Validation and clinical application of a targeted next-generation sequencing gene panel for solid and hematologic malignancies.

BACKGROUND: Next-generation sequencing (NGS) is a high-throughput technology that has become widely integrated in molecular diagnostics laboratories. Among the large diversity of NGS-based panels, the Trusight Tumor 26 (TsT26) enables the detection of low-frequency variants across 26 genes using the MiSeq platform. METHODS: We describe the inter-laboratory validation and subsequent clinical application of the panel in 399 patients presenting a range of tumor types, including gastrointestinal (GI, 29%), hematologic (18%), lung (13%), gynecological and breast (8% each), among others. RESULTS: The panel is highly accurate with a test sensitivity of 92%, and demonstrated high specificity and positive predictive values (95% and 96%, respectively). Sequencing testing was successful in two-thirds of patients, while the remaining third failed due to unsuccessful quality-control filtering. Most detected variants were observed in the TP53 (28%), KRAS (16%), APC (10%) and PIK3CA (8%) genes. Overall, 372 variants were identified, primarily distributed as missense (81%), stop gain (9%) and frameshift (7%) altered sequences and mostly reported as pathogenic (78%) and variants of uncertain significance (19%). Only 14% of patients received targeted treatment based on the variant determined by the panel. The variants most frequently observed in GI and lung tumors were: KRAS c.35G > A (p.G12D), c.35G > T (p.G12V) and c.34G > T (p.G12C). CONCLUSIONS: Prior panel validation allowed its use in the laboratory daily practice by providing several relevant and potentially targetable variants across multiple tumors. However, this study is limited by high sample inadequacy rate, raising doubts as to continuity in the clinical setting.

Validation of Cell-Free DNA Collection Tubes for Determination of EGFR Mutation Status in Liquid Biopsy from NSCLC Patients.

INTRODUCTION: Precision medicine has revolutionized the understanding and treatment of cancer by identifying subsets of patients who are amenable to specific treatments according to their molecular characteristics, as exemplified by epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC). Although tissue biopsy is the gold standard for determining molecular alterations in tumors, its limitations have prompted the development of new techniques for studying tumor biomarkers in liquid biopsies, such as mutation analysis in cell-free DNA (cfDNA). cfDNA analysis can accurately determine tumor progression and prognosis and more effectively identify appropriate targeted therapies. However, cfDNA is vulnerable, particularly during plasma sample shipping. OBJECTIVE: We compared the cell- and DNA-stabilizing properties of cell-free DNA blood collection tubes (BCTs) with those of the traditional shipping method (frozen plasma) for EGFR mutation testing using the cobas® EGFR Mutation Test v2 in a prospective cohort of 49 patients from three different Spanish hospitals. METHODS: In total, 98 NSCLC samples, two from each patient, were studied; five of the 49 cases were considered invalid by cobas® with one of the two shipping methods analyzed. After excluding these samples, we analyzed 88 samples from 44 patients. Considering the current methodology (frozen plasma) for sending samples as the gold standard, we evaluated the sensitivity and specificity of cfDNA BCT shipment. RESULTS: The global agreement between the two methods was 95.4%, with 100% sensitivity and 94.6% specificity for the cfDNA BCTs. cfDNA BCTs had a positive predictive value of 81.8% and negative predictive value of 100%. CONCLUSION: cfDNA BCTs have the same sensitivity for EGFR mutation analysis in liquid biopsy as the current methodology and very high specificity. They also have some additional advantages in terms of collection and further shipment. Therefore, cfDNA BCTs can be perfectly incorporated into the routine practice for EGFR mutation determination. FUNDING: Roche Farma S.A., Spain.

The umbilical cord, preeclampsia and the VEGF family.

