Familial component of early-onset colorectal cancer: opportunity for prevention.

BACKGROUND: Individuals with a non-syndromic family history of colorectal cancer are known to have an increased risk. There is an opportunity to prevent early-onset colorectal cancer (age less than 50 years) (EOCRC) in this population. The aim was to explore the proportion of EOCRC that is preventable due to family history of colorectal cancer. METHODS: This was a retrospective multicentre European study of patients with non-hereditary EOCRC. The impact of the European Society of Gastrointestinal Endoscopy (ESGE), U.S. Multi-Society Task Force (USMSTF), and National Comprehensive Cancer Network (NCCN) guidelines on prevention and early diagnosis was compared. Colorectal cancer was defined as potentially preventable if surveillance colonoscopy would have been performed at least 5 years before the age of diagnosis of colorectal cancer, and diagnosed early if colonoscopy was undertaken between 1 and 4 years before the diagnosis. RESULTS: Some 903 patients with EOCRC were included. Criteria for familial colorectal cancer risk in ESGE, USMSTF, and NCCN guidelines were met in 6.3, 9.4, and 30.4 per cent of patients respectively. Based on ESGE, USMSTF, and NCCN guidelines, colorectal cancer could potentially have been prevented in 41, 55, and 30.3 per cent of patients, and diagnosed earlier in 11, 14, and 21.1 per cent respectively. In ESGE guidelines, if surveillance had started 10 years before the youngest relative, there would be a significant increase in prevention (41 versus 55 per cent; P = 0.010). CONCLUSION: ESGE, USMSTF, and NCCN criteria for familial colorectal cancer were met in 6.3, 9.4, and 30.4 per cent of patients with EOCRC respectively. In these patients, early detection and/or prevention could be achieved in 52, 70, and 51.4 per cent respectively. Early and accurate identification of familial colorectal cancer risk and increase in the uptake of early colonoscopy are key to decreasing familial EOCRC.

Activating mutations in BRAF disrupt the hypothalamo-pituitary axis leading to hypopituitarism in mice and humans.

Germline mutations in BRAF and other components of the MAPK pathway are associated with the congenital syndromes collectively known as RASopathies. Here, we report the association of Septo-Optic Dysplasia (SOD) including hypopituitarism and Cardio-Facio-Cutaneous (CFC) syndrome in patients harbouring mutations in BRAF. Phosphoproteomic analyses demonstrate that these genetic variants are gain-of-function mutations leading to activation of the MAPK pathway. Activation of the MAPK pathway by conditional expression of the BrafV600E/+ allele, or the knock-in BrafQ241R/+ allele (corresponding to the most frequent human CFC-causing mutation, BRAF p.Q257R), leads to abnormal cell lineage determination and terminal differentiation of hormone-producing cells, causing hypopituitarism. Expression of the BrafV600E/+ allele in embryonic pituitary progenitors leads to an increased expression of cell cycle inhibitors, cell growth arrest and apoptosis, but not tumour formation. Our findings show a critical role of BRAF in hypothalamo-pituitary-axis development both in mouse and human and implicate mutations found in RASopathies as a cause of endocrine deficiencies in humans.

Effects of Dry Needling on Muscle Stiffness in Latent Myofascial Trigger Points: A Randomized Controlled Trial.

The aim of this study was to analyze the effects of dry needling (DN) in upper trapezius latent trigger points (LTrPs) on muscle stiffness. A total of 51 recreational physically active subjects with LTrPs in the upper trapezius volunteered to participate and were randomly divided into a DN-group (n = 27) and a sham-DN group (n = 24). Volunteers received 1-session of DN or placebo treatment. Muscle stiffness, measured with strain and shear-wave elastography, pressure pain threshold (PPT), post-needling soreness, and muscle thickness were evaluated before treatment, and at 30-min, 24-hours, and 72-hours follow-up after treatment. The DN-group showed lower values from baseline for muscle stiffness measured with shear-wave elastrography at 24-hours (from 44.44 ± 15.97 to 35.78 ± 11.65 kpa; P < .01) and at 72-hours (35.04 ± 12.61 kpa; P < .01) and with strain elastography at 72-hours (from 1.75 ± 0.50 to 1.36 ± 0.40 AU; P < .01). The DN-group showed higher values of PPT than the sham-DN group at 72-hours (4.23 ± 0.75 vs. 5.19 ± 1.16 kg/cm2; P < .05). There was a progressive decrease in post-needling soreness compared to pain during needling of 33.13 ± 21.31% at 30-min, 80.92 ± 10.06% at 24-hours, and a total decrease in post-needling soreness in all participants at 72-hours. DN therapy is effective in reducing short-term muscle stiffness and increasing the PPT in volunteers with LTrPs in the upper trapezius after a treatment session. PERSPECTIVE: This study found that one session of DN intervention in latent trigger points of the upper trapezius muscle reduced muscle stiffness and the pressure pain threshold for the dry needling group compared to the sham dry needling group.

