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INTRODUCTION: Helicobacter pylori is a major risk factor for gastric cancer. In addition to eradication therapy, early-phase detection of gastric cancer through screening programs using high-vision endoscopy is also widely known to reduce mortality. Although European and US guidelines recommend evaluation of atrophy and intestinal metaplasia by high-vision endoscopy and pathological findings, the guideline used in Japan - the Kyoto classification of gastritis - is based on endoscopic evaluation, and recommends the grading of risk factors. This system requires classification into three endoscopic groups: H. pylori-negative, previous H. pylori infection (inactive gastritis), and current H. pylori infection (active gastritis). Major endoscopic findings in active gastritis are diffuse redness, enlarged folds, nodularity, mucosal swelling, and sticky mucus, while those in H pylori-related gastritis - irrespective of active or inactive status - are atrophy, intestinal metaplasia, and xanthoma. AREAS COVERED: This review describes the endoscopic characteristics of current H. pylori infection, and how characteristic endoscopic findings should be evaluated. EXPERT OPINION: Although the correct evaluation of endoscopic findings related to H. pylori remains necessary, if findings of possible infection are observed, it is important to diagnose infection by detection methods with high sensitivity and specificity, including the stool antigen test and urea breath test.
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Despite significant advancements in systemic therapy for renal cell carcinoma (RCC), the prognosis for patients with metastatic RCC remains poor, as they are often incurable. Consequently, there is an urgent need for innovative therapeutic strategies to further enhance the efficacy of RCC treatment and improve patient outcomes. One such promising avenue lies in targeting histone deacetylase (HDAC) 6, a protein known to regulate numerous crucial biological processes implicated in cancer progression by modulating the acetylation status of various cytoplasmic proteins. To explore the therapeutic potential of HDAC6 inhibition in RCC, our study focused on investigating the effects of HDAC6 inhibitors on cultured RCC cells. Utilizing a panel of 12 small molecule selective HDAC6 inhibitors and employing genetic knockdown techniques, we examined the impact of HDAC6 inhibition on RCC cellular dynamics. Our findings revealed that HDAC6 inhibition exerted a profound effect on RCC cells, resulting in decreased cell viability and DNA replication. Importantly, this effect was attributed to the induction of apoptosis. Our study provides valuable insights into the mechanisms underlying the anticancer effects of selective HDAC6 inhibitors on RCC. A detailed understanding of the molecular mechanisms underlying the anticancer effects of HDAC6 inhibition is important to explore new therapeutic strategies for metastatic RCC.
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Patients receiving hemodialysis (HD) often develop gastrointestinal diseases. Recently, although in general population, clinical guidelines for Helicobacter pylori have strongly recommended its eradication in patients to prevent gastric cancer, optimal eradication regimen and optimal dosage of drugs for patients receiving HD have not been established, due to possible incidence of adverse events. Some antimicrobial agents used in eradication therapy, particularly amoxicillin, can exacerbate renal dysfunction. Given the delayed pharmacokinetics of drugs in patients receiving HD compared with those in healthy individuals, drug regimen and dosage should be considered to minimize adverse effects. Although previous studies have investigated the benefits of eradication therapy for patients receiving HD, because most studies were small in terms of the number of enrolled patients, it is hard to show evidence. The numbers of eradication in HD patients have recently increased, and it is important to provide an optimal regimen. The consideration of eradication in patients undergoing HD with a reduction in the drug dose by 1/2-1/3 may prevent adverse events. Additionally, another important consideration is whether adverse events can be prevented while maintaining a similar eradication rate with reduced drug dosages. Recent meta-analysis findings indicate comparable eradication rates in patients receiving HD and healthy individuals, both with the same dosage regimen and at a reduced dosage regimen, with no significant differences (relative risk [RR] for successful eradication: 0.85 [95% confidence interval (CI): 0.48-1.50]). Unlike with the same dosage regimen (RR for adverse events: 3.15 [95% CI: 1.93-5.13]), the adverse events in the dosage reduction regimen were similar to those in healthy individuals (RR: 1.26 [95% CI: 0.23-6.99]). From a pharmacological perspective, the eradication regimen in patients receiving HD should consider the dosage (1/2-1/3 dosage), dosing number (bid), dosing timing of drugs (after HD), and susceptibility to antimicrobial agents.