Introduction: The VEGF family has been identified as abnormal in preeclampsia (PE). Hypertensive disorders of pregnancy (HDP) are major contributors to maternal and neonatal morbidity and mortality worldwide; likewise, umbilical cord anatomical abnormalities (UCAA) are linked to poor neonatal outcomes. Based on the relationship described between PE and UCAA and the role of the VEGF family in PE, this study explored VEGF expression in placental and UC tissued from patients with PE and with UCAA. Methods: We performed an observational, analytical study on placentas, comparing protein and mRNA expression in four groups: patients with PE, patients with UC abnormalities, patients with both, and patients with none of them. Using immunohistochemistry, we studied VEGF A, VEGF R1 (FLT1), MMP1, and PLGF. With quantitative reverse transcription polymerase chain reaction we described mRNA expression of PLGF, VEGF and sFLT1, and sFLT1/PLGF ratio. Results: Forty newborns were included. Sixty-seven percent of mothers and 45% of newborns developed no complications. Immunohistochemistry was performed on UC and placental disc paraffin-embedded tissue; in the latter, the mRNA of the VEGF family was also measured. Statistically significant differences were observed among different expressions in both HDP and UCAA groups. Interestingly, the UCAA group exhibited lower levels of sFLT1 and VEGF-A in comparison with other groups, with significant P-value for sFLT1 (P=0000.1). Conclusion: The origin of UCAA abnormalities and their relation with HDP are still unknown. VEGF family alterations could be involved in both. This study provides the first approach related to molecules linked to UCAA.

RAS/MAPK pathway hyperactivation determines poor prognosis in undifferentiated pleomorphic sarcomas.

BACKGROUND: Undifferentiated pleomorphic sarcoma (UPS) constitutes the most common subtype of soft tissue sarcoma. However, UPS is clinically and molecularly poorly understood, in great extent due to its intrinsic phenotypic and cytogenetic complexity, which in turn results in the absence of specific prognostic or predictive biomarkers. The RAS/mitogen-activated protein kinases (MAPK) and phosphoinositide 3-kinase inhibitor (PI3K)/mammalian target of rapamycin (mTOR) pathways are considered to be 2 major mechanisms for sarcoma proliferation and survival and to the authors' knowledge their role in UPS remains unclear. The objective of the current study was to investigate whether the RAS/MAPK and PI3K/mTOR pathways are activated in UPS, and whether pathway activation is associated with outcome. METHODS: Records for patients diagnosed and treated for UPS in the study institution between 2000 and 2009 were reviewed. Phosphorylation status of 4E-binding protein (4E-BP1), eukaryotic translation initiation factor 4E (eIF-4E), S6-RP, and ERK 1/2, together with total forms of 4E-BP1 and eIF-4E, were assessed using immunohistochemistry in paraffin-embedded tumor tissue. Mutational analysis for KRAS; NRAS; BRAF; and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) oncogenic mutations was performed as well. RESULTS: Critical lymph nodes within the RAS/MAPK and PI3K/mTOR pathways were found to be activated in >80% of UPS cases. Hyperactivation of the RAS/MAPK pathway, as assessed by expression of phosphorylated ERK 1/2, was found to independently predict a higher risk of disease recurrence and impaired overall survival. Only a KRAS A146V mutation was detected in 1 tumor. CONCLUSIONS: The RAS/MAPK and PI3K/mTOR pathways are activated in the majority of cases of UPS. The RAS/MAPK pathway distinguishes a subgroup of patients with localized UPS with a worse outcome.

Identification of somatic gene mutations in penile squamous cell carcinoma.

There is a lack of studies on somatic gene mutations and cell signaling driving penile carcinogenesis. Our objective was to analyze somatic mutations in genes downstream of EGFR in penile squamous cell carcinomas, especially the mTOR and RAS/MAPK pathways. We retrospectively analyzed somatic mutations in 10 in situ and 65 invasive penile squamous cell carcinomas by using Sequenom's Mass Spectrometry iPlex Technology and Oncocarta v1.0 Panel. The DNA was extracted from FFPE blocks and we identified somatic missense mutations in three in situ tumors and in 19 invasive tumors, mostly in PIK3CA, KRAS, HRAS, NRAS, and PDGFA genes. Somatic mutations in the PIK3CA gene or RAS family genes were neither associated with tumor grade, stage or outcome, and were equally often identified in hrHPV positive and in hrHPV negative tumors that showed no p53 expression. Mutations in PIK3CA, KRAS, and HRAS are frequent in penile squamous cell carcinoma and likely play a role in the development of p53-negative tumors. Although the presence of these mutations does not seem to correlate with tumoral behavior or outcome, they could be biomarkers of treatment failure with anti-EGFR mAb in patients with penile squamous cell carcinoma.

