IL-2- or IL-15-activated NK cells enhance Cetuximab-mediated activity against triple-negative breast cancer in xenografts and in breast cancer patients.

Triple-negative breast cancer (TNBC) patients do not benefit from target-specific treatments and is associated with a high relapse rate. Epidermal growth factor receptor is frequently expressed in TNBC and is a candidate for new therapies. In this work, we studied Cetuximab-mediated immune activity by NK cells. Thirteen activating/inhibitory receptors were examined on peripheral blood and tumor infiltrating NK cells. NK-cell functionality was evaluated using as effectors tumor-modulated NK cells and NK cells from patients. We evaluated the treatment with Cetuximab plus IL-2 or IL-15 in vivo in TNBC xenografts. Tumor NK-cells receptor profile showed upregulation of inhibitory receptors and downregulation of activating ones. Tumor-modulated NK cells were less cytotoxic. They could perform antibody-dependent cellular cytotoxicity (ADCC) triggered by Cetuximab, although impaired, it could still be restored by stimulation with IL-2 or IL-15. Patients with advanced disease displayed diminished levels of ADCC compared to healthy volunteers. ADCC was restored and potentiated with both cytokines, which were also effective in enhancing the therapeutic activity of Cetuximab in vivo. The combination of Cetuximab with IL-15 and IL-2 may be considered an attractive therapeutic approach to enhance the clinical efficacy of Cetuximab in TNBC.

Chromogranin A as a biochemical marker for the management of neuroendocrine tumors: a multicenter study developed in Argentina.

Elevated circulating levels of chromogranin A (CgA) are found in the neuroendocrine tumors (NETs), but diagnostic usefulness of this marker is still debatable. To assess the role of CgA for the identification and follow up of gastroenteropancreatic neuroendocrine tumors (GEP-NET), a multicenter prospective longitudinal study has been carried out in Argentina. CgA was measured by RIA in 119 histologically proven GEP-NET patients and in 39 healthy controls. A cutoff value of 2.8 nmol/L was established from a receiver-operating characteristic (ROC) curve, as discriminating between controls and patients with active disease (specificity 100% and sensitivity 92.3%). CgA levels were higher in functioning than in no functioning tumors (median 55 nmol/L vs 5 nmol/L, p < 0.05). Metastases were present in 83 patients and their CgA levels were significantly higher than levels in the 36 patients without metastases (median 44 nmol/L vs 64 nmol/L, p < 0.0001). CgA levels are strongly correlated with tumor metastatic spread. Sensitivity differed between patients with localized disease (median 6 nmol/L), extensive disease (median 22 nmol/L) and very extensive disease (median 44 nmol/L) (p < 0.001). In conclusion, due to its high sensitivity and specificity, CgA is useful in a newly discovered GEP-NET especially when no abnormal hormone secretion can be demonstrated. CgA levels were significantly higher in functioning tumors than in non-functioning tumors and increased with metastatic spread. If serial evaluation of CgA levels is sufficient for the detection of tumor growth changes remains to be prospectively demonstrated.

Human leukocyte antigen-E protein is overexpressed in primary human colorectal cancer.

HLA-E is a non-classical MHC molecule whose expression by tumour cells has been recently reported in several human cancer types. We studied HLA-E expression in colorectal cancer patients, its clinical significance and prognostic value, as well as characterized its expression in colorectal cancer cell lines. We analysed HLA-E expression at the transcript level by qRT-PCR in micro-dissected samples and at the protein level by semiquantitative immunohistochemistry on paraffin-embedded tissue sections from 42 biopsies of colorectal cancer patients. We observed that HLA-E transcript and protein are spontaneously overexpressed in a significant proportion of colorectal tumour biopsies, as compared to normal mucosae. We also found a negative correlation between HLA-E expression and the CD57+ cells infiltrate. Moreover, we analysed HLA-E expression in several colorectal cancer cell lines and demonstrated that IFN-gamma upregulates the expression of membrane HLA-E in vitro. Interestingly, we demonstrated that colorectal cancer cell lines overexpressing HLA-E at the cell surface inhibited NK-mediated cell lysis. Although IFN-gamma regulatory role needs further investigation, we provide evidence suggesting that this cytokine, within the tumour microenvironment, could promote HLA-E translocation to the surface of tumour epithelial cells. Furthermore, we showed that upregulation of HLA-E could be a marker of shorter disease-free survival in Dukes' C patients and we suggest that this molecule renders tumours less susceptible to immune attack.

Galectin-3 expression correlates with apoptosis of tumor-associated lymphocytes in human melanoma biopsies.

