Severe toxicity in adult patients with lung cancer under treatment with pemetrexed: a prospective cohort study.

Pemetrexed is an antimetabolite approved for treatment of non-small cell lung cancer. Harbouring interindividual variability in both the pharmacokinetic and pharmacogenetic profiles may lead to life-threatening toxicities. A prospective cohort study of adult patients initiating treatment with pemetrexed in combination with platinum between 2013 and 2015 were follow up. Primary exposure were the methylenetetrahydrofolate reductase (MTHFR) single base polymorphisms in exon 4 and 7 and 5'-UTR- thymidylate synthase (TYMS) VNTR genotypes, in addition to baseline clinical and demographic variables. We used a Cox regression model to evaluate patient's survival and toxicity experience and its association with both baseline characteristics, and a-priori determined genetic polymorphisms. Seventy two patients were included, 52.7% developed severe hematologic toxicity during follow-up. None of the tested genotypes were significantly associated with the main outcome on multivariate analysis, nor other basal clinical variables. Overall survival between patients experiencing the outcome was not different from those without it, but hospital admissions were more frequent. MTHFR and 5'-UTR-TYMS genotypes were not useful for predicting high grade toxicity events in patients under treatment with pemetrexed.

Clinical relevance of galectin-1 expression in non-small cell lung cancer patients.

BACKGROUND: Identification of biomarkers in lung cancer, a leading cause of cancer-related mortality, has a meaningful clinical relevance in the quest of novel prognostic factors and therapeutic targets. The glycan-binding protein galectin-1 (Gal-1) modulates tumor progression by mediating cell-cell and cell-extracellular matrix interactions, as well as angiogenesis and tumor immune-escape. Previous works reported the expression of Gal-1 in lung cancer, although its clinical significance remains uncertain. OBJECTIVE: To assess the clinicopathologic relevance and prognostic value of Gal-1 expression in a cohort of 103 Stage I-III non-small cell lung cancer (NSCLC) patients. METHODS: Gal-1 expression was determined by immunohistochemistry in tumor tissue samples. The percentage of immunoreactive tumor cells and stroma, as well as the presence of blood vessels with positively stained endothelium in the tumor and surrounding normal tissue, were recorded. Results were correlated with the clinicopathologic factors of the patients (Spearman's rank correlation coefficient, chi-square test) and overall survival by univariate (Kaplan Meier) and multivariate analyses (Cox regression hazard model). RESULTS: We did not observe significant associations between Gal-1 expression and relevant clinicopathologic features at diagnosis of NSCLC. However, Kaplan Meier analysis revealed a significant association between Gal-1 expression and overall survival, when Gal-1 expression was analyzed on tumor cells alone ("tumor cell percentage") or when an integrated score accounting for tumor cell as well as stromal expression of Gal-1 ("total score") was assessed. Patients showing high Gal-1 expression evidenced a poorer clinical outcome. Furthermore, "total score" remained significantly associated with survival by multivariate Cox regression analysis in the whole cohort of patients, even when controlling for the classical predictors and prognostic factors of NSCLC. CONCLUSION: We conclude that Gal-1 expression may be a useful biomarker for better prediction of the clinical outcome and management of NSCLC patients.

TGF-beta specifically enhances the metastatic attributes of murine lung adenocarcinoma: implications for human non-small cell lung cancer.

Lung cancer is the most frequent and one of the most deadly cancer types and is classified into small cell lung cancer and non-small cell lung cancer (NSCLC). Transforming growth factor beta (TGFß) regulates a wide array of cell functions and plays a major role in lung diseases, including NSCLC. TGFß signals through the complex of TGFß type I and type II receptors, triggering Smad and non-Smad signaling pathways such as PI3K/Akt and MEK1/ERK. We investigated the role of TGFß1 on the progression of the murine lung adenocarcinoma cell line LP07. Furthermore, we undertook a retrospective study with tissue samples from stage I and II NSCLC patients to assess the clinical pathologic role and prognostic significance of TßRI expression. We demonstrated that although lung cancer cell monolayers responded to TGFß1 anti-mitogenic effects and TGFß1 pulse (24 h treatment) delayed tumor growth at primary site; a switch towards malignant progression upon TGFß1 treatment was observed at the metastatic site. In our model, TGFß1 modulated in vitro clonogenicity, protected against stress-induced apoptosis and increased adhesion, spreading, lung retention and metastatic outgrowth. PI3K and MEK1 signaling pathways were involved in TGFß1-mediated metastasis stimulation. Several of these TGFß responses were also observed in human NSCLC cell lines. In addition, we found that a higher expression of TßRI in human lung tumors is associated with poor patient's overall survival by univariate analysis, while multivariate analysis did not reach statistical significance. Although additional detailed analysis of the endogenous signaling in vivo and in vitro is needed, these studies may provide novel molecular targets for the treatment of lung cancer.

