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BACKGROUND AND AIM: The incidence of early-onset colorectal neoplasms has been increasing in both Western and Eastern countries. However, the risks and preventive factors for these neoplasms in Eastern countries remain unclear. METHODS: The data of 5580 patients who underwent colonoscopy between 2016 and 2021 were retrospectively evaluated. The primary outcome was advanced colorectal neoplasm (ACRN), defined as advanced adenomas (adenoma ≥10 mm, or with high-grade dysplasia or villous component) or adenocarcinoma. The clinical factors associated with ACRNs were determined for each age category (≤50 and >50 years), and the differences between the two categories were assessed. Odds ratios adjusted for age and sex were calculated. RESULTS: Among 1001 patients (age ≤50 years), ACRN was found in 94 (9.4%). In this younger category, male sex (adjusted odds ratio [aOR]:2.34, 95% confidence interval [CI]:1.51-3.63) and a family history of colorectal cancer (aOR:2.14, 95% CI:1.17-3.89) were significantly associated with higher odds of developing ACRNs. ACRNs were detected in 726 (15.9%) of 4579 patients (age >50 years). In the older age category, smoking (aOR:1.32, 95% CI:1.08-1.63) was significantly associated with a higher risk of ACRNs. Exercise of >3.5 metabolic equivalent of task (METs) (aOR,0.80; 95% CI:0.67-0.96) was significantly associated with a lower risk of ACRNs. CONCLUSION: The development of early-onset ACRNs was primarily associated with congenital factors, whereas that of late-onset ACRNs was associated with acquired ones. Colonoscopy is recommended for young male patients, particularly for those with a family history of colorectal cancer.
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Adenoma , Neoplasias Colorrectales , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Estudios Retrospectivos , Colonoscopía/efectos adversos , Adenoma/patología , Neoplasias Colorrectales/patologíaRESUMEN
OBJECTIVES: Covered self-expandable metal stent (cSEMS) for gastric outlet obstruction (GOO) has been developed to overcome tumor ingrowth but is prone to be associated with an increased risk of migration. Clinical impact of the novel large-bore cSEMS for malignant GOO remains unclear. METHODS: A total of 117 patients undergoing endoscopic cSEMS placement for malignant GOO were enrolled in this multicenter retrospective study. Technical and clinical success, adverse events, recurrent GOO, and survival after stent placement were compared between 24 mm-cSEMS (n = 49) and 20 mm-cSEMS (n = 68). RESULTS: Patient characteristics were well-balanced and thus similar survival was observed between the two groups (136 days vs. 89 days, P = 0.60). Technical success rate of 100% and clinical success rate of 96% were achieved both in 24 mm-cSEMS and 20 mm-cSEMS, respectively. The median cumulative time to recurrent GOO was significantly longer in 24 mm-cSEMS than in 20 mm-cSEMS (380 days vs. 138 days, P = 0.01). The incidence of adverse events and recurrent GOO was comparable: 12% vs. 15% (P = 0.91), and 16% vs. 31% (P = 0.11); however, no stent migration was observed in 24 mm-cSEMS. In a subgroup analysis, the superiority of 24 mm-cSEMS to 20 mm-cSEMS was demonstrated in extrinsic cancers (380 days vs. 121 days, P = 0.01) but not in intrinsic cancers (151 days vs. not reached, P = 0.47). CONCLUSIONS: The 24 mm-cSEMS may improve time to recurrent GOO with ensuring acceptable safety in patients with malignant GOO.