The immune system recognizes diverse melanoma antigens. However, tumors can evade the immune response, therefore growing and progressing. It has been reported that galectin-3 and galectin-1 can induce apoptosis of activated lymphocytes. However, there is strong evidence indicating that the regulation of galectins function in the human tumor microenvironment is a complex process that is influenced by diverse biological circumstances. Here, we have investigated 33 biopsies (eight primary and 25 metastases) from 24 melanoma patients (15-72 years old) and describe the correlation between the expression of galectin-3 or galectin-1 and the level of apoptosis of tumor-associated lymphocytes using immunohistochemistry and an in situ nick translation assay. The range of galectin-3-positive tumor cells varied between 0% and 93% and that of galectin-1-positive tumor cells varied between 5% and 97%. In addition, 23 +/- 27% of tumor-associated lymphocytes were apoptotic. Although our results show a correlation between galectin-3 expression and apoptosis of tumor-associated lymphocytes, we could not find such correlation with galectin-1. Considering the complex process of cancer immunoediting, various interacting factors must be considered.

Patología pulmonar en pacientes con tratamiento oncológico sistémico: hallazgos tomográficos y resultados anatomopatológicos / Pulmonary disease in the oncologic immunosupressed patient: CT and pathologic examination findings

Las complicaciones pulmonares agudas son una importante causa de morbimortalidad en los pacientes con tratamiento oncológico sistémico. El propósito de este estudio fue determinar la utilidad de la TC en la evaluación de las complicaciones pulmonares que se presentan en estos pacientes. Se revisaron retrospectivamente estudios tomográficos de tórax de 26 pacientes con tratamiento oncológico sistémico (transplante de médula ósea, quimioterapia, radioterapia). El rango etario de los pacientes fue de 6 a 66 años (media de 37,96 años) y se incluyeron 14 mujeres y 12 varones. Dieciocho casos recibieron transplante de médula ósea (alogénico o autólogo) y doce pacientes tuvieron examen histopatológico. En 13 casos, la consolidación del espacio aéreo fue el hallazgo predominante por TC. Concluimos que los patrones tomográficos en pacientes con tratamiento oncológico sistémico son relativamente inespecíficos. Por lo tanto, los hallazgos tomográficos deberán ser siempre interpretados en el contexto clínico adecuado

Carcinoma de pulmón no a pequeñas células (CPNPC): estrategia combinada en enfermedad localmente avanzada / Stage III non-small cell lung cancer (NSCLC): multidisciplinary treatment in local advance disease

Introducción: a pesar de los recientes avances en el tratamiento multidisciplinario, el pronóstico del cáncer de pulmón no a pequeñas células continúa siendo pobre. Objetivos: analizar la actividad, toxicidad de la quimioterapia de inducción seguida de cirugía o radioterapia. Evaluar la supervivencia. Lugar de aplicación: Hospital Municipal e Institución privada. Diseño: dos estudios prospectivos fase II. Población: 56 pacientes con diagnóstico de cáncer de pulmón no a pequeñas células estadíos III. Método: el tratamiento es 2-4 ciclos de quimioterapia con gemcitabine (1,25 gr/m²/días 1, 8 y 15 en 30 minutos) + cisplatino 100 mg/m² cada 28 días; o paclitaxel 200 mg/m² en 3 horas + cisplatino 60 mg/m² días 2-3 cada 21 días. Pacientes con enfermedad estable o respuesta reciben 1-2 ciclos adicionales y luego tratamiento local. Resultados: edad mediana 56 años (rango 39-71): performance status 0-1-2: 9-41-6 pacientes; estadío IIIb (T4)-IIIB(N3): 31-12-13 pacientes. Histología: adenocarcinoma-escamoso-otros: 25-25-6. Toxicidad: se registró toxicidad grado 3-4: trombocitopenia 15 por ciento, neutropenia 7 por ciento, anemia 8 por ciento, neutropenia febril 1 por ciento, vómitos severos 3 por ciento, neurotoxicidad periférica 37 por ciento. Sólo se registró un caso de toxicidad letal por quimioterapia. Un paciente falleció en el postoperatorio de neumonectomía. Respuestas: hubieron 6 respuestas completas y 33 parciales (67 por ciento); 16 pacientes con enfermedad estable; un paciente no evaluable y ninguno progresado. 29 (80 por ciento) pacientes fueron resecables. Veintidós lobectomías y 7 neumonectomías. En dieciocho pacientes se constató respuesta patológica, 4 fueron completas. La supervivencia media fue 19 meses (24 meses en IIIa y 18 meses en IIIb). Conclusiones: las combinaciones de taxol/gemcitabine y cisplatino son efectivas como inducción en estadío III de cáncer de pulmón. No hubo exceso de morbimortalidad quirúrgica asociada