Estrogen receptor ß and epidermal growth factor receptor as early-stage prognostic biomarkers of non-small cell lung cancer.

As 20% of stage I NSCLC patients develop recurrent and often incurable cancer, the identification of prognostic markers has a meaningful clinical application. The biological significance of steroid hormone and EGF receptors, able to regulate key physiological functions, remains elusive in NSCLC. Our aim was to investigate the prognostic input of estrogen receptors (ERα, ERß), progesterone receptors (PR) and EGFR in tumors from 58 stage I NSCLC patients. Antigen expression was analyzed by immunohistochemistry. Prognostic evaluation was performed with the multivariate Cox model. We found that about 70 and 40% of samples expressed ERα or ERß at cytoplasmic or nuclear level, respectively. Besides, only 12.1% of samples weakly expressed nuclear PR and 62.7% showed membrane EGFR staining. Correlation studies indicated an inverse association between EGFR expression and smoking status (p<0.01). Multivariate studies showed that the lack of nuclear ERß or the loss of EGFR expression were independent prognosis markers associated with shorter overall survival. We also found that patients whose tumors were negative for these two biomarkers presented the worst outcome. In conclusion, our findings could be useful for selecting stage I NSCLC patients with poor prognosis to apply an earlier treatment that impacts on survival.

Evaluation of the exposure equivalence of oral versus intravenous temozolomide.

PURPOSE: Oral temozolomide is approved in many countries for malignant glioma and for melanoma in some countries outside the USA. This study evaluated the exposure equivalence and safety of temozolomide by intravenous infusion and oral administration. METHODS: Subjects with primary central nervous system malignancies (excluding central nervous system lymphoma) received 200 mg/m(2) of oral temozolomide on days 1, 2 and 5. On days 3 and 4, subjects received 150 mg/m(2) temozolomide either as a 90-min intravenous infusion on one day or by oral administration on an alternate day. RESULTS: Ratio of log-transformed means (intravenous:oral) of area under the concentration-time curve and maximum concentration of drug after dosing for temozolomide and 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC) met exposure equivalence criteria (90% confidence interval = 0.8-1.25). Treatment-emergent adverse events were consistent with those reported previously in subjects with recurrent glioma treated with oral temozolomide, except for mostly mild and transient injection site reactions with intravenous administration. CONCLUSIONS: This study demonstrated an exposure equivalence of a 90-min intravenous infusion of temozolomide and an equivalent oral dose.

[Retinoid expression (RARbeta and CRBP1) in non-small-cell lung carcinoma]. / Retinoides (RARbeta y CRBP1) en carcinoma de pulmón a celulas no pequeñas.

Although early-stage non-small-cell lung carcinoma (NSCLC) patients have a relative by favorable prognosis, the risk of a bad outcome remains substantial. Identification of reliable prognostic markers for disease recurrence and death has meaningful clinical application. Retinoids are involved in cell growth and differentiation and may antagonize cancer progression. Their effects are mediated through nuclear receptors called Retinoic Acid Receptor (RAR) and regulated by molecules such as Cellular Retinol-Binding Protein 1 (CRBP1) that function in retinol storage. The aim of this work was to analyze by immunohistochemistry the expression patterns of RARbeta and CRBP1, involved in retinoid-mediated signaling, in the tumoral tissue of a cohort of stage I/II NSCLC patients (n = 49) who underwent a successful surgical resection. Prognostic evaluation was performed with the multivariate Cox proportional hazard model: 44.9% of tumors were positive for RARbeta staining at cytoplasmic level, while 34.7% showed nuclear staining. CRBP1 staining was observed in 61.2% of the lung tumors. No relationship was found between the number of cells expressing the studied molecules and clinical pathological features, including sex, T and N (stage), histopathology and p53 expression. Univariate analysis showed a significant association between positive cytoplasmatic expression of RARbeta with shorter overall survival (Log-rank test 4.17, p = 0.0412). Multivariate studies indicated that RARbeta expression was not influenced by other clinical pathological parameters. In conclusion, in this cohort of stage I and II NSCLC, only the expression of RARbeta at cytoplasmatic level is a significant independent unfavorable prognostic factor.

