Impact of age at diagnosis on long-term prognosis in patients with intestinal Behçet's disease.

BACKGROUND AND AIM: Although age at disease onset is considered to be a significant factor in the prognosis of Crohn's disease, little is known about its influence on the long-term prognosis of those with intestinal Behçet's disease (BD). This study aimed to evaluate the long-term clinical outcomes of patients with intestinal BD according to age of disease onset. METHODS: Patients diagnosed with intestinal BD at < 18, 18-60, and > 60 years of age were classified into early-onset, adult-onset, and late-onset groups, respectively. The influence of disease onset time on clinical prognosis, including specific medical requirements, BD-related intestinal surgery, hospitalization, and emergency room visits, was compared using the log-rank test in a large cohort of patients with intestinal BD. RESULTS: Among 780 patients, 21 (2.7%), 672 (86.2%), and 87 (11.1%) comprised the early-onset, adult-onset, and late-onset groups, respectively. Patients in the early-onset group were more likely to require immunosuppressants than those in the adult-onset group (P = 0.048). Nine (42.9%), 158 (23.5%), and 18 (20.7%) patients in the early-onset, adult-onset, and late-onset groups, respectively, underwent intestinal resection. The early-onset group exhibited a higher risk for intestinal resection than the late-onset (P = 0.043) and adult-onset (P = 0.030) groups. The late-onset group exhibited a higher risk for BD-related hospitalization than the adult-onset group (P = 0.023). CONCLUSIONS: Age at diagnosis affected the clinical course of intestinal BD, including intestinal surgery, hospitalization, and specific medical requirements. Different treatment strategies should be established according to age at diagnosis.

Effectiveness and Tolerability of Methotrexate Combined with Biologics in Patients with Crohn's Disease: A Multicenter Observational Study.

BACKGROUND: Methotrexate (MTX) combination therapy with biological agents has gained increasing interest. Here, we assessed the efficacy and tolerability of the MTX combination therapy in patients with Crohn's disease (CD). METHODS: We performed a multicenter observational study with 185 patients with CD with MTX and biologics combination therapy; the patients were recruited from three IBD Clinics in Korea. We evaluated the outcomes of the MTX combination therapy and examined the predictive factors of clinical and endoscopic remission. RESULTS: MTX was administered orally to 62.7% of patients; the mean dose was 15.5 mg per week, and the mean treatment duration was 36 months. Of the 169 patients treated with MTX combination therapy for over 6 months, the steroid-free clinical remission rates were 34.3%, 26.0%, 29.8%, and 32.7% at 4, 12, 18, and 24 months, respectively. Previous thiopurine use was a significant negatively associated independent factor (p < 0.001), and a higher dose of MTX (≥ 15 mg/week) was a positively associated independent factor of steroid-free clinical remission (p = 0.035). Ninety-six patients underwent follow-up endoscopy after 28 months, and 36 (37.5%) achieved endoscopic remission. Longer disease duration (p = 0.006), ileocolonic type of Montreal location (p = 0.036), and baseline C-reactive protein (CRP) level of more than 5 mg/L (p = 0.035) were significant negatively associated independent factors and a higher dose of MTX (≥ 15 mg/week) was a positively associated independent factor of endoscopic remission (p = 0.037). CONCLUSIONS: MTX combination therapy with biologics was effective and tolerable in patients with CD.

Risk factors for post-polypectomy bleeding in patients with end-stage renal disease undergoing colonoscopic polypectomy.

BACKGROUND AND AIMS: Little is known about the risk factors of bleeding after colonoscopic polypectomy in patients with end-stage renal disease (ESRD). This study investigated the incidence and risk factors of post-polypectomy bleeding (PPB), including immediate and delayed bleeding, in patients with ESRD. METHODS: Ninety-two patients with ESRD who underwent colonoscopic polypectomy between September 2005 and June 2020 at a single tertiary referral center were included. The patients' medical records were retrospectively reviewed. Patient- and polyp-related factors associated with immediate PPB (IPPB) were analyzed using logistic regression analysis. Additionally, the optimal cutoff polyp size related to a significant increase in the risk of IPPB was determined by performing receiver operating characteristic (ROC) analysis and calculating the area under the ROC curve (AUC). RESULTS: In total, 286 polyps were removed. IPPB occurred in 24 (26.1%) patients and 46 (16.1%) polyps and delayed PPB occurred in 2 (2.2%) patients. According to multivariate analysis, the polyp size (> 7 mm), old age (> 70), and endoscopic mucosal resection (EMR) as the polypectomy method (EMR versus non-EMR) were found to be independent risk factors for IPPB. According to the Youden index method, the optimal cutoff polyp size to identify high-risk polyps for IPPB was 7 mm (AUC = 0.755; sensitivity, 76.1%; specificity, 69.6%). CONCLUSIONS: Colonoscopic polypectomy should be performed with caution in patients with ESRD, especially in those with the following risk factors: advanced age (> 70 years), polyp size > 7 mm, and EMR as the polypectomy method.

Long-term clinical outcomes of intestinal Behçet's disease: A 30-year cohort study at a tertiary hospital in South Korea.

