Non-invasive assessment of severe liver fibrosis in patients with Fontan-associated liver disease: The VALDIG-EASL FONLIVER cohort.

BACKGROUND & AIMS: Fontan-type surgery is used as a palliation for congenital heart disease with univentricular physiology but may, in the long term, lead to advanced chronic liver disease. This study assessed the accuracy of conventional non-invasive models in assessing liver fibrosis and introduces a new risk score employing non-invasive tools. METHODS: A prospective, cross-sectional, observational study was conducted across five European centers and encompassing all consecutive adult patients with Fontan circulation, liver biopsy and non-invasive tests (elastography, APRI, FIB-4, Fibrosis score, Doha, GUCI, and AAR). The primary outcome was the identification of severe liver fibrosis on biopsy. Multivariable logistic regression identified non-invasive predictors of severe fibrosis, leading to the development and internal validation of a new scoring model named the FonLiver risk score. RESULTS: In total, 217 patients (mean [standard deviation] age, 27.9 [8.9] years; 50.7% males) were included. Severe liver fibrosis was present in 47.9% (95% CI 41.2%-54.5%) and correlated with a lower functional class, protein-losing enteropathy, and compromised cardiopulmonary and systemic hemodynamics. The final FonLiver risk score incorporated liver stiffness measurement using transient elastography and platelet count and demonstrated strong discrimination and calibration (area under the receiver operating curve [AUROC] of 0.81). The FonLiver risk score outperformed conventional prediction models (APRI, FIB-4, Fibrosis score, Doha, GUCI, and AAR), which all exhibited worse performance in our cohort (AUROC < 0.70 for all). CONCLUSION: Severe liver fibrosis is prevalent in adults following Fontan-type palliation and can be effectively estimated using with the novel FonLiver risk score. This scoring system can be easily incorporated into the routine assessment of patients with Fontan circulation.

Pneumonectomy following penetrating trauma with ECMO as postoperative support: case report - (Lung trauma and ECMO).

BACKGROUND: Penetrating thoracic injuries have a significant risk of morbi-mortality. Despite the advancements in damage control methods, a subset of patients with severe pulmonary vascular lesions and bronchial injuries persists. In some of these cases, post-traumatic pneumonectomy is required, and perioperative extracorporeal membrane oxygenation (ECMO) support may be required due to right ventricular failure and respiratory failure. CASE DESCRIPTION: A male was brought to the emergency department (ED) with a penetrating thoracic injury, presenting with massive right hemothorax and active bleeding that required ligation of the right pulmonary hilum to control the bleeding. Subsequently, he developed right ventricular dysfunction and ARDS, necessitating a dynamic hybrid ECMO configuration to support his condition and facilitate recovery. CONCLUSIONS: Penetrating thoracic injuries with severe pulmonary vascular lesions may need pneumonectomy to control bleeding. ECMO support reduces the associated mortality by decreasing the complications rate. A multidisciplinary team is essential to achieve good outcomes in severe compromised patients.

Demographic Trends in Liver Transplant Survivors After 3 Decades of Program Implementation: The Impact of Cohort and Period Effects on Life Expectancy.

Background: Demographic analyses may reveal current patterns of change in the outcomes of rapidly developing medical procedures because they incorporate the period perspective. Methods: We analyzed the changes in size, age structure, and hospitalizations in the population of liver transplantation (LT) survivors in our center during the last 30 y (n = 1114 patients) and generated projections, including life expectancy (LE), considering cohort and period effects. Life tables were used to project the complete LE (overall 1990-2020 experience), the cohort LE (according to the decade of surgery: 1990-2000, 2000-2010, and 2010-2020), and the period LE (current 2015-2020 experience). Results: The population of LT recipients in follow-up continued to experience progressive growth and aging since 1990 (492 patients [41.9% >65 y] in 2020), and the magnitude of these phenomena may double in the next 30 y. However, the number of admissions and days of admission has been decreasing. The complete LE at LT was 12.4 y, whereas the period LE was 15.8 y. The cohort LE (limited to 10 y) was 5.3, 6.3, and 7.3 y for the 1990-2000, 2000-2010, and 2010-2020 cohorts, respectively. Conclusions: The target population of our medical care after LT is growing and aging. The prevalence of both of these phenomena is expected to increase in the coming years and is associated with a current improvement in LE. However, the hospitalization burden associated with LT survivors is declining. The period effect should be considered for generating up-to-date information on these current trends, which are crucial when designing health policies for LT survivors.