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Antibacterianos , Infecções por Helicobacter , Helicobacter pylori , Diálise Renal , Humanos , Infecções por Helicobacter/tratamento farmacológico , Diálise Renal/efeitos adversos , Antibacterianos/efeitos adversos , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Antibacterianos/farmacocinética , Helicobacter pylori/efeitos dos fármacosRESUMO
The relationship between blood group and rebleeding in acute lower gastrointestinal bleeding (ALGIB) remains unclear. This study aimed to investigate the association between blood group O and clinical outcomes in patients with ALGIB. The study included 2336 patients with ALGIB whose bleeding source was identified during initial endoscopy (from the CODE BLUE-J Study). The assessed outcomes encompassed rebleeding and other clinical parameters. The rebleeding rates within 30 days in patients with blood group O and those without blood group O were 17.9% and 14.9%, respectively. Similarly, the rates within 1 year were 21.9% for patients with blood group O and 18.2% for those without blood group O. In a multivariate analysis using age, sex, vital signs at presentation, blood test findings, comorbidities, antithrombotic medication, active bleeding, and type of endoscopic treatment as covariates, patients with blood group O exhibited significantly higher risks for rebleeding within 30 days (odds ratio [OR] 1.31; 95% confidence interval [CI] 1.04-1.65; P = 0.024) and 1 year (OR 1.29; 95% CI 1.04-1.61; P = 0.020) compared to those without blood group O. However, the thrombosis and mortality rates did not differ significantly between blood group O and non-O patients. In patients with ALGIB, blood group O has been identified as an independent risk factor for both short- and long-term rebleeding.
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Sistema ABO de Grupos Sanguíneos , Hemorragia Gastrointestinal , Recidiva , Humanos , Hemorragia Gastrointestinal/etiologia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Fatores de Risco , Estudos de Coortes , Doença AgudaRESUMO
The study aimed to identify prognostic factors for patients with acute lower gastrointestinal bleeding and to develop a high-accuracy prediction tool. The analysis included 8254 cases of acute hematochezia patients who were admitted urgently based on the judgment of emergency physicians or gastroenterology consultants (from the CODE BLUE J-study). Patients were randomly assigned to a derivation cohort and a validation cohort in a 2:1 ratio using a random number table. Assuming that factors present at the time of admission are involved in mortality within 30 days of admission, and adding management factors during hospitalization to the factors at the time of admission for mortality within 1 year, prognostic factors were established. Multivariate analysis was conducted, and scores were assigned to each factor using regression coefficients, summing these to measure the score. The newly created score (CACHEXIA score) became a tool capable of measuring both mortality within 30 days (ROC-AUC 0.93) and within 1 year (C-index, 0.88). The 1-year mortality rates for patients classified as low, medium, and high risk by the CACHEXIA score were 1.0%, 13.4%, and 54.3% respectively (all P < 0.001). After discharge, patients identified as high risk using our unique predictive score require ongoing observation.