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Obstrucción de la Salida Gástrica , Stents Metálicos Autoexpandibles , Neoplasias Gástricas , Humanos , Estudios Retrospectivos , Stents Metálicos Autoexpandibles/efectos adversos , Stents/efectos adversos , Obstrucción de la Salida Gástrica/diagnóstico , Obstrucción de la Salida Gástrica/etiología , Obstrucción de la Salida Gástrica/cirugía , Neoplasias Gástricas/patología , Cuidados Paliativos , Resultado del TratamientoRESUMEN
BACKGROUND AND AIMS: Accurate risk stratification for gastric cancer is required for optimal endoscopic surveillance in patients with chronic gastritis. We aimed to develop a machine learning (ML) model that incorporates endoscopic and histologic findings for an individualized prediction of gastric cancer incidence. METHODS: We retrospectively evaluated 1099 patients with chronic gastritis who underwent EGD and biopsy sampling of the gastric mucosa. Patients were randomly divided into training and test sets (4:1). We constructed a conventional Cox proportional hazard model and 3 ML models. Baseline characteristics, endoscopic atrophy, and Operative Link on Gastritis-Intestinal Metaplasia Assessment (OLGIM)/Operative Link on Gastritis Assessment (OLGA) stage at initial EGD were comprehensively assessed. Model performance was evaluated using Harrel's c-index. RESULTS: During a mean follow-up of 5.63 years, 94 patients (8.55%) developed gastric cancer. The gradient-boosting decision tree (GBDT) model achieved the best performance (c-index from the test set, .84) and showed high discriminative ability in stratifying the test set into 3 risk categories (P < .001). Age, OLGIM/OLGA stage, endoscopic atrophy, and history of malignant tumors other than gastric cancer were important predictors of gastric cancer incidence in the GBDT model. Furthermore, the proposed GBDT model enabled the generation of a personalized cumulative incidence prediction curve for each patient. CONCLUSIONS: We developed a novel ML model that incorporates endoscopic and histologic findings at initial EGD for personalized risk prediction of gastric cancer. This model may lead to the development of effective and personalized follow-up strategies after initial EGD.
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Gastritis Atrófica , Gastritis , Infecciones por Helicobacter , Helicobacter pylori , Neoplasias Gástricas , Atrofia/patología , Endoscopía Gastrointestinal/efectos adversos , Mucosa Gástrica/diagnóstico por imagen , Mucosa Gástrica/patología , Gastritis/patología , Gastritis Atrófica/patología , Infecciones por Helicobacter/epidemiología , Humanos , Incidencia , Aprendizaje Automático , Metaplasia/patología , Estudios Retrospectivos , Factores de Riesgo , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/epidemiología , Neoplasias Gástricas/etiologíaRESUMEN
BACKGROUND AND AIMS: Recent studies have suggested that right- and left-sided colorectal cancers (CRCs) are molecularly distinct. In this study, we examined the association between the risk of right- and left-sided CRC and drug use to estimate their chemopreventive effects METHODS: This multicenter retrospective cohort study was conducted using the data of hospitalized patients between 2014 and 2019 from nine hospital databases. The primary outcomes were right- and left-sided CRC. We evaluated the association of CRCs with drug use and clinical factors. Odds ratios adjusted for age, sex, Charlson Comorbidity Index scores, and smoking status were calculated. We also compared the transcriptional profiling in precancerous lesions, including sessile serrated lesions (SSLs) RESULTS: A total of 307,938 patients, including 2745 with right-sided CRC and 4819 with left-sided CRC, were analyzed. The use of nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, cyclooxygenase-2 inhibitors, and steroids was associated with a lower risk of both right- and left-sided CRCs. In contrast, statins, other lipid-lowering agents, and metformin were associated with a lower risk of left-sided CRC. Transcriptomic analysis showed that SSL, which predominantly develops in the right colon, was associated with a lower expression of lipid metabolism-related genes. CONCLUSIONS: Targeting lipid metabolism may be useful for chemoprevention of left-sided CRCs, while development of right-sided CRCs may be independent of this pathway.