BACKGROUND AND AIM: We aimed to identify the long-term clinical outcomes of and prognostic factors for intestinal Behçet's disease (BD). METHODS: A cohort of 780 patients with intestinal BD between 1997 and 2021 was investigated to determine long-term clinical outcomes and prognostic factors at an inflammatory bowel disease clinic at Severance Hospital, Seoul, Korea. RESULTS: During the median follow-up period of 12.7 ± 7.2 years, 5-aminosalicylic acids, corticosteroids, immunomodulators, and anti-tumor necrosis factor-alpha (TNF-α) agents were required in 94.9%, 67.2%, 43.8%, and 14.6% of the patients, respectively. The cumulative rates of anti-TNF-α use were 3.7%, 7.5%, 8.5%, 12.1%, 17.6%, and 24.0%, and those for abdominal surgery were 5.7%, 10.9%, 12.6%, 16.5%, 21.6%, and 28.3%, at 1, 3, 5, 10, 20, and 30 years, respectively, after initial diagnosis of intestinal BD. The cumulative rates of hospitalization were 11.8%, 21.9%, 27.9%, 38.8%, 54.4%, and 74.8%, and those of emergency room visits were 10.0%, 19.8%, 22.7%, 31.6%, 50.0%, and 65.0% at 1, 3, 5, 10, 20, and 30 years. Older age at primary diagnosis, previous appendectomy history, higher disease activity index for intestinal Behçet's disease score, systemic BD, multiple intestinal ulcers, deep intestinal ulcers, higher C-reactive protein, lower hemoglobin, and lower albumin levels were associated with poor prognosis. Married status, higher body mass index, oral ulceration, and arthritis were negatively associated with poor prognosis. CONCLUSIONS: Data on the long-term clinical outcomes of intestinal BD and their prognostic factors could guide physicians in patient monitoring and in optimizing individualized treatment.

The Impact of Head Elevation on Prevalence and Severity of Emergence Cough in Male Patients during Endotracheal Extubation.

BACKGROUND Emergence cough during endotracheal extubation can lead to complications. This cough is triggered by the deviation of the endotracheal tube from the airway anatomy, causing pressure on the airway mucosal wall. Head elevation has the potential to align the airway passage with the tube's configuration. In this study, we aimed to investigate the impact of head elevation using a pillow on the prevalence and severity of emergence cough in male patients. MATERIAL AND METHODS A total of 71 male patients undergoing laparoscopic cholecystectomy were randomly assigned to either the head elevation group (n=35) or the control group (n=36). The head elevation group maintained a position with a neck flexion angle of 35º using a pillow, while the control group remained in a neutral position after anesthetic induction. The severity of cough was assessed before, during, and after extubation using a 4-point scale, with grades 2 and 3 indicating cough and grade 3 indicating severe cough. RESULTS The characteristics and intraoperative data of the patients were similar between the two groups. There was no significant difference in the incidence of cough and severe cough between the groups. However, the severity of cough was significantly lower in the head elevation group compared to the control group before extubation (cough scale: 0/5/8/23 vs 1/2/17/15 in the control group vs the head elevation group, P=0.039). The time to extubation, respiratory complications, nausea, pain, and the number of patients receiving fentanyl were comparable between the groups. CONCLUSIONS Head elevation using a pillow effectively reduced the severity of cough before endotracheal extubation during anesthesia emergence in male patients. However, it did not significantly reduce the incidence of cough. These findings highlight the potential benefits of head elevation in minimizing the discomfort associated with emergence cough.

Application of Multigene Panel Testing in Patients With High Risk for Hereditary Colorectal Cancer: A Descriptive Report Focused on Genotype-Phenotype Correlation.