Oxidative stress and cancer: an overview.

Reactive species, which mainly include reactive oxygen species (ROS), are products generated as a consequence of metabolic reactions in the mitochondria of eukaryotic cells. In normal cells, low-level concentrations of these compounds are required for signal transduction before their elimination. However, cancer cells, which exhibit an accelerated metabolism, demand high ROS concentrations to maintain their high proliferation rate. Different ways of developing ROS resistance include the execution of alternative pathways, which can avoid large amounts of ROS accumulation without compromising the energy demand required by cancer cells. Examples of these processes include the guidance of the glycolytic pathway into the pentose phosphate pathway (PPP) and/or the generation of lactate instead of employing aerobic respiration in the mitochondria. Importantly, ROS levels can be used as a thermostat to monitor the damage that cells can bear. The implications for ROS regulation are highly significant for cancer therapy because commonly used radio- and chemotherapeutic drugs influence tumor outcome through ROS modulation. Moreover, the discovery of novel biomarkers that are able to predict the clinical response to pro-oxidant therapies is a crucial challenge to overcome to allow for the personalization of cancer therapies.

BRAF V600E and KRAS G12S mutations in peripheral nerve sheath tumours.

AIMS: Benign (BPNST) and malignant (MPNST) peripheral nerve sheath tumours occur either sporadically or are related to neurofibromatosis (NF). The mechanisms involved are well known in NF-related tumours, but still remain unclear in sporadic cases. Somatic BRAF and KRAS mutations represent the most frequent genetic events in melanocytic neoplastic lesions. Because melanocytes and Schwann cells both derive from neural crest cells, we hypothesized that BRAF and KRAS mutations might influence BPNST and MPNST development. METHODS AND RESULTS: BRAF exon 15 and KRAS exons 2 and 3 polymerase chain reaction (PCR) sequencing was performed in formalin-fixed/paraffin-embedded samples of 99 BPNST and MPNST, related and non-related to NF types 1 and 2. Oncogenic BRAF V600E mutations were found in four of 40 schwannomas (including one acoustic neuroma) and one of 13 MPNST, not associated with NF. A KRAS G12S mutation was also evident in one sporadic schwannoma. CONCLUSION: Our findings suggest that RAS pathway activation due to BRAF V600E and KRAS mutations is an important event in a subset of peripheral nerve sheath tumours not related to NF.

Valor pronóstico de las isoenzimas de LDH en pacientes con linforma no hodgkin / Prognostic value of LDH isoenzymes in patients with non-Hodgkin linforma

La enzima lactato deshidrogenasa (LDH) es un factor pronóstico en Linfoma No Hodgkin (LNH). El objetivo del trabajo consistió en evaluar prospectivamente el valor pronóstico de las isoenzimas de LDH en pacientes con LNH. Se estudiaron 67 pacientes de primera consulta con diagnóstico de LNH, sin tratamiento previo, VIH negativo y sin otras enfermedades, tiempo promedio de seguimiento 30 meses (rango 3-48 meses). Las muestras de suero se recolectaron previas al tratamiento. La LDH total (LDHT) e isoenzimas de LDH se determinaron respectivamente por método cinético y electroforesis de proteínas en gel de agarosa. Se procesaron muestras de 122 controles sanos para establecer los valores de referencia de las isoenzimas de LDH. 49(73%) LNH agresivos y 18(27%) LNH indolentes y según el Índice Pronóstico Internacional (IPI), 60 (90%) bajo riesgo y 7(10%) alto riesgo. Las isoenzimas LDH1, LDH2, LDH3, LDH4 y LDH5 presentaron niveles absolutos significativamente elevados en 25 (37%), 29 (43%), 32 (48%), 20 (39%) y 11 (16%) de los casos respectivamente (p<0,0001). La actividad porcentual de LDH4 en los pacientes con LNH agresivos fue significativamente superior respecto al grupo de LNH indolentes (p=0,01). En el análisis univariado, valores absolutos elevados de LDH1 se asociaron significativamente con una sobrevida global disminuida (p=0,0064) en el grupo total de pacientes. LDH1 conservó su valor pronóstico aún en el grupo de pacientes con valores normales de LDHT (p=0,04). En pacientes con LNH agresivos, valores elevados de LDHT e IPI alto riesgo se asociaron significativamente con una menor sobrevida global (p<0,05). En el análisis multivariado la LDHT e IPI resultaron factores pronósticos independientes de la sobrevida. Alteraciones específicas del patrón de isoenzimas de LDH sugieren la relación de LDH4 con la biología del tumor y su actividad proliferativa en LNH agresivos y el valor pronóstico de LDH1 como factor adverso de la sobrevida en el análisis univariado.

