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AIMS: Visceral adipose tissue inflammation is a fundamental mechanism of insulin resistance in obesity and type 2 diabetes. Translocation of intestinal bacteria has been suggested as a driving factor for the inflammation. However, although bacterial DNA was detected in visceral adipose tissue of humans with obesity, it is unclear to what extent this is contamination or whether the gut microbiota is causally involved. Effects of fecal microbiota transplantation (FMT) on bacterial translocation and visceral adipose tissue inflammation in individuals with obesity and insulin resistance were assessed. MATERIAL AND METHODS: Eight individuals with clinically severe obesity (body mass index [BMI] >35 kg/m2) and metabolic syndrome received lean donor FMT 4 weeks prior to elective bariatric surgery. The participants were age-, sex-, and BMI-matched to 16 controls that underwent no fecal transplantation. Visceral adipose tissue was collected during surgery. Bacterial translocation was assessed by 16S rRNA gene sequencing of adipose tissue and feces. Pro-inflammatory cytokine expression and histopathological analyses of visceral adipose tissue were performed to assess inflammation. RESULTS: Fecal microbiota transplantation significantly altered gut microbiota composition. Visceral adipose tissue contained a very low quantity of bacterial DNA in both groups. No difference in visceral bacterial DNA content between groups was observed. Also, visceral expression of pro-inflammatory cytokines and macrophage infiltration did not differ between groups. No correlation between inflammatory tone and bacterial translocation was observed. CONCLUSIONS: Visceral bacterial DNA content and level of inflammation were not altered upon FMT. Thus, bacterial translocation may not be the main driver of visceral adipose tissue inflammation in obesity.
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BACKGROUND: Rapid weight loss is a major risk factor for the formation of cholesterol gallstones. Consequently, patients with morbid obesity undergoing bariatric surgery frequently develop symptomatic gallstone disease. This trial assessed the efficacy of ursodeoxycholic acid versus placebo for the prevention of symptomatic gallstone disease after bariatric surgery. METHODS: This multicentre, double-blind, randomised, placebo-controlled superiority trial enrolled patients with an intact gallbladder scheduled for laparoscopic Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy in three hospitals in the Netherlands. Patients were randomly assigned (1:1) by a web-based randomisation module to receive 900 mg ursodeoxycholic acid daily for 6 months or matched placebo. Randomisation was stratified by the presence of asymptomatic gallstones at baseline and type of surgery. Patients, clinicians, and study staff were masked to treatment allocation. The primary endpoint was symptomatic gallstone disease within 24 months, assessed in the modified intention-to-treat population (all randomly assigned eligible patients with any post-randomisation measurement). Prespecified subgroup analyses were done based on the stratification groups. Safety was assessed in all patients who took at least one dose of the study drug. This trial is registered with the Netherlands Trial Register, NL5954. FINDINGS: Between Jan 11, 2017, and Oct 22, 2018, 985 patients were randomly assigned to receive either ursodeoxycholic acid (n=492) or placebo (n=493). 967 patients were included in the modified intention-to-treat population, of whom 959 had data available for primary endpoint assessment. 189 (20%) patients had asymptomatic gallstones at baseline and 78 (8%) received a sleeve gastrectomy. Symptomatic gallstone disease occurred in 31 (6·5%) of 475 patients in the ursodeoxycholic acid group and in 47 (9·7%) of 484 patients in the placebo group (relative risk 0·67, 95% CI 0·43-1·04, p=0·071). Logistic regression showed a significant interaction between ursodeoxycholic acid and the presence of asymptomatic gallstones at baseline (p=0·046), with an effect of ursodeoxycholic acid in patients without (0·47, 0·27-0·84, p=0·0081), and no effect in patients with asymptomatic gallstones at baseline (1·22, 0·61-2·47, p=0·57). The effect was stronger in patients without gallstones at baseline undergoing RYGB (0·37, 0·20-0·71, p=0·0016), whereas the subgroup of patients undergoing sleeve gastrectomy was too small to draw clear conclusions. Adverse events were rare. In the ursodeoxycholic acid group, diarrhoea occurred in four (0·9%) of 444 patients and skin rash in two (0·5%) patients. In the placebo group, diarrhoea occurred in two (0·4%) of 453 patients and skin rash in two (0·4%) patients. The total number of serious adverse events did not significantly differ between the trial groups (75 [17%] in 444 patients in the ursodeoxycholic acid group and 102 [23%] in 453 patients in the placebo group). The most common serious adverse events were abdominal pain and internal hernia. No serious adverse event was attributed to the study drug. INTERPRETATION: Ursodeoxycholic acid prophylaxis did not significantly reduce the occurrence of symptomatic gallstone disease in all patients after bariatric surgery. In patients without gallstones before RYGB surgery, ursodeoxycholic acid treatment reduced the occurrence of symptomatic gallstone disease compared with placebo. Further research is needed to assess the efficacy of ursodeoxycholic acid after sleeve gastrectomy. FUNDING: The Netherlands Organization for Health Research and Development, Zambon Netherlands BV, Foundation for Clinical Research of the Slotervaart Hospital, the Spaarne Gasthuis Academy, and Amsterdam Gastroenterology Endocrinology Metabolism.