BACKGROUND: The genetic test solely based on the clinical features of hereditary colorectal cancer has limitations in clinical practice. OBJECTIVE: This study aimed to analyze the results of comprehensive multigene panel tests based on clinical findings. DESIGN: This was a cross-sectional study based on a prospectively compiled database. SETTING: The study was conducted at a tertiary hospital. PATIENTS: A total of 381 patients with high risk for hereditary colorectal cancer syndromes were enrolled between March 2014 and December 2019. MAIN OUTCOME MEASURES: The primary outcome was to describe the mutational spectrum based on genotype-phenotype concordance and discordance. RESULTS: Germline mutations were identified in 89 patients for polyposis hereditary colorectal cancer genes (76 in APC; 4 in PTEN; 4 in STK11; 3 in BMPR1A; 1 in POLE; 1 in POLD1), 89 patients for nonpolyposis hereditary colorectal cancer genes (41 in MLH1; 40 in MSH2; 6 in MSH6; and 2 in PMS2), and 12 patients for other cancer predisposition genes (1 in ATM; 2 in BRCA1; 1 in BRCA2; 1 in BRIP1; 1 in MLH3; 1 in NBN; 1 in PMS1; 1 in PTCH1; 1 in TP53; and 2 in monoallelic MUTYH). If we had used direct sequencing tests of 1 or 2 major genes based on phenotype, 48 (25.3%) of 190 mutations would not have been detected due to technical differences (12.1%), less frequent genotype (4.2%), unclear phenotype (3.7%), and genotype-phenotype discordance (4.7%). The genotype-phenotype discordance is probably linked to compound heterozygote, less distinctive phenotype, and insufficient information for colorectal cancer risk. LIMITATIONS: This study included a small number of patients with insufficient follow-up duration. CONCLUSIONS: A comprehensive multigene panel is expected to identify more genetic mutations than phenotype-based direct sequencing, with special utility for unclear phenotype or genotype-phenotype discordance. See Video Abstract at http://links.lww.com/DCR/B844. APLICACIN DE PRUEBAS DE PANEL MULTIGNICO EN PACIENTES CON ALTO RIESGO DE CNCER COLORRECTAL HEREDITARIO INFORME DESCRIPTIVO ENFOCADO EN LA CORRELACIN GENOTIPOFENOTIPO: ANTECEDENTES:La prueba genética basada únicamente en la característica clínica del cáncer colorrectal hereditario tiene limitaciones en la práctica clínica.OBJETIVO:Este estudio tuvo como objetivo analizar el resultado de pruebas integrales de panel multigénico basadas en hallazgos clínicos.DISEÑO:Este fue un estudio transversal basado en una base de datos recopilada prospectivamente.AJUSTE:El estudio se realizó en un hospital terciario.PACIENTES:Se inscribió un total de 381 pacientes con alto riesgo de síndromes de cáncer colorrectal hereditario entre marzo del 2014 y diciembre del 2019.PRINCIPALES MEDIDAS DE RESULTADO:El resultado principal fue describir el espectro mutacional basado en la concordancia y discordancia genotipo-fenotipo.RESULTADOS:Se identificaron mutaciones de la línea germinal en 89 pacientes para genes de cáncer colorrectal hereditario con poliposis (76 en APC; 4 en PTEN; 4 en STK11; 3 en BMPR1A; 1 en POLE; 1 en POLD1), 89 pacientes para genes de CCR hereditario sin poliposis (41 en MLH1; 40 en MSH2; 6 en MSH6; y 2 ​​en PMS2) y 12 pacientes por otro gen de predisposición al cáncer (1 en ATM; 2 en BRCA1; 1 en BRCA2; 1 en BRIP1; 1 en MLH3; 1 en NBN; 1 en PMS1; 1 en PTCH1; 1 en TP53; y 2 ​​en MUTYH monoalélico). Si hubiéramos utilizado pruebas de secuenciación directa de uno o dos genes principales basados ​​en el fenotipo, 48 (25,3%) de 190 mutaciones no se habrían detectado debido a diferencias técnicas (12,1%), genotipo menos frecuente (4,2%), fenotipo poco claro (3,7%) y discordancia genotipo-fenotipo (4,7%). La discordancia genotipo-fenotipo probablemente esté relacionada con el heterocigoto compuesto, el fenotipo menos distintivo y la información insuficiente para el riesgo de cáncer colorrectal.LIMITACIONES:Este estudio incluyó una pequeña cantidad de pacientes con una duración de seguimiento insuficiente.CONCLUSIONES:Se espera que un panel multigénico completo identifique más mutaciones genéticas que la secuenciación directa basada en el fenotipo, con especial utilidad para la discordancia de fenotipo o genotipo-fenotipo poco clara. Consulte Video Resumen en http://links.lww.com/DCR/B844. Traducción- Dr. Francisco M. Abarca-Rendon).

Comparative effectiveness of second-line biological therapies for ulcerative colitis and Crohn's disease in patients with prior failure of anti-tumour necrosis factor treatment.

BACKGROUND: Therapeutic options for inflammatory bowel disease (IBD) have increased since the introduction of tumour necrosis factor (TNF) inhibitors a few decades ago. However, direct comparisons of the effectiveness of second-line biological agents in patients with ulcerative colitis (UC) and Crohn's disease (CD) are lacking. METHODS: Patients with UC or CD who experienced anti-TNF treatment failure and subsequently used vedolizumab, ustekinumab, or tofacitinib as a second-line drug were retrospectively recruited. The primary outcomes were the clinical remission rate at week 16 and the cumulative relapse rate 48 weeks after receiving induction therapy. RESULTS: A total of 94 patients with UC or CD experienced anti-TNF treatment failure and received vedolizumab (UC: 37; CD: 28), ustekinumab (CD: 16), or tofacitinib (UC: 13). The clinical remission rates were not significantly different between the vedolizumab and tofacitinib groups in UC patients (56.8% vs. 46.2%, p = 0.509). In CD patients, the clinical remission rates were not significantly different between the vedolizumab and ustekinumab groups (53.6% vs. 50.0%, p = 0.820). Moreover, the cumulative rates of clinical relapse were not significantly different between the vedolizumab and tofacitinib groups in UC patients and between the vedolizumab and ustekinumab groups in CD patients (p = 0.396 and p = 0.692, respectively). Safety profiles were also similar among the treatment groups in both UC and CD patients. CONCLUSIONS: After prior anti-TNF therapy failure, vedolizumab and tofacitinib in UC patients and vedolizumab and ustekinumab in CD patients were not significantly different in terms of the efficacy in inducing and maintaining a clinical response.