Lactate dehydrogenase (LDH) is a prognostic factor in non-Hodgkin lymphoma (NHL). Our objective was to evaluate prospectively the prognostic value of LDH isoenzymes in patients with NHL. We studied 67 newly diagnosed NHL patients, previously untreated, HIV-negative and free from other disease, median follow-up of 30 month (range 3-48 month). Before starting treatment serum samples were collected for the determination of total LDH (LDHT) and LDH isoenzymes that were respectively assayed by kinetic method and protein electrophoresis in agarose gel. In order to set reference values of LDH isoenzymes samples from122 healthy controls were processed. Results: 49(73%) of the patients were aggressive NHL and 18(27%) indolent NHL and according to the International Prognostic Index (IPI), 60(90 %) low risk and 7(10%) high risk. High absolute values of LDH1, LDH2, LDH3, LDH4 and LDH5 isoenzymes were significantly elevated in 25 (37%), 29 (43%), 32 (48%), 20 (39%) and 11 (16%) of cases respectively (p<0,0001). The percentage value of LDH4 activity in aggressive NHL patients was significantly higher compared to indolent NHL group (p=0,01). In univariate analysis increased LDH1 absolute values were significantly associated with decreased overall survival in the total group of patients (p = 0.0064). LDH1 remained a prognostic factor for survival even when considering the group of patients with normal serum LDHT values (p = 0.04). In patients with aggressive NHL increased values of LDHT and high risk IPI were significantly associated with decreased overall survival (p<0.05). In a multivariate analysis LDHT and IPI score were independent prognostic factor for survival.

Increased voltage-dependent K+ channel Kv1.3 and Kv1.5 expression correlates with leiomyosarcoma aggressiveness.

Voltage-dependent K+ channels (Kv) are involved in the proliferation and differentiation of mammalian cells, since Kv antagonists impair cell cycle progression. Although myofibers are terminally differentiated, some myoblasts may re-enter the cell cycle and proliferate. Since Kv1.3 and Kv1.5 expression is remodeled during tumorigenesis and is involved in smooth muscle proliferation, the purpose of this study was to analyze the expression of Kv1.3 and Kv1.5 in smooth muscle neoplasms. In the present study, we examined human samples of smooth muscle tumors together with healthy specimens. Thus, leiomyoma (LM) and leiomyosarcoma (LMS) tumors were analyzed. Results showed that Kv1.3 was poorly expressed in the healthy muscle and indolent LM specimens, whereas aggressive LMS showed high levels of Kv1.3 expression. Kv1.5 staining was correlated with malignancy. The findings show a remodeling of Kv1.3 and Kv1.5 in human smooth muscle sarcoma. A correlation of Kv1.3 and Kv1.5 expression with tumor aggressiveness was observed. Thus, our results indicate Kv1.5 and Kv1.3 as potential tumorigenic targets for aggressive human LMS.

ErbB3 expression predicts sensitivity to elisidepsin treatment: in vitro synergism with cisplatin, paclitaxel and gemcitabine in lung, breast and colon cancer cell lines.