A methodology based on multiple criteria decision analysis for combining antibiotics in empirical therapy.

BACKGROUND: The current situation of critical progression in resistance to more effective antibiotics has forced the reuse of old highly toxic antibiotics and, for several reasons, the extension of the indications of combined antibiotic therapy as alternative options to broad spectrum empirical mono-therapy. A key aspect for selecting an appropriate and adequate antimicrobial therapy is that prescription must be based on local epidemiology and knowledge since many aspects, such as prevalence of microorganisms and effectiveness of antimicrobials, change from hospitals, or even areas and services within a single hospital. Therefore, the selection of combinations of antibiotics requires the application of a methodology that provides objectivity, completeness and reproducibility to the analysis of the detailed microbiological, epidemiological, pharmacological information on which to base a rational and reasoned choice. METHODS: We proposed a methodology for decision making that uses a multiple criteria decision analysis (MCDA) to support the clinician in the selection of an efficient combined empiric therapy. The MCDA includes a multi-objective constrained optimization model whose criteria are the maximum efficacy of therapy, maximum activity, the minimum activity overlapping, the minimum use of restricted antibiotics, the minimum toxicity of antibiotics and the activity against the most prevalent and virulent bacteria. The decision process can be defined in 4 steps: (1) selection of clinical situation of interest, (2) definition of local optimization criteria, (3) definition of constraints for reducing combinations, (4) manual sorting of solutions according to patient's clinical conditions, and (5) selection of a combination. EXPERIMENTS AND RESULTS: In order to show the application of the methodology to a clinical case, we carried out experiments with antibiotic susceptibility tests in blood samples taken during a five years period at a university hospital. The validation of the results consists of a manual review of the combinations and experiments carried out by an expert physician that has explained the most relevant solutions proposed according to current clinical knowledge and their use. CONCLUSION: We show that with the decision process proposed, the physician is able to select the best combined therapy according to different criteria such as maximum efficacy, activity and minimum toxicity. A method for the recommendation of combined antibiotic therapy developed on the basis of a multi-objective optimization model may assist the physicians in the search for alternatives to the use of broad-spectrum antibiotics or restricted antibiotics for empirical therapy. The decision proposed can be easily reproduced for any local epidemiology and any different clinical settings.

Hierro carboximaltosa por vía intravenosa para tratamiento de la anemia ferropénica en pacientes con hemorragia uterina anormal / Intravenous ferric carboxymaltose injection for treatment iron deficiency anemia in abnormal uterine bleeding

Resumen OBJETIVO: Evaluar la eficacia y seguridad de la administración de altas dosis de hierro carboximaltosa en el tratamiento de pacientes con anemia ferropénica secundaria a hemorragia uterina anormal. MATERIAL Y MÉTODOS: Estudio cuasiexperimental de intervención, no controlado, con la variedad antes y después de un solo grupo (pretest-postest) efectuado en el Hospital Río de la Loza entre mayo de 2014 y septiembre de 2018. Criterios de inclusión: pacientes de 18 años o mayores con anemia y hemorragia uterina anormal severa. Criterios de exclusión: transfusión de concentrados eritrocitarios o administración de hierro parenteral en las ocho semanas previas al estudio, etc. Variables de estudio: hemoglobina, hematocrito, volumen corpuscular medio, concentración de hemoglobina corpuscular media, plaquetas y concentraciones de ferritina y plaquetas. RESULTADOS: Se analizaron los datos de 18 pacientes con anemia ferropénica secundaria a hemorragia uterina anormal 13 de 18 experimentaron un incremento de 2 g/dL o mayor de hemoglobina , 9 de 18 obtuvieron un incremento de 2.5 o mayor y solo 7 de 18 obtuvieron un incremento de 3 g/dL o mayor, los incrementos fueron dependientes de las dosis administrada. La ferritina sérica final promedio fue de 33.44 mcg/L. No hubo efectos adversos graves reportados. CONCLUSIONES: En este grupo de pacientes con anemia ferropénica, la administración de hierro carboximaltosa por vía intravenosa a dosis altas fue segura en la corrección de la carencia del mineral secundaria a hemorragia uterina anormal y en el reabastecimiento de los depósitos de hierro.

