Carlos Pastor

Identification of a biomarker profile associated with resistance to neoadjuvant chemoradiation therapy in rectal cancer

Objective:To identify a biomarker profile associated with tumor response to chemoradiation (CRT) in locally advanced rectal cancer. Background:Rectal cancer response to neoadjuvant CRT is variable. Whereas some patients have a minimal response, others achieve a pathologic complete response (pCR) and have no viable cancer cells in their surgical specimens. Identifying biomarkers of response will help select patients more likely to benefit from CRT. Methods:This study includes 132 patients with locally advanced rectal cancer treated with neoadjuvant CRT followed by surgery. Tumor DNA from pretreatment tumor biopsies and control DNA from paired normal surgical specimens was screened for mutations and polymorphisms in 23 genes. Genetic biomarkers were correlated with tumor response to CRT (pCR vs non-pCR), and the association of single or combined biomarkers with tumor response was determined. Results:Thirty-three of 132 (25%) patients achieved a pCR and 99 (75%) patients had non-pCR. Three individual markers were associated with non-pCR; v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog mutation (P = 0.0145), cyclin D1 G870A (AA) polymorphism (P = 0.0138), and methylenetetrahydrofolate reductase (NAD(P)H) C677T (TT) polymorphism (P = 0.0120). Analysis of biomarker combinations revealed that none of the 27 patients with both tumor protein p53 (p53) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog mutations had a pCR. Further, in patients with both p53 and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog mutations or the cyclin D1 G870A (AA) polymorphism or the methylenetetrahydrofolate reductase (NAD(P)H) C677T (TT) polymorphism (n = 52) the association with non-pCR was further strengthened; 51 of 52 (98%) of patients were non-pCR. These biomarker combinations had a validity of more than 70% and a positive predictive value of 97% to 100%, predicting that patients harboring these mutation/polymorphism profiles will not achieve a pCR. Conclusions:A specific biomarker profile is strongly associated with non-pCR to CRT and could be used to select optimal oncologic therapy in rectal cancer patients. ClinicalTrials.org Identifier: NCT00335816.

Influence of Morbid Obesity and Insulin Resistance on Gene Expression Levels of AQP7 in Visceral Adipose Tissue and AQP9 in Liver

BackgroundGlycerol production and its efflux from adipocytes to the liver are key to modulate lipid and glucose homeostasis. Aquaporin 7 (AQP7) is an aquaglyceroporin that acts as the adipose glycerol channel, whereas aquaporin 9 (AQP9) is the specific channel operating in the liver. The aim of the present work was to evaluate the effect of obesity and type 2 diabetes mellitus (T2DM) on gene expression levels of AQP7 in visceral adipose tissue (VAT) and AQP9 in liver.MethodsVAT and liver biopsies obtained from 20 women were used in the study. Patients were classified as lean or obese with the last group being further subclassified as normoglycemic (NG), patients with impaired glucose tolerance (IGT), or with T2DM. Anthropometric measurements as well as circulating metabolites, hormones, and adipokines were determined. Real-time polymerase chain reaction analyses were performed to quantify transcript levels of AQP7 in VAT and AQP9 in the liver.ResultsGene expression levels of AQP7 in VAT showed a tendency toward an increase (P = 0.065) in obese patients (both NG and T2DM) compared to lean subjects. AQP9 showed a significant downregulation in the hepatic biopsies obtained from obese T2DM patients compared to obese NG and IGT patients (P = 0.028).ConclusionThe tendency toward an elevation of mRNA expression of VAT AQP7 in obesity together with the decreased hepatic AQP9 expression observed in obese T2DM subjects suggests a potential role in facilitating glycerol release from adipose tissue and reducing glycerol entry into hepatocytes in obesity and T2DM, respectively.

Increased cardiovascular risk markers in obesity are associated with body adiposity: role of leptin.