Irvalec® (elisidepsin trifluoroacetate, PM02734) is a novel marine-derived cyclic peptide belonging to the Kahaladide family of compounds, currently in clinical trials with preliminary evidence of antitumor activity. Previous studies have shown a correlation between elisidepsin sensitivity and expression of the ErbB3 receptor in a panel of NSCLC cell lines. We have studied the effect of elisidepsin on the ErbB3 pathway, characterizing the expression of all members of the ErbB (HER) family of receptors and their main downstream signaling effectors, such as Akt and MAPK. Interestingly, we observed a downregulation of ErbB3 upon elisidepsin treatment that correlates with a reduction in the Akt phosphorylation levels in the most sensitive cell lines, whereas ErbB3 levels are not affected in the less sensitive ones. Also, we observed that the basal levels of ErbB3 protein expression show a significant correlation with cell viability response against elisidepsin treatment in 14 different cell lines. Furthermore, we analyzed the combination of elisidepsin with different chemotherapeutics agents, such as cisplatin, paclitaxel and gemcitabine, in a panel of different breast (MDA-MB-435, MDA-MB-231 and MCF7), lung (HOP62, DV90 and A549) and colorectal cancer cell lines (DLD1 and HT29). IC50 values for the different drugs were tested. We observed a synergistic effect in all cell lines tested with any chemotherapeutic agent. More importantly, the two in vitro elisidepsin-resistant cell lines (MDA-MB-231 and HOP62) presented a synergistic effect in combination with cisplatin and paclitaxel, respectively. These results provide a rationale for further development of these combinations in an ongoing clinical trial.

Differential expression of Kv1.3 and Kv1.5 voltage-dependent K+ channels in human skeletal muscle sarcomas.

Because Kv1.3 and Kv1.5 K(+) channels are remodeled during tumorigenesis and participate in skeletal muscle proliferation, we analyzed their expression in human skeletal muscle sarcomas. Aggressive alveolar rhabdomyosarcoma (ARMS) and embryonal rhabdomyosarcoma (ERMS) were studied. Kv1.5 expression was moderate in adult muscle and low in ERMS, whereas it was notable in ARMS and embryonic samples. Kv1.3 expression showed no major differences between RMS and healthy samples. We found a correlation of Kv1.3 and Kv1.5 expression with the tumor malignancy.

Perfil de las isoenzimas de LDH en linfoma no Hodgkin: correlación con marcadores tumorales / Profiles of LDH isoenzymes in non-Hodking`s lymphoma: correlation with tumor markers

Lactate dehydrogenase (LDH) consists of five isoenzymes and is an important prognostic factor in non-Hodgkin’s lymphoma (NHL) patients. Our objective was to study the pattern of LDH isoenzymes in patients with NHL and its correlation with clinical pathological and biological tumor markers. We evaluated 67 newly diagnosed NHL patients clinically and histologically confirmed, previously untreated, HIV-negative and free from other diseases, during the period 1999-2004, the average follow-up time of 30 months (range 3-48), median age of 55 years (range 18-79), the International Prognostic Index (IPI ) 60 (90%) of low risk and 7 (10%) of high risk. Serum and whole blood samples were collected for the determination of LDH, LDH isoenzymes, enzymes (AST, ALT, phosphatase alkaline), Beta 2 Microglobulin, CA125, and IL-6, sRáIL-2, C Reactive protein, serum albumin and ESR. Serum samples were processed from healthy controls in order to set reference values of LDH isoenzymes. Serum levels of LDH and absolute values of LDH isoenzymes were significantly higher in patients compared to controls (p<0.001). Frequencies of high absolute values of LDH1, LDH2, LDH3, LDH4 and LDH5 isoenzymes were significantly elevated in 25 (37%), 29 (43%), 32 (48%), 20 (39%) and 11 (16%) of cases, respectively. LDH1 activity associated and correlated with adverse clinical pathological, biological factors and high risk IPI, suggets that it is an indicator of cell turnover and disease activity. LDH2 changes reflected its association and correlation with clinical pathological and biological factors which are indicators of disease progression, tumor proliferative activity, adverse IPI and the patient’s response to the illness. LDH3 was elevated with greater frecuency and its activity was associated with clinical pathological and biological prognostic factors reflecting the patient’s response against the tumor, as well as inflammatory activity and disease extension...