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Colagogos y Coleréticos/uso terapéutico , Colelitiasis/prevención & control , Complicaciones Posoperatorias/prevención & control , Ácido Ursodesoxicólico/uso terapéutico , Adulto , Cirugía Bariátrica/efectos adversos , Estudios de Casos y Controles , Colagogos y Coleréticos/administración & dosificación , Colagogos y Coleréticos/efectos adversos , Colelitiasis/epidemiología , Colelitiasis/etiología , Método Doble Ciego , Femenino , Gastrectomía/efectos adversos , Derivación Gástrica/efectos adversos , Humanos , Laparoscopía/métodos , Masculino , Persona de Mediana Edad , Países Bajos/epidemiología , Obesidad Mórbida/complicaciones , Obesidad Mórbida/epidemiología , Obesidad Mórbida/cirugía , Evaluación de Resultado en la Atención de Salud , Placebos/administración & dosificación , Seguridad , Resultado del Tratamiento , Ácido Ursodesoxicólico/administración & dosificación , Ácido Ursodesoxicólico/efectos adversosRESUMEN
BACKGROUND: After laparoscopic Roux-en-Y gastric bypass many patients present with complaints for which an upper endoscopy is performed. However, often no abnormalities are found. OBJECTIVES: To investigate the incidence of relevant findings at upper endoscopy and identify patient characteristics associated with a relevant finding. SETTING: A high-volume bariatric center. METHODS: A retrospective cohort study was performed. All patients presenting with complaints after laparoscopic Roux-en-Y gastric bypass who consequently underwent a diagnostic upper endoscopy were identified from a prospective endoscopic database. Primary outcomes were the number and type of relevant findings at upper endoscopy and its association with patient characteristics. Relevant findings were defined as abnormalities requiring treatment. RESULTS: Ninety-eight (39.2%) of 250 patients had a relevant finding at upper endoscopy, mostly marginal ulcer and stomal stenosis. Male sex (odds ratio [OR] 3.47 [1.12-10.76]), alcohol consumption (OR 7.27 [1.58-33.36]), dysphagia or suspicion of bleeding as referral reason (OR 3.62 [1.54-8.52] and 39.93 [4.96-321.47], respectively, compared with abdominal pain), an abnormal upper gastrointestinal series (OR 6.81 [2.06-22.48]), and no abdominal ultrasound (OR 7.41 [1.48-37.08] compared with a normal ultrasound) were significantly associated with a relevant finding at upper endoscopy. CONCLUSIONS: In this study sex, alcohol consumption, referral reason, and prior imaging studies were associated with a relevant finding at upper endoscopy after laparoscopic Roux-en-Y gastric bypass.
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Derivación Gástrica , Laparoscopía , Obesidad Mórbida , Derivación Gástrica/efectos adversos , Gastroscopía , Humanos , Masculino , Obesidad Mórbida/cirugía , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
BACKGROUND AND AIM: In the phase 3 CONCUR trial (NCT01584830), regorafenib improved overall survival (OS) versus placebo in Asian patients with treatment-refractory metastatic colorectal cancer (mCRC). We conducted a post hoc subgroup analysis of Chinese patients in CONCUR. METHODS: Adults with mCRC progressing despite at least two prior treatment regimens and Eastern Cooperative Oncology Group performance status 0-1 were randomized 2:1 to regorafenib 160 mg once daily or placebo for the first 3 weeks of each 4-week cycle. Dose modifications were permitted. The primary endpoint was OS. Secondary endpoints included progression-free survival, objective overall response, disease control rate, and safety. RESULTS: A total of 172 Chinese patients were randomized and treated (regorafenib n = 112, placebo n = 60). OS was significantly improved with regorafenib versus placebo (8.4 vs 6.2 months, respectively; hazard ratio [HR] 0.56, 95% CI 0.39-0.80; one-sided P = 0.000632), as was progression-free survival (HR 0.32, 95% CI 0.22-0.47; one-sided P < 0.000001). The most common drug-related grade ≥ 3 treatment-emergent adverse events (TEAEs; regorafenib, placebo) were hand-foot skin reaction (19%, 0%), hypertension (13%, 3%), hypophosphatemia (7%, 0%), increased alanine aminotransferase (6%, 0%), and increased aspartate aminotransferase (5%, 0%). In patients receiving regorafenib and placebo, respectively, TEAEs led to treatment discontinuation in 14% and 7%, dose reduction in 39% and 0%, and dose interruption in 64% and 20%. CONCLUSIONS: This retrospective analysis showed that regorafenib provided an OS benefit over placebo for Chinese patients with previously treated mCRC. TEAEs were consistent with the regorafenib safety profile and manageable with treatment modifications.