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Neoplasias Colorrectales , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Metformina , Humanos , Antiinflamatorios no Esteroideos/uso terapéutico , Aspirina/uso terapéutico , Quimioprevención , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/prevención & control , Neoplasias Colorrectales/tratamiento farmacológico , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Lípidos , Estudios RetrospectivosRESUMEN
OBJECTIVES: Colorectal stenting is widely performed using self-expandable metallic stents (SEMSs), but the mechanical properties have not been evaluated. Therefore, we conducted an in vitro study to evaluate the mechanical properties of colorectal SEMSs. METHODS: Eighteen individual types and sizes of uncovered SEMSs were evaluated for their mechanical properties. Radial force was measured using a measurement machine. Axial force (AF) was measured by two methods: a conventional manual method and a new method using a measurement machine. The correlation of these two methods was evaluated. We also proposed an "AF zero border" that was defined as the angle at which the torque force disappeared. RESULTS: Radial force versus diameter curves and AF versus angle curves were influenced by the structure and the size of each stent. There was excellent correlation of AFs measured by the new and conventional manual method (y = 21.434x, R = 0.881, P < 0.0001). Colorectal SEMSs could be categorized into five subgroups according to the mechanical properties. Most hook-wired SEMSs had the AF of zero border. CONCLUSIONS: This is the first report to evaluate the mechanical properties of colorectal SEMSs, and these data may provide useful information for the clinical use and development of colorectal SEMS. Furthermore, the new measurement machine might standardize the measuring method of AF.
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Neoplasias Colorrectales , Stents Metálicos Autoexpandibles , Neoplasias Colorrectales/cirugía , Humanos , Fenómenos Mecánicos , Stents , Resultado del TratamientoRESUMEN
Hepatitis B virus (HBV) infection is a major health concern worldwide. To prevent HBV-related mortality, elimination of viral proteins is considered the ultimate goal of HBV treatment; however, currently available nucleos(t)ide analogs rarely achieve this goal, as viral transcription from episomal viral covalently closed circular DNA (cccDNA) is not prevented. HBV regulatory protein X was recently found to target the protein structural maintenance of chromosomes 5/6 (Smc5/6) for ubiquitination and degradation by DDB1-CUL4-ROC1 E3 ligase, resulting in enhanced viral transcription from cccDNA. This ubiquitin-dependent proteasomal pathway requires an additional ubiquitin-like protein for activation, neuronal precursor cell-expressed developmentally down-regulated protein 8 (NEDD8). Here, we show that pevonedistat, a NEDD8-activating enzyme inhibitor, works efficiently as an antiviral agent. Pevonedistat significantly restored Smc5/6 protein levels and suppressed viral transcription and protein production in the HBV minicircle system in in vitro HBV replication models and in human primary hepatocytes infected naturally with HBV. Conclusion: These results indicate that pevonedistat is a promising compound to treat chronic HBV infection.
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Ciclopentanos/farmacología , Virus de la Hepatitis B/efectos de los fármacos , Pirimidinas/farmacología , Enzimas Activadoras de Ubiquitina/antagonistas & inhibidores , Proteínas de Ciclo Celular/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Ciclopentanos/uso terapéutico , Evaluación Preclínica de Medicamentos , Células HEK293 , Células Hep G2 , Hepatitis B/tratamiento farmacológico , Humanos , Cultivo Primario de Células , Pirimidinas/uso terapéutico , Ubiquitina-Proteína Ligasas/metabolismo , Replicación Viral/efectos de los fármacosRESUMEN
BACKGROUND AND AIM: To examine whether our convolutional neural network (CNN) system based on deep learning can reduce the reading time of endoscopists without oversight of abnormalities in the capsule-endoscopy reading process. METHODS: Twenty videos of the entire small-bowel capsule endoscopy procedure were prepared, each of which included 0-5 lesions of small-bowel mucosal breaks (erosions or ulcerations). At another institute, two reading processes were compared: (A) endoscopist-alone readings and (B) endoscopist readings after the first screening by the proposed CNN. In process B, endoscopists read only images detected by CNN. Two experts and four trainees independently read 20 videos each (10 for process A and 10 for process B). Outcomes were reading time and detection rate of mucosal breaks by endoscopists. Gold standard was findings at the original institute by two experts. RESULTS: Mean reading time of small-bowel sections by endoscopists was significantly shorter during process B (expert, 3.1 min; trainee, 5.2 min) compared to process A (expert, 12.2 min; trainee, 20.7 min) (P < 0.001). For 37 mucosal breaks, detection rate by endoscopists did not significantly decrease in process B (expert, 87%; trainee, 55%) compared to process A (expert, 84%; trainee, 47%). Experts detected all eight large lesions (>5 mm), but trainees could not, even when supported by the CNN. CONCLUSIONS: Our CNN-based system for capsule endoscopy videos reduced the reading time of endoscopists without decreasing the detection rate of mucosal breaks. However, the reading level of endoscopists should be considered when using the system.