La enzima lactato deshidrogenasa (LDH) está conformada por cinco isoenzimas y es un importante factor pronóstico en pacientes con Linfoma No Hodgkin (LNH). Nuestro objetivo fue estudiar el patrón de las isoenzimas de LDH en pacientes con LNH y su correlación con marcadores tumorales clínico-patológicos y biológicos. Se evaluaron 67 pacientes de primera consulta con diagnóstico de LNH confirmados clínica e histopatológicamente, sin tratamientos previo, VHI negativo y sin presentar otras enfermedades, durante el período 1999-2004, siendo el tiempo promedio de seguimiento de 30 meses (rango 3-48 meses), edad promedio 55 años (rango 18-79), Índice Pronóstico Internacional (IPI) 60 (90 por ciento) bajo riesgo y 7 (10 por ciento) alto riesgo. Se recolectaron muestras de sangre, para la obtención de suero y sangre total para la determinación de LDH, Isoenzimas de LDH, enzimas (AST, ALT, fosfatasa alcalina), Beta 2 Microglobulina, CA125,IL-6,sRIL-2, Proteína C Reactiva, Albúmina sérica y VSG. Se procesaron muestras de suero de controles sanos para establecer los valores de referencia de las isoenzimas de LDH. Los nieveles séricos de la LDH y los valores absolutos de las isoenzimas de LDH fueron significativamente superiores en los pacientes respecto al grupo control (p<0,001). Las frecuencias de las isoenzimas LDH1, LDH2, LDH3, LDH4 y LDH5 resultaron con niveles absolutos significativamente elevados en 25 (37 por ciento), 29 (43 por ciento), 32 (48 por ciento), 20 (39 por ciento) y 11 (16 por ciento) de los casos respectivamente. La asociación y correlación de la actividad de LDH1 con los factores clínico-patológicos adversos, IPI alto riesgo y marcadores biológicos alterados , sugieren su expresión como un indicador de recambio celular y actividad de la enfermedad. Los cambios en el patrón de la LDH2 reflejaron su asociación y correlación con factores clínico-patológico y biológicos indicadores de la pregresión de la enfermedad...

Voltage-dependent potassium channels Kv1.3 and Kv1.5 in human fetus.

Voltage-dependent K(+) channels (Kv) control repolarization and membrane potential in electrically excitable cells. In addition, Kv channels are involved in the maintenance of vascular smooth muscle tone, insulin release, epithelial K(+) transport, cell proliferation and leukocyte activation. Kv1.3 and Kv1.5 are widely distributed throughout the body and are involved in a variety of physiological processes taking place in the immune system, brain and muscle. Since the developmental pattern of Kv channels has an essential role in the maturing human, we aimed to study Kv1.3 and Kv1.5 channels in 8-10 week human fetal tissues. We chose that gestational age because all organs are in place and the nervous system, although not fully developed. However, the human embryo is undergoing major changes, which will lead to a defined adult pattern. Our results indicated that numerous tissues expressed Kv1.3 and Kv1.5. While Kv1.3 overlapped with the central and peripheral nervous systems, Kv1.5 was mostly localized in the central nervous system. In addition, both channels were abundantly expressed in the hematopoietic fetal liver. Finally, Kv1.5 heavily stained skeletal muscle and heart, whereas Kv1.3 was slightly present. This is the first study to analyze Kv1.3 and Kv1.5 in human during the beginning of fetal development.

Valor pronóstico de los niveles séricos del CA-125 en pacientes con linfoma no hodgkin / Prognostic value of serum CA 125 levels in non-hodgkin's lymphoma patients