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Ensayos Clínicos Fase III como Asunto , Neoplasias Colorrectales/tratamiento farmacológico , Compuestos de Fenilurea/administración & dosificación , Piridinas/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Pueblo Asiatico , Neoplasias Colorrectales/mortalidad , Supervivencia sin Enfermedad , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Compuestos de Fenilurea/efectos adversos , Piridinas/efectos adversos , Estudios Retrospectivos , SeguridadRESUMEN
BACKGROUND: Roux-en-Y gastric bypass (RYGB) is an effective treatment for morbid obesity, but many patients have increased gastrointestinal symptoms. OBJECTIVES: To evaluate gastrointestinal symptoms and food intolerance before and after RYGB over time in a large cohort of morbidly obese patients. SETTING: A high-volume bariatric center of excellence. METHODS: A prospective cohort study was performed in patients who underwent RYGB between September 2014 and July 2015, with 2-year follow-up. Consecutive patients screened for bariatric surgery answered the Gastrointestinal Symptom Rating Scale (GSRS) and a food intolerance questionnaire before RYGB and 2 years after surgery. The prevalence of gastrointestinal symptoms before and after surgery and the association between patient characteristics and postoperative gastrointestinal symptoms were assessed. RESULTS: Follow-up was 86.2% (n = 168) for patients undergoing primary RYGB and 93.3% (n = 28) for revisional RYGB. The total mean GSRS score increased from 1.69 to 2.31 after surgery (P < .001), as did 13 of 16 of the individual scores. Preoperative GSRS score is associated with postoperative symptom severity (B = .343, P < .001). Food intolerance was present in 16.1% of patients before primary RYGB, increasing to 69.6% after surgery (P < .001). Patients who underwent revisional RYGB had a symptom severity and prevalence of food intolerance comparable with that among patients with primary RYGB, even though they had more symptoms before revisional surgery. CONCLUSIONS: Two years after surgery, patients who underwent primary RYGB have increased gastrointestinal symptoms and food intolerance compared with the preoperative state. It is important that clinicians are aware of this and inform patients before surgery.
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Intolerancia Alimentaria/epidemiología , Derivación Gástrica/efectos adversos , Enfermedades Gastrointestinales/epidemiología , Obesidad Mórbida/cirugía , Complicaciones Posoperatorias/epidemiología , Dolor Abdominal/epidemiología , Adulto , Femenino , Pirosis/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
BACKGROUND: It is essential to understand the mechanisms responsible for hepatocellular carcinoma (HCC) progression and chemoresistance in order to identify prognostic biomarkers as well as potential therapeutic avenues. Recent findings have shown that SLIT3 appears to function as a novel tumor suppressor gene in various types of cancers, yet its clinical correlation and role in HCC has not been understood clearly. METHODS: We determined the transcript levels of Slit3 in tumor and adjacent normal tissues within two cohorts (N = 40 and 25) of HCC patients, and correlated the gene expression with the clinicopathological data. Subsequently, the functional effects and underlying molecular mechanisms of Slit3 overexpression and/or repression were studied using cell-line and mouse models. RESULTS: Our results demonstrated a repression in Slit3 expression in nearly 50% of the HCC patients, while the overall expression of Slit3 inversely correlated with the size of the tumor in both cohorts of patients. Stable down-regulation of Slit3 in HCC cell-lines induced cell proliferation in vitro and tumor growth in vivo, while stable Slit3 overexpression repressed these effects. Molecular investigations showed that the stable Slit3 repression-induced cell proliferation was associated with a higher expression of ß-catenin and a repressed GSK3ß activity. Moreover, Slit3-repression induced chemoresistance to sorafenib, oxaliplatin and 5-FU through impairment of ß-catenin degradation and induction of cyclin D3 and survivin levels. The effects induced by stable Slit3-repression were diminished by transient repression of ß-catenin by siRNA approach. CONCLUSION: This study suggests that Slit3 acts as a tumor suppressor in HCC by repressing the tumor growth and thus tumor progression. Low Slit3 level indicates a poor response of HCC cells to chemotherapy. Restoration or overexpression of Slit3 is a potential therapeutic approach to repress the tumor growth and enhance the efficacy of chemotherapeutic agents.
