Real-life analysis on safety and efficacy of asciminib for ponatinib pretreated patients with chronic myeloid leukemia.

Failure of second-generation tyrosine kinase inhibitors (2GTKI) is a challenging situation in patients with chronic myeloid leukemia (CML). Asciminib, recently approved by the US Federal Drug Administration, has demonstrated in clinical trials a good efficacy and safety profile after failure of 2GTKI. However, no study has specifically addressed response rates to asciminib in ponatinib pretreated patients (PPT). Here, we present data on responses to asciminib from 52 patients in clinical practice, 20 of them (38%) with prior ponatinib exposure. We analyzed retrospectively responses and toxicities under asciminib and compared results between PPT and non-PPT patients.After a median follow-up of 30 months, 34 patients (65%) switched to asciminib due to intolerance and 18 (35%) due to resistance to prior TKIs. Forty-six patients (88%) had received at least 3 prior TKIs. Regarding responses, complete cytogenetic response was achieved or maintained in 74% and 53% for non-PPT and PPT patients, respectively. Deeper responses such as major molecular response and molecular response 4.5 were achieved in 65% and 19% in non-PPT versus 32% and 11% in PPT, respectively. Two patients (4%) harbored the T315I mutation, both PPT.In terms of toxicities, non-PPT displayed 22% grade 3-4 TEAE versus 20% in PPT. Four patients (20% of PPT) suffered from cross-intolerance with asciminib as they did under ponatinib.Our data supports asciminib as a promising alternative in resistant and intolerant non-PPT patients, as well as in intolerant PPT patients; the resistant PPT subset remains as a challenging group in need of further therapeutic options.

Inflammatory status is different in relationship to insulin resistance in severely obese people and changes after bariatric surgery or diet-induced weight loss.

AIM: To assess if insulin resistance is related to a different inflammatory status (especially lymphocyte subpopulations) in severely obese people and to evaluate changes after weight loss either following a very-low calorie diet (VLCD) or bariatric surgery. RESEARCH METHODS & PROCEDURES: Severely obese patients were consecutively recruited in our Obesity Unit. Blood lymphocyte subpopulations and inflammatory parameters were measured baseline, after a VLCD during 6 weeks and one year after biliopancreatic diversion. Insulin resistance was evaluated by Homeostasis Model Assessment (HOMA) index. RESULTS: After excluding diabetic patients, 58 patients were studied. HOMA index classified 63.8% of them as insulin resistant (IR). Serum baseline levels of inflammatory cytokines were not significantly different between IR and insulinsensitive (IS) patients but, regarding lymphocyte subpopulations, Natural Killer (NK) cells were higher in IR patients [(305.0 (136.7) vs. 235.0 (80.7) cells/µL, p=0.047]. NK cells showed a significant positive correlation with HOMA index (r=0.484, p=0.000) and with the carbohydrate content of the diet (r=0.420, p=0.001). After VLCD, NK cells significantly decreased, but only in IR patients and in those losing more than 10% of their initial weight. After biliopancreatic diversion, total and CD8 T Lymphocytes, B lymphocytes and NK cells also decreased but only in IR individuals. CONCLUSION: NK cells are significantly increased in IR severely obese people in respect to IS, suggesting a slightly different immune status in these patients with a probable dietary relationship. Weight loss could reverse this increase either after VLCD or after bariatric surgery.

[Effects of preoperative weight loss with a very low calorie diet (VLCD) on weight loss after biliopancreatic diversion in patients with severe obesity]. / Efectos de la pérdida de peso mediante una dieta muy baja en calorías (VLCD) sobre la pérdida de peso tras derivación biliopancreática en pacientes con obesidad severa.