El CA 125 ha sido considerado un nuevo marcador pronóstico en linfoma No Hodgkin (LNH). El objetivo del trabajo consistió en evaluar la significancia pronostica de los niveles del CA 125 en pacientes con LNH, asociación y correlación con factores clínicos patológicos, biológicos y sobrevida. Se procesaron muestras de suero de 67 pacientes con diagnóstico de LNH, de primera consulta, pretratamiento, VIH negativo y sin presentar otras enfermedades, edad promedio 55 años (rango 18-79 años), LNH agresivos 49 (73%) y LNH indolentes 18 (27%), IPI 60 (90%) de bajo riesgo y 7 (10%) de alto riesgo, tiempo promedio de seguimiento 30 meses (rango 3-48 meses). CA 125, B2M e IL-6 se determinaron por inmunoensayos enzimáticos y Proteína C Reactiva, Albúmina sérica, LDH, AST, ALT y fosfatasa alcalina por métodos de aglutinación directa, colorimétrico y cinético, respectivamente. 16 (24%) de los pacientes expresaron niveles elevados de CA 125 (>35u/ml) (p<0,001). Asociación significativa (p≤0,05) de CA 125 (35u/ml) con estadío clínico (EC) III-IV, enfermedad voluminosa (EV)>10cm, síntomas B (SB), enfermedad abdominal (EAb) y níveles elevados de LDH y B2M. Correlación significativa y directa con EC, EV, SB, LDH, B2M y AST (p≤0,05) y correlación inversa con albúmina sérica (p=0,02). El análisis univariado mostró una significativa disminución de la sobrevida global en los pacientes con LNH agresivos y niveles elevados de CA 125(>35u/ml) (p=0,03), LDH (p=0,048) y B2M(p=0,02). Según el análisis multivariado, Ca 125 perdió su significancia, LDH (p=0,04) y B2M (p=0,003) mantuvieron su valor pronóstico independiente. Los resultados del presente trabajo sugieren la utilidad pronóstica de los niveles séricos del CA 125, siendo recomendable su inclusión en la evaluación clínica inicial e los pacienten con LNH.

CA 125 has been considered a new prognostic marker in Non-Hodgkin lymphoma (NHL). The objetive of this study was to determine the prognostic significance of CA 125 levels in NHL patients, the association and correlation with clinical pathological and biological factos and survival. We processed 67 serum samples from newly diagnosed NHL patients previously untreated, HIV-negative and free from other diseases, mean age 55 years (range 18-79 Years), agressive NHL 49 (73%) and indolent NHL 18 (27%), IPI: 60 (90%) of low risk and 7 (10%) high risk, the average time of follow up was 30 months (range 3-48 months). CA 125, B2M and IL-6 were determined by enzyme immunoassay methods. C-reactive protein, serum albumin, LDH, AST, ALT and alkaline phosphatase were determined by direct agglutination, colorimetric and kinetic methods, respectively. Elevted levels of CA 125 (>35u/ml) were expressed in 16 (24%) of the patients (p<0.001). CA 125 levels (>35u/ml) were significantly (p≥0.05) associated with the follwing factors: clinicals stage (CS) III-IV, bulky disease (BD)>10 cm, B symptoms (BS), abdominal disease (ABD) and elevated levels of LDH and B2M. There was a significant and direct correlation (p≤0.05) with CS, BD, BS, LDH, B2M and AST and inversely with serum albumin (p=0,02). Univariate analysis showed a significant decreased of overall survival in patients with aggressive NHL with elevated levels of CA 125 (p<0.048), LDH (p=0.048) and B2M (p=0,02). In multivariate analysis Ca 125 lost its prognostic significance, LDH (p=0.04) and B2M (p=0.003) remained their independent prognostic value. The results of this study suggest the prognostic value of serum levels of CA 125, being recommended for inclusion in the initial clinical evaluation of patients with NHI.

Tratamiento de la enfermedad de hodgkin: esquema MOPP/ABV toxicidad (2a neoplasia): seguimiento durante 10 años / Treatment of the Hodgkin`s disease: scheme MOPP/ABV toxicity (2 neoplasms) follow-up for 10 years