IL-6 and IL-8, secreted by myofibroblasts in the tumor microenvironment, activate HES1 to expand the cancer stem cell population in early colorectal tumor.

Interaction between a tumor and its microenvironment is important for tumor initiation and progression. Cancer stem cells (CSCs) within the tumor interact with a microenvironmental niche that controls their maintenance and differentiation. We investigated the CSC-promoting effect of factors released from myofibroblasts into the microenvironment of early colorectal cancer tumors and its molecular mechanism. By messenger RNA microarray analysis, expression of HES1, a Notch signaling target, significantly increased in Caco-2 cells cocultured with 18Co cells (pericryptal myofibroblasts), compared to its expression in Caco-2 cells cultured alone. Caco-2 cells cultured in 18Co-conditioned media (CM) showed a significant increase in CD133+CD44+ cells and HES1 expression compared to that in Caco-2 cells cultured in regular media. Significant amounts of interleukin-6 (IL-6) and IL-8 were detected in 18Co-CM compared to levels in regular media. The 18Co-CM-induced increase in CD133+CD44+ cells was attenuated by IL-6- and IL-8-neutralizing antibodies. Furthermore, these neutralizing antibodies and inhibitors of STAT3 and gamma-secretase reduced the expression of HES1 induced in Caco-2 cells cultured in 18Co-CM. Immunohistochemical analysis of human tissues revealed that IL-6, IL-8, and HES1 expression increased from normal to adenoma, and from adenoma to cancer tissues. In addition, IL-6 and HES1 expression was positively correlated in early colorectal cancer tissues. In conclusion, the increase of CSCs by myofibroblasts could be mediated by IL-6/IL-8-induced HES1 activation in the tumor microenvironment. Based on these data, the IL-6/IL-8-mediated Notch/HES1 and STAT3 pathway, through which CSCs interact with their microenvironment, might be a potential target for the prevention and treatment of colorectal tumors.

Incidence and risk factors of micronutrient deficiency in patients with IBD and intestinal Behçet's disease: folate, vitamin B12, 25-OH-vitamin D, and ferritin.

BACKGROUND: Patients with inflammatory bowel disease (IBD) and intestinal Behçet's disease (BD) are vulnerable to micronutrient deficiencies due to diarrhea-related gastrointestinal loss and poor dietary intake caused by disease-related anorexia. However, few studies have investigated the incidence and risk factors for micronutrient deficiency. METHODS: We retrospectively analyzed 205 patients with IBD who underwent micronutrient examination, including folate, vitamin B12, 25-OH-vitamin D, and/or ferritin level quantification, with follow-up blood tests conducted 6 months later. RESULTS: Eighty patients (39.0%), who were deficient in any of the four micronutrients, were classified as the deficiency group, and the remaining 125 (61.0%) were classified as the non-deficient group. Compared to those in the non-deficiency group, patients in the deficiency group were much younger, had more Crohn's disease (CD) patients, more patients with a history of bowel operation, and significantly less 5-amino salicylic acid usage. Multivariate analysis revealed that CD and bowel operation were significant independent factors associated with micronutrient deficiency. CONCLUSIONS: The incidence of micronutrient deficiency was high (39.0%). Factors including CD, bowel operation, and younger ages were found to be associated with higher risks of deficiency. Therefore, patients with IBD, especially young patients with CD who have undergone bowel resection surgery, need more attention paid to micronutrition.

C-reactive protein is associated with postoperative outcomes in patients with intestinal Behçet's disease.

BACKGROUND: Patients with intestinal Behçet's disease (BD) frequently undergo intestinal resections, which significantly affects postoperative morbidity and mortality. The aim of this study was to identify the association between C-reactive protein (CRP) levels and postoperative outcomes in patients with intestinal BD who underwent surgical bowel resection. METHODS: Patients who were diagnosed with intestinal BD and underwent intestinal surgery due to BD at Severance Hospital between November 2005 and April 2018 were retrospectively investigated. Clinical relapse was defined as a disease activity index of BD (DAIBD) > 40, existence of newly added medications, re-hospitalization, or re-operation related to intestinal BD. The relationship between CRP level and postoperative outcomes was analyzed, and a receiver operating characteristic (ROC) curve was drawn to specify a cut-off value. RESULTS: Ninety patients with intestinal BD were included. Among them, 44 were male (48.9%), and the median age at diagnosis was 38 years (range, 11-69 years). The median total disease follow-up duration was 130 months (range, 3-460 months). Forty patients (44.4%) underwent laparoscopic surgery. A higher CRP level immediately after surgery was significantly associated with postoperative complications (OR 1.01, 95% CI 1.004-1.018, p < 0.01), re-operation (hazard ratio [HR] 1.01, 95% CI 1.005-1.020, p < 0.01), and re-admission (HR 1.01, 95% CI 1.006-1.017 p < 0.01). The ROC curve showed that CRP predicts the risk of postoperative complications (p < 0.01) at a cut-off value of 41.9% with a sensitivity of 60.0% and specificity of 67.7%. CONCLUSIONS: Postoperative CRP levels in patients with intestinal BD undergoing surgical resection were associated with postoperative outcomes.