The development and implementation of a low-cost mechanical ventilator in a low-middle-income country during the COVID-19 pandemic: The Unisabana-HERONS.

Background: The COVID-19 pandemic in Latin America generated the need to develop low-cost, fast-manufacturing mechanical ventilators. The Universidad de La Sabana and the Fundacion Neumologica Colombiana designed and manufactured the Unisabana-HERONS (USH) ventilator. Here, we present the preclinical and clinical study results to evaluate its effectiveness and safety characteristics in an animal model (Yorkshire Sow) and five patients with acute respiratory failure receiving mechanical ventilatory support for 24 h. Methods: The effectiveness and safety outcomes included maintaining arterial blood gases and pulse oximetry saturation (SpO2), respiratory pressures and volumes (during continuous monitoring) in the range of ARDS and lung-protective strategy goals, and the occurrence of barotrauma. A significance level of 0.05 was used for statistical tests. This clinical trial was registered on Clinicaltrials.gov (NCT04497623) and approved by the ethics committee. Results: Among patients treated with the Unisabana-HERONS, the most frequent causes of acute respiratory failure were pneumonia in 3/5 (60 %) and ARDS in 2/5 (40 %). During the treatment, the ventilatory parameters related to lung protection protocols were kept within the safety range, and vital signs and blood gas were stable. The percentage of time that the respiratory pressures or volumes were out of safety range were plateau pressure >30 cm H2O: 0.00 %; driving pressure >15 cm H2O: 0.06 %; mechanical power >15 J/min: 0.00 %; and Tidal volume >8 mL/kg: 0.00 %. There were no adverse events related to the ventilator. The usability questionnaire retrieved a median score for all items between 9 and 10 (best score: 10), indicating great ease of use. Conclusion: The Unisabana-HERONS ventilator effectively provided adequate gas exchange and maintained the ventilatory parameters in the range of lung protection strategies in humans and an animal model. Furthermore, it is straightforward to use and is a low-cost medical device.

Surgical stabilization of rib fractures under extracorporeal membrane oxygenation: A case report.

A 47-year-old male patient was referred to a level 1 trauma center with refractory acute respiratory distress syndrome, bilateral lung contusions, and flail chest after initial management for injuries sustained 5 days prior from an 8-m fall from a tower crane. Surgical stabilization of the rib fractures was achieved under extracorporeal membrane oxygenation support, with successful decannulation 4 days after surgery. The patient was discharged after 42 days and following multidisciplinary interventions. Use of extracorporeal membrane oxygenation support in blunt chest trauma patients presents a valuable opportunity as it may enable earlier surgical intervention and reduce in-hospital complications.

MR-LINAC, a New Partner in Radiation Oncology: Current Landscape.

Technological advances in radiation oncology are oriented towards improving treatment precision and tumor control. Among these advances, magnetic-resonance-image-guided radiation therapy (MRgRT) stands out, with technological advances to deliver targeted treatments adapted to a tumor's anatomy on the day while minimizing incidental exposure to organs at risk, offering an unprecedented therapeutic advantage compared to X-ray-based IGRT delivery systems. This new technology changes the traditional workflow in radiation oncology and requires an evolution in team coordination to administer more precise treatments. Once implemented, it paves the way for newer indication for radiation therapy to safely deliver higher doses than ever before, with better preservation of healthy tissues to optimize patient outcomes. In this narrative review, we assess the technical aspects of the novel linear accelerators that can deliver MRgRT and summarize the available published experience to date, focusing on oncological results and future challenges.

Hepatic hemodynamic study: More than just HVPG measurement.

Evaluation and staging of liver disease is essential in the clinical decision-making process of liver tumors. The severity of portal hypertension (PH) is the main prognostic factor in advanced liver disease. Performing an accurate hepatic venous pressure gradient (HVPG) measurement is not always possible, especially when veno-venous communications are present. In those complex cases, a refinement in HVPG measurement with a thorough evaluation of each of the components of PH is mandatory. We aimed at describing how some technical modifications and complementary procedures may contribute to an accurate and complete clinical evaluation to improve therapeutic decisions.