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Carcinoma Hepatocelular/patología , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Neoplasias Hepáticas/patología , Proteínas de la Membrana/metabolismo , beta Catenina/metabolismo , Adulto , Anciano , Animales , Línea Celular Tumoral , Proliferación Celular/fisiología , Resistencia a Antineoplásicos/fisiología , Femenino , Genes Supresores de Tumor/fisiología , Xenoinjertos , Humanos , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , Transducción de Señal/fisiologíaRESUMEN
BACKGROUND: Hepatocellular carcinoma (HCC) is highly prevalent in Hong Kong due to the high prevalence of chronic hepatitis B infection. Liver cancer is the fourth most common cancer and the third most common cause of cancer death. Due to the high case load, there is a high level of local expertise in treating HCC, and the full spectrum of treatment modalities is available. This document summarizes how these modalities should be used based on the latest evidence. SUMMARY: In 2 meetings held in early 2017, a multidisciplinary group of Hong Kong clinicians, including liver surgeons, interventional radiologists, clinical oncologists, and medical oncologists, met to update local consensus statements for management of HCC. These statements are based on the latest evidence and give detailed guidance on how to deploy these modalities, in particular for cases of HCC which are not suited to surgical resection. KEY MESSAGES: These statements give detailed information on how to decide if a patient is a candidate for resection, methods to improve candidacy for resection, and guidance for use of various nonsurgical interventions to manage patients ineligible for resection.
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BACKGROUND: Staple line leakage after bariatric surgery can be treated by endoscopic placement of a self-expandable stent. The success rate of stent placement is generally high, but migration is a frequent adverse event that hampers successful treatment. The Niti-S Beta stent is a fully covered double-bump stent that was specifically designed to prevent migration. This study aimed to evaluate the effectiveness and adverse event rate of the Niti-S Beta stent. METHODS: A retrospective study was performed in three high-volume bariatric centers. All consecutive patients between 2009 and 2016 who underwent placement of a Beta stent for staple line leakage were included. Primary outcome was resolution of the leakage; secondary outcome was the adverse event rate including migration. RESULTS: Thirty-eight patients were included. Twenty-five (66%) had resolution of the leakage. Success rate was higher in patients who were treated with implantation of a Beta stent as initial treatment (100%) than in patients who were treated with a stent after revisional surgery had failed (55%, p = 0.013). Migration occurred in 12 patients (32%). There were two severe adverse events requiring surgical intervention, including a bleeding from an aorto-esophageal fistula. CONCLUSIONS: The success rate and the migration rate of the Beta stent seem comparable to other stents in this retrospective study. Despite the novel double-bump structure of the stent, the migration rate does not seem to be decreased.
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Fuga Anastomótica/cirugía , Cirugía Bariátrica/efectos adversos , Materiales Biocompatibles Revestidos , Endoscopía , Stents Metálicos Autoexpandibles , Grapado Quirúrgico/efectos adversos , Fuga Anastomótica/etiología , Femenino , Migración de Cuerpo Extraño/complicaciones , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
BACKGROUND: The number of bariatric interventions for morbid obesity is increasing worldwide. Rapid weight loss is a major risk factor for gallstone development. Approximately 11 % of patients who underwent Roux-en-Y gastric bypass develop symptomatic gallstone disease. Gallstone disease can lead to severe complications and often requires hospitalization and surgery. Ursodeoxycholic acid (UDCA) prevents the formation of gallstones after bariatric surgery. However, randomized controlled trials with symptomatic gallstone disease as primary endpoint have not been conducted. Currently, major guidelines make no definite statement about postoperative UDCA prophylaxis and most bariatric centers do not prescribe UDCA. METHODS: A randomized, placebo-controlled, double-blind multicenter trial will be performed for which 980 patients will be included. The study population consists of consecutive patients scheduled to undergo Roux-en-Y gastric bypass or sleeve gastrectomy in three bariatric centers in the Netherlands. Patients will undergo a preoperative ultrasound and randomization will be stratified for pre-existing gallstones and for type of surgery. The intervention group will receive UDCA 900 mg once daily for six months. The placebo group will receive similar-looking placebo tablets. The primary endpoint is symptomatic gallstone disease after 24 months, defined as admission or hospital visit for symptomatic gallstone disease. Secondary endpoints consist of the development of gallstones on ultrasound at 24 months, number of cholecystectomies, side-effects of UDCA and quality of life. Furthermore, cost-effectiveness, cost-utility and budget impact analyses will be performed. DISCUSSION: The UPGRADE trial will answer the question whether UDCA reduces the incidence of symptomatic gallstone disease after Roux-en-Y gastric bypass or sleeve gastrectomy. Furthermore it will determine if treatment with UDCA is cost-effective. TRIAL REGISTRATION: Netherlands Trial Register (trialregister.nl) 6135 . Date registered: 21-Nov-2016.