Abstract OBJECTIVE: The objective was to evaluate efficacy and safety of rapid, large-dose intravenous (IV) administration of ferric carboxymaltose in correcting iron deficiency anemia due to abnormal uterine bleeding. MATERIAL AND METHODS: Quasi-experimental study of intervention, not controlled, with the variety before and after a single group (pretest-posttest) carried out in the Hospital Río de la Loza, Mexico, between May 2014 and September 2018. Inclusion criteria: patients 18 years of age or older with anemia and severe abnormal uterine hemorrhage. Exclusion criteria: transfusion of erythrocyte concentrates or administration of parenteral iron in the eight weeks prior to the study, etc. Study variables: hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin concentration, platelets and concentrations of ferritin and platelets. RESULTS: 13 patients of 18 obtained an increase of 2 g/dL or greater of hemoglobin, 9 of 18 obtained an increase of 2.5 or greater and only 7 of 18 obtained an increase of 3g/dL or greater, the increases were dependent on the administered dose. The average final serum ferritin was 33.44 mcg/L. There were no serious adverse effects reported. CONCLUSIONS: The use of iron carboxymaltose intravenously at high doses is a safe treatment in the correction of iron deficiency anemia secondary to abnormal uterine hemorrhage and in the replenishment of iron stores.

A 3-Arm Randomized Trial for Achilles Tendinopathy: Eccentric Training, Eccentric Training Plus a Dietary Supplement Containing Mucopolysaccharides, or Passive Stretching Plus a Dietary Supplement Containing Mucopolysaccharides.

BACKGROUND: Tendinopathy is an overuse tendon injury that occurs in loaded tendons and results in pain and functional impairment. Although many treatments for painful tendons are described, the scientific evidence for most of the conservative and surgical treatments is not always conclusive. OBJECTIVES: This study was designed to evaluate the efficacy of 3 different interventions in patients with Achilles tendinopathy. The interventions include the combination of 2 physical therapy programs (eccentric training [EC] or passive stretching [PS]) with a supplement containing mucopolisaccharides. The efficacy of the interventions was evaluated depending on the stage of the disease. METHODS: Fifty-nine patients were randomly assigned to 1 of 3 treatment groups, and classified according to the disease stage: reactive versus degenerative tendinopathy. Treatment groups were EC; EC + a dietary supplement containing mucopolisaccharides, type I collagen, and vitamin C (MCVC); and a passive stretching program + MCVC. Patients were evaluated at baseline, 6 weeks, and 12 weeks with the Victorian Institute of Sports Assessment-Achilles questionnaire for function, a visual analog scale for pain, and ultrasound characterization for the evolution of tendon structure. RESULTS: A significant improvement in Victorian Institute of Sports Assessment-Achilles questionnaire score, pain at rest, and pain during activity were detected in all 3 treatment groups at 6 and 12 weeks' follow-up when compared with baseline. In patients with reactive tendinopathy, the reduction in pain at rest was greater in the groups who took the supplemental MCVC than in the EC alone group (P < 0.05). CONCLUSIONS: MCVC seems to be therapeutically useful for management of tendinopathies, providing some additional benefit to physical therapy. This is especially evident in early stages of the disease, when the tendon does not present severe matrix and vascular changes. CLINICALTRIALSGOV IDENTIFIER: NCT01691716.

Cardiovascular risk factors in patients with asymptomatic primary hyperparathyroidism.