Epidemiological studies have shown that obesity is associated with increased blood concentrations of proinflammatory factors and markers of endothelial dysfunction such as fibrinogen, C-reactive protein (CRP), and von Willebrand factor (vWF). We analyzed the association of these markers with percentage of body fat (BF), and the influence of leptin in a cross-sectional study of 1,089 subjects (366 men) aged 44 (34-53) [median (interquartile range)] years, who were classified as obese or nonobese according to BF estimated by whole-body air displacement plethysmography. Obesity was defined as BF >or= 25% in men and >or= 35% in women. Compared with non-obese subjects (mean +/- SD), obese patients had higher concentrations of fibrinogen (312 +/- 78 vs. 342 +/- 81 mg/dl, P < 0.001), CRP (0.41 +/- 0.75 vs. 0.75 +/- 1.04 mg/l, P = 0.014), vWF (107 +/- 29 vs. 123 +/- 55%, P < 0.001), and leptin (10.4 +/- 6.5 vs. 37.5 +/- 26.1 ng/ml, P < 0.0001). A positive correlation was observed between BF and fibrinogen (r = 0.266; P < 0.0001), logCRP (r = 0.409; P < 0.0001), and vWF (r = 206; P < 0.0001). Leptin was correlated with fibrinogen (r = 0.219, P < 0.0001), logCRP (r = 0., P < 0.0001), and vWF (r = 0.124, P = 0.002), but the statistical significance was lost after including BF in adjusted-correlation and multivariate analysis, suggesting that they are not regulated by leptin per se. In conclusion, the obesity-associated increase in the circulating concentrations of fibrinogen, CRP, and vWF is highly associated to BF and apparently not determined by leptin.

Analysis of Early Postoperative Morbidity Among Patients with Rectal Cancer Treated with and without Neoadjuvant Chemoradiotherapy

BackgroundThe impact of neoadjuvant treatment and their subsequent early complications in the treatment of rectal cancer has not been adequately assessed. The aim of this prospective study was to evaluate early postoperative morbidity and mortality among patients with rectal cancer treated with adjuvant radiotherapy and chemotherapy followed by surgery, compared with patients treated with surgery alone. We also identified independent risk factors associated with early major complications.MethodsBetween 1995 and 2004, 273 consecutive patients underwent treatment for rectal cancer. A total of 170 patients (group A) received preoperative radiotherapy with a total of 45–50.4 Gy (180 cGy per day) and 5-fluorouracil-based chemotherapy, followed by surgery; 103 patients (group B) were treated with surgery alone. Dependent variables related to patients, treatment, radiotherapy, and tumor were analyzed.ResultsBoth groups were similar with regard to age, sex, body mass index, American Society of Anesthesiologists (ASA) score, and tumor location but not for ileostomy (27% in group A vs. 6.8% in group B). The number of complications was similar in both groups (43.1% in group A vs. 44.6% in group B). No differences in wound infection (8.2% vs. 7.8%), intra-abdominal abscess (4.7% vs. 4.9%), anastomotic dehiscence (4.2% vs. 3.8%), postoperative hemorrhage (3.5% vs. 3.9%), urinary complications (6.5% vs. 4.9%), paralytic ileus (8.9% vs. 9.7%), or general complications (7.1% vs. 9.6%) were found. The global mortality in the first 30 days after surgery was .7%. An ASA score of III–IV and surgery duration longer than 3 hours were identified as independent prognostic factors for early complications.ConclusionsPreoperative chemoradiation in patients with rectal cancer treated with surgery is not associated with a higher incidence of early postoperative complications. The patient’s preoperative clinical condition and lengthy surgery time are prognostic factors for early complications.