Total neoadjuvant therapy approach for the treatment of locally advanced rectal cancer. Where do we stand?

BACKGROUND: for the management of locally advanced rectal cancer (LARC), initial treatment with neoadjuvant chemoradiotherapy followed by surgery and chemotherapy in selected patients is considered one of the recommended options by the main international clinical guidelines. Nonetheless, the administration of all chemotherapy before definitive treatment (total neoadjuvant therapy or TNT) is an optimal alternative with a growing level of evidence that must be evaluated in multidisciplinary boards. This review summarizes the available data and controversies in this scenario. SUMMARY: we have analyzed the characteristics of the main published studies that assess the use of TNT in patients with LARC, evaluating their inclusion criteria and distinguishing between the employed radiotherapy fractionations, systemic agents, timing, and the implications of these treatments in regard to surgery and long-term oncological results. Our aim is to describe the evidence that supports the use of a specific regime in everyday clinical practice. KEY POINTS: there is solid evidence for the use of TNT in patients with LARC. There is no data indicating the superiority of one specific TNT scheme among all the existing options. International clinical guidelines leave the door open to choose the most adequate treatment based on the clinical and pathological characteristics of each patient. This review shows the different approaches to TNT and assesses the best options based on clinical evidence.

Portal hypertension increases the risk of hepatic decompensation after 90Yttrium radioembolization in patients with hepatocellular carcinoma: a cohort study.

Background: Transarterial radioembolization (TARE) is increasingly used in patients with hepatocellular carcinoma (HCC). This treatment can induce or impair portal hypertension, leading to hepatic decompensation. TARE also promotes changes in liver and spleen volumes that may modify therapeutic decisions and outcomes after therapy. Objectives: We aimed to investigate the impact of TARE on the incidence of decompensation events and its predictive factors. Design: In all, 63 consecutive patients treated with TARE between February 2012 and December 2018 were retrospectively included. Methods: We assessed clinical (including Barcelona Clinic Liver Cancer stage, portal hypertension assessment, and liver decompensation), laboratory parameters, and liver and spleen volumes before and 6 and 12 weeks after treatment. A multivariate analysis was performed. Results: In total, 18 out of 63 (28.6%) patients had liver decompensation (ascites, variceal bleeding, jaundice, or encephalopathy) within the first 3 months after therapy, not associated with tumor progression. Clinically significant portal hypertension (CSPH) and bilobar treatment independently predicted the development of liver decompensation after TARE. A significant volume increase in the non-treated hemi-liver was observed only in patients with unilobar treatment (median volume increase of 20.2% in patients with right lobe TARE; p = 0.007), especially in those without CSPH. Spleen volume also increased after TARE (median volume increase of 16.1%; p = 0.0001) and was associated with worsening liver function scores and decreased platelet count. Conclusion: Bilobar TARE and CSPH may be associated with an increased risk of liver decompensation in patients with intermediate or advanced HCC. A careful assessment considering these variables before therapy may optimize candidate selection and improve treatment planning.

CT-derived liver and spleen volume accurately diagnose clinically significant portal hypertension in patients with hepatocellular carcinoma.