BACKGROUND: Weight loss before bariatric surgery, achieved by means of a very low calorie diet (VLCD) has been recently reported to be related to a lower rate of postoperative complications. However, it is controversial if preoperative weight loss after VLCD could improve postoperative weight loss. AIMS: To assess the effectiveness of a preoperative VLCD for 6 weeks in weight loss one year after bariatric surgery. To evaluate the changes obtained in anthropometric measures and biochemical parameters after VLCD. METHODS: Prospective uncontrolled study including severely obese patients undergoing biliopancreatic diversion in our Obesity Unit in 2008-2010. Patients included followed a VLCD providing 840 kcal and 60 g of protein (Optisource®). Descriptive data are presented as mean (standard deviation) and after checking a normal distribution is followed, they were analyzed by Student s T test, ANOVA or Pearson correlation. RESULTS: We evaluated 107 obese patients, 43.5 (10.2) years-old, 72% women, with initial weight 122.4 (18.6) Kg and BMI 46.8 (5.5) kg/m(2). 24.5% of them lost more than 10 % of initial weight and 73.5% more than 5% after following VLCD. Mean percentage of excess weight loss (% PSP) one year after surgery was 59.6 (13.4)%, and although it was higher for those patients losing more weight after VLCD, a significant correlation was not found: those who lost more than 5% showed %PSP 59.5 (13.8) % after twelve months and 68.4 (16.2) % of percentage of excess BMI loss (%PEIMC), vs 57,9 (13,1) % and 68.5 (16.6) % if they didn t lose that amount of weight. Those patients losing more than 10% achieved %PSP 63.3 (13.7) and %PEIMC 70.9 (14.7) vs 58.2 (14.0) y 67.7 (16.7) vs those not losing that amount. Significant correlations between preoperative loss with VLCD and %PSP or %PEIMC at 3,6,9 and 12 months were not found, and only %PSP 1 month after surgery correlated with %PSP after VLCD (r = 0.454, p = 0.003). CONCLUSIONS: Preoperative weight loss with VLCD in severely obese patients did not show to improve either %PSP or %PEIMC one year after bariatric surgery.

Introducción: Se ha comunicado recientemente que la reducción de peso previa a cirugía bariátrica mediante dieta muy baja en calorías (VLCD) durante 2 semanas supone menor tasa de complicaciones postoperatorias. Es debatido, sin embargo, si la pérdida de peso preoperatoria con VLCD puede favorecer pérdida de peso postoperatoria. Objetivos: Valorar la eficacia de una VLCD, seguida durante 6 semanas preoperatorias, en el descenso de peso conseguido al 2013 de la cirugía bariátrica. Evaluar los cambios en parámetros antropométricos y bioquímicos conseguidos con dicha dieta. Metodología: Estudio prospectivo no controlado en los pacientes obesos sometidos a derivación biliopancréatica en la Unidad de Obesidad de referencia en el periodo 2008-2010. Los pacientes recibieron durante 6 semanas previas a la intervención una VLCD que aportaba diariamente 840 kcal y 60 g de proteínas (Optisource®). Los datos descriptivos se presentan como media y desviación estándar (DS), y tras comprobar su distribución normal, fueron analizados mediante prueba t de Student, ANOVA o correlación de Pearson. Resultados: Fueron valorados 107 pacientes obesos, de 43,5 (10,2) 2013s, el 72 % fueron mujeres con peso inicial 122,4 (18,6) Kg e IMC de 46,8 (5,5) kg/m2. Un 24,5% perdieron más de 10 % de su peso inicial y un 73,5% más de 5% tras VLCD. La media de porcentaje pérdida de exceso de peso (% PSP) a los 12 meses de la intervención fue 59,6 (13,4)%, y aunque fue mayor en los pacientes que habían perdido peso con VLCD, no se asoció de forma significativa: aquellos pacientes con pérdida mayor de 5% perdieron a los 12 meses 59,5 (13,8)% de PSP y 68,4 (16,2) % de exceso de IMC (%PEIMC), frente a 57,9 (13,1) % y 68,5 (16,6) % si no conseguían esa pérdida. El grupo de pacientes con pérdida mayor de 10 % consiguió %PSP de 63,3 (13,7) y %PEIMC de 70,9 (14,7) vs 58,2 (14,0) y 67,7 (16,7) si no perdieron >10% del peso inicial. No se encontró correlación entre la pérdida preoperatoria con VLCD y %PSP ni de exceso de IMC (%PEIMC) a 3,6,9 y 12 meses, sólo el %PSP a 1 mes se correlacionó con %PSP con VLCD (r = 0,454, p = 0,003). Conclusiones: La pérdida de peso preoperatoria mediante VLCD en pacientes obesos mórbidos no hademostrado favorecer la pérdida de exceso de peso ni de exceso de IMC al 2013 de la cirugía bariátrica.

Similar gene expression profiles in smokers and patients with moderate COPD.

