomitante antitumoral (RC) es el fenómeno según el cual un individuo portador de tumor inhibe el crecimiento de implantes tumorales secundarios y metástasis. Si bien desde hace tiempo se sabe que la RC inducida por tumores inmunogénicos de pequeño tamaño es generada por mecanismos inmunológicos dependientes de células T, por otro lado, la manifestación más universal de la RC, generada tanto por tumores inmunogénicos como no-inmunogénicos de gran tamaño, había sido asociada con un (unos) factor sérico antitumoral cuya naturaleza permaneció elusiva por años. En un trabajo reciente, nuestro grupo de trabajo identificó este factor como la mezcla equi-molar de meta-tirosina y orto-tirosina, dos isómeros de tirosina que no están presentes en proteínas normales y que demostraron ser responsables del 90% y 10%, respectivamente, de la actividad antitumoral total del suero. En este trabajo, continuamos nuestras investigaciones demostrando que la administración periódica de meta-tirosina reducía drásticamente el número de metástasis pulmonares y hepáticas en ratones portadores de dos tumores murinos altamente metastásicos y disminuía dramáticamente la mortandad (de 100% a 25%) de ratones con metástasis ya establecidas al momento de la extirpación quirúrgica del tumor. Estos efectos anti-metastásicos se lograron aun con muy bajas concentraciones de meta-tirosina y sin efectos tóxicos perceptibles, lo que sugiere que su uso puede ayudar a diseñar nuevas y menos nocivas estrategias para el tratamiento del cáncer, especialmente aquellas destinadas a controlar el crecimiento metastásico, que es el problema más grave en la enfermedad oncológica.

Meta-tyrosine: A powerful anti-metastatic factor with undetectable toxic-side effects

Concomitant tumor resistance (CR) is a phenomenon in which a tumor-bearing host is resistant to the growth of secondary tumor implants and metastasis. While former studies have indicated that T-cell dependent processes mediate CR in hosts bearing immunogenic small tumors, the most universal manifestation of CR induced by immunogenic and non-immunogenic large tumors had been associated with an antitumor serum factor that remained an enigma for many years. In a recent paper, we identified that elusive factor(s) as an equi-molar mixture of meta-tyrosine and ortho-tyrosine, two isomers of tyrosine that are not present in normal proteins and that proved to be responsible for 90% and 10%, respectively, of the total serum anti-tumor activity. In this work, we have extended our previous findings demonstrating that a periodic intravenous administration of meta-tyrosine induced a dramatic reduction of lung and hepatic metastases generated in mice bearing two different metastatic murine tumors and decreased the rate of death from 100% up to 25% in tumor-excised mice that already exhibited established metastases at the time of surgery. These anti-metastatic effects were achieved even at very low concentrations and without displaying any detectable toxic-side effects, suggesting that the use of meta-tyrosine may help to develop new and less harmful means of managing malignant diseases, especially those aimed to control the growth of metastases that is the most serious problem in cancer pathology.(AU)

La resistencia concomitante antitumoral (RC) es el fenómeno según el cual un individuo portador de tumor inhibe el crecimiento de implantes tumorales secundarios y metástasis. Si bien desde hace tiempo se sabe que la RC inducida por tumores inmunogénicos de pequeño tamaño es generada por mecanismos inmunológicos dependientes de células T, por otro lado, la manifestación más universal de la RC, generada tanto por tumores inmunogénicos como no-inmunogénicos de gran tamaño, había sido asociada con un (unos) factor sérico antitumoral cuya naturaleza permaneció elusiva por años. En un trabajo reciente, nuestro grupo de trabajo identificó este factor como la mezcla equi-molar de meta-tirosina y orto-tirosina, dos isómeros de tirosina que no están presentes en proteínas normales y que demostraron ser responsables del 90% y 10%, respectivamente, de la actividad antitumoral total del suero. En este trabajo, continuamos nuestras investigaciones demostrando que la administración periódica de meta-tirosina reducía drásticamente el número de metástasis pulmonares y hepáticas en ratones portadores de dos tumores murinos altamente metastásicos y disminuía dramáticamente la mortandad (de 100% a 25%) de ratones con metástasis ya establecidas al momento de la extirpación quirúrgica del tumor. Estos efectos anti-metastásicos se lograron aun con muy bajas concentraciones de meta-tirosina y sin efectos tóxicos perceptibles, lo que sugiere que su uso puede ayudar a diseñar nuevas y menos nocivas estrategias para el tratamiento del cáncer, especialmente aquellas destinadas a controlar el crecimiento metastásico, que es el problema más grave en la enfermedad oncológica.(AU)

Regulatory cells induced by acute toxoplasmosis prevent the development of allergic lung inflammation.