Background & Aims: Clinically significant portal hypertension (CSPH) is a landmark in the natural history of cirrhosis, influencing clinical decisions in patients with hepatocellular carcinoma (HCC). Previous small series suggested that splanchnic volume measurements may predict portal hypertension. We aimed to evaluate whether volumetry obtained by standard multidetector computerised tomography (MDCT) can predict CSPH in patients with HCC. Methods: We included 175 patients with HCC, referred for hepatic venous pressure gradient (HVPG) evaluation, in whom contemporary MDCT was available. Liver volume, spleen volume (SV) and liver segmental volume ratio (LSVR: volume of the segments I-III/volume of the segments IV-VIII) were calculated semi-automatically from MDCT. Other non-invasive tests (NITs) were also employed. Results: Volume parameters could be measured in almost 100% of cases with an excellent inter-observer agreement (intraclass correlation coefficient >0.950). SV and LSVR were independently associated with CSPH (HVPG ≥10 mmHg) and did not interact with aetiology. The volume Index (VI), calculated as the product of SV and LSVR, predicted CSPH (AUC 0.83; 95% CI 0.77-0.89). Similar results were observed in an external cohort (n = 23) (AUC 0.87; 95% CI 0.69-1.00). Setting a sensitivity and specificity of 98%, VI could have avoided 35.9% of HVPG measurements. The accuracy of VI was similar to that of other NITs. VI also accurately predicted HVPG greater than 12, 14, 16 and 18 mmHg (AUC 0.81 [95% CI 0.74-0.88], 0.84 [95% CI 0.77-0.91], 0.85 [95% CI 0.77-0.92] and 0.87 [95% CI 0.79-0.94], respectively). Conclusions: Quantification of liver and spleen volumes by MDCT is a simple, accurate and reliable method of CSPH estimation in patients with compensated cirrhosis and HCC. Impact and implications: An increase in portal pressure strongly impacts outcomes after surgery in patients with early hepatocellular carcinoma (HCC). Direct measurement through hepatic vein catheterization remains the reference standard for portal pressure assessment, but its invasiveness limits its application. Therefore, we evaluated the ability of CT scan-based liver and spleen volume measurements to predict portal hypertension in patients with HCC. Our results indicate that the newly described index, based on quantification of liver and spleen volume, accurately predicts portal hypertension. These results suggest that a single imaging test may be used to diagnose and stage HCC, while providing an accurate estimation of portal hypertension, thus helping to stratify surgical risks.

Liver and spleen volumes are associated with prognosis of compensated and decompensated cirrhosis and parallel its natural history.

OBJECTIVE: Cirrhosis is characterized by the complex interplay among biological, histological and haemodynamic events. Liver and spleen remodelling occur throughout its natural history, but the prognostic role of these volumetric changes is unclear. We evaluated the relationship between volumetric changes assessed by multidetector computerised tomography (MDCT) and landmark features of cirrhosis. METHODS: We included consecutive cirrhotic patients who underwent liver transplantation (LT) or hepatocellular carcinoma (HCC) resection in whom dynamic MDCT was available. Different volumetric indices were calculated. Fibrosis was evaluated by the collagen proportional area and Laennec sub-stages. Correlation and logistic regression analysis were performed to explore associations of volumetric indexes and fibrosis with key prognostic features across the clinical stages of cirrhosis. RESULTS: 185 patients were included (146 LT; 39 HCC); the predominant aetiology was viral hepatitis (51.35%); 65.9% had decompensated disease and 85.08% clinically significant portal hypertension (CSPH). The standardised liver volume and liver-spleen volume ratio negatively correlated with Model for End-stage Liver Disease (MELD), albumin and hepatic venous pressure gradient (HVPG) and were significantly lower in decompensated patients. The liver segmental volume ratio (segments I-III/segments IV-VIII) best captured the characteristic features of the compensated phase, showing a positive correlation with HVPG and a good discrimination between patients with and without CSPH and varices. Volumetric changes and fibrosis severity were independently associated with key prognostic events, with no association between these two parameters. CONCLUSIONS: Liver and spleen volumetric indices evolve differently along the natural history of cirrhosis and are associated with key prognostic factors in each phase, regardless of fibrosis severity and portal hypertension.

A Model Based on Noninvasive Markers Predicts Very Low Hepatocellular Carcinoma Risk After Viral Response in Hepatitis C Virus-Advanced Fibrosis.

