Spectrum and Frequency of Tumors, Cancer Risk and Survival in Chilean Families with Lynch Syndrome: Experience of the Implementation of a Registry.

Lynch syndrome (LS) is associated with the highest risk of colorectal (CRC) and several extracolonic cancers. In our effort to characterize LS families from Latin America, this study aimed to describe the spectrum of neoplasms and cancer risk by gender, age and gene, and survival in 34 Chilean LS families. Of them, 59% harbored path_MLH1, 23% path_MSH2, 12% path_PMS2 and 6% path_EPCAM variants. A total of 866 individuals at risk were identified, of which 213 (24.6%) developed 308 neoplasms. In males, CRC was the most common cancer (72.6%), while females showed a greater frequency of extracolonic cancers (58.4%), including uterus and breast (p < 0.0001). The cumulative incidence of extracolonic cancers was higher in females than males (p = 0.001). Path_MLH1 variants are significantly more associated with the development of CRC than extracolonic tumors (59.5% vs. 40.5%) when compared to path_MSH2 (47.5% vs. 52.5%) variants (p = 0.05018). The cumulative incidence of CRC was higher in path_MLH1/path_MSH2 carriers compared to path_PMS2 carriers (p = 0.03). In addition, path_MSH2 carriers showed higher risk of extracolonic tumors (p = 0.002). In conclusion, this study provides a snapshot of the LS profile from Chile and the current LS-associated diagnostic practice and output in Chile. Categorizing cancer risks associated with each population is relevant in the genetic counselling of LS patients.

Numerical validation of a subject-specific parameter identification approach of a quadriceps femoris EMG-driven model.

Muscle models can be used to estimate muscle forces in motor tasks. Muscle model parameters can be estimated by optimizing cost functions based on error between measured and model-estimated joint torques. This paper is a numerical simulation study addressing whether this approach can accurately identify the parameters of the quadriceps femoris. The simulated identification task is a single joint maximum voluntary knee concentric-eccentric extension in an isokinetic dynamometer, keeping the hip fixed at a neutral position. A curve considered as the nominal torque was obtained by simulating the quadriceps femoris model exerting a maximum knee extension torque using a set of known parameter values. Three parameters, with different expected sensitivities of force estimations by Hill-type muscle models, were studied: very sensitive, sensitive and not sensitive, corresponding to slack tendon length, maximum isometric force, and pennation angle, respectively. The initial values of the parameters were randomly changed, simulating an ignorance of nominal values. EMG generation and torque measurement error models were used to obtain realistic simulated data corrupted by noise. Simulated annealing was chosen as the optimization algorithm. Different sequences of parameter identification and cost functions were tested. The best nominal torque curve reconstruction was obtained by optimizing the parameters sequentially, starting from slack tendon length using the Euclidean norm cost function. However, the simultaneous estimation of all parameters resulted in the most accurate values for the parameters, although dispersion was relatively large. In conclusion, in the present simulation study using realistic synthetic torque and EMG data, the optimization approach based on torque error curve was able to closely approximate the parameter values of the model's quadriceps femoris muscle.

Reversal of the Hartmann's procedure: A comparative study of laparoscopic versus open surgery.

BACKGROUND: The Hartmann's operation, although less frequently performed today, is still used when initial colonic anastomosis is too risky in the short term. However, the subsequent procedure to restore gastrointestinal continuity is associated with significant morbidity and mortality. PATIENTS AND METHODS: The review of an institutional review board (IRB)-approved prospectively maintained database provided data on the Hartmann's reversal procedure performed by either laparoscopic or open technique at our institution. The data collected included: demographic data, operative approach, conversion for laparoscopic cases and perioperative morbidity and mortality. RESULTS: Over a 14-year period from January 1997 to August 2011, 74 Hartmann's reversal procedures were performed (laparoscopic surgery-49, open surgery-25). The average age was 55 years for the laparoscopic and 57 years for the open surgery group, respectively. Male patients represent 61% of both groups. There was no significant difference in operative time between the two groups (149 min vs 151 min; P = 0.95), and there was a tendency to lower morbidity (3/49-7.3% vs 4/25-16%; P = 0.24) in the laparoscopic surgery group. In the laparoscopic group, eight patients (16.3%) were converted to open surgery, mostly due to severe adhesions. The length of hospital stay was significantly shorter for the laparoscopic group (5 days vs 7 days; P = 0.44). CONCLUSIONS: The Hartmann's reversal procedure can be safely performed in the majority of the cases using a laparoscopic approach with a low morbidity rate and achieving a shorter hospital stay.