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Líquidos Corporais , Caquexia , Humanos , Hemorragia Gastrointestinal/terapia , Hospitalização , Alta do Paciente , Estudos RetrospectivosRESUMO
BACKGROUND: The rebleeding risks and outcomes of endoscopic treatment for acute lower gastrointestinal bleeding (ALGIB) may differ depending on the bleeding location, type, and etiology of stigmata of recent hemorrhage (SRH) but have yet to be fully investigated. We aimed to identify high risk endoscopic SRH and to propose an optimal endoscopic treatment strategy. METHODS: We retrospectively analyzed 2699 ALGIB patients with SRH at 49 hospitals (CODE BLUE-J Study), of whom 88.6â% received endoscopic treatment. RESULTS: 30-day rebleeding rates of untreated SRH significantly differed among locations (left colon 15.5â% vs. right colon 28.6â%) and etiologies (diverticular bleeding 27.5â% vs. others [e.âg. ulcerative lesions or angioectasia] 8.9â%), but not among bleeding types. Endoscopic treatment reduced the overall rebleeding rate (adjusted odds ratio [AOR] 0.69; 95â%CI 0.49-0.98), and the treatment effect was significant in right-colon SRH (AOR 0.46; 95â%CI 0.29-0.72) but not in left-colon SRH. The effect was observed in both active and nonactive types, but was not statistically significant. Moreover, the effect was significant for diverticular bleeding (AOR 0.60; 95â%CI 0.41-0.88) but not for other diseases. When focusing on treatment type, the effectiveness was not significantly different between clipping and other modalities for most SRH, whereas ligation was significantly more effective than clipping in right-colon diverticular bleeding. CONCLUSIONS: A population-level endoscopy dataset allowed us to identify high risk endoscopic SRH and propose a simple endoscopic treatment strategy for ALGIB. Unlike upper gastrointestinal bleeding, the rebleeding risks for ALGIB depend on colonic location, bleeding etiology, and treatment modality.
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Divertículo do Colo , Hemostase Endoscópica , Humanos , Estudos Retrospectivos , Japão/epidemiologia , Hemorragia Gastrointestinal/etiologia , Hemorragia Gastrointestinal/terapia , Endoscopia Gastrointestinal/efeitos adversos , Hemostase Endoscópica/efeitos adversos , Divertículo do Colo/complicações , Colonoscopia/efeitos adversosRESUMO
A 44-year-old woman with Lynch syndrome was referred to our hospital for treatment of recurrence of microsatellite instability-high rectal cancer. [18F]Fluorodeoxyglucose (18FDG)-positron emission tomography revealed a peritoneal metastasis with invasion to the small intestine and left ureter. The peritoneal metastasis was diagnosed initially as unresectable because of extensive invasion to the left ureter requiring nephrectomy. Hence, first-line treatment with pembrolizumab was started. After the first course of pembrolizumab, she developed hydronephrosis and a resulting urinary tract infection (UTI). A percutaneous nephrostomy was performed to control the UTI. After six courses of pembrolizumab, 18FDG-positron emission tomography showed that the peritoneal metastasis was smaller with significantly reduced 18FDG uptake, and it was then diagnosed as resectable without nephrectomy. She underwent R0 resection of the peritoneal metastasis with partial resection of the small intestine. Intraoperatively, the peritoneal metastasis showed no invasion of the left ureter, allowing its preservation. The percutaneous nephrostomy was removed postoperatively, and she has not developed any subsequent UTIs. Histopathologically, the tumor showed a pathological complete response to pembrolizumab. To the best of our knowledge, this is the first case of conversion therapy with pembrolizumab for peritoneal metastasis with hydronephrosis.
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Anticorpos Monoclonais Humanizados , Neoplasias Colorretais Hereditárias sem Polipose , Hidronefrose , Neoplasias Peritoneais , Neoplasias Retais , Humanos , Hidronefrose/etiologia , Feminino , Adulto , Neoplasias Peritoneais/secundário , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/complicações , Neoplasias Retais/patologia , Neoplasias Retais/complicações , Neoplasias Retais/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Neoplasias Colorretais Hereditárias sem Polipose/complicações , Antineoplásicos Imunológicos/uso terapêutico , Infecções Urinárias/tratamento farmacológico , Nefrostomia PercutâneaRESUMO
OBJECTIVES: Regarding the relationship between donor kidney quality and renal graft function after deceased kidney transplantation (KTx) following donation after cardiac death (DCD), the evaluation timing varies depending on the study. Evaluation of histology and changes in long-term renal graft function is limited. METHODS: A retrospective single-center study included 71 recipients who underwent 0-hour biopsy for KTx from DCD. The recipients were divided into two groups to evaluate factors related to renal graft function (study1). The two groups were categorized as stable graft function and poor graft function with the change of estimated glomerular filtration rate (eGFR) after KTx. The recipients were then divided into four groups to assess whether the factors identified in study1 were related to the change in long-term renal graft function (study2). They were categorized as follows: Improved, Stable, Deteriorated, and Primary non-function with the change of eGFR after KTx. RESULTS: In study1, donor age ≥ 50 years (29.5% vs. 65.2%; p = 0.09), banff arteriolar hyalinosis (ah) score (0.66 ± 0.78 vs. 1.2 ± 1.0; p = 0.018), and presence of glomerulosclerosis (43.2% vs. 76.2%; p = 0.017) were significant risk factors for poor long-term graft function. When the recipients were divided into four groups, the severity of ah correlated well with changes in long-term renal function. CONCLUSIONS: We can predict the shift in long-term renal graft function after KTx from DCD according to the severity of ah by 0-hour biopsy.