BACKGROUND AND AIMS: Patients with hepatitis C virus (HCV) and advanced fibrosis remain at risk of hepatocellular carcinoma (HCC) after sustained viral response (SVR) and need lifelong surveillance. Because HCC risk is not homogenous and may decrease with fibrosis regression, we aimed to identify patients with low HCC risk based on the prediction of noninvasive markers and its changes after SVR. APPROACH AND RESULTS: This is a multicenter cohort study, including patients with HCV and compensated advanced fibrosis that achieved SVR after direct antivirals. Clinical and transient elastography (TE) data were registered at baseline, 1 year, and 3 years after the end of treatment (EOT). All patients underwent liver ultrasound scan every 6 months. Patients with clinical evaluation 1 year after EOT were eligible. Univariate and multivariate Cox regression analysis were performed, and predictive models were constructed. HCC occurrence rates were evaluated by Kaplan-Meier. Nine hundred and ninety-three patients were eligible (56% male; 44% female; median age 62 years), 35 developed HCC (3.9%), and the median follow-up was 45 months (range 13-53). Baseline liver stiffness measurement (LSM) (HR 1.040; 95% CI 1.017-1.064), serum albumin (HR 0.400; 95% CI 0.174-0.923), 1-year DeltaLSM (HR 0.993; 95% CI 0.987-0.998), and 1-year FIB-4 score (HR 1.095; 95% CI 1.046-1.146) were independent factors associated with HCC. The TE-based HCC risk model predicted 0% of HCC occurrence at 3 years in patients with score 0 (baseline LSM ≤ 17.3 kPa, albumin >4.2 g/dL, and 1-year DeltaLSM > 25.5%) versus 5.2% in patients with score 1-3 (Harrell's C 0.779; log-rank 0.002). An alternative model with FIB-4 similarly predicted HCC risk. CONCLUSIONS: A combination of baseline and dynamic changes in noninvasive markers may help to identify patients with a very low risk of HCC development after SVR.

Transjugular Intrahepatic Portosystemic Shunt for Very Severe Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) after Unmanipulated Haploidentical Hematopoietic Stem Cell Transplantation with Post-transplantation Cyclophosphamide.

Hepatic veno-occlusive disease or sinusoidal obstruction syndrome (VOD/SOS) is a threatening complication after both autologous and allogeneic hematopoietic stem cell transplantation (HSCT), with high mortality rates despite early medical treatment, including the use of defibrotide (DF). We retrospectively analyzed 185 unmanipulated haploidentical (haplo-) HSCT with post-transplantation cyclophosphamide as graft-versus-host disease prophylaxis performed consecutively between 2011 and June 2019 in a single center. Seventeen patients (9.2%) were diagnosed with VOD/SOS. Based on revised European Society for Blood and Marrow Transplantation severity criteria, the VOD/SOS cases were classified as mild in 2 patients (11.7%), moderate in 2 (11.7%), severe in 2 (11.7%), and very severe in 11 (64.9%). Thirteen patients (76%) were treated with DF, including all patients with severe or very severe VOD/SOS, except 1 patient with CNS hemorrhage. Sixteen patients (94%) were alive at day +100 after HSCT. Seven patients (41%) with very severe VOD/SOS were treated with transjugular intrahepatic portosystemic shunt (TIPS) owing to rapid clinical or analytical deterioration or refractory hepatorenal syndrome despite medical treatment, including DF. TIPS insertion was performed at a median time since VOD/SOS diagnosis of 4 days (range, 1 to 28 days) without technical complications in any case. The median hepatic venous pressure gradient before and after TIPS treatment was 24 mmHg (range, 14 to 29 mmHg) and 7 mmHg (range, 2 to 11 mmHg), respectively, with a median drop of 16 mmHg (range, 9 to 19 mmHg). Following TIPS insertion, all patients showed clinical improvement with hepatomegaly, ascites, and renal failure resolution, and all showed analytical improvement with reduced alanine aminotransferase (ALT), creatinine, and international normalized ratio values, except for patient 2, whose indication for TIPS was refractory hepatorenal syndrome with a normal ALT level. The 6 patients who had initiated DF before TIPS insertion completed 21 days of treatment. All patients met the criteria for complete remission (CR) at a median of 8 days after TIPS insertion (range, 2 to 82 days). The 100-day overall survival was 100%. For patients with rapid progressive VOD/SOS, early TIPS insertion allowed completion of DF therapy. The use of TIPS together with DF resulted in CR and no associated complications with no VOD/SOS-associated mortality despite high severity. In our experience, timely and individualized use of TIPS significantly improves outcomes of very severe VOD/SOS after haplo-HSCT. Therefore, TIPS should be promptly considered in rapidly progressive cases.