Chronic obstructive pulmonary disease (COPD) is characterized by multiple cellular and structural changes affecting the airways, lung parenchyma and vasculature, some of which are also identified in smokers without COPD. The molecular mechanisms underlying these changes remain poorly understood. With the aim of identifying mediators potentially implicated in the pathogenic processes that occur in COPD and their potential relationship with cigarette smoking, we evaluated the mRNA expression of genes involved in inflammation, tissue remodeling and vessel maintenance. Lung tissue samples were obtained from 60 patients who underwent lung resection (nonsmokers, n=12; smokers, n=12; and moderate COPD, n=21) or lung transplant (severe-to-very severe COPD, n=15). PCR arrays containing 42 genes coding for growth factors/receptors, cytokines, metalloproteinases, adhesion molecules, and vessel maintenance mediators were used. Smoking-induced changes include the up-regulation of inflammatory genes (IL-1ß, IL-6, IL-8, CCL2, and CCL8) and the decreased expression of growth factor/receptor genes (BMPR2, CTGF, FGF1, KDR and TEK) and genes coding for vessel maintenance factors (EDNRB). All these genes exhibited a similar profile in moderate COPD patients. The up-regulation of MMP1 and MMP9 was the main change associated with COPD. Inflammatory genes as well as the endothelial selectin gene (SELE) were down-regulated in patients with more severe COPD. Clustering analysis revealed a closer relationship between moderate COPD and smokers than between both subsets of COPD patients for this selected set of genes. The study reveals striking similarities between smokers and COPD patients with moderate disease emphasizing the crucial role of cigarette smoking in the genesis of these changes, and provides additional evidence of the involvement of the matrix metalloproteinase's in the remodeling process of the lung in COPD.

Usefulness of an index score as a predictor of hepatic fibrosis in obese patients undergoing bariatric surgery.

OBJECTIVE: To evaluate the usefulness of a non-invasive clinical score to predict liver fibrosis in the steatosis associated with morbid obesity. PATIENTS AND METHODS: We included 88 patients, who underwent bariatric surgery in the Sanitary Area of León, Spain, and who showed a liver biopsy with steatosis greater than 5%. This is a retrospective study in which the rate of fibrosis is calculated from tests performed during the preoperative period, and is then compared to data from intraoperative hepatic biopsies. The analysis population was grouped according to the presence of advanced fibrosis in the liver biopsy (grade 3-4) or its absence (grade 0-2). The cutoff used for diagnosing advanced fibrosis was 0.676 (high cutoff point), and the cutoff point to exclude advanced fibrosis was -1.455 (low cutoff). RESULTS: The prevalence of advanced fibrosis in the histological samples was 5.5%, and 65.9% of patients had no fibrosis. The cutoff for a low negative predictive value was 100%, and sensitivity was 100%. The cutoff point for a high positive predictive value was 1.7%, and specificity was 31.3%. CONCLUSIONS: This scoring system for morbidly obese patients eligible for bariatric surgery allows to identify those without advanced fibrosis, but cannot predict who may have advanced fibrosis.

Programa de trasplante hepático en el Hospital de Pediatría Juan P. Garrahan: 16 años de experiencia / Liver transplant program at the Hospital de Pediatría Juan P. Garrahan: 16 years of experience