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Transplante de Rim , Humanos , Pessoa de Meia-Idade , Transplante de Rim/efeitos adversos , Estudos Retrospectivos , Sobrevivência de Enxerto , Doadores de Tecidos , Biópsia , Rim/cirurgia , Rim/patologiaRESUMO
BACKGROUND: Current evidence on the surgical rate, indication, procedure, risk factors, mortality, and postoperative rebleeding for acute lower gastrointestinal bleeding (ALGIB) is limited. METHODS: We constructed a retrospective cohort of 10,342 patients admitted for acute hematochezia at 49 hospitals (CODE BLUE J-Study) and evaluated clinical data on the surgeries performed. RESULTS: Surgery was performed in 1.3% (136/10342) of the cohort with high rates of colonoscopy (87.7%) and endoscopic hemostasis (26.7%). Indications for surgery included colonic diverticular bleeding (24%), colorectal cancer (22%), and small bowel bleeding (16%). Sixty-four percent of surgeries were for hemostasis for severe refractory bleeding. Postoperative rebleeding rates were 22% in patients with presumptive or obscure preoperative identification of the bleeding source and 12% in those with definitive identification. Thirty-day mortality rates were 1.5% and 0.8% in patients with and without surgery, respectively. Multivariate analysis showed that surgery-related risk factors were transfusion need ≥ 6 units (P < 0.001), in-hospital rebleeding (P < 0.001), small bowel bleeding (P < 0.001), colorectal cancer (P < 0.001), and hemorrhoids (P < 0.001). Endoscopic hemostasis was negatively associated with surgery (P = 0.003). For small bowel bleeding, the surgery rate was significantly lower in patients with endoscopic hemostasis as 2% compared to 12% without endoscopic hemostasis. CONCLUSIONS: Our cohort study elucidated the outcomes and risks of the surgery. Extensive exploration including the small bowel to identify the source of bleeding and endoscopic hemostasis may reduce unnecessary surgery and improve the management of ALGIB.