Mutación homocigota en la línea germinal del gen MUTYH en una paciente chilena con poliposis adenomatosa familiar / Homozygous germline mutation in MUTYH gene in familial adenomatous polyposis

Recently, MUTYH mutations have been reported to predispose to the development of polyposis. However, polyposis caused by mutations in MUTYH has been characterized as an autosomal recessive hereditary disease, different from the autosomal dominant pattern observed in polyposis caused by APC mutations. We report a 41-year-old female consulting for anemia. Colonoscopy detected multiple sessile polyps and a cecal carcinoma. The patient was operated and in the surgical piece, the tumor invaded serosa and there was lymph node involvement. Approximately 100 polyps were found. The patient received 5-fluorouracil, as adjuvant therapy. The patient had a sister (of a total of 12 brothers) with a colorectal carcinoma. The genetic study identified a homozygous mutation of the MUTYH gene, called c.340T > C, that produces an amino acid change of tyrosine for histidine called p.Y114H. The sister with colorectal cancer was a heterozygous carrier of this mutation.

Caracterización clínica y genética de las poliposis intestinales hereditarias / Clinics and genetic characteristics in hereditary colon polyposis

Se denomina pólipo intestinal a una lesión visible elevada o tumor que se proyecta desde la superficie epitelial al lumen visceral. En relación al número, presencia de antecedentes familiares, manifestaciones extraintestinales y estudios genéticos es que se constituyen diversas poliposis intestinales. Si bien, las poliposis intestinales se manifiestan en general en la edad adulta, existen manifestaciones que pueden hacer sospechar la presencia de un síndrome poliposico hereditario en la infancia. Además en una proporción considerable estas poliposis presentan manifestaciones extraintestinales, tanto benignas como tumores en otros órganos. Es por esto, que una alta tasa de sospecha, en particular frente a pacientes con antecedentes familiares, puede conducir a un diagnóstico y tratamiento oportuno, además de considerar a la familia como potenciales pacientes e ingresar al grupo familiar a un registro de tumores hereditarios. Diversas técnicas de biología molecular han permitido la identificación de las mutaciones que son heredadas en estas enfermedades, permitiendo realizar conductas preventivas al saber el riesgo de cada persona en una familia afectada. El objetivo de esta revisión, es caracterizar las distintas poliposis intestinales, en cuanto a sus manifestaciones clínicas, clasificaciones, estudio genético y enfrentamiento multidisciplinario.

Polyps are solid or tumoral elevated lesions that arise from the intestinal epithelium so that they become visible in the intestinal epithelium so that they become visible in the intestinal lumen. Information regarding familial history, number, extraintestinal manifestations and genetic studies of polyps, assemble different types of intestinal polyposis. Generally, clinical manifestations occur in adult patients, although in children there are several signs that should make the physician suspect a hereditary polyposis syndrome. In addition it is important to know extraintestinal manifestations which are mostly benign but tumors may be present in other organs too. Bearing in mind that high clínical suspicion of hereditary polyposis syndrome especially if familial history is present, provides early diagnosis and appropriate treatment for the patient and eventually for the family members that could be affected, entering that family in a registry of hereditary tumors. Molecular biology has created different techniques to identify the presence of hereditary mutations that are specific for intestinal polyposis. Acknowledgment of these mutations establishes risks groups allowing adequate prevention strategies. The objective of this revision is to characterize and different types of intestinal polyposis, according to clinical manifestations, classification, genetic study and multidisciplinary approach.