Retinoides (RARβ y CRBP1) en carcinoma de pulmón a células no pequeñas / Retinoid expression (RARβ and CRBP1) in non-small-cell lung carcinoma

Aunque los pacientes con cáncer de pulmón a células no pequeñas en estadios tempranos (NSCLC) tienen buen pronóstico, el 20-30% recae, siendo relevante la identificación de biomarcadores pronósticos. Los retinoides regulan crecimiento y diferenciación, y pueden antagonizar la progresión tumoral. Su efecto depende del transporte citosólico mediado por moléculas como CRBP1, y de la unión a receptores específicos (RARβ). Alteraciones en esta vía se asociaron con cáncer. Nuestro objetivo fue estudiar la expresión, mediante inmunohistoquímica, de RARβ y CRBP1 en el tejido tumoral de 49 pacientes NSCLC Estadio I/II, obtenido durante la cirugía. La supervivencia se analizó mediante los test Log Rank y multivariado de Cox. El 44.9% de los tumores fueron positivos para RARβ con expresión a nivel citoplasmático, mientras que el 34.7% lo expresó a nivel nuclear. La tinción para CRBP1 se observó en el 61.2% de los tumores. No se encontró asociación entre la expresión de ambas moléculas y las características clinicopatológicas (sexo, tamaño tumoral, nódulos línfáticos comprometidos, histopatología y p53). Tampoco se encontró asociación con el hábito de fu-mar. La presencia de células tumorales en el lavado pleural se asoció significativamente con la expresión de CRBP1. Por otro lado, se demostró asociación entre la expresión elevada de RARβ citoplasmático y menor supervivencia global (LR 4.17, p=0.0412). El análisis multivariado no mostró asociación con otras variables de pronóstico en NSCLC. En conclusión, en este grupo de pacientes NSCLC Estadio I/II, RARβ pareciera predecir la supervivencia global en forma independiente.

Although early-stage non-small-cell lung carcinoma (NSCLC) patients have a relative by favorable prognosis, the risk of a bad outcome remains substantial. Identification of reliable prognostic markers for disease recurrence and death has meaningful clinical application. Retinoids are involved in cell growth and differentiation and may antagonize cancer progression. Their effects are mediated through nuclear receptors called Retinoic Acid Receptor (RAR) and regulated by molecules such as Cellular Retinol-Binding Protein 1 (CRBP1) that function in retinol storage. The aim of this work was to analyze by immunohistochemistry the expression patterns of RARβ and CRBP1, involved in retinoid-mediated signaling, in the tumoral tissue of a cohort of stage I/II NSCLC patients (n=49) who underwent a successful surgical resection. Prognostic evaluation was performed with the multivariate Cox proportional hazard model: 44.9% of tumors were positive for RARβ staining at cytoplasmic level, while 34.7% showed nuclear staining. CRBP1 staining was observed in 61.2% of the lung tumors. No relationship was found between the number of cells expressing the studied molecules and clinical pathological features, including sex, T and N (stage), histopathology and p53 expression. Univariate analysis showed a significant association between positive cytoplasmatic expression of RARβ with shorter overall survival (Log-rank test 4.17, p=0.0412). Multivariate studies indicated that RARβ expression was not influenced by other clinical pathological parameters. In conclusion, in this cohort of stage I and II NSCLC, only the expression of RARβ at cytoplasmatic level is a significant independent unfavorable prognostic factor.

Association between mast cells of different phenotypes and angiogenesis in colorectal cancer.