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Neoplasias Colorretais , Hemostase Endoscópica , Humanos , Estudos de Coortes , Estudos Retrospectivos , Hemorragia Gastrointestinal/etiologia , Hemorragia Gastrointestinal/cirurgia , Hemostase Endoscópica/métodos , Fatores de Risco , Neoplasias Colorretais/etiologiaRESUMO
BACKGROUND AND AIMS: Pharmacokinetic parameters, such as drug plasma level at trough, time to maximum plasma concentration (Tmax), and coagulation factor Xa (FXa) activity generally predict factors for the anticoagulant effects of direct oral anticoagulants (DOACs). Although GI bleeding is a major adverse event after endoscopic submucosal dissection (ESD), little is known about the association between post-ESD bleeding in patients taking DOACs and the pharmacologic parameters. This study aimed to evaluate pharmacologic risk factors for post-ESD bleeding in patients taking DOACs. METHODS: We prospectively evaluated the incidence of post-ESD bleeding in patients taking DOACs between April 2018 and May 2022 at 21 Japanese institutions and investigated the association with post-ESD bleeding and pharmacologic factors, including plasma concentration and FXa activity at trough and Tmax. RESULTS: The incidence of post-ESD bleeding was 12.8% (14 of 109; 95% confidence interval [CI], 7.2-20.6). Although plasma DOAC concentration and plasma level/dose ratio at trough and Tmax varied widely among individuals, a significant correlation with plasma concentration and FXa activity was observed (apixaban: correlation coefficient, -0.893; P < .001). On multivariate analysis, risk factors for post-ESD bleeding in patients taking DOACs were higher age (odds ratio [OR], 1.192; 95% CI, 1.020-1.392; P = .027) and high anticoagulant ability analyzed by FXa activity at trough and Tmax (OR, 6.056; 95% CI, 1.094-33.529; P = .039). CONCLUSIONS: The incidence of post-ESD bleeding in patients taking DOACs was high, especially in older patients and with high anticoagulant effects of DOACs. Measurement of pharmacokinetic parameters of DOACs may be useful in identifying patients at higher risk of post-ESD bleeding.
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AIM: No studies have compared the clinical outcomes of early and delayed feeding in patients with acute lower gastrointestinal bleeding (ALGIB). This study aimed to evaluate the benefits and risks of early feeding in a nationwide cohort of patients with ALGIB in whom haemostasis was achieved. METHODS: We reviewed data for 5910 patients with ALGIB in whom haemostasis was achieved and feeding was resumed within 3 days after colonoscopy at 49 hospitals across Japan (CODE BLUE-J Study). Patients were divided into an early feeding group (≤1 day, n = 3324) and a delayed feeding group (2-3 days, n = 2586). Clinical outcomes were compared between the groups by propensity matching analysis of 1508 pairs. RESULTS: There was no significant difference between the early and delayed feeding groups in the rebleeding rate within 7 days after colonoscopy (9.4% vs. 8.0%; p = 0.196) or in the rebleeding rate within 30 days (11.4% vs. 11.5%; p = 0.909). There was also no significant between-group difference in the need for interventional radiology or surgery or in mortality. However, the median length of hospital stay after colonoscopy was significantly shorter in the early feeding group (5 vs. 7 days; p < 0.001). These results were unchanged when subgroups of presumptive and definitive colonic diverticular bleeding were compared. CONCLUSION: The findings of this nationwide study suggest that early feeding after haemostasis can shorten the hospital stay in patients with ALGIB without increasing the risk of rebleeding.
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Colonoscopia , Hemorragia Gastrointestinal , Humanos , Tempo de Internação , Hemorragia Gastrointestinal/etiologia , Hemorragia Gastrointestinal/terapia , Colonoscopia/métodos , Doença Aguda , Estudos de Coortes , Estudos Retrospectivos , Estudos Multicêntricos como AssuntoRESUMO
INTRODUCTION: Weekend admissions showed increased mortality in several medical conditions. This study aimed to examine the weekend effect on acute lower gastrointestinal bleeding (ALGIB) and its mortality and other outcomes. METHODS: This retrospective cohort study (CODE BLUE-J Study) was conducted at 49 Japanese hospitals between January 2010 and December 2019. In total, 8,120 outpatients with acute hematochezia were enrolled and divided into weekend admissions and weekday admissions groups. Multiple imputation (MI) was used to handle missing values, followed by propensity score matching (PSM) to compare outcomes. The primary outcome was mortality; the secondary outcomes were rebleeding, length of stay (LOS), blood transfusion, thromboembolism, endoscopic treatment, the need for interventional radiology, and the need for surgery. Colonoscopy and computed tomography (CT) management were also evaluated. RESULTS: Before PSM, there was no significant difference in mortality (1.3% vs. 0.9%, p = 0.133) between weekend and weekday admissions. After PSM with MI, 1,976 cases were matched for each admission. Mortality was not significantly different for weekend admissions compared with weekday admissions (odds ratio [OR] 1.437, 95% confidence interval [CI] 0.785-2.630; p = 0.340). No significant difference was found with other secondary outcomes in weekend admissions except for blood transfusion (OR 1.239, 95% CI 1.084-1.417; p = 0.006). Weekend admission had a negative effect on early colonoscopy (OR 0.536, 95% CI 0.471-0.609; p < 0.001). Meanwhile, urgent CT remained significantly higher in weekend admissions (OR 1.466, 95% CI 1.295-1.660; p < 0.001). CONCLUSION: Weekend admissions decrease early colonoscopy and increase urgent CT but do not affect mortality or other outcomes except transfusion.