The Anticancer Effect of Natural Plant Alkaloid Isoquinolines.

Isoquinoline alkaloids-enriched herbal plants have been used as traditional folk medicine for their anti-inflammatory, antimicrobial, and analgesic effects. They induce cell cycle arrest, apoptosis, and autophagy, leading to cell death. While the molecular mechanisms of these effects are not fully understood, it has been suggested that binding to nucleic acids or proteins, enzyme inhibition, and epigenetic modulation by isoquinoline alkaloids may play a role in the effects. This review discusses recent evidence on the molecular mechanisms by which the isoquinoline alkaloids can be a therapeutic target of cancer treatment.

Genotype-based Treatment With Thiopurine Reduces Incidence of Myelosuppression in Patients With Inflammatory Bowel Diseases.

BACKGROUND & AIMS: Thiopurine-related myelosuppression (most frequently leukopenia) interferes with thiopurine therapy for patients with inflammatory bowel diseases (IBD). We investigated whether pretreatment analyses genetic variants associated with thiopurine-induced leukopenia could be used to effectively identify patients who required dose adjustments. METHODS: We performed a multicenter, prospective study of patients with IBD at 5 tertiary medical centers in Korea, from January 2016 through September 2018. Seventy-two patients were randomly assigned to a group that underwent genotype analysis for the NUDT15 variant (rs116855232) and FTO variant (rs79206939) and 3 common TPMT variants (rs1800460, rs1800462, rs1142345) associated with myelosuppression and 92 patients were assigned to a group that did not undergo genotype analysis (non-genotyping group). Patients heterozygous for any variant received 50 mg azathioprine equivalents, whereas those who were homozygous for any variant received alternative drugs. Patients who did not carry any of the genetic variants and patients in the non-genotyping group received 50 mg azathioprine equivalents followed by dose escalation up to 2-2.5 mg/kg. Myelosuppression was defined as white blood cell counts below 3000/µL, levels of hemoglobin 10 g/dL, or platelet counts below 100 K/µL. RESULTS: Twelve patients (16.7%) in the genotype analysis group and 33 patients (35.9%) in the non-genotyping group developed myelosuppression (P=.005). A multivariate analysis revealed that body mass indices above 21 kg/m2 (hazard ratio [HR], 0.43; 95% CI, 0.22-0.81; P = .009), pretreatment genotype analysis (HR, 0.37; 95% CI, 0.18-0.77; P = .008), and the maximum dose of thiopurines (HR, 0.34; 95% CI, 0.19-0.59; P < .001) independently decreased risk of myelosuppression. Pretreatment genotype analysis reduced numbers of outpatient clinic visit and numbers of patients with drug discontinuation or dose reductions. CONCLUSIONS: In a randomized controlled study of patients undergoing thiopurine therapy for IBD, we found that selection of therapy based on genetic variants associated with thiopurine-induced leukopenia significantly reduced the proportion of patients with myelosuppression during treatment. ClinicalTrials.gov no: NCT03719118.

Survival Benefit for Metformin Through Better Tumor Response by Neoadjuvant Concurrent Chemoradiotherapy in Rectal Cancer.