El propósito de este trabajo es mostrar la experiencia de 16 años del programa de traplante hepático del Hospital de Pediatría Juan P. Garrahan iniciado en Noviembre de 1992. Material y método: la metodología de este trabajo es de tipo retrospectivo, descriptivo y observacional. Se revisaron la base de datos del servicio y las historias clínicas de 430 pacientes que fueron sometidos a uno o más trasplantes hepáticos entre noviembre de 1992 hasta marzo de 2009, en nuestro hospital. Se describieron los datos demográficos, las indicaciones de trasplante, el tipo de injerto utilizado, la compatibilidad del rupo ABO entre el donante y el receptor, la relación de peso entre donante receptor, la utilización de injertos arteriales y venosos, las complicaciones quirúrgicas, los episodios de rechazo agudo y crónico, la severidad de los mismos, los episodios de infecciones, la incidencia de enfemedad linfoproliferativa, la sobrevida del injerto y del paciente y las causas de muerte. Resultados: desde noviembre de 1992 hasta marzo de 2009 se realizaron 469 trasplantes en 430 pacientes. La causa más frecuente de trasplante en nuestra serie es la atresia de vías biliares con 162 casos que representan el 34,5 por ciento de los pacientes. En 126 casos se realizó el trasplante con donante vivo emparentado, en todos ellos se utilizó el segmento lateral izquierdo (segmeto II-III) del donante. Los 343 restantes fueron efectuados con donantes cadavéricos donde a 298 higados se le efectuó algún tipo de reducción hepática. Las complicaciones más frecuentes fueron biliares: 58 (13,5 por ciento) pacientes tuvieron fístulas y 52 (12 por ciento) estenosis. Se comprobó trombosis de la arteria hepática en 23 pacientes y portal en 19. Presentaron 248 pacientes (52 por ciento) uno o más episodios de rechazo agudo celular. el rechazo cronico se presentó en 24 casos ( (5 por ciento). La sobrevida actuarial del paciente y del injerto fue de 74,45 por ciento y 72,5 por ciento al año.

[Analysis of the characteristics of patients with bladder cancer diagnosed of multiple neoplasms in the health district of León (Spain)]. / Análisis de las características de los pacientes con cáncer vesical diagnosticados de neoplasias múltiples en el área sanitaria de León.

OBJECTIVE: We analyzed the characteristics of the patients with bladder neoplasms who developed a multiple malignant primary neoplasm (MMPN) in the health district of León, the impact on survival and the prognostic variables. MATERIAL AND METHODS: We have used the data from the Tumor Registry of the Hospital of León and selected all those patients who were diagnosed of a bladder tumor between 1993 and 2002. They were classified into two groups: the first with 71 patients with MMPN and a second group with 159 patients with single bladder tumors diagnosed between 1996 and 1997. RESULTS: Incidence of MMPN was of 7.1 percent. More than half of the patients had familial oncologic background. The second most frequently diagnosed neoplasms were urologic, followed by gastrointestinal and respiratory. Survival of patients with MMPN was 21 percent lower than single neoplasms. Variables with prognosis significance were the stage of the second neoplasm, diagnosis of a second urologic neoplasm and surgery treatment for the second tumor. CONCLUSIONS: MMPN in patients with bladder tumors are frequent in our geographic area. The high frequency of familial oncologic antecedents in these patients suggest a genetic background. Prognosis of MMPN patients is worse than single tumors patients, but no differences were observed regarding prognosis in patients with synchronous or metachronous MMPN.

Liver infiltrating mononuclear cells in children with type 1 autoimmune hepatitis.

OBJECTIVE: To investigate infiltrating cells in the liver of children with type 1 autoimmune hepatitis (AH-1). METHODS: liver biopsies from 24 untreated AH-1 patients (14 children, 10 adults), five patients with hepatitis C virus related chronic hepatitis (HCV), and 10 control liver specimens (CL) were processed for immunohistochemical cell characterisation. RESULTS: Two different cell distribution patterns were detected in the liver of patients with AH-1: (1) CD4(+) and CD20(+) cells were found in the central areas of the portal tracts (portal distribution); (2) CD8(+) cells were observed at the periphery of the portal space (periportal distribution). Some cell subsets, like CD56, CD57, Fas-L, and Bak, showed a non-defined distribution pattern. The presence of two well defined patterns of cell distribution was not observed in HCV and CL (CD4(+), CD20(+), and CD8(+) cells were uniformly distributed in the portal space). In AH-1 and CL, the NK markers CD56 and CD57 were found scattered throughout the liver parenchyma. However, in HCV biopsies, CD56(+) cells were also clearly increased in both the portal and the periportal areas. Biopsies of AH-1 and HCV patients showed a uniform distribution of Fas-L and Bak in the portal and periportal areas, with Bak staining also detected in the hepatic parenchyma. CONCLUSIONS: Despite clinical and genetic differences, there was a similar distribution of liver infiltrating mononuclear cells in children and adults with AH-1. These results raise the possibility of reclassifying cryptogenic chronic hepatitis by immunohistochemical analysis of infiltrating liver cells.

Multiple malignant primary neoplasms in patients with gatric neoplasms in the health district of León.