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Hemorragia Gastrointestinal , Admissão do Paciente , Humanos , Japão/epidemiologia , Estudos Retrospectivos , Mortalidade Hospitalar , Fatores de Tempo , Tempo de Internação , Hemorragia Gastrointestinal/terapia , Doença AgudaRESUMO
The prognosis of patients with advanced renal cell carcinoma (RCC) has improved with newer therapies, including molecular-targeted therapies and immuno-oncology agents. Despite these therapeutic advances, many patients with metastatic disease remain uncured. Inhibition of glycogen synthase kinase-3ß (GSK-3ß) is a promising new therapeutic strategy for RCC; however, the precise regulatory mechanism has not yet been fully elucidated. MicroRNAs (miRNAs) act as post-translational regulators of target genes, and we investigated the potential regulation of miRNAs on GSK-3ß in RCC. We selected nine candidate miRNAs from three databases that could potentially regulate GSK-3ß. Among these, hsa-miR-4465 (miR-4465) was downregulated in RCC cell lines and renal cancer tissues. Furthermore, luciferase assays revealed that miR-4465 directly interacted with the 3' untranslated region of GSK-3ß, and Western blot analysis showed that overexpression of miR-4465 significantly decreased GSK-3ß protein expression. Functional assays showed that miR-4465 overexpression significantly suppressed cell invasion of A498 and Caki-1 cells; however, cell proliferation and migration were suppressed only in Caki-1 and A498 cells, respectively, with no effect on cell cycle and apoptosis. In conclusion, miR-4465 regulates GSK-3ß expression but does not consistently affect RCC cell function as a single molecule. Further comprehensive investigation of regulatory networks is required in this field.
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INTRODUCTION: Length of stay (LOS) in hospital affects cost, patient quality of life, and hospital management; however, existing gastrointestinal bleeding models applicable at hospital admission have not focused on LOS. We aimed to construct a predictive model for LOS in acute lower gastrointestinal bleeding (ALGIB). METHODS: We retrospectively analyzed the records of 8,547 patients emergently hospitalized for ALGIB at 49 hospitals (the CODE BLUE-J Study). A predictive model for prolonged hospital stay was developed using the baseline characteristics of 7,107 patients and externally validated in 1,440 patients. Furthermore, a multivariate analysis assessed the impact of additional variables during hospitalization on LOS. RESULTS: Focusing on baseline characteristics, a predictive model for prolonged hospital stay was developed, the LONG-HOSP score, which consisted of low body mass index, laboratory data, old age, nondrinker status, nonsteroidal anti-inflammatory drug use, facility with ≥800 beds, heart rate, oral antithrombotic agent use, symptoms, systolic blood pressure, performance status, and past medical history. The score showed relatively high performance in predicting prolonged hospital stay and high hospitalization costs (area under the curve: 0.70 and 0.73 for derivation, respectively, and 0.66 and 0.71 for external validation, respectively). Next, we focused on in-hospital management. Diagnosis of colitis or colorectal cancer, rebleeding, and the need for blood transfusion, interventional radiology, and surgery prolonged LOS, regardless of the LONG-HOSP score. By contrast, early colonoscopy and endoscopic treatment shortened LOS. CONCLUSIONS: At hospital admission for ALGIB, our novel predictive model stratified patients by their risk of prolonged hospital stay. During hospitalization, early colonoscopy and endoscopic treatment shortened LOS.