The increased prevalence of allergies in developed countries has been attributed to a reduction of some infections. Supporting epidemiological studies, we previously showed that both acute and chronic Toxoplasma gondii infection can diminish allergic airway inflammation in BALB/c mice. The mechanisms involved when sensitization occurs during acute phase would be related to the strong Th1 response induced by the parasite. Here, we further investigated the mechanisms involved in T. gondii allergy protection in mice sensitized during acute T. gondii infection. Adoptive transference assays and ex vivo co-cultures experiments showed that not only thoracic lymph node cells from infected and sensitized mice but also from non-sensitized infected animals diminished both allergic lung inflammation and the proliferation of effector T cells from allergic mice. This ability was found to be contact-independent and correlated with high levels of CD4(+)FoxP3(+) cells. IL-10 would not be involved in allergy suppression since IL-10-deficient mice behaved similar to wild type mice. Our results extend earlier work and show that, in addition to immune deviation, acute T. gondii infection can suppress allergic airway inflammation through immune suppression.

Regulatory B cells present in lymph nodes draining a murine tumor.

In cancer, B cells have been classically associated with antibody secretion, antigen presentation and T cell activation. However, a possible role for B lymphocytes in impairing antitumor response and collaborating with tumor growth has been brought into focus. Recent reports have described the capacity of B cells to negatively affect immune responses in autoimmune diseases. The highly immunogenic mouse tumor MCC loses its immunogenicity and induces systemic immune suppression and tolerance as it grows. We have previously demonstrated that MCC growth induces a distinct and progressive increase in B cell number and proportion in the tumor draining lymph nodes (TDLN), as well as a less prominent increase in T regulatory cells. The aim of this research was to study B cell characteristics and function in the lymph node draining MCC tumor and to analyze whether these cells may be playing a role in suppressing antitumor response and favoring tumor progression. Results indicate that B cells from TDLN expressed increased CD86 and MHCII co-stimulatory molecules indicating activated phenotype, as well as intracellular IL-10, FASL and Granzyme B, molecules with regulatory immunosuppressive properties. Additionally, B cells showed high inhibitory upon T cell proliferation ex vivo, and a mild capacity to secrete antibodies. Our conclusion is that even when evidence of B cell-mediated activity of the immune response is present, B cells from TDLN exhibit regulatory phenotype and inhibitory activity, probably contributing to the state of immunological tolerance characteristic of the advanced tumor condition.

Regulatory B cells present in lymph nodes draining a murine tumor

In cancer, B cells have been classically associated with antibody secretion, antigen presentation and T cell activation. However, a possible role for B lymphocytes in impairing antitumor response and collaborating with tumor growth has been brought into focus. Recent reports have described the capacity of B cells to negatively affect immune responses in autoimmune diseases. The highly immunogenic mouse tumor MCC loses its immunogenicity and induces systemic immune suppression and tolerance as it grows. We have previously demonstrated that MCC growth induces a distinct and progressive increase in B cell number and proportion in the tumor draining lymph nodes (TDLN), as well as a less prominent increase in T regulatory cells. The aim of this research was to study B cell characteristics and function in the lymph node draining MCC tumor and to analyze whether these cells may be playing a role in suppressing antitumor response and favoring tumor progression. Results indicate that B cells from TDLN expressed increased CD86 and MHCII co-stimulatory molecules indicating activated phenotype, as well as intracellular IL-10, FASL and Granzyme B, molecules with regulatory immunosuppressive properties. Additionally, B cells showed high inhibitory upon T cell proliferation ex vivo, and a mild capacity to secrete antibodies. Our conclusion is that even when evidence of B cell-mediated activity of the immune response is present, B cells from TDLN exhibit regulatory phenotype and inhibitory activity, probably contributing to the state of immunological tolerance characteristic of the advanced tumor condition.