BACKGROUND: Metformin may reduce cancer risk and mortality and improve radiotherapy responses in several malignancies. OBJECTIVE: This study aimed to compare tumor responses and prognoses of metformin and nonmetformin groups of diabetic patients receiving neoadjuvant concurrent chemoradiotherapy for rectal cancer. DESIGN: This is a retrospective study. SETTING: This study was conducted at a single institution in the Republic of Korea. PATIENTS: Between January 2000 and November 2017, 104 patients with rectal cancer who were taking diabetes medication and treated with neoadjuvant concurrent chemoradiotherapy followed by radical surgery were reviewed. Patients were divided into those taking (n = 62) and not taking metformin (n = 42). Tumor responses, survival, and other outcomes were analyzed. MAIN OUTCOME MEASURES: Tumor response, rectal cancer-specific survival, and disease-free survival rates were measured. RESULTS: Tumor regression grade (p = 0.002), pathological complete response (p = 0.037), and N downstaging (p < 0.001) after neoadjuvant concurrent chemoradiotherapy were significantly higher in the metformin group than in the nonmetformin group. In analysis of cancer-specific mortality, metformin use, differentiation (well, moderate vs poor), pathological Union for International Cancer Control stage (3 vs 1-2), ypN stage (1-2 vs 0), and N downstaging (HR, 0.256 (95% CI, 0.082-0.794), p = 0.018; HR, 0.147 (95% CI, 0.031-0.697), p = 0.016; HR, 3.693 (95% CI, 1.283-10.635), p = 0.015; HR, 3.181 (95% CI, 1.155-8.759), p = 0.025, and HR, 0.175 (95% CI, 0.040-0.769), p = 0.021) were significant factors related to mortality in diabetic patients with rectal cancer. In addition, in the multivariate analysis of cancer recurrence, the interaction between metformin use and lymph node downstaging was a significant predictive factor (HR, 0.222 (95% CI, 0.077-0.639); p = 0.005). LIMITATIONS: This was a small retrospective study conducted at a single institution. CONCLUSIONS: Metformin use was associated with better tumor responses and cancer-specific survival, as well as a lower risk of cancer recurrence, in patients with diabetes mellitus who had lymph node downstaging after neoadjuvant concurrent chemoradiotherapy in rectal cancer. See Video Abstract at http://links.lww.com/DCR/B185. BENEFICIO EN SUPERVIVENCIA CON METFORMINA A TRAVÉS DE UNA MEJOR RESPUESTA TUMORAL CON QUIMIORRADIOTERAPIA CONCURRENTE NEOADYUVANTE EN CÁNCER RECTAL: La metformina puede reducir el riesgo de cáncer y la mortalidad y mejorar las respuestas a la radioterapia en varios tumores malignos.Comparar las respuestas tumorales y los pronósticos de los grupos con metformina y sin metformina de pacientes diabéticos que reciben quimiorradioterapia concurrente neoadyuvante para cáncer de recto.Estudio retrospectivo.Institución única en la República de Corea.Se revisaron 104 pacientes entre enero de 2000 y noviembre de 2017, con cáncer rectal que tomaban medicamentos para diabetes y que fueron tratados con quimiorradioterapia concurrente neoadyuvante seguida de cirugía radical. Los pacientes se dividieron en aquellos que tomaban (n = 62) y los que no tomaban metformina (n = 42). Se analizaron las respuestas tumorales, la supervivencia y otros resultados.Se midieron las tasas de la respuesta tumoral, la supervivencia específica de cáncer rectal y de la supervivencia libre de enfermedad.El grado de regresión tumoral (p = 0.002), la remisión patológica completa (p = 0.037) y la reducción de la etapa N (p < 0.001) después de la quimiorradioterapia concurrente neoadyuvante fueron significativamente mayores en el grupo de metformina que en el grupo sin metformina. En el análisis de la mortalidad específica por cáncer, el uso de metformina, la diferenciación (bien, moderada vs pobre), el estadio patológico UICC (3 vs 1-2), el estadio ypN (1-2 vs 0) y la disminución de la etapa N (hazard ratios [intervalos de confianza 95%]: 0.256 [0.082-0.794], p = 0.018; 0.147 [0.031-0.697], p = 0.016; 3.693 [1.283-10.635], p = 0.015; 3.181 [1.155-8.759], p = 0.025 y 0.175 [0.040-0.769], p = 0.021, respectivamente) fueron factores significativos relacionados con la mortalidad en pacientes diabéticos con cáncer rectal. Adicionalmente, en el análisis multivariado de la recurrencia del cáncer, la interacción entre el uso de metformina y la disminución de la etapa ganglionar (N) fue un factor predictivo significativo (hazard ratios [intervalos de confianza del 95%]: 0.222 [0.077-0.639]; p = 0.005).Este fue un estudio retrospectivo pequeño realizado en un solo instituto.El uso de metformina se asoció con mejores respuestas tumorales y supervivencia específica de cáncer, así como un menor riesgo de recurrencia del cáncer, en pacientes con disminución de la etapa ganglionar (N) después de quimiorradioterapia concurrente neoadyuvante en pacientes con cáncer rectal y diabetes. Consulte Video Resumen en http://links.lww.com/DCR/B185. (Traducción-Dr. Jorge Silva Velazco).

High-Definition Chromoendoscopy Versus High-Definition White Light Colonoscopy for Neoplasia Surveillance in Ulcerative Colitis: A Randomized Controlled Trial.

OBJECTIVES: Although chromoendoscopy is currently the recommended mode of surveillance in patients with long-standing ulcerative colitis, it is technically challenging and requires a long procedure time. The aim of this study was to compare the dysplasia detection rate of high-definition white light endoscopy with random biopsy (HDWL-R) vs high-definition chromoendoscopy with targeted biopsy (HDCE-T). METHODS: This was a multicenter, prospective randomized controlled trial involving 9 tertiary teaching hospitals in South Korea. A total of 210 patients with long-standing ulcerative colitis were randomized to undergo either the HDWL-R group (n = 102) or HDCE-T group (n = 108). The detection rates of colitis-associated dysplasia (CAD) or all colorectal neoplasia from each trial arm were compared. RESULTS: There was no significant difference in the CAD detection rate between HDCE-T and HDWL-R groups (4/102, 3.9% vs 6/108, 5.6%, P = 0.749). However, HDCE-T showed a trend toward improved colorectal neoplasia detection compared with HDWL-R (21/102, 20.6% vs 13/108, 12.0%, P = 0.093). The median (range) time for colonoscopy withdrawal between the 2 groups was similar (17.6 [7.0-43.3] minutes vs 16.5 [6.3-38.1] minutes; P=0.212; for HDWL-R and HDCE-T, respectively). The total number of biopsies was significantly larger in the HDWL-R group (34 [12-72]) compared with the HDCE-T group (9 [1-20]; P < 0.001). DISCUSSION: On the basis of our prospective randomized controlled trial, HDCE-T was not superior to HDWL-R for detecting CADs.