Consideraciones anestésicas en el paciente con enfermedad por virus dengue / Anesthetic considerations in the patient with dengue virus disease

El dengue continúa siendo un problema de salud pública en América. Suele presentarse como una enfermedad febril leve, sin embargo, los pacientes con enfermedad grave pueden presentar síndromes hemorrágicos y choque por dengue. Diferentes circunstancias pueden surgir en el curso evolutivo de los pacientes con dengue impactando en la posibilidad de que sea necesario realizar en ellos una intervención quirúrgica, ante lo cual es necesario plantear las consideraciones anestésicas que deben ser tenidas en cuenta para el correcto abordaje. El presente texto tiene como objetivo establecer consideraciones clínicas útiles para el manejo anestésico en el paciente con enfermedad por dengue para reducir el riesgo de complicaciones peri-operatorias y muerte.

Dengue fever continues to be a public health problem in America. It usually presents as a mild febrile illness, however, patients with severe disease may have hemorrhagic syndromes and dengue shock. Different circumstances can arise in the evolutionary course of patients with dengue impacting on the possibility that it is necessary to perform a surgical intervention, before which it is necessary to raise the anesthetic considerations that must be taken into account for the correct approach. The present text aims to establish useful clinical considerations for anesthetic management in the patient with dengue disease to reduce the risk of peri-operative complications and death.

Mutational spectrum in breast cancer associated BRCA1 and BRCA2 genes in Colombia.

INTRODUCTION: The risk of developing breast and ovarian cancer is higher in families that carry mutations in BRCA1 or BRCA2 genes, and timely mutation detection is critical. OBJECTIVE: To identify the presence of mutations in the Colombian population and evaluate two testing strategies. METHODS: From a total universe of 853 individual blood samples referred for BRCA1 and BRCA2 typing, 256 cases were analyzed by complete direct sequencing of both genes in Myriad Genetics, and the remaining 597 cases were studied by partial sequencing based on founder mutations in a PCR test designed by ourselves ("Profile Colombia"). RESULTS: We found 107 patients carrying deleterious mutations in this group of patients, 69 (64.5%) located in BRCA1, and 38 (35.5%) in BRCA2. Overall, we detected 39 previously unreported mutations in Colombia (22 in BRCA1 and 17 in BRCA2) and only 4 out of the 6 previously reported founder mutations. Sixty four out of 597 patients (10.7%) studied by "Profile Colombia" showed mutations in BRCA1 or BRCA2, and 41/256 patients (16%) showed mutations by complete BRCA1-BRCA2 sequencing. CONCLUSIONS: The spectrum of 44 different mutations in Colombia as detected in our study is broader than the one previously reported for this country. "Profile Colombia" is a useful screening test to establish both founder and new mutations (detection rate of 10.7%) in cases with family history of breast cancer. Complete sequencing shows a detection rate of 16.0%, and should complement the study of the genetic basis of this disease.

INTRODUCCIÓN: El riesgo de desarrollar cáncer de mama y cáncer de ovario puede transmitirse en familias que porten mutaciones en los genes BRCA1 o BRCA2. La detección de estas mutaciones permite tomar decisiones oportunas en el ámbito de la medicina preventiva. OBJETIVO: Estudiar el espectro de mutaciones en la población colombiana y evaluar dos estrategias de detección. METODOS: Se incluyeron en total 853 pacientes con diagnóstico de cáncer de mama y con solicitud de análisis de los genes BRCA1 y BRCA2. Un total de 256 pruebas se analizaron mediante secuencia directa completa de estos genes en Myriad Genetics, y las restantes 597 se estudiaron mediante secuencia parcial basada en mutaciones fundadoras a través de la prueba "Perfil Colombia", implementada por nosotros. RESULTADOS: Se detectaron 107 pacientes portadores de mutaciones en pacientes colombianos, 69 de las cuales estaban localizadas en BRCA1 y 38 en BRCA2. De estas 39 mutaciones son nuevas (22 en BRCA1 y 17 en BRCA2) y solo se hallaron 4 de las 6 mutaciones reportadas previamente como fundadoras en Colombia. En 64/597 pacientes analizados mediante el "Perfil Colombia" se detectaron mutaciones en BRCA1 o BRCA2, así como en 41/256 pacientes que solicitaron la secuenciación completa de los genes BRCA1 y BRCA2. CONCLUSIONES: El espectro de mutaciones fundadoras en Colombia es más amplio que el reportado anteriormente para este país. El "Perfil Colombia" es una prueba que revela a la vez mutaciones fundadoras y mutaciones nuevas, con una tasa de detección del 10.7%. La secuenciación completa presenta una tasa de detección del 16.0% y puede complementar el diagnóstico de la base genética de esta enfermedad.