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Colagogos y Coleréticos/uso terapéutico , Cálculos Biliares/prevención & control , Derivación Gástrica/efectos adversos , Complicaciones Posoperatorias/prevención & control , Ácido Ursodesoxicólico/uso terapéutico , Colagogos y Coleréticos/efectos adversos , Colagogos y Coleréticos/economía , Protocolos Clínicos , Análisis Costo-Beneficio , Método Doble Ciego , Estudios de Seguimiento , Cálculos Biliares/etiología , Humanos , Obesidad Mórbida/cirugía , Complicaciones Posoperatorias/etiología , Calidad de Vida , Ácido Ursodesoxicólico/efectos adversos , Ácido Ursodesoxicólico/economíaRESUMEN
BACKGROUND: Total pancreatectomy (TP) is offered as a last treatment option for pain relief in patients with chronic pancreatitis. Concurrent islets autotransplantation (TP-IAT) may improve glucose control. METHODS: We analyzed results in 20 recent patients who underwent TP-IAT at The University of Chicago. The median observation period was 28 months (2-38). Data were collected prospectively then analyzed retrospectively. RESULTS: The number of patients requiring opioids daily for pain control decreased from 16 (80%) prior to surgery to 2 (13%) 1 year after, with only 1 (6.5%) patient experiencing persistent phantom pancreatic pain. Opioid requirements decreased from a median 56.3 (0-240) morphine equivalent dose to 5 (0-130) on day 75 and to 0 (0-30) at 1-year follow up. Five patients (25%) completely stopped insulin support prior to day 75 while maintaining hemoglobin A1c of 5.9% (5-6.3). Eight (53%) patients were insulin free at 1 year with A1c of 6% (5.5-6.8) and a similar rate persisted in next 2 years. For the remaining patients, the more islet function that was preserved, the less insulin they required and A1c was closer to optimal. Quality of Life (QoL) measured by SF36 Physical (PCS) and Mental (MCS) Component Score improved on day 75 (P < .001) and maintained improvement later on. Both PCS and MCS improved regardless of whether patient requires insulin support or not. CONCLUSIONS: Improvements of QoL with pain resolution and good glucose control can be achieved after TP-IAT in properly selected patients with CP and intractable pain, regardless of patient insulin support status.
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Glucemia , Trasplante de Islotes Pancreáticos/métodos , Dolor Postoperatorio/epidemiología , Pancreatectomía/efectos adversos , Pancreatitis Crónica/cirugía , Calidad de Vida , Adulto , Femenino , Humanos , Trasplante de Islotes Pancreáticos/efectos adversos , Masculino , Persona de Mediana Edad , Manejo del Dolor , Pancreatectomía/métodos , Estudios Retrospectivos , Trasplante Autólogo , Resultado del TratamientoRESUMEN
BACKGROUND: BETA-2 score using a single fasting blood sample was developed to estimate beta-cell function after islet transplantation (ITx) and was validated internally by a high ITx volume center (Edmonton). The goal was to validate BETA-2 externally, in our center. METHODS: Areas under receiver operating characteristic curves (AUROCs) were obtained to see if beta score or BETA-2 would better detect insulin independence and glucose intolerance. RESULTS: We analyzed values from 48 mixed meal tolerance tests (MMTTs) in 4 ITx recipients with a long-term follow-up to 140 months (LT group) and from 54 MMTTs in 13 short-term group patients (ST group). AUROC for no need for insulin support was 0.776 (95% confidence interval [CI] 0.539-1, P = .02) and 0.922 (95% CI 0.848-0.996, P < .001) for beta score and 0.79 (95% CI 0.596-0.983, P = .003) and 0.941 (95% CI 0.86-1, P < .001) for BETA-2, in LT and ST groups, respectively, and did not differ significantly. In LT group BETA-2 score ≥ 13.03 predicted no need for insulin supplementation with sensitivity of 98%, specificity of 50%, positive predictive value (PPV) of 93%, and negative predictive value (NPV) of 75%. In ST group the optimal cutoff was ≥13.63 with sensitivity of 92% and specificity, PPV, and NPV 82% to 95%. For the detection of glucose intolerance BETA-2 cutoffs were <19.43 in LT group and <17.23 in ST group with sensitivity > 76% and specificity, PPV, and NPV > 80% in both groups. CONCLUSION: BETA-2 score was successfully validated externally and is a practical tool allowing for frequent and reliable assessments of islet graft function based on a single fasting blood sample.
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Glucemia/análisis , Péptido C/análisis , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Trasplante de Islotes Pancreáticos , Adulto , Área Bajo la Curva , Diabetes Mellitus Tipo 1/cirugía , Femenino , Hemoglobina Glucada/análisis , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Curva ROCRESUMEN
Purpose: This phase I/II single-arm study evaluated the safety, pharmacokinetics, pharmacodynamics, and activity of foretinib, an oral multikinase inhibitor of MET, ROS, RON, AXL, TIE-2, and VEGFR2, in the first-line setting in advanced hepatocellular carcinoma patients.Experimental Design: In the phase I part, advanced hepatocellular carcinoma patients were dose escalated on foretinib (30-60 mg) every day using the standard 3+3 design. Once the maximum tolerated dose (MTD) was determined, an additional 32 patients were dosed at the MTD in the phase II expansion cohort for assessment of efficacy and safety. Exploratory analyses were conducted to assess potential biomarkers that might correlate with clinical efficacy and survival.Results: The MTD of foretinib was established as 30 mg every day. The most frequent adverse events were hypertension, decreased appetite, ascites, and pyrexia. When dosed at 30 mg every day in the first-line setting, foretinib demonstrated promising antitumor activity. According to the modified mRECIST, the objective response rate was 22.9%, the disease stabilization rate 82.9%, and the median duration of response 7.6 months. The median time to progression was 4.2 months and the median overall survival (OS) was 15.7 months. Fifteen candidate biomarkers whose levels in the circulation were significantly altered in response to foretinib treatment were elucidated. Multivariate analyses identified IL6 and IL8 as independent predictors of OS.Conclusions: Foretinib demonstrated promising antitumor activity and good tolerability in the first-line setting in Asian advanced hepatocellular carcinoma patients. Baseline plasma levels of IL6 or IL8 might predict the response to foretinib. Clin Cancer Res; 23(10); 2405-13. ©2016 AACR.