Outcomes of stent insertion and mortality in obstructive stage IV colorectal cancer patients through 10 year duration.

BACKGROUND: Colorectal stents are frequently used in patients with stage IV colorectal cancer with obstruction. However, there are only few studies on changes in outcomes of these patients and on the effect of stents on outcome over a long period of time with ongoing changes in therapeutic strategy, including chemotherapy. METHODS: We retrospectively evaluated 353 patients with bowel obstruction in stage IV colorectal cancer who underwent colonic stenting between years 2005 and 2014. The study population was divided into three groups based on time periods: 2005-2008, 2009-2011, and 2012-2014. RESULTS: The frequency of colorectal stent insertion procedure increased over the time periods (13.8%, 18.3%, and 20.8%, respectively). There were no changes in success rate and total complication rate. However, the early complication rate in the 3rd period was significantly lower than in the other periods (15.4% vs. 17.1% vs. 7.2%; P = 0.039). In the multivariate analysis, carcinomatosis (hazard ratio, 1.478; 95% confidence interval, 1.016-2.149; P = 0.041) and covered or partial-covered stent (hazard ratio, 1.733; 95% confidence interval, 1.144-2.624; P = 0.009; hazard ratio, 1.988; 95% confidence interval, 1.132-3.493; P = 0.017, respectively) were associated with increased complication rate. Stent-related perforation was an independent risk factor related with increased mortality. Although survival duration increased over time (P = 0.042), the mortality rate was unchanged across the three time periods. CONCLUSIONS: Over 10 years, the targeted agent use and survival duration increased, and early complication rate was decreased, without change in late complication rate or mortality rate during the three time periods in patients with obstructive stage IV colorectal cancer and stent insertion.

Complications of percutaneous endoscopic and radiologic gastrostomy tube insertion: a KASID (Korean Association for the Study of Intestinal Diseases) study.

BACKGROUND: Gastrostomy tube insertion is beneficial to selected patients, and percutaneous endoscopic gastrostomy (PEG) and percutaneous radiological gastrostomy (PRG) are two of the frequently used methods in gastrostomy. This study aimed to investigate the indications and complications of both PEG and PRG. METHODS: This was a retrospective multicenter cohort study. Patients who underwent initial PEG or PRG tube insertion for nutritional purpose between January 2010 and December 2015 at five university hospitals were included in the study. We analyzed the indications and all complications related to gastrostomy, which were divided into the major (systemic or life-threatening) and minor (local and non-life-threatening) categories. RESULTS: A total of 418 patients who underwent PEG (n = 324) and PRG (n = 94) were reviewed. The indications for gastrostomy tube insertion were different and included mainly neurological disease (n = 240, 74.1%) such as cerebrovascular accident in the PEG group (n = 119, 36.7%) and mainly surgical disease (n = 28, 29.8%) such as head and neck cancer (n = 16, 17.0%) in the PRG group (p = 0.05). There were no differences in the minor (16.4% vs. 19.1%, p = 0.52) and major (12.3% vs. 14.9%, p = 0.51) complication rates between the PEG and PRG groups. The risk factors for complications were age [yearly increments; odds ratio (OR) 1.03, 95% confidence interval (CI) 1.01-1.06], tube diameter (1-Fr increments; OR 1.26, 95% CI 1.01-1.58), insertion time (1-min increments; OR 1.07, 95% CI 1.01-1.13), and neurological disease as the gastrostomy indication (vs. surgical disease; OR 4.61 95% CI 1.47-14.42). CONCLUSIONS: In our study, both PEG and PRG provided a safe route for nutrition delivery despite their different indications. Our data suggest that PEG might be the procedure of choice for patients with medical or neurological disease and PRG for patients with surgical disease in whom PEG is technically difficult or contraindicated.

Promotion of Cell Death in Cisplatin-Resistant Ovarian Cancer Cells through KDM1B-DCLRE1B Modulation.

Ovarian cancer is the gynecological malignancy with the poorest prognosis, in part due to its high incidence of recurrence. Platinum agents are widely used as a first-line treatment against ovarian cancer. Recurrent tumors, however, frequently demonstrate acquired chemo-resistance to platinum agent toxicity. To improve chemo-sensitivity, combination chemotherapy regimens have been investigated. This study examined anti-tumor effects and molecular mechanisms of cytotoxicity of Oldenlandia diffusa (OD) extracts on ovarian cancer cells, in particular, cells resistant to cisplatin. Six ovarian cancer cells including A2780 and cisplatin-resistant A2780 (A2780cis) as representative cell models were used. OD was extracted with water (WOD) or 50% methanol (MOD). MOD significantly induced cell death in both cisplatin-sensitive cells and cisplatin-resistant cells. The combination treatment of MOD with cisplatin reduced viability in A2780cis cells more effectively than treatment with cisplatin alone. MOD in A2780cis cells resulted in downregulation of the epigenetic modulator KDM1B and the DNA repair gene DCLRE1B. Transcriptional suppression of KDM1B and DCLRE1B induced cisplatin sensitivity. Knockdown of KDM1B led to downregulation of DCLRE1B expression, suggesting that DCLRE1B was a KDM1B downstream target. Taken together, OD extract effectively promoted cell death in cisplatin-resistant ovarian cancer cells under cisplatin treatment through modulating KDM1B and DCLRE1B.