Analysis of POSSUM score and postoperative morbidity in patients with rectal cancer undergoing surgery

BackgroundThe Physiological and Operative Severity Score for the enUmeration of Mortality andmorbidity (POSSUM) and later modifications (P-POSSUM y CR-POSSUM) have been used to predictmorbidity and mortality rates among patients with rectal cancer undergoing surgery. These calculations needsome adjustment, however. The aim of this study was to assess the applicability of POSSUM to a group ofpatients with rectal cancer undergoing surgery, analysing surgical morbidity by means of several variables.Methods between January 1995 and December 2004, 273 consecutive patients underwent surgery forrectal cancer. Information was gathered about the patients, tumour and therapy. To assess the predictioncapacity of POSSUM, subgroups for analysis were created according to variables related to operativemorbidity and mortality.ResultsThe global morbidity rate was 23.6% (31.2% predicted by POSSUM). The mortality rate was 0.7%(6.64, 1.95 and 2.08 predicted by POSSUM, P-POSSUM and CR-POSSUM respectively). POSSUMpredictions may be more accurate for patients younger than 51 years, older than 70 years, with low anaesthetic risk (ASA I/II), DUKES stage C and D, surgery duration of less than 180 minutes and for thosereceiving neoadjuvant therapy.ConclusionPOSSUM is a good instrument to make results between different institutions and publicationcomparable. We found prediction errors for some variables related to morbidity. Modifications of surgicalvariables and specifications for neoadjuvant therapy as well as physiological variables including life stylemay improve future prediction of surgical risk. More research is needed to identify further potential riskfactors for surgical complications.

Secuelas tras inyección ilegal de silicona líquida como técnica de aumento mamario: presentación de 2 casos

Resumen La utilizacion de silicona liquida con el fin de aumentar el volumen mamario tuvo una amplia difusion en la decada de los anos sesenta del siglo pasado, pero a finales de esta, tras la publicacion de numerosos estudios que describian la aparicion de un gran numero de complicaciones locales, asi como la migracion a distancia de pequenas cantidades de silicona, su practica se abandono. Su empleo dificulta posteriormente el diagnostico temprano del cancer de mama, por lo que este grupo de pacientes no debe incluirse en los programas habituales de cribado, sino que han de seguir controles periodicos y exhaustivos. En este contexto, la resonancia magnetica es la mejor prueba de imagen para la deteccion temprana de procesos malignos mamarios. La presencia de complicaciones locales, la sospecha de una lesion maligna o el deseo de la paciente por evitar ambas situaciones son indicacion de la mastectomia subcutanea.

Enfermedad de Paget de la mama: análisis de una serie de 27 casos

Resumen Objetivo Analizar las caracteristicas de una serie, con especial referencia a su histogenesis y las posibilidades de la cirugia conservadora. Material y metodos Se reviso a 27 pacientes portadoras con cancer de mama (CM) y afectacion del pezon con caracteristicas de enfermedad de Paget (EP). Resultados Las pacientes tenian una media de 56,5 anos, los motivos de consulta fueron: eccema de pezon (48,1%), presencia de tumor mamario (26%) y secrecion por el pezon (18,5%). El examen fisico advirtio la lesion eccematosa en 26/27 casos. En 11 casos la imagen mamografica se localizo a nivel retroareolar, en 13 casos distal al pezon y en 3 casos la mamografia fue normal. En 15 casos correspondio a un carcinoma intraductal, y en los 12 restantes a carcinoma ductal infiltrante. En uno la EP fue hallazgo del estudio seriado de la pieza de mastectomia. Se practico una cirugia conservadora en 5 casos y mastectomia en 22 (6 con reconstruccion inmediata). Tras 6,5 anos de seguimiento medio, 2 pacientes presentaron diseminacion a distancia y una de las pacientes sometida a cirugia conservadora presento recidiva local. Conclusiones La EP representa el 1,4 % de los CM en nuestra serie y el signo diagnostico caracteristico es el eccema de pezon-areola. La mamografia muestra una baja sensibilidad diagnostica; se puede recurrir a la resonancia magnetica en los casos de EP sin patologia mamografica y se debe realizar biopsia de la lesion ante la menor duda diagnostica. El tratamiento mas utilizado fue la mastectomia, y se recurrio a la cirugia conservadora en casos seleccionados de EP limitada al pezon, o con lesion subareolar circunscrita, conociendo los riesgos de un tumor subyacente inadvertido.