Caracterización clínica y genética de las poliposis intestinales hereditarias / Clinics and genetic characteristics in hereditary colon polyposis

Se denomina pólipo intestinal a una lesión visible elevada o tumor que se proyecta desde la superficie epitelial al lumen visceral. En relación al número, presencia de antecedentes familiares, manifestaciones extraintestinales y estudios genéticos es que se constituyen diversas poliposis intestinales. Si bien, las poliposis intestinales se manifiestan en general en la edad adulta, existen manifestaciones que pueden hacer sospechar la presencia de un síndrome poliposico hereditario en la infancia. Además en una proporción considerable estas poliposis presentan manifestaciones extraintestinales, tanto benignas como tumores en otros órganos. Es por esto, que una alta tasa de sospecha, en particular frente a pacientes con antecedentes familiares, puede conducir a un diagnóstico y tratamiento oportuno, además de considerar a la familia como potenciales pacientes e ingresar al grupo familiar a un registro de tumores hereditarios. Diversas técnicas de biología molecular han permitido la identificación de las mutaciones que son heredadas en estas enfermedades, permitiendo realizar conductas preventivas al saber el riesgo de cada persona en una familia afectada. El objetivo de esta revisión, es caracterizar las distintas poliposis intestinales, en cuanto a sus manifestaciones clínicas, clasificaciones, estudio genético y enfrentamiento multidisciplinario.(AU)

Polyps are solid or tumoral elevated lesions that arise from the intestinal epithelium so that they become visible in the intestinal epithelium so that they become visible in the intestinal lumen. Information regarding familial history, number, extraintestinal manifestations and genetic studies of polyps, assemble different types of intestinal polyposis. Generally, clinical manifestations occur in adult patients, although in children there are several signs that should make the physician suspect a hereditary polyposis syndrome. In addition it is important to know extraintestinal manifestations which are mostly benign but tumors may be present in other organs too. Bearing in mind that high clínical suspicion of hereditary polyposis syndrome especially if familial history is present, provides early diagnosis and appropriate treatment for the patient and eventually for the family members that could be affected, entering that family in a registry of hereditary tumors. Molecular biology has created different techniques to identify the presence of hereditary mutations that are specific for intestinal polyposis. Acknowledgment of these mutations establishes risks groups allowing adequate prevention strategies. The objective of this revision is to characterize and different types of intestinal polyposis, according to clinical manifestations, classification, genetic study and multidisciplinary approach.(AU)

[Homozygous germline mutation in MUTYH gene in familial adenomatous polyposis]. / Mutación homocigota en la línea germinal del gen MUTYH en una paciente chilena con poliposis adenomatosa familiar.

Recently, MUTYH mutations have been reported to predispose to the development of polyposis. However, polyposis caused by mutations in MUTYH has been characterized as an autosomal recessive hereditary disease, different from the autosomal dominant pattern observed in polyposis caused by APC mutations. We report a 41-year-old female consulting for anemia. Colonoscopy detected multiple sessile polyps and a cecal carcinoma. The patient was operated and in the surgical piece, the tumor invaded serosa and there was lymph node involvement. Approximately 100 polyps were found. The patient received 5-fluorouracil, as adjuvant therapy. The patient had a sister (of a total of 12 brothers) with a colorectal carcinoma. The genetic study identified a homozygous mutation of the MUTYH gene, called c.340T > C, that produces an amino acid change of tyrosine for histidine called p.Y114H. The sister with colorectal cancer was a heterozygous carrier of this mutation.

Characterization of the novel ST2/IL-33 system in patients with inflammatory bowel disease.

BACKGROUND: ST2 has been proposed to be a regulator of inflammation and Th1/Th2 balance. ST2L is the IL-33 membrane receptor and belongs to the IL-1R family. The soluble variant, ST2s, is identical to the extracellular region of ST2L and competes for IL-33 binding, inhibiting receptor signaling. Although ST2s has been associated with inflammatory processes in patients with sepsis, trauma, asthma, and autoimmunity, until now there are no reported studies showing the role of ST2/IL-33 in inflammatory bowel disease (IBD). METHODS: Expression of ST2 and IL-33 was determined in serum and colonic biopsies from IBD patients. ST2 transcript and protein was determined by reverse-transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA)/immunoblot, respectively, and IL-33 protein by ELISA. Intestinal mucosa localization of ST2 and IL-33 was conducted by immunofluorescence. RESULTS: ST2s transcript in the colonic mucosa was mainly expressed in UC patients rather than Crohn's disease or control; however, ST2L mRNA remained constant in all samples. Total ST2 protein was significantly higher in mucosa samples from patients with active UC, with a predominant induction of ST2s that strongly correlates with serum ST2 levels. Mucosa IL-33 levels were higher in UC patients and serum levels were barely detected in all patient groups. ST2 and IL-33 are both abundantly expressed in the cytoplasm of epithelial cells of control subjects; however, in ulcerative colitis patients ST2 decreases and IL-33 showed cytoplasm-nuclear redistribution. CONCLUSIONS: The novel association between the ST2/IL-33 system and IBD seems to identify that variations in this axis might regulate the inflammatory process in these diseases.