Regulatory B cells present in lymph nodes draining a murine tumor. / Regulatory B cells present in lymph nodes draining a murine tumor.

In cancer, B cells have been classically associated with antibody secretion, antigen presentation and T cell activation. However, a possible role for B lymphocytes in impairing antitumor response and collaborating with tumor growth has been brought into focus. Recent reports have described the capacity of B cells to negatively affect immune responses in autoimmune diseases. The highly immunogenic mouse tumor MCC loses its immunogenicity and induces systemic immune suppression and tolerance as it grows. We have previously demonstrated that MCC growth induces a distinct and progressive increase in B cell number and proportion in the tumor draining lymph nodes (TDLN), as well as a less prominent increase in T regulatory cells. The aim of this research was to study B cell characteristics and function in the lymph node draining MCC tumor and to analyze whether these cells may be playing a role in suppressing antitumor response and favoring tumor progression. Results indicate that B cells from TDLN expressed increased CD86 and MHCII co-stimulatory molecules indicating activated phenotype, as well as intracellular IL-10, FASL and Granzyme B, molecules with regulatory immunosuppressive properties. Additionally, B cells showed high inhibitory upon T cell proliferation ex vivo, and a mild capacity to secrete antibodies. Our conclusion is that even when evidence of B cell-mediated activity of the immune response is present, B cells from TDLN exhibit regulatory phenotype and inhibitory activity, probably contributing to the state of immunological tolerance characteristic of the advanced tumor condition.

Lymphadenectomy exacerbates tumor growth while lymphadenectomy plus the adoptive transfer of autologous cytotoxic cells and low-dose cyclophosphamide induces regression of an established murine fibrosarcoma.

Tumor-draining lymph node (TDLN) ablation is routinely performed in the management of cancer; nevertheless, its usefulness is at present a matter of debate. TDLN are central sites where T cell priming to tumor antigens and onset of the antitumor immune response occur. However, tumor-induced immunosuppression has been demonstrated at TDLN, leading to downregulation of antitumor reaction and tolerance induction. Tolerance in turn is a main impairment for immunotherapy trials. We used a murine immunogenic fibrosarcoma that evolves to a tolerogenic state, to study the cellular and molecular mechanisms underlying tolerance induction at the level of TDLN and to design an appropriate immunotherapy. We determined that following a transient activation, the established tumor induces signs of immunosuppression at TDLN that coexist with local and systemic evidences of antitumor response. Therefore, we evaluated the feasibility of removing TDLN in order to eliminate a focus of immunosuppression and favor tumor rejection; but instead, a marked exacerbation of tumor growth was induced. Combining TDLN ablation with the in vivo depletion of regulatory cells by low-dose cyclophosphamide and the restoring of the TDLN-derived cells into the donor mouse by adoptive transference, resulted in lowered tumor growth, enhanced survival and a considerable degree of tumor regression. Our results demonstrate that important antitumor elements can be eliminated by lymphadenectomy and proved that the concurrent administration of low-dose chemotherapy along with the reinoculation of autologous cytotoxic cells provides protection. We suggest that this protocol may be useful, especially in the cases where lymphadenectomy is mandatory.

Anti-inflammatory pretreatment enables an efficient dendritic cell-based immunotherapy against established tumors.