Mutational spectrum in breast cancer associated BRCA1 and BRCA2 genes in Colombia / Espectro de mutaciones en los genes BRCA1 y BRCA2 asociados a cáncer de mama en Colombia

Abstract Introduction: The risk of developing breast and ovarian cancer is higher in families that carry mutations in BRCA1 or BRCA2 genes, and timely mutation detection is critical. Objective: To identify the presence of mutations in the Colombian population and evaluate two testing strategies. Methods: From a total universe of 853 individual blood samples referred for BRCA1 and BRCA2 typing, 256 cases were analyzed by complete direct sequencing of both genes in Myriad Genetics, and the remaining 597 cases were studied by partial sequencing based on founder mutations in a PCR test designed by ourselves ("Profile Colombia"). Results: We found 107 patients carrying deleterious mutations in this group of patients, 69 (64.5%) located in BRCA1, and 38 (35.5%) in BRCA2. Overall, we detected 39 previously unreported mutations in Colombia (22 in BRCA1 and 17 in BRCA2) and only 4 out of the 6 previously reported founder mutations. Sixty four out of 597 patients (10.7%) studied by "Profile Colombia" showed mutations in BRCA1 or BRCA2, and 41/256 patients (16%) showed mutations by complete BRCA1-BRCA2 sequencing. Conclusions: The spectrum of 44 different mutations in Colombia as detected in our study is broader than the one previously reported for this country. "Profile Colombia" is a useful screening test to establish both founder and new mutations (detection rate of 10.7%) in cases with family history of breast cancer. Complete sequencing shows a detection rate of 16.0%, and should complement the study of the genetic basis of this disease.

Resumen Introducción: El riesgo de desarrollar cáncer de mama y cáncer de ovario puede transmitirse en familias que porten mutaciones en los genes BRCA1 o BRCA2. La detección de estas mutaciones permite tomar decisiones oportunas en el ámbito de la medicina preventiva. Objetivo: Estudiar el espectro de mutaciones en la población colombiana y evaluar dos estrategias de detección. Metodos: Se incluyeron en total 853 pacientes con diagnóstico de cáncer de mama y con solicitud de análisis de los genes BRCA1 y BRCA2. Un total de 256 pruebas se analizaron mediante secuencia directa completa de estos genes en Myriad Genetics, y las restantes 597 se estudiaron mediante secuencia parcial basada en mutaciones fundadoras a través de la prueba "Perfil Colombia", implementada por nosotros. Resultados: Se detectaron 107 pacientes portadores de mutaciones en pacientes colombianos, 69 de las cuales estaban localizadas en BRCA1 y 38 en BRCA2. De estas 39 mutaciones son nuevas (22 en BRCA1 y 17 en BRCA2) y solo se hallaron 4 de las 6 mutaciones reportadas previamente como fundadoras en Colombia. En 64/597 pacientes analizados mediante el "Perfil Colombia" se detectaron mutaciones en BRCA1 o BRCA2, así como en 41/256 pacientes que solicitaron la secuenciación completa de los genes BRCA1 y BRCA2. Conclusiones: El espectro de mutaciones fundadoras en Colombia es más amplio que el reportado anteriormente para este país. El "Perfil Colombia" es una prueba que revela a la vez mutaciones fundadoras y mutaciones nuevas, con una tasa de detección del 10.7%. La secuenciación completa presenta una tasa de detección del 16.0% y puede complementar el diagnóstico de la base genética de esta enfermedad.

Real-World Multicenter Experience of Immunosuppression Minimization Among 661 Liver Transplant Recipients.