Determinar la eficacia de un régimen híbrido de siete drogas en pacientes con enfermedad de Hodgkin en estadios avanzados y en estadios tempranos II-B con factores pronósticos desfavorables. Entre enero de 1988 y diciembre de 1998 fueron tratados 126 pacientes, (edad promedio: 33 años), y un seguimiento promedio de 5,6 años. Los estadios clínicos fueron II-B en 42 pacientes (33 por ciento), estadio III en 55 pacientes (44 por ciento), y estadio IV en 29 pacientes (23 por ciento). Los factores pronósticos (FP) evaluados fueron: edad> 45 años, sexo masculino, síntomas B, MM > 30 por ciento, EC IV y VSG> 50 mm 1° hora. Todos recibieron 6 ciclos de quimioterapia (MOPP/ABV). Ciento siete pacientes (84 por ciento) obtuvieron remisión completa; remisión parcial en 16 (13 por ciento); progresaron al final del tratamiento en 3 (3 por ciento); y 13/107 (12 por ciento) recayeron. La tasa de sobrevida total y la tasa de sobrevida libre de falla de todo el grupo a los 10 años fueron de 76 por ciento y 62 por ciento, respectivamente. La toxicidad hematológica aguda incluyó neutropenia, trombocitopenia y anemia. La toxicidad tardía fue de nódulo tiroideo de 4 por ciento leucemia mieloide aguda en 3 por ciento afectación cardíaca en 1,6 por ciento y tumor sólido (esófago) en 0,8 por ciento. Las tasas de incidencia fueron altas para segundo tumor, cáncer de esófago y leucemia secundaria. Por lo que, a pesar de los resultados obtenidos debimos descontinuar el uso de esta combinación

Linfoma no hodgkin (LNH) difuso en pacientes con la infección por el virus de inmunodeficiencia humana (VIH) tratamiento con: ciclofosfamida-doxorrubicina-vincristina-prednison (CHOP): reporte final / Diffuse non-hodgkin lymphoma in patients with human immnunodeficiency virus infection treatment with: ciclophosphamid-doxorrubicin-vincristina-prednison (CHOP): final report

El LNH difuso es una manifestación tardía en pacientes con infección por el VIH, esta entidad afecta hasta un 5 por ciento de ellos. Nosotros estudiamos 12 pacientes masculinos (9 homosexuales y 3 heterosexuales), entre 27 y 60 años de edad (edad promedio, 36 años), con LNH difuso e infección pór el VIH. El diagnóstico histológico fue: 7 (células grandes), 3 (células pequeñas y grandes) y 2 (células pequeñas y hendidas). El estado clínico fue: IE(4), IIA (I), IIIA(I), IVA(3) y IVB(3). Ellos fueron tratados con CHOP (entre 1 y 8 ciclos). La respuesta clínica fue la siguiente: 41 por ciento remisión completa (RC), 41 por ciento remisión parcial, 9 por ciento enfermedad estable y 9 por ciento progresión. La toxicidad fue leve y aceptable. Las principales causas de muerte en 10 pacientes fueron las infecciones por oportunitas. La sobrevida media global fue 12 meses (rango, 2 a 70). La sobrevida media global del grupo que alcanzo RC fue 22.6 meses (rango, 4 a 70). Finalmente, el CHOP es efectivo en el manejo de los linfomas relacionados con la infección por el VIH

Tratamiento del linfoma no-hodgkin difuso en pacientes con la infección por el virus de inmunodeficiencia humana con ciclofosfamida-doxorubicina-vincristina-prednisona (CHOP) reporte final / Treatment of the non-hodgkin lymphoma diffuse in patients with human immunodeficiency virus (HIV) infection with cyclophosphamide-doxorubicine-vincristine-prednisone (CHOP) end report

El LNH difuso es una manifestación tardía en pacientes con infección por el VIH, esta entidad afecta hasta un 5 por ciento de ellos. Nosotros estudiamos 12 pacientes masculinos (9 homosexuales y 3 heterosexuales), entre 27 y 60 años de edad (edad promedio, 36 años), con LNH difuso e infección por el VIH. El diagnóstico histológico fue: 7(células pequeñas y grandes) y 2(células pequeñas y hendidas). El estadio clínico fue: IE(4), III(3) y IVB(3). Ellos fueron tratados con CHOP (entre 1 y 8 ciclos). La respuesta clínica fue la siguiente: 41 por ciento remisión completa (RC), 41 por ciento remisión parcial, 9 por ciento enfermedad estable y 9 por ciento progresión. La toxicidad fue leve y aceptable. Las principales causas de muerte en 10 pacientes fueron las infecciones por oportunistas. La sobrevida media global fue 12 meses (rango, 2 a 70). La sobrevida media global del grupo que alcanzó RC fue 22.6 meses (rango, 4 a 70). Finalmente, el CHOP es efectivo en el manejo de los linfomas relacionados con la infección por VIH, y produce poca toxicidad