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Hemorragia Gastrointestinal , Qualidade de Vida , Humanos , Tempo de Internação , Estudos Retrospectivos , Hemorragia Gastrointestinal/diagnóstico , Hemorragia Gastrointestinal/etiologia , Hemorragia Gastrointestinal/terapia , ColonoscopiaRESUMO
Background and Aim: While short and long attachment caps are available for colonoscopy, it is unclear which type is more appropriate for stigmata of recent hemorrhage (SRH) identification in acute hematochezia. This study aimed to compare the performance of short versus long caps in acute hematochezia diagnoses and outcomes. Methods: We selected 6460 patients who underwent colonoscopy with attachment caps from 10 342 acute hematochezia cases in the CODE BLUE-J study. We performed propensity score matching (PSM) to balance baseline characteristics between short and long cap users. Then, the proportion of definitive or presumptive bleeding etiologies found on the initial colonoscopy and SRH identification rates were compared. We also evaluated rates of blood transfusions, interventional radiology, or surgery, as well as the rate of rebleeding and mortality within 30 days after the initial colonoscopy. Results: A total of 3098 patients with acute hematochezia (1549 short cap and 1549 long cap users) were selected for PSM. The rate of colonic diverticular bleeding (CDB) diagnosis was significantly higher in long cap users (P = 0.006). While the two groups had similar rates of the other bleeding etiologies, the frequency of unknown etiologies was significantly lower in long cap users (P < 0.001). The rate of SRH with active bleeding was significantly higher in long cap users (P < 0.001). Other clinical outcomes did not differ significantly. Conclusion: Compared to that with short caps, long cap-assisted colonoscopy is superior for the diagnosis of acute hematochezia, especially CDB, and the identification of active bleeding.
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Tight junctions (TJs) are the most apical components of the cell-cell adhesion machinery in epithelial and endothelial cells and they play essential roles in homeostasis. Recent studies have revealed that aberrant expression of tight junction proteins (TJPs) is frequently observed in various type of cancers. Here we review cancer-associated aberrant expression of TJPs with focus on transmembrane-type TJPs including claudins, junctional adhesion molecule-A (JAM-A), and occludin. Some transmembrane-type TJPs are upregulated at the early neoplastic stage and their expression persists during dedifferentiation. Aberrant expression of TJPs contributes to proliferation, invasion, and dysregulated signaling of cancer cells. In addition to an increase in their expression level, their localization is altered from a TJ-restricted pattern to distribution throughout the whole cell membrane, making them suitable as therapeutic targets. Extracellular domains of transmembrane-type TJPs can be approached by target drugs not only from the lumen side (apical side) but also from the extracellular matrix side (basal side), including blood vessels. Aberrantly expressed TJPs are potential useful diagnostic markers as well as therapeutic targets for cancers.
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Neoplasias , Proteínas de Junções Íntimas , Humanos , Proteínas de Junções Íntimas/metabolismo , Células Endoteliais , Claudinas , Junções Íntimas/metabolismo , Neoplasias/metabolismo , Ocludina/metabolismoRESUMO
Advanced bladder cancer (BC) (local invasive and/or metastatic) is not curable even with cytotoxic chemotherapy, immune checkpoint inhibitors, and targeted treatment. Targeting GSK-3ß is a promising novel approach in advanced BC. The induction of autophagy is a mechanism of secondary resistance to various anticancer treatments. Our objectives are to investigate the synergistic effects of GSK-3ß in combination with autophagy inhibitors to evade GSK-3ß drug resistance. Small molecule GSK-3ß inhibitors and GSK-3ß knockdown using siRNA promote the expression of autophagy-related proteins. We further investigated that GSK-3ß inhibition induced the nucleus translocation of transcription factor EB (TFEB). Compared to the GSK-3ß inhibition alone, its combination with chloroquine (an autophagy inhibitor) significantly reduced BC cell growth. These results suggest that targeting autophagy potentiates GSK-3ß inhibition-induced apoptosis and retarded proliferation in BC cells.