Although animals can be immunized against the growth of some tumor implants, most of the attempts to use immunotherapy to cause the regression of animal and human tumors once they have become established have been disappointing even when strongly immunogenic tumors were used as target. In this paper, we demonstrate that the failure to achieve an efficient immunological treatment against an established strongly immunogenic murine fibrosarcoma was paralleled with the emergence of a state of immunological unresponsiveness (immunological eclipse) against tumor antigens observed when the tumor surpassed the critical size of 500 mm(3). In turn, the onset of the immunological eclipse was coincidental with the onset of a systemic inflammatory condition characterized by a high number of circulating and splenic polymorphonucleated neutrophils (PMN) displaying activation and Gr1(+)Mac1(+) phenotype and an increasing serum concentration of the pro-inflammatory cytokines TNF-alpha, IL-1beta and IL-6 cytokines and C-reactive protein (CRP) and serum A amyloid (SAA) phase acute proteins. Treatment of tumor-bearing mice with a single low dose (0.75 mg/kg) of the synthetic corticoid dexamethasone (DX) significantly reduced all the systemic inflammatory parameters and simultaneously reversed the immunological eclipse, as evidenced by the restoration of specific T-cell-dependent concomitant immunity, ability of spleen cells to transfer anti-tumor activity and recovery of T-cell signal transduction molecules. Two other anti-inflammatory treatments by using indomethacin or dimeric TNF-alpha receptor, also partially reversed the immunological eclipse although the effect was not as striking as that observed with DX. The reversion of the immunological eclipse was not enough on its own to inhibit the primary growing tumor. However, when we used the two-step strategy of inoculating DX to reverse the eclipse and then dendritic cells loaded with tumor antigens (DC) as an immunization booster, a significant inhibition of the growth of both established tumors and remnant tumor cells after excision of large established tumors was observed, despite the fact that the vaccination alone (DC) had no effect or even enhanced tumor growth in certain circumstances. The two-step strategy of tumor immunotherapy that we present is based on the rationale that it is necessary to eliminate or ameliorate the immunological eclipse as a precondition to allow an otherwise ineffective anti-tumor immunological therapy to have a chance to be successful.

Compensatory renal growth protects mice against Shiga toxin 2-induced toxicity.

Uninephrectomy (Unx) is followed by the compensatory renal growth (CRG) of the remaining kidney. Previous evidence has shown that during CRG, renal tissue is resistant to a variety of pathologies. We tested the hypothesis that the functional changes that take place during CRG could attenuate Shiga toxin (Stx) toxicity in a mouse model of Stx2-induced hemolytic uremic syndrome (HUS). The participation of nitric oxide (NO) was analyzed. After CRG induction with Unx, mice were exposed to a lethal dose of Stx2, and the degree of renal damage and mortality was measured. Stx2 effects on the growth, renal blood flow (RBF) and NO synthase (NOS) intrarenal expression in the remaining kidney were then studied. The induction of CRG strongly prevented Stx2-mediated mortality and renal damage. Administration of the NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME) during CRG partially impaired the protection. Both Stx2 and L-NAME interfered with the hypertrophic and hyperplastic responses to Unx, as well as with the increase in RBF. In intact mice, Stx2 decreased renal perfusion, inhibited endothelial NOS basal expression and enhanced inducible NOS expression; all of these effects were attenuated by prior Unx. It is concluded that during CRG mice are highly protected against Stx2 toxicity and lethality. The protective capacity of CRG could be related to the enhancement of renal perfusion and preservation of eNOS renal expression, counterbalancing two major pathogenic mechanisms of Stx2.

[Activation of innate and specific immune responses in hemolytic uremic syndrome (HUS)-patients]. / Activación de la respuesta inmune innata y específica en los pacientes con síndrome urémico hemolítico. Papel dual a traves de la participacion en los mecanismos patogenicos y protectores.

The central role of the immune system is the preservation of the health against several pathogenic microbes and injury agents. However, on special conditions defensive mechanisms triggered towards the foreign agent can damage the host. Clinical and experimental evidence indicate that inflammatory reaction triggered by the main components of Shiga toxin (Stx)-producing Escherichia coil (STEC), participate in the evolution to the complete form of HUS. When children are diagnosed of HUS, they present evidence that have suffered a very strong and early inflammatory response. These features include: the presence of a marked neutrophilia, the polymorfonuclear leucocytes (PMN) are "deactivated or exhausted" and the monocytes are differentiated towards an inflammatory phenotype (CD14-reduced and CD16-enhanced membrane expression). In addition, HUS-patients show a marked reduction in the absolute and relative number of leucocytes carrying the receptor (CX3CR1) for the chemokine "Fractalkine" (FKN, CX3CL1), which are the classic monocytes and Natural Killer cells (NK). All these cells express a high cytotoxic potencial. The chemokine FKN is expressed in endothelial and epithelial renal cells, and is involved in the pathogenic mechanism of different nephropathies. Noteworthy, we found a significant correlation between the severity of the renal damage (as days of anuria) and the alterations described above. Finally, the protective role of specific immune response, mainly through the antibody production with Stx-neutralizing capacity, is discussed.