OBJECTIVES: Patients with primary hyperparathyroidism (PHP), even asymptomatic, have an increased cardiovascular risk. However, data on reversibility or improvement of cardiovascular disorders with surgery are controversial. Our aims were to assess the prevalence of classic cardiovascular risk factors in patients with asymptomatic PHP, to explore their relationship with calcium and PTH levels, and analyze the effect of parathyroidectomy on those cardiovascular risk factors. PATIENTS AND METHODS: A retrospective, observational study of two groups of patients with asymptomatic PHP: 40 patients on observation and 33 patients who underwent surgery. Clinical and biochemical data related to PHP and various cardiovascular risk factors were collected from all patients at baseline and one year after surgery in the operated patients. RESULTS: A high prevalence of obesity (59.9%), type 2 diabetes mellitus (25%), high blood pressure (47.2%), and dyslipidemia (44.4%) was found in the total sample, with no difference between the study groups. Serum calcium and PTH levels positively correlated with BMI (r=.568, P=.011, and r=.509, P=.026 respectively) in non-operated patients. One year after parathyroidectomy, no improvement occurred in the cardiovascular risk factors considered. CONCLUSIONS: Our results confirm the high prevalence of obesity, type 2 diabetes mellitus, high blood pressure, and dyslipidemia in patients with asymptomatic PHP. However, parathyroidectomy did not improve these cardiovascular risk factors.

Dietary fiber enhances TGF-ß signaling and growth inhibition in the gut.

Dietary fiber intake links to decreased risk of colorectal cancers. The underlying mechanisms remain unclear. Recently, we found that butyrate, a short-chain fatty acid produced in gut by bacterial fermentation of dietary fiber, enhances TGF-ß signaling in rat intestinal epithelial cells (RIE-1). Furthermore, TGF-ß represses inhibitors of differentiation (Ids), leading to apoptosis. We hypothesized that dietary fiber enhances TGF-ß's growth inhibitory effects on gut epithelium via inhibition of Id2. In this study, Balb/c and DBA/2N mice were fed with a regular rodent chow or supplemented with a dietary fiber (20% pectin) and Smad3 level in gut epithelium was measured. In vitro, RIE-1 cells were treated with butyrate and TGF-ß(1), and cell functions were evaluated. Furthermore, the role of Ids in butyrate- and TGF-ß-induced growth inhibition was investigated. We found that pectin feeding increased Smad3 protein levels in the jejunum (1.47 ± 0.26-fold, P = 0.045, in Balb/c mice; 1.49 ± 0.19-fold, P = 0.016, in DBA/2N mice), and phospho-Smad3 levels (1.92 ± 0.27-fold, P = 0.009, in Balb/c mice; 1.83 ± 0.28-fold, P = 0.022, in DBA/2N mice). Butyrate or TGF-ß alone inhibited cell growth and induced cell cycle arrest. The combined treatment of butyrate and TGF-ß synergistically induced cell cycle arrest and apoptosis in RIE-1 cells and repressed Id2 and Id3 levels. Furthermore, knockdown of Id2 gene expression by use of small interfering RNA caused cell cycle arrest and apoptosis. We conclude that dietary fiber pectin enhanced Smad3 expression and activation in the gut. Butyrate and TGF-ß induced cell cycle arrest and apoptosis, which may be mediated by repression of Id2. Our results implicate a novel mechanism of dietary fiber in reducing the risk of colorectal cancer development.

Prognostic factors for disease-free survival in patients with T3-4 or N+ rectal cancer treated with preoperative chemoradiation therapy, surgery, and intraoperative irradiation.

PURPOSE: Fluoropyrimidine-radiosensitizing agents in conjunction with preoperative radiotherapy have proven to induce tumor and nodal downstaging effects, sphincter preservation promotion, and mid-term favorable survival rates. Intraoperative electron beam radiation therapy may improve pelvic control in patients with locally advanced rectal cancer stages. Potential predictive factors for response and disease-free survival, with intense local multidisciplinary approach, are analyzed. METHODS AND MATERIALS: One hundred fifteen patients with rectal cancer were treated with oral 5-fluorouracil or Tegafur with preoperative radiotherapy, surgery, and intraoperative electron beam radiation therapy to identify potential pre- and on-treatment characteristics that might be of prognostic value for disease outcome. Univariate and multivariate analyses were performed. RESULTS: Older patients and those treated with Tegafur were more likely to achieve a major histologic response, categorized as persistence of minimal residual microscopic disease foci in the surgical specimen ("mic" response). Factors unfavorably associated with disease-free survival in the multivariate model were male gender and persistence of macroscopic disease in the rectal wall ("mac" response). Accordingly, 3-year disease-free survival rates in the groups of patients with 0, 1, or 2 of these risk factors were 100%, 81%, and 53%, respectively (p < 0.001). CONCLUSIONS: Females with an intense pathologic response (pT(mic) residue) to preoperative chemoradiotherapy have an excellent 3-year disease-free survival. This information might be of interest for stratification of patients in the development of adjuvant treatment trials.