Análisis del tratamiento ambulatorio y hospitalario en pacientes con enfermedad inflamatoria intestinal: ¿estamos haciendo lo correcto / Analysis of the ambulatory and hospitalized treatment in patients with inflammatory bowel disease: are we having the appropiate behavior

The inflammatory bowel diseases (IBD) like Crohn‘s disease (CD) and Ulcerative colitis (UC) requires prolonged treatments. Frequently a low adherence is observed and affects the prognosis and quality of life of these patients. Aim: Assess the medical indications in patients with IBD and their impact on disease progression. Methods: A retrospective study of patients with IBD admited in the University Hospital of the University of Chile between January and December 2006. Results: We included a total of 41 hospitalized patients (35 UC and 5 CD), being 27 of them (66 percent) due to relapse, 7 due the debut of their illness (17 percent), 3 by the need of surgery and 4 patients for other causes (10 percent). Among the patients with relapses, half presented low adherence to treatment. With regard to ambulatory management it was found insufficient doses, indication of permanent use of steroids and/or patients without treatment in a 52 percent. During hospitalization, 8 percent of patients were treated with non-steroidal anti-inflammatory drug (NSAID) and 23 percent of them did not receive indication of folic acid or calcium at discharge. In the treatment after discharge, 14 percent of the patients received indication of prolonged steroid therapy. Regarding outcome, 35 percent of patients presented a new crisis and 22 percent needed hospitalization for a new reactivation of IBD. Conclusion: Our study confirms an inadequate management of patients with IBD in ambulatory and hospitalized scenario. Only a better understanding of the IBD by patients and medical team will optimize the treatment improving their prognosis and outcome of the disease.

Las Enfermedades Inflamatorias Intestinales (EII) como la Enfermedad de Crohn (EC) y la Colitis Ulcerosa (CU) requieren tratamientos prolongados. Por otro lado, suelen tener una baja adherencia que afecta el pronóstico y la calidad de vida de estos pacientes. Objetivo: Evaluar las indicaciones médicas que recibieron los pacientes y su repercusión en la evolución de la enfermedad. Método: Estudio retrospectivo de pacientes con diagnóstico de EII hospitalizados en el Hospital Clínico de la Universidad de Chile, entre Enero y Diciembre de 2006. Resultados: Se incluyó un total de 41 pacientes (36 CU y 5 EC), siendo 27 de ellos (66 por ciento) hospitalizados por recaídas, 7 por debut de su enfermedad (17 por ciento), 3 por necesidad de cirugía (7 por ciento) y 4 por otras causas (10 por ciento). Dentro de los pacientes con recaídas, la mitad presentaba una mala adherencia al tratamiento. En cuanto al manejo ambulatorio, se encontró dosis insuficientes, uso de esteroides a permanencia y/o pacientes sin tratamiento en un 52 por ciento de los ingresos. Durante la hospitalización, un 8 por ciento fue tratado con antiinflamatorios no esteroidales (AINES) y un 23 por ciento de ellos no recibió indicación de ácido fólico o calcio al momento del alta. Durante el tratamiento post hospitalario, un 13,8 por ciento de los pacientes mantuvo la indicación de esteroides a permanencia. En cuanto a la evolución posterior, el 35 por ciento de los pacientes presentó una nueva crisis y un 22 por ciento requirió una nueva hospitalización por reactivación de su EII. Conclusión: Nuestro estudio confirma un manejo inadecuado de los pacientes con EII tanto en su tratamiento ambulatorio como intrahospitalario. Una mayor comprensión de las EII por parte de los pacientes y del equipo médico, permitiría optimizar el tratamiento de estas patologías mejorando su pronóstico y evolución.