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Neoplasias da Bexiga Urinária , Humanos , Glicogênio Sintase Quinase 3 beta/farmacologia , Linhagem Celular Tumoral , Neoplasias da Bexiga Urinária/tratamento farmacológico , Autofagia , Apoptose/genética , Proliferação de CélulasRESUMO
Delayed bleeding is a major and serious adverse event of endoscopic submucosal dissection (ESD) for early-stage gastrointestinal tumors. The rate of post-ESD bleeding for gastric cancer is higher (around 5%-8%) than that for esophagus, duodenum and colon cancer (around 2%-4%). Although investigations into the risk factors for post-ESD bleeding have identified several procedure-, lesion-, physician- and patient-related factors, use of antithrombotic drugs, especially anticoagulants [direct oral anticoagulants (DOACs) and warfarin], is thought to be the biggest risk factor for post-ESD bleeding. In fact, the post-ESD bleeding rate in patients receiving DOACs is 8.7%-20.8%, which is higher than that in patients not receiving anticoagulants. However, because clinical guidelines for management of ESD in patients receiving DOACs differ among countries, it is necessary for endoscopists to identify ways to prevent post-ESD delayed bleeding in clinical practice. Given that the pharmacokinetics (e.g., plasma DOAC level at both trough and Tmax) and pharmacodynamics (e.g., anti-factor Xa activity) of DOACs are related to risk of major bleeding, plasma DOAC level and anti-FXa activity may be useful parameters for monitoring the anti-coagulate effect and identifying DOAC patients at higher risk of post-ESD bleeding.
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Ressecção Endoscópica de Mucosa , Neoplasias Gástricas , Humanos , Ressecção Endoscópica de Mucosa/efeitos adversos , Hemorragia Pós-Operatória/prevenção & controle , Hemorragia Pós-Operatória/induzido quimicamente , Estudos Retrospectivos , Anticoagulantes/efeitos adversos , Neoplasias Gástricas/complicações , Fatores de Risco , Mucosa Gástrica/patologiaRESUMO
BACKGROUND & AIMS: Currently, large, nationwide, long-term follow-up data on acute lower gastrointestinal bleeding (ALGIB) are scarce. We investigated long-term risks of recurrence after hospital discharge for ALGIB using a large multicenter dataset. METHODS: We retrospectively analyzed 5048 patients who were urgently hospitalized for ALGIB at 49 hospitals across Japan (CODE BLUE-J study). Risk factors for the long-term recurrence of ALGIB were analyzed by using competing risk analysis, treating death without rebleeding as a competing risk. RESULTS: Rebleeding occurred in 1304 patients (25.8%) during a mean follow-up period of 31 months. The cumulative incidences of rebleeding at 1 and 5 years were 15.1% and 25.1%, respectively. The mortality risk was significantly higher in patients with out-of-hospital rebleeding episodes than in those without (hazard ratio, 1.42). Of the 30 factors, multivariate analysis showed that shock index ≥1 (subdistribution hazard ratio [SHR], 1.25), blood transfusion (SHR, 1.26), in-hospital rebleeding (SHR, 1.26), colonic diverticular bleeding (SHR, 2.38), and thienopyridine use (SHR, 1.24) were significantly associated with increased rebleeding risk. Multivariate analysis of colonic diverticular bleeding patients showed that blood transfusion (SHR, 1.20), in-hospital rebleeding (SHR, 1.30), and thienopyridine use (SHR, 1.32) were significantly associated with increased rebleeding risk, whereas endoscopic hemostasis (SHR, 0.83) significantly decreased the risk. CONCLUSIONS: These large, nationwide follow-up data highlighted the importance of endoscopic diagnosis and treatment during hospitalization and the assessment of the need for ongoing thienopyridine use to reduce the risk of out-of-hospital rebleeding. This information also aids in the identification of patients at high risk of rebleeding.