OBJECTIVES: We analyzed the characteristics of patients with gastric tumors diagnosed with multiple malignant primary neoplasm (MMPN) in the Health District of León. MATERIAL AND METHODS: Using the information in the Tumor Registry at León Hospital patients selected were those with gastric neoplasms diagnosed between 1993 and 2002. A follow-up was performed until December 31, 2004, and the characteristics of patients diagnosed with a second neoplasm were analyzed. RESULTS: MMPN prevalence was 1,96%; 56% of patients had a history of cancer in first-degree relatives. The most frequent second neoplasms were digestive (26%) and urologic (21%); 87% of patients were diagnosed with a second neoplasm within the first two years. No significative differences in survival were observed among patients with synchronous or metachronous MMPN. CONCLUSIONS: MMPN in patients with gastric neoplasms is a relevant problem. While external carcinogenic agents could act as promoters in the development of second neoplasms, these patients seem to have a genetic background favoring the development of MMPN. Secondary prevention is the best measure to avoid MMPN development.

[Needle-knife sphincterotomy for biliary access: a prospective study]. / Esfinterotomía de aguja como técnica de acceso a la vía biliar: estudio prospectivo.

OBJECTIVE: Needle-knife sphincterotomy (NKS) is used to achieve biliary access when routine cannulation methods have been unsuccessful. The aim of this study was to analyze the results of NNS in patients with an inaccessible common bile duct (difficult cannulation) using standard techniques in endoscopic retrograde cholangiopancreatography and the factors associated with the success of this procedure and complications. MATERIAL AND METHODS: We performed a prospective study of 72 patients who underwent NKS performed by the same endoscopist (J.E.) because of difficult cannulation of the common bile duct between January 1998 and December 2004. The results were analyzed in terms of successful biliary access, whether this was achieved in one or more sessions, its possible association with the underlying disease, and the incidence and severity of complications. RESULTS: Seventy-two NKS were performed from a total of 1062 sphincterotomies (6.7%). A total of 77.7% of the patients underwent prior implantation of a pancreatic prosthesis (NKS-PP). The final diagnosis was: choledocholithiasis (31.9%), cancer of the pancreas (16.6%), cholangiocarcinoma (13.8%), benign stenosis (8.3%), dysfunction of the sphincter of Oddi (6.9%), normal (6.9%), and miscellaneous (13.8%). Cannulation was successful in 87.5% (63/72), and was achieved in the first session in 73% (46/63). Biliary access was achieved in 72.7% of patients (16/22) with biliopancreatic neoplasms versus 94% (47/50) of those with other diagnoses (p = 0.03). Eleven patients (15.2%) presented 12 complications (16.6%) (6 pancreatitis, 4 cholangitis, 1 papillary hemorrhage, and 1 portal vein filling). The use of a pancreatic prosthesis was related to a higher success rate and significantly fewer complications (p = 0.03). CONCLUSIONS: NKS-PP can be a safe procedure in patients with difficult cannulation of the common bile duct. The presence of biliopancreatic neoplasm is a risk factor for failure to achieve biliary access compared with other diagnoses. The complication rate was similar to that found in other studies. No cases of severe pancreatitis or perforations were found.

[Enteral prostheses for palliative treatment of gastroduodenal obstruction: endoscopic procedure]. / Prótesis enterales en el tratamiento paliativo de la obstrucción gastroduodenal: técnica endoscópica.

Malignant gastroduodenal obstruction may cause significant morbidity. Insertion of enteral prostheses as a palliative treatment is an acceptable option to achieve an appropriate gastric voiding without the morbidity associated to palliative surgery, with a lesser procedure-related mortality and a lower cost, while providing a better quality of life. Its is important to unify and consolidate the endoscopic procedure for the placement of enteral prostheses, avoiding variations that may preclude an adequate analysis of this procedure outcome.

[Primary hepatic leiomyosarcoma in a patient with gastric non-Hodgkin lymphoma]. / Leiomiosarcoma hepático primario en un paciente con linfoma no hodgkiniano gástrico.

Primary leiomyosarcoma of the liver is a rare entity and fewer than 100 cases have been reported in the medical literature. Even more unusual is the association with another previous tumour. We report the case of a 84-year-old man who had been treated for a gastric non-Hodgkin lymphoma two years previously. He presented with a painful mass in the right upper abdomen. An ultrasound scan showed a large mass in the right lobe of the liver and chest radiography showed pulmonary metastases. Liver biopsy was performed and immunohistochemical analysis revealed a malignant leiomyosarcoma. We discuss this case and review the available literature.