BACKGROUND Long-term morbidity and mortality in liver transplant recipients is frequently secondary to immunosuppression toxicity. However, data are scarce regarding immunosuppression minimization in clinical practice. MATERIAL AND METHODS In this cross-sectional, multicenter study, we reviewed the indications of immunosuppression minimization (defined as tacrolimus levels below 5 ng/mL or cyclosporine levels below 50 ng/mL) among 661 liver transplant recipients, as well as associated factors and the effect on renal function. RESULTS Fifty-three percent of the patients received minimized immunosuppression. The median time from transplantation to minimization was 32 months. The most frequent indications were renal insufficiency (49%), cardiovascular risk (19%), de novo malignancy (8%), and cardiovascular disease (7%). The factors associated with minimization were older age at transplantation, longer post-transplant follow-up, pre-transplant diabetes mellitus and renal dysfunction, and the hospital where the patients were being followed. The patients who were minimized because of renal insufficiency had a significant improvement in renal function (decrease of the median serum creatinine level, from 1.50 to 1.34 mg/dL; P=0.004). Renal function significantly improved in patients minimized for other indications, too. In the long term, glomerular filtration rate significantly decreased in non-minimized patients and remained stable in minimized patients. CONCLUSIONS Immunosuppression minimization is frequently undertaken in long-term liver transplant recipients, mainly for renal insufficiency. Substantial variability exists regarding the use of IS minimization among centers.

Effectiveness, safety and clinical outcomes of direct-acting antiviral therapy in HCV genotype 1 infection: Results from a Spanish real-world cohort.

BACKGROUND & AIMS: Clinical trials evaluating second-generation direct-acting antiviral agents (DAAs) have shown excellent rates of sustained virologic response (SVR) and good safety profiles in patients with chronic hepatitis C virus (HCV) genotype 1 infection. We aimed to investigate the effectiveness and safety of two oral DAA combination regimens, ombitasvir/paritaprevir/ritonavir plus dasabuvir (OMV/PTV/r+DSV) and ledipasvir/sofosbuvir (LDV/SOF), in a real-world clinical practice. METHODS: Data from HCV genotype 1 patients treated with either OMV/PTV/r+DSV±ribavirin (RBV) (n=1567) or LDV/SOF±RBV (n=1758) in 35 centers across Spain between April 1, 2015 and February 28, 2016 were recorded in a large national database. Demographic, clinical and virological data were analyzed. Details of serious adverse events (SAEs) were recorded. RESULTS: The two cohorts were not matched with respect to baseline characteristics and could not be compared directly. The SVR12 rate was 96.8% with OMV/PTVr/DSV±RBV and 95.8% with LDV/SOF±RBV. No significant differences were observed in SVR according to HCV subgenotype (p=0.321 [OMV/PTV/r+DSV±RBV] and p=0.174 [LDV/SOF]) or degree of fibrosis (c0.548 [OMV/PTV/r/DSV±RBV] and p=0.085 [LDV/SOF]). Only baseline albumin level was significantly associated with failure to achieve SVR (p<0.05) on multivariate analysis. Rates of SAEs and SAE-associated treatment discontinuation were 5.4% and 1.7%, in the OMV/PTV/r+DSV subcohort and 5.5% and 1.5% in the LDV/SOF subcohort, respectively. Hepatocellular carcinoma (HCC) recurred in 30% of patients with a complete response to therapy for previous HCC. Incident HCC was reported in 0.93%. CONCLUSIONS: In this large cohort of patients managed in the real-world setting in Spain, OMV/PTV/r+DSV and LDV/SOF achieved high rates of SVR12, comparable to those observed in randomized controlled trials, with similarly good safety profiles. LAY SUMMARY: In clinical trials, second-generation direct-acting antiviral agents (DAAs) have been shown to cure over 90% of patients chronically infected with the genotype 1 hepatitis C virus and have been better tolerated than previous treatment regimens. However, patients enrolled in clinical trials do not reflect the real patient population encountered in routine practice. The current study, which includes almost 4,000 patients, demonstrates comparable rates of cure with two increasingly used DAA combinations as those observed in the clinical trial environment, confirming that clinical trial findings with DAAs translate into the real-world setting, where patient populations are more diverse and complex.