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Anilidas/administración & dosificación , Carcinoma Hepatocelular/tratamiento farmacológico , Interleucina-6/sangre , Interleucina-8/sangre , Neoplasias Hepáticas/tratamiento farmacológico , Quinolinas/administración & dosificación , Adulto , Anciano , Anilidas/farmacocinética , Biomarcadores Farmacológicos/sangre , Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/patología , Femenino , Humanos , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/patología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Quinolinas/farmacocinética , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Receptor TIE-2/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Tirosina Quinasa del Receptor AxlRESUMEN
We study experimentally the dynamics of granular media in a discharging hopper. In such flows, there often appears to be a critical outlet size D_{c} such that the flow never clogs for D>D_{c}. We report on the time-averaged velocity distributions, as well as temporal intermittency in the ensemble-averaged velocity of grains in a viewing window, for both D
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The programmed cell death protein 1 (PD1) is one of the checkpoints that regulates the immune response. Ligation of PD1 with its ligands PDL1 and PDL2 results in transduction of negative signals to T-cells. PD1 expression is an important mechanism contributing to the exhausted effector T-cell phenotype. The expression of PD1 on effector T-cells and PDL1 on neoplastic cells enables tumor cells to evade anti-tumor immunity. Blockade of PD1 is an important immunotherapeutic strategy for cancers. Pembrolizumab (Keytruda) is a humanized monoclonal anti-PD1 antibody that has been extensively investigated in numerous malignancies. In melanoma refractory to targeted therapy, pembrolizumab induced overall response rates (ORRs) of 21-34%. It was superior to another immune checkpoint inhibitor ipilimumab (Yervoy) in stage III/IV unresectable melanoma. In refractory non-small cell lung cancer (NSCLC), pembrolizumab induced ORRs of 19-25%. Based on these results, pembrolizumab was approved by the USA FDA for the treatment of advanced melanoma and NSCLC. Tumor cell PDL1 expression may be a valid response predictor. Molecular analysis also showed that tumors with high gene mutation burdens, which might result in the formation of more tumor-related neo-antigens, had better responses to pembrolizumab. In malignancies including lymphomas and other solid tumors, preliminary data showed that ORRs of around 20-50 % could be achieved. Adverse events occurred in up to 60% of patients, but grade 3/4 toxicities were observed in <10% of cases. Immune-related adverse events including thyroid dysfunction, hepatitis and pneumonitis are more serious and may lead to cessation of treatment.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos/efectos adversos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Humanos , Resultado del Tratamiento , Estados UnidosRESUMEN
BACKGROUND: Roux-en-Y gastric bypass (RYGB) causes several alterations in gastrointestinal function. We hypothesized that levels of three commonly used fecal tests change after RYGB. METHODS: Fecal levels of calprotectin, elastase, and alpha-1-antitrypsin were determined in 122 patients without signs of gastrointestinal disease 1 to 2 years after RYGB. Medians, distribution of values, and the percentage of patients with levels above or below reference values were determined. RESULTS: Median fecal calprotectin level was 163.5 (<30-1587) µg/g; in 87 % of patients, it was above the reference value (<50 µg/g). Median fecal elastase level was 444 (<15-647) µg/g; 13 % was below the reference value (>200 µg/g). Median fecal alpha-1-antitrypsin level was 0.51 (<0.20-2.20) mg/g, comparable to the reference values. CONCLUSIONS: Fecal calprotectin levels are significantly higher than the reference value in most patients after RYGB. Fecal elastase is significantly lower. This might indicate that the validity of fecal calprotectin testing is impaired after RYGB and the specificity for fecal elastase is decreased. Clinical awareness of altered fecal markers after RYGB is essential to prevent unnecessary diagnostic tests, such as colonoscopy. Fecal alpha-1-antitrypsin is not influenced by RYGB.