[Incidence of digestive tumors in the health district of Leon, Spain in 1993-1997: high incidence of colorectal carcinoma]. / Incidencia de los tumores digestivos en el Area de Salud de León en el quinquenio 1993-1997: alta incidencia del carcinoma colorrectal.

AIM: To determine the incidence of various digestive tumors in the health district of Leon. PATIENTS AND METHODS: All digestive tumors registered in the Hospital Tumor Registry in Leon from 1993-1997 were included. Unadjusted and adjusted incidence rates of each kind of tumor, using the ICD-9 classification, were calculated. RESULTS: A total of 9,913 cancer cases were included. Diagnosis was confirmed by the Department of Pathology in 93.4%. Of these, 25.38% originated primarily in the digestive system, which represents an unadjusted incidence of 151.73 new cases per 100,000 inhabitants/year. A total of 58.07% were male and 41.93% female. Colon cancer was the most frequent (31.5%), followed by gastric cancer (25.7%) and rectal cancer (20.3%). The highest incidence, both unadjusted and adjusted, was in colon cancer (52.8 and 25.9) followed by gastric cancer (47.4 and 24.3) and rectal cancer (36.1 and 18.3, all they 10(5)/year. CONCLUSIONS: Incidence of digestive cancer in Leon is very high and that of colorectal cancer is higher than in any other region in Spain. This is only partly due to the marked aging of our population.

[Multiple hepatic focal nodular hyperplasia: its presentation in childhood and atypical evolution]. / Hiperplasia nodular focal múltiple hepática: presentación en la infancia y evolución atípica.

Multiple focal nodular hyperplasia is an uncommon benign liver tumor although its incidence has been increasing in the last few years. A case of focal nodular hyperplasia in a young woman is described, which was discovered in infancy and which presented two nodules in each lobe. The diagnosis was subsequently confirmed by large surgical biopsy. Conservative therapy was given for 16 years during which time there was progressive tumor growth, increase of pain and cholestatic enzymes. The unusual presentation this benign lesion may have, a strategy for its diagnosis and the generally conservative management that is currently favored are discussed.

Reversión de la hipertensión pulmonar con óxido nítrico inhalado en un modelo animal / Reversal of pulmonary hypertension with inhaled nitric oxide in an animal model

El óxido nítrico (NO) esun potente vasodilatador endógeno. Es posible que en algunas patologías, tales como la hipertensión pulmonar (HP) persistente del recién nacido y la del período postoperatorio de ciertas cardiopatías congénitas, la producción de NO esté disminuída. El tratamiento de estas condiciones ha estado limitado por la falta deun agente vasodilatador pulmonar selectivo. Reportes recientes han demostrado que el NO inhalado puede producir un incremento de la oxigenación en niños con HPsevera, mediante su acción vasodilatadora pulmonar selectiva. El objetivo del estudio fue evaluar la respuesta al tratamiento con dosis progresivas de NO inhalado en animales con HP inducida por la hipoxia. Material y métodos: Diseño experimental, prospectivo, descriptivo y controlado. Se creó un modelo de HP inducidapor la hipoxia con Fi02, subambiental (14 por ciento) en 4 cerdos de menos de 45 días. Se midieron la Presión Arterial Sistémica (PAS) y Presión Arterial Pulmonar (PAP). El NO se administró en dosis crecientes entre 5 y 80 ppm. Se realizó la medición contínua de NO y NO2 mediante un analizador de celdas electroquímicas. Se midieron los niveles de metahemoglobinemia a las distintas dosis de N0. Resultados: Se comprobó un descenso importante y significativo (p<0.05) de la PAP media, siendo el efecto mayor a dosis más altas de NOi (40 y 80 ppm). No hubo cambios en la PAS durante las distintas dosis evaluadas (p>0.05). Los niveles de metahemoglobinemia se mantuvieron por debajo de 1 por ciento. Los resultados confirman la acción eficaz del NOi en el tratamiento de la HP inducida por la hipoxia en animales en edad neonatal, sin producir efectos indeseables en la PAS ni niveles tóxicos de metahemoglobinemia.