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Endoscopía Capsular , Aprendizaje Profundo , Diagnóstico por Computador , Enfermedades Intestinales/diagnóstico , Intestino Delgado , Competencia Clínica , Humanos , Mucosa Intestinal , Estudios Retrospectivos , Factores de TiempoRESUMEN
BACKGROUND & AIMS: Little is known about the mechanisms by which chronic inflammation contributes to carcinogenesis, such as the development of colon tumors in patients with inflammatory bowel diseases. Specific microRNA (miRNAs) can function as suppressors or oncogenes, and widespread alterations in miRNA expression have been associated with tumorigenesis. We studied whether alterations in miRNA function contribute to inflammation-associated colon carcinogenesis. METHODS: We studied the effects of inflammatory cytokines, such as tumor necrosis factor, interleukin-1α (IL1A), and IL1ß (IL1B), on miRNA function, measured by activity of reporter constructs containing miRNA-binding sites in their 3' untranslated regions, in human 293T embryonic kidney, Caco-2, HT29, and HCT116 colon carcinoma cells, as well as dicer+/+ and dicer-/-, and Apobec3+/+ and Apobec3-/- mouse embryonic fibroblasts. Cells were analyzed by immunoblots, immunohistochemistry, and flow cytometry. We generated transgenic mice expressing reporter constructs regulated by LET7B, MIR122, and MIR29b response elements; some mice were given injections of miRNA inhibitors (anti-MIR122 or anti-LET7B), a negative control, or tumor necrosis factor. Liver tissues were collected and analyzed by immunoblotting. Reporter mice were given azoxymethane followed by dextran sulfate sodium to induce colitis and colon tumors; some mice were given the ROCK inhibitor fasudil along with these agents (ROCK inhibitors increase miRNA function). Colon tissues were collected and analyzed by immunohistochemistry, immunoblots, and fluorescence microscopy. RESULTS: Incubation of cell lines with inflammatory cytokines reduced the ability of miRNAs to down-regulate expression from reporter constructs; dicer was required for this effect, so these cytokines relieve miRNA-dependent reductions in expression. The cytokines promoted degradation of APOBEC3G, which normally promotes miRNA loading into argonaute 2-related complexes. Mice with colitis had reduced miRNA function, based on increased expression of reporter genes. Administration of fasudil to mice did not reduce the severity of colitis that developed but greatly reduced the numbers of colon tumors formed (mean 2 tumors/colon in mice given fasudil vs 9 tumors/colon in mice given control agent). We made similar observations in IL10-deficient mice. CONCLUSIONS: We found inflammatory cytokines to reduce the activities of miRNAs. In mice with colitis, activities of miRNAs are reduced; administration of an agent that increases miRNA function prevents colon tumor formation in these mice. This pathway might be targeted to prevent colon carcinogenesis in patients with inflammatory bowel diseases.