It is known that mast cells proliferate in solid tumours and increase tumour angiogenesis. Nevertheless, there is no consensus regarding their role in colorectal cancer (CRC). In this study, we aimed to clarify the relationship of mast cells positive for tryptase (MCts) and tryptase-chymase (MCtcs) with microvessel density (MVD) in the intratumoral zone and the invasive edge of 80 CRC patient tumours. We evaluated these parameters and associated their expression with clinicopathological parameters, including survival rate. Tumour sections from each patient were immunostained for tryptase to evaluate MCts, chymase to evaluate MCtcs, and CD34 to evaluate microvessel counts under x100 microscopy. The number of MCs of both phenotypes and the MVD counts were higher in the invasive edge than in the intratumoral zone (p<0.001). MCt numbers were higher than those of MCtcs in all Astler-Coller stages in both regions. A positive correlation between MVD and MCts or MCtcs was observed (Pearson's test p<0.001). Neither the number of MCs nor MVD was associated with overall survival (log rank test). However, only 8.3% of patients with low numbers of MCtcs in the invasive edge succumbed to the disease, compared to 32% with high numbers of MCtcs. Our results indicate that angiogenesis and MC hyperplasia are events which appear early during CRC development. The correlation of MC phenotypes with MVD is in agreement with the role attributed to MCs, that of angiogenesis enhancement. Collectively, these findings suggest that screening during the early malignization of CRC can provide valuable clinical information.

Prognostic value of E-cadherin, beta-catenin, MMPs (7 and 9), and TIMPs (1 and 2) in patients with colorectal carcinoma.

BACKGROUND AND OBJECTIVES: Therapy of colorectal tumors (CRC) based on histology and clinical factors is insufficient to predict the evolution of each patient. The finding of molecular abnormalities able to differentiate subgroups of patients with bad prognosis will improve our ability to treat them successfully. Our purpose was to analyze retrospectively the prognostic input of E-cadherin, beta-catenin, metalloproteinases (MMPs) (7 and 9), and tissue inhibitors of metalloproteinases (TIMPs) (1 and 2) in patients with a follow-up period of 5 years. METHODS: Antigen expression was analyzed by immunohistochemistry. Prognostic evaluation was performed with the multivariate proportional hazards model. RESULTS: We demonstrated a concomitant loss of E-cadherin and beta-catenin at membranous level and an abnormal accumulation of nuclear beta-catenin. Besides, we found that all MMPs and TIMPs studied were overexpressed in CRC tissue. There was no association between the expression of any of these molecules and the known clinical-pathological parameters employed in CRC pathology. A multivariate analysis demonstrated that the overall survival could be independently predicted by the loss of E-cadherin and the overexpression of TIMP-2. CONCLUSIONS: The expression of E-cadherin and TIMP-2 could be relevant in determining the prognosis of CRC patients and providing a more accurate mechanism for their classification.

EGF-R and PDGF-R, but not bcl-2, overexpression predict overall survival in patients with low-grade astrocytomas.

BACKGROUND AND OBJECTIVES: Therapy of malignant glioma tumors is based on histology and clinical factors. However, comparable lesions may correspond with important prognostic differences. Our purpose was to analyze retrospectively the prognostic input of platelet-derived growth factor receptor (PDGF-R), epidermal growth factor (EGF-R), and bcl-2 expression in 103 malignant gliomas from uniformly treated patients. METHODS: The expression of the antigens was analyzed by immunohistochemistry (IHC). Prognostic evaluation was performed with the multivariate proportional hazards model. The follow-up period lasted 19 (5-122) months for survivors. RESULTS: We observed that almost 50% of gliomas showed high expression of PDGF-R, while a lower expression of EGF-R and bcl-2 was found. No association between the main prognostic factors in malignant glioma (sex, age, histological grade, and Karnofsky score) and the labeling index (LI) of these antigens was observed. We found that only PDGF-R and EGF-R overexpression were associated with a shorter survival in patients with World Health Organization (WHO) II astrocytomas, being both associations independent of known prognostic factors, as shown by Cox model. Besides, we confirmed other authors' results that high histological grade and low performance score were associated with worse prognosis. CONCLUSIONS: PDGF-R and EGF-R expression could be relevant in determining the prognosis of low-grade astrocytomas (LGAs) and in providing a more objective mechanism for their classification.

CD44 expression in human gliomas.