La inestabilidad de microsatélites predice un mejor pronóstico en los pacientes intervenidos de carcinoma colorrectal / Microsatellite instability predicts better outcome in colorectal cancer patients

FUNDAMENTO Y OBJETIVO: En el carcinoma colorrectal se describen 2 vías genéticas diferentes implicadas en la génesis del tumor: la inestabilidad cromosómica, debida a la alteración de genes supresores o protooncogenes, y la inestabilidad de microsatélites, originada por alteraciones en los genes reparadores del ADN. PACIENTES Y MÉTODO: En este estudio se determina la frecuencia y el significado clínico de la vía de la inestabilidad de microsatélites en una cohorte prospectiva consecutiva de 106 pacientes intervenidos por carcinoma colorrectal por un mismo cirujano. Para la determinación de la inestabilidad de microsatélites se han seguido los criterios propuestos por el National Cancer Instituteen 1998. RESULTADOS: El 9,4% de los pacientes muestra una alta inestabilidad y el 11,3% una inestabilidad baja. Ambos grupos presentan diferentes características clínico patológicas (edad, sexo, localización del tumor y tipo histológico). En el análisis multivariante de la supervivencia global y de la supervivencia libre de enfermedad, la alta inestabilidad presenta un valor pronóstico independiente del resto de las variables clínico patológicas analizadas (p < 0,0001). CONCLUSIONES: La alteración genética que supone la alta inestabilidad de microsatélites confierea los pacientes con cáncer colorrectal un mejor pronóstico

BACKGROUND AND OBJECTIVE: Two different pathways for the development of tumor have been described in colorectal carcinoma: the chromosomic instability, raised by suppressor genes and protooncogene alterations, and the microsatellite instability (MSI), caused by alterations in DNA repairing genes. PATIENTS AND METHOD: The frequency and the clinical meaning of the Microsatellites instability pathway were determined in a consecutive prospective cohort of 106 patients who underwent surgical resection of colorectal carcinoma by a single surgeon. Microsatellite instability determination was established according to the criteria proposed by the National Cancer Institute in1998. RESULTS: 9.4% of patients had a high instability and it was low in 11.3%; both groups displayed different clinico-pathological characteristics (age, sex, tumor site and histologic type). In the multivariant analysis of overall survival and disease free survival, high instability exhibited prognostic value independent of the rest of variables evaluated (p < 0.0001). CONCLUSIONS: The genetic alterations giving rise to microsatellite instability lead to a better prognosis in patients with colorectal cancer

Resultados de la cirugía con tratamiento neoadyuvante del cáncer de recto / Results of surgery with neoadjuvant treatment in rectal cancer

Objetivo. El tratamiento neoadyuvante en el cáncer de recto está cada vez más establecido como la forma más adecuada de complementar la resección quirúrgica en lesiones localmente avanzadas. Los centros con especial interés en el tratamiento multidisciplinario del cáncer de recto evalúan diversas modalidades de tratamiento adyuvante preoperatorio. El presente trabajo es una revisión crítica de las diversas formas de tratamiento empleadas. Resultados. La adyuvancia preoperatoria se tolera de forma aceptable, controla la progresión de la enfermedad, facilita la resección de lesiones grandes y, en las localizadas en el tercio inferior, ayuda a la preservación esfinteriana. Mejora las cifras de recidiva local y aumenta la tasa de supervivencia libre de enfermedad. La tendencia actual es asociar quimioterapia durante la radioterapia, aun cuando el beneficio de esta asociación debe ser validado por estudios aleatorizados que están pendientes de resultados. Este tratamiento no está exento de efectos secundarios, tales como alteración de la función anorrectal y sexual, por lo que debe seleccionarse a los pacientes que se beneficiarán de este esquema terapéutico. Conclusiones. El tratamiento neoadyuvante es de elección en los pacientes con tumores en estadios II y III. En el futuro, nuevos esquemas y agentes quimioterápicos, y sistemas que sean capaces de identificar a los pacientes con tumores que sean respondedores a estas formas de tratamiento complementario, harán posible un mejor uso de estas opciones terapéuticas. (AU)