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Carcinogénesis/efectos de los fármacos , Carcinoma/genética , Colitis/metabolismo , Colon/efectos de los fármacos , Neoplasias del Colon/genética , Citocinas/farmacología , Fibroblastos/efectos de los fármacos , MicroARNs/efectos de los fármacos , Animales , Azoximetano/toxicidad , Células CACO-2 , Carcinogénesis/genética , Carcinoma/inducido químicamente , Línea Celular Tumoral , Colitis/inducido químicamente , Colon/metabolismo , Neoplasias del Colon/inducido químicamente , Citidina Desaminasa/genética , ARN Helicasas DEAD-box/genética , Sulfato de Dextran/toxicidad , Fibroblastos/metabolismo , Citometría de Flujo , Células HCT116 , Células HT29 , Humanos , Immunoblotting , Inmunohistoquímica , Inflamación , Interleucina-1alfa/farmacología , Interleucina-1beta/farmacología , Ratones , MicroARNs/genética , Ribonucleasa III/genética , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
Major histocompatibility complex class I polypeptide-related sequence A (MICA) is a prototypical NKG2D ligand. Because immune cells, such as natural killer (NK) cells, recognize virally infected or transformed cells and eliminate them through the interaction between NKG2D receptors on NK cells and NKG2D ligands on pathogenic cells, MICA expression levels are associated with NK cell-mediated immunity. Here, we report that an engineered clustered regularly interspaced short palindromic repeats-Cas9-related complex targeting MICA gene promoter sequences activates transcription of the MICA gene from its endogenous locus. Inhibiting microRNA function, which targets the 3' untranslated region of the MICA gene, enhances this activation. These results demonstrate that the combination of Cas9-based transcriptional activators and simultaneous modulation of microRNA function may be a powerful tool for enhancing MICA protein expression and efficient anti-pathogenic cell immunity.
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Regiones no Traducidas 3' , Sistemas CRISPR-Cas , Antígenos de Histocompatibilidad Clase I/genética , MicroARNs/genética , Activación Transcripcional , Secuencia de Bases , Línea Celular Tumoral , Citometría de Flujo , Ingeniería Genética , Células Hep G2 , Antígenos de Histocompatibilidad Clase I/inmunología , Humanos , Inmunidad Innata , MicroARNs/inmunología , Regiones Promotoras GenéticasRESUMEN
The biological roles of microRNAs (miRNAs) have been extensively studied. miRNA122 represents more than half of the miRNAs expressed in the liver and has various physiological and pathological functions, which include enhancing hepatitis virus replication, regulating lipid metabolism and suppressing hepatocellular carcinoma. miRNAs, whether globally or individually, have been linked with hepatocarcinogenesis. Furthermore, some miRNAs have been shown to be involved in the pathogenesis of nonalcoholic steatohepatitis. Using nucleotide-based strategies, these miRNAs may be developed as potential therapeutic targets. Because changes in miRNA expression can be measured in sera, they may be used as non-invasive biomarkers if they correctly reflect the pathological state of the liver. In this review, we show the biological roles of representative miRNAs in liver disease and discuss the current issues that remain to be clarified for future clinical applications.
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Carcinoma Hepatocelular/genética , Hepatopatías/genética , Neoplasias Hepáticas/genética , MicroARNs/genética , Biomarcadores/sangre , Regulación de la Expresión Génica , Humanos , Hígado/metabolismo , Hígado/patología , MicroARNs/sangre , Modelos Genéticos , Enfermedad del Hígado Graso no Alcohólico/genéticaRESUMEN
BACKGROUND & AIMS: Colorectal cancer (CRC) is the third most common cancer in the world. Gut microbiota has recently been implicated in the development of CRC. Actinomyces odontolyticus is one of the most abundant bacteria in the gut of patients with very early stages of CRC. A odontolyticus is an anaerobic bacterium existing principally in the oral cavity, similar to Fusobacterium nucleatum, which is known as a colon carcinogenic bacterium. Here we newly determined the biological functions of A odontolyticus on colonic oncogenesis. METHODS: We examined the induction of intracellular signaling by A odontolyticus in human colonic epithelial cells (CECs). DNA damage levels in CECs were confirmed using the human induced pluripotent stem cell-derived gut organoid model and mouse colon tissues in vivo. RESULTS: A odontolyticus secretes membrane vesicles (MVs), which induce nuclear factor kappa B signaling and also produce excessive reactive oxygen species (ROS) in colon epithelial cells. We found that A odontolyticus secretes lipoteichoic acid-rich MVs, promoting inflammatory signaling via TLR2. Simultaneously, those MVs are internalized into the colon epithelial cells, co-localize with the mitochondria, and cause mitochondrial dysfunction, resulting in excessive ROS production and DNA damage. Induction of excessive DNA damage in colonic cells by A odontolyticus-derived MVs was confirmed in the gut organoid model and also in mouse colon tissues. CONCLUSIONS: A odontolyticus secretes MVs, which cause chronic inflammation and ROS production in colonic epithelial cells, leading to the initiation of CRC.