BACKGROUND AND OBJECTIVES: Glioma invasiveness involves the attachment of tumor cells to the brain extracellular matrix, rich in hyaluronic acid (HA). CD44, the principal receptor for HA is found as a standard molecule (CD44s) or as variants (CD44v). We undertook a retrospective study to evaluate the expression pattern of CD44s, the isoforms CD44v3, v4/5 and v6 and to correlate their expression with clinical-anatomopathological parameters and survival rate. METHODS: The expression of these molecules was evaluated immunohistochemically in 84 gliomas. RESULTS: No expression of CD44v was detected in any tumors. CD44s staining of tumor cells was found in 70 of 84 (83.3%) of the gliomas. In 23 of 39 (59.0%) of the GBM more than the 70% of the cells were stained, while only 2 of 21 (9.5%) of LGA showed high expression. The association between CD44 and histological grade remained when the prognostic variables were considered in a multivariate analysis. Higher expression of CD44 was associated with worse overall survival rate; however, the Cox analysis indicated that survival was not associated with CD44. CONCLUSIONS: Our results suggest that overexpression of CD44s could be relevant in determining the highly invasive behaviour of gliomas, though it does not behave as an independent prognostic factor for survival.

Características de los tratamientos quimioterápicos / Characteristics of chemotherapy treatments

Generalmente se efectúan trabajos tendientes a demostrar la efectividad de los tratamientos propuestos pero olvidamos observar que le pasa al paciente mientras lo realiza. Con el objetivo de describir las características de los tratamientos, de los pacientes y del personal que lo asiste realizamos el siguiente trabajo: durante 10 meses fueron recolectados por enfermería oncológica datos referentes a las características de los tratamientos realizados. Se registraron 997 ciclos de quimioterapia (444 en hombres y 553 en mujeres). No hubo aumento en el número de intentos en colocar las vías parenterales según el número creciente de ciclos realizados, el tipo de vía utilizada, diferentes enfermeros o el sexo. Las mujeres tuvieron peor acceso vascular (p<0,024). No hubo diferencias en cuanto al uso de vías tipo "Abbocath" o "Butterfly". Las complicaciones más frecuentes fueron: la ansiedad 19,06 por ciento y la infiltración/extravasación 3,5 por ciento. En los días de trabajo más intenso se registraron mayor número de complicaciones. La infiltración/extravasación fue mayor a medida que aumentaba el número de ciclos que había recibido el paciente. Hubo diferencias significativas al considerar mejor la cooperación del paciente respecto al sexo masculino (p<0,018), número de intentos en colocar la vía (p<0,001) el tipo de acceso vascular (p<0,0001), si había tenido infiltración/extravasación (p<0,001) y según el uso de catéter implantable (p<0,02). Durante los tratamientos quimioterápicos entran en juego factores independientes del paciente, de la enfermera y del médico. Su conocimiento y mejoramiento pueden lograr una mejor calidad en la atención y bienestar para el paciente

Características de los tratamientos quimioterápicos / Characteristics of chemotherapy treatments

Generalmente se efectúan trabajos tendientes a demostrar la efectividad de los tratamientos propuestos pero olvidamos observar que le pasa al paciente mientras lo realiza. Con el objetivo de describir las características de los tratamientos, de los pacientes y del personal que lo asiste realizamos el siguiente trabajo: durante 10 meses fueron recolectados por enfermería oncológica datos referentes a las características de los tratamientos realizados. Se registraron 997 ciclos de quimioterapia (444 en hombres y 553 en mujeres). No hubo aumento en el número de intentos en colocar las vías parenterales según el número creciente de ciclos realizados, el tipo de vía utilizada, diferentes enfermeros o el sexo. Las mujeres tuvieron peor acceso vascular (p<0,024). No hubo diferencias en cuanto al uso de vías tipo "Abbocath" o "Butterfly". Las complicaciones más frecuentes fueron: la ansiedad 19,06 por ciento y la infiltración/extravasación 3,5 por ciento. En los días de trabajo más intenso se registraron mayor número de complicaciones. La infiltración/extravasación fue mayor a medida que aumentaba el número de ciclos que había recibido el paciente. Hubo diferencias significativas al considerar mejor la cooperación del paciente respecto al sexo masculino (p<0,018), número de intentos en colocar la vía (p<0,001) el tipo de acceso vascular (p<0,0001), si había tenido infiltración/extravasación (p<0,001) y según el uso de catéter implantable (p<0,02). Durante los tratamientos quimioterápicos entran en juego factores independientes del paciente, de la enfermera y del médico. Su conocimiento y mejoramiento pueden lograr una mejor calidad en la atención y bienestar para el paciente