Results from South Korea's 2018 Report Card on physical activity for children and youth.

BACKGROUND/OBJECTIVE: South Korea's 2018 Report Card on Physical Activity for Children and Youth is the second comprehensive evaluation of physical activity and the sources of influence based on the 10 core indicators provided by the Active Healthy Kids Global Alliance. It will serve as an advocacy tool to promote physical activity among children and youth. METHODS: Three national surveillance data (i.e., 2017 Korea Youth Risk Behavior Web-based Survey, 2016 Korea National Health and Nutrition Examination Survey, 2016 Physical Activity Promotion System) were used as main sources to evaluate the indicators. Descriptive statistics were performed to obtain prevalence estimates of physical activity-related indicators. In addition, expert opinions as well as the most recently available published or unpublished relevant sources were synthesized. RESULTS: South Korea's 2018 Report Card, compared to the 2016 Report Card, showed favourable changes in the Active Transportation (B+), Organized Sports Participation (C), Sedentary Behaviours (D), and School (D+) indicators, while unfavourable changes were shown in Overall Physical Activity (F) and Government (D). Physical Fitness was graded as D+. In parallel with the 2016 Report Card, Active Play, Family and Peers, and Community and Environment remain ungraded due to insufficient data. CONCLUSIONS: Successes as well as gaps and research needs were identified in the 2018 Report Card. Though some indicators have shown improvement, most children and youth continue to be insufficiently physically active with overall poor grades (Average of D+). To achieve substantial improvement in all grades in future Report Cards, more institutional and governmental support and investment is needed to promote physical activity. Furthermore, effort should be made to generate data pertaining to the indicators that were ungraded.

Protective effects of guggulsterone against colitis are associated with the suppression of TREM-1 and modulation of macrophages.

Triggering receptor expressed on myeloid cells 1 (TREM-1)-expressing intestinal macrophages are significantly increased in the colons of patients with inflammatory bowel disease (IBD). We focused here on the effects of guggulsterone on macrophage modulation in colitis as a potential therapeutic molecule in human IBD and explore the underlying mechanisms. Gene expression in macrophages was examined and wound-healing assay using HT-29 cells was performed. Colitis in wild-type and IL-10-, Toll-like receptor 4 (TLR4)-, and myeloid differentiation primary response 88 (MyD88)-deficient mice was induced via the administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) into the colon. In both in vitro and in vivo experiments, guggulsterone suppressed intestinal inflammation amplified by TREM-1 stimulation, in which the suppression of NF-κB, activating protein-1, and proteasome pathways was involved. In the TNBS-induced colitis model, guggulsterone reduced disease activity index scores and TREM-1 expression, stimulated IL-10 production, and improved survival in wild-type mice. These effects were not observed in IL-10-, TLR4-, and MyD88-deficient mice. Guggulsterone also suppressed M1 polarization, yet induced the M2 phenotype in macrophages from IBD patients as well as from mice. These findings indicate that guggulsterone blocks the hyperactivation of macrophages via TREM-1 suppression and induces M2 polarization via IL-10 mediated by the TLR4 signaling pathway. Furthermore, this study provides a new rationale for the therapeutic potential of guggulsterone in the treatment of IBD. NEW & NOTEWORTHY We found that guggulsterone attenuates triggering receptor expressed on myeloid cells 1 (TREM-1)-mediated hyperactivation of macrophages and polarizes macrophages toward the M2 phenotype. This was mediated by IL-10 and partly Toll-like receptor 4 signaling pathways. Overall, these data support that guggulsterone as a natural plant sterol modulates macrophage phenotypes in colitis, which may be of novel therapeutic importance in inflammatory bowel disease treatment.

Predictive Value of Intraoperative Pulmonary Vascular Resistance in Liver Transplantation.

We aimed to evaluate the association between intraoperative pulmonary vascular resistance (PVR) and clinical outcome of liver transplantation (LT). Cardiovascular involvement of end-stage liver disease is relatively common, and hemodynamic instability during LT can be fatal to recipients. However, the clinical impact of intraoperative PVR in LT remains undetermined. A total of 363 adult recipients with intraoperative right heart catheterization from January 2011 to May 2016 were analyzed. Patients were divided into 2 groups according to PVR. Two separate analyses were performed according to the time point of measurement: at the beginning and at the end of LT. The primary outcome was all-cause death or graft failure during the follow-up period. Increased PVR was observed in 11.8% (43/363) of recipients at the beginning and 12.7% (46/363) of recipients at the end of LT. PVR at the beginning of LT had no significant effect on the rate of death or graft failure in the multivariate analysis (hazard ratio [HR], 1.24; 95% confidence interval [CI], 0.64-2.38; P = 0.52). In contrast, PVR at the end of LT was significantly associated with death or graft failure during the overall follow-up period (HR, 2.00; 95% CI, 1.13-3.54; P = 0.02). In conclusion, PVR at the end of LT, rather than the beginning, is associated with clinical outcome. Larger trials are needed to support this finding.