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Colon , Células Madre Pluripotentes Inducidas , Ratones , Animales , Humanos , Colon/microbiología , Especies Reactivas de Oxígeno , Composición de Base , Filogenia , ARN Ribosómico 16S , Análisis de Secuencia de ADN , Células Epiteliales , Bacterias/genéticaRESUMEN
Trastuzumab deruxtecan (T-DXd) has demonstrated remarkable efficacy as a third- or later-line chemotherapy for human epidermal growth factor receptor 2 (HER2)-positive advanced gastric and gastroesophageal junction adenocarcinomas. However, it may cause pneumonitis, and its efficacy in rare histologies such as gastric adenocarcinoma with enteroblastic differentiation (GAED) remains unclear. A 74-year-old woman with unresectable HER2-positive GAED and lung metastasis received T-DXd as a fifth-line chemotherapy. Treatment was discontinued after 15 cycles owing to drug-induced pneumonitis; however, the patient achieved a sustained complete response for 14 months without subsequent chemotherapy or the exacerbation of pneumonitis. T-DXd was effective in HER2-positive GAED.
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BACKGROUND/AIMS: Mechanical properties (MPs) and axial and radial force (AF and RF) may influence the efficacy and complications of self-expandable metallic stent (SEMS) placement. We measured the MPs of various SEMSs and examined their influence on the SEMS clinical ability. METHODS: We evaluated the MPs of 29 types of 10-mm SEMSs. RF was measured using a conventional measurement device. AF was measured using the conventional and new methods, and the correlation between the methods was evaluated. RESULTS: A high correlation in AFs was observed, as measured by the new and conventional manual methods. AF and RF scatterplots divided the SEMSs into three subgroups according to structure: hook-and-cross-type (low AF and RF), cross-type (high AF and low RF), and laser-cut-type (intermediate AF and high RF). The hook-and-cross-type had the largest axial force zero border (>20°), followed by the laser-cut and cross types. CONCLUSION: MPs were related to stent structure. Hook-and-cross-type SEMSs had a low AF and high axial force zero border and were considered safest because they caused minimal stress on the biliary wall. However, the increase in RF must be overcome.
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Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis due to the difficulty of its diagnosis. Because human satellite II (HSATII) RNA, a satellite repeat RNA, is highly and specifically expressed in human PDAC, the serum HSATII RNA level may be a biomarker of PDAC. To measure the serum HSATII RNA level with high sensitivity and reproducibility, we previously developed a convenient method, tandem repeat amplification by nuclease protection (TRAP) combined with droplet digital PCR (ddPCR). Here, we refined the original method by simultaneously measuring the serum miR-21-5p level to enhance the detection of PDAC. The resulting PDAC-Index, constructed using serum HSATII RNA and miR-21-5p levels, discriminated patients with PDAC with high accuracy. We verified the clinical usefulness of the PDAC-Index as a supportive test in difficult-to-diagnose cases. The PDAC-Index has satisfactory diagnostic performance and may routinely be applied for detecting PDAC.
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Evidence of the efficacy and safety of colorectal stent placement for palliation remains insufficient. This single-arm, prospective, multicenter study with a WallFlex enteral colonic stent included 200 consecutive patients with malignant large bowl obstruction in the palliation cohort. The technical and clinical success, as well as stent patency and complications as short-term (≤7 days) and long-term (>7 days) outcomes, of high axial force self-expandable metal stent (SEMS) placement was evaluated. The technical and clinical success rates were 98.5% and 94.5%, respectively. Non-recurrent colorectal obstruction at 1 year was 63.9%, and 71.2% of the patients remained free of recurrent colorectal obstruction until death or the last follow-up. Fifty-six patients (28.0%) received chemotherapy, and five patients were administered bevacizumab after stent placement. The overall complication rate was 47%, including four (2.0%) early-onset and ten (5.0%) late-onset perforations, mostly due to stent-edge injury. Only the use of a long SEMS was a risk factor for perforation. In conclusion, endoscopic colorectal stenting using high axial force SEMS is an effective and safe procedure for palliation in patients with malignant colorectal obstruction. However, care should be taken to avoid perforation at the stent edge when using a long SEMS.