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Heces/química , Derivación Gástrica , Complejo de Antígeno L1 de Leucocito/análisis , Obesidad/cirugía , Elastasa Pancreática/análisis , alfa 1-Antitripsina/análisis , Adulto , Biomarcadores/análisis , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Obesidad/metabolismo , Adulto JovenRESUMEN
BACKGROUND: The Oncotype DX Breast Cancer Assay is validated to assess risk of distant recurrence and likelihood of chemotherapy (CT) benefit in estrogen receptor-positive ESBC in various populations. In Hong Kong, > 80% of breast cancers are early stage breast cancer (ESBC) and > 60% of these women receive CT. This prospective study measured changes in CT type and recommendations, as well as physician impression of assay impact in a homogenous Chinese population. METHODS: Consecutive patients with estrogen receptor-positive, T1-3 N0-1mi M0 ESBC were offered enrollment. After surgery, physicians discussed treatment options with patients, then ordered the assay, then reassessed treatment recommendation considering assay results. Changes in treatment recommendation, CT utilization, physician confidence, and physician rating of influence on their treatment recommendations were measured. RESULTS: A total of 146 evaluable patients received pre- and post-testing treatment recommendations. CT recommendations (including changes in intensity of CT) were changed for 34 of 146 patients (23.3%; 95% confidence interval, 16.7%-31.0%); change in intensity occurred in 7 of 146 (4.8%). There were 27 changes in treatment recommendations of adding or removing CT altogether (18.5% change; 95% confidence interval, 12.6%-25.8%). CT recommendations decreased from 52.1% to 37.7%, a net absolute reduction of 14.4% (P < .001; 27.6% net relative reduction). Pre-assay, 96% of physicians agreed/strongly agreed that they were confident in their treatment recommendation; post-assay, 90% of physicians agreed/strongly agreed with the same statement. Thirty percent of physicians agreed/strongly agreed that the test had influenced their recommendation, similar to the proportion of changed recommendations. CONCLUSIONS: The Oncotype DX Assay appears to influence physician ESBC adjuvant treatment recommendations in Hong Kong.
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Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Toma de Decisiones Clínicas/métodos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Adulto , Anciano , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Quimioterapia Adyuvante/estadística & datos numéricos , Femenino , Perfilación de la Expresión Génica/métodos , Hong Kong , Humanos , Metástasis Linfática , Persona de Mediana Edad , Estadificación de Neoplasias , Estudios Prospectivos , Receptores de Estrógenos/metabolismo , Medición de Riesgo/métodos , Encuestas y Cuestionarios , Resultado del TratamientoRESUMEN
Proton pump inhibitor (PPI)-induced hypomagnesemia is currently a major topic. Patients undergoing Roux-en-Y gastric bypass are generally prescribed PPI prophylaxis after surgery. We investigated the prevalence of hypomagnesemia in our bariatric population. We reviewed the files of 1000 postoperative patients for serum magnesium level during PPI use. We found only five cases of hypomagnesemia, none of which was evidently related to PPI use. We conclude that the risk of hypomagnesemia during 1 year of prophylactic PPI use after Roux-en-Y gastric bypass (RYGB) is minimal and laboratory screening is probably not necessary.
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Derivación Gástrica/efectos adversos , Magnesio/sangre , Obesidad Mórbida/cirugía , Inhibidores de la Bomba de Protones/efectos adversos , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Obesidad Mórbida/sangre , Inhibidores de la Bomba de Protones/uso terapéuticoRESUMEN
BACKGROUND: Common mental disorders (CMD) are among the most significant contributors to disability worldwide. Patient-reported disability outcomes should be included as a key metric in the comparative assessment of value across global mental health interventions. This study aims to evaluate the validity of a widely used, cross-cultural tool - the 12-item World Health Organization Disability Assessment Schedule II (WHODAS) - as a functional outcome measure for CMD treatment. METHODS: The study population includes 1024 participants with CMD enrolled in the MANAS trial in India. CMD was assessed using the Revised Clinical Interview Schedule (CIS-R). Disability was assessed using the 12-item WHODAS II plus a measure of disability days. This analysis presents the correlations between these disability items and CMD symptom severity at 2 months after enrollment (convergent validity) and the items' associations with CMD recovery 4 months later (external responsiveness). RESULTS: All items showed a positive correlation of disability with CMD symptom severity (p < 0.001). The WHODAS items of 'standing,' 'household responsibilities,' and 'emotional disturbance' explained the most variance in CMD symptom severity. Improvements in 'disability days,' 'emotional disturbance,' 'standing,' 'household responsibilities,' 'day-to-day work,' and 'concentrating' were significantly associated with CMD recovery over follow-up. CONCLUSIONS: Further research is recommended on a CMD-specific WHODAS subscale comprised of the six WHODAS items found to be most strongly associated with CMD severity and recovery. This shorter, CMD-specific disability subscale would critically serve as a common metric to compare intervention impact on patient-centered outcomes and, in turn, to allocate global mental health resources efficiently.
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BACKGROUND: This study investigates whether there has been any survival improvement for hepatocellular carcinoma patients with resectable and unresectable lung metastases over time. METHODS: The data of 280 hepatocellular carcinoma patients who developed metachronous lung metastases after hepatectomy with curative intent were analysed. Overall survival was compared in patients with resectable and unresectable lung metastases and in different periods (Era I: 1989-1995, Era II: 1996-2010). RESULTS: The median overall survival of patients with unresectable and resectable diseases was 7.46 and 40.36 months, respectively (P < 0.0001). In Era I, the median overall survival of patients with unresectable and resectable diseases was 5.59 and 43.15 months, respectively (P < 0.0001). The corresponding figures in Era II were 8.38 and 32.90 months (P < 0.0001). The overall survival of patients with resectable disease did not differ significantly in the two eras but there was a significant improvement in survival of patients with unresectable disease in Era II. Their 1-year, 3-year and 5-year survival rates in Era I versus Era II were 11.1% versus 38.4%, 5.6% versus 9.1% and 2.8% versus 3.5%, respectively (P = 0.041). The corresponding figures for their counterparts in the resectable group were 90% versus 85.8%, 80% versus 45.9% and 40% versus 29.5%, respectively (P = 0.443). CONCLUSIONS: Patients with resectable lung metastases had better overall survival than those with unresectable lung metastases. Notably, patients with unresectable lung metastases had significant improvement in survival over the years.
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Carcinoma Hepatocelular/cirugía , Neoplasias Hepáticas/cirugía , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/cirugía , Neoplasias Primarias Secundarias/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Manejo de la Enfermedad , Femenino , Humanos , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Neoplasias Primarias Secundarias/mortalidad , Neoplasias Primarias Secundarias/terapia , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: In the international randomised phase 3 CORRECT trial (NCT01103323), regorafenib significantly improved overall survival versus placebo in patients with treatment-refractory metastatic colorectal cancer. Of the 760 patients in CORRECT, 111 were Asian (mostly Japanese). This phase 3 trial was done to assess regorafenib in a broader population of Asian patients with refractory metastatic colorectal cancer than was studied in CORRECT. METHODS: In this randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial done in 25 hospitals in mainland China, Hong Kong, South Korea, Taiwan, and Vietnam, we recruited Asian patients aged 18 years or older with progressive metastatic colorectal cancer who had received at least two previous treatment lines or were unable to tolerate standard treatments. Patients had to have an Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 3 months, and adequate bone marrow, liver, and renal function, without other uncontrolled medical disorders. We randomly allocated patients (2:1; with a computer-generated unicentric randomisation list [prepared by the study funder] and interactive voice response system; block size of six; stratified by metastatic site [single vs multiple organs] and time from diagnosis of metastatic disease [<18 months vs ≥18 months]) to receive oral regorafenib 160 mg once daily or placebo on days 1-21 of each 28 day cycle; patients in both groups were also to receive best supportive care. Participants, investigators, and the study funder were masked to treatment assignment. The primary endpoint was overall survival, and we analysed data on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01584830. FINDINGS: Between April 29, 2012, and Feb 6, 2013, we screened 243 patients and randomly assigned 204 patients to receive either regorafenib (136 [67%]) or placebo (68 [33%]). After a median follow-up of 7·4 months (IQR 4·3-12·2), overall survival was significantly better with regorafenib than it was with placebo (hazard ratio 0·55, 95% CI 0·40-0·77, one-sided p=0·00016; median overall survival 8·8 months [95% CI 7·3-9·8] in the regorafenib group vs 6·3 months [4·8-7·6] in the placebo group). Drug-related adverse events occurred in 132 (97%) of 136 regorafenib recipients and 31 (46%) of 68 placebo recipients. The most frequent grade 3 or higher regorafenib-related adverse events were hand-foot skin reaction (22 [16%] of 136 patients in the regorafenib group vs none in the placebo group), hypertension (15 [11%] vs two [3%] of 68 patients in the placebo group), hyperbilirubinaemia (nine [7%] vs one [1%]), hypophosphataemia (nine [7%] vs none), alanine aminotransferase concentration increases (nine [7%] vs none), aspartate aminotransferase concentration increases (eight [6%] vs none), lipase concentration increases (six [4%] vs one [1%]), and maculopapular rash (six [4%] vs none). Drug-related serious adverse events occurred in 12 (9%) patients in the regorafenib group and three (4%) in the placebo group. INTERPRETATION: This phase 3 trial is the second to show an overall survival benefit with regorafenib compared with placebo in patients with treatment-refractory metastatic colorectal cancer, substantiating the role of regorafenib as an important treatment option for patients whose disease has progressed after standard treatments. In this trial, preceding standard treatments did not necessarily include targeted treatments. Adverse events were generally consistent with the known safety profile of regorafenib in this setting. FUNDING: Bayer HealthCare Pharmaceuticals.