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BACKGROUND AND OBJECTIVE: Laparoscopic resection for obstructive colon cancer (CC) after insertion of self-expanding metallic stents (SEMSs) is reportedly difficult. However, this has not yet been thoroughly investigated. Therefore, we investigated the influence of SEMS insertion on laparoscopic resection. METHODS: This retrospective comparative study included 87 patients with obstructive left-sided CC (December 2011-December 2019). Patients were assigned to two groups based on elective laparoscopic surgery for (1) obstructive CC necessitating emergent decompression with SEMS insertion (SEMS group) and (2) obstructive CC without emergent decompression (control group). RESULTS: The SEMS group had a longer operation time (283.3 ± 79.3 min vs 222.2 ± 79.4 min, P = 0.002) and greater blood loss (204.8 ± 417.6 mL vs 53.7 ± 166.1 mL, P = 0.029) on univariate analysis; however, in multiple linear regression analysis, SEMS was not an independent risk factor for both operation time (Δ operation time 25.5 min: P = 0.19) and blood loss (Δ blood loss 33.6 mL: P = 0.58). The complication rate based on Clavien-Dindo grade II did not differ significantly (17% vs 20%, P = 1.00), whereas the rates of conversion to laparotomy (17% vs 2%, P = 0.016) and stoma creation (26% vs 2%, P = 0.001) were higher in the SEMS group. In oncological outcomes, there was no intergroup difference in the 5-year disease-free survival (80.0% vs 72.2%, P = 0.76) and overall survival (100% vs 86.3%, P = 0.25). CONCLUSIONS: Laparoscopic surgery after SEMS for left-sided CC is demanding due to higher conversion rates to open surgery. However, this study also revealed that it is as safe as laparoscopic surgery for cases without SEMS because of comparable complication rate and long-term outcomes.
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Neoplasias del Colon , Neoplasias Colorrectales , Obstrucción Intestinal , Laparoscopía , Neoplasias del Colon/complicaciones , Neoplasias del Colon/cirugía , Neoplasias Colorrectales/complicaciones , Neoplasias Colorrectales/cirugía , Humanos , Obstrucción Intestinal/complicaciones , Obstrucción Intestinal/cirugía , Laparoscopía/efectos adversos , Estudios Retrospectivos , Stents/efectos adversos , Resultado del TratamientoRESUMEN
PURPOSE: Obstructive colitis (OC) is a risk factor of anastomotic leakage in colorectal cancer resection. We aimed to clarify the relationship between the severity of OC and clinicopathological findings and to detect predictive factors of OC. METHODS: We retrospectively reviewed 43 cases of colectomy after self-expandable metallic stent placement for left-sided colorectal cancer. Preoperative diagnosis of OC was made by multiple modalities (initial computed tomography (CT), presurgical CT, and colonoscopy). We classified OC macroscopically in resected specimens into five groups (Grade 0: none, 1: mild [mild edema], 2: moderate [severe edema, redness, erosion], 3: severe [ulceration, bleeding], 4: very severe [necrosis, perforation]), and investigated the relationship between the preoperative assessment, surgical findings and the severity of OC. RESULTS: OC of Grade 2 or more (53.5%) was significantly correlated with severe edema in initial CT. There was no significant correlation between OC and anastomosis rate. The creation of covering stoma was significantly higher in the Grade 2 or more OC group. No leakage was observed in either group. CONCLUSIONS: Initial CT may be most useful for prediction of OC. It is important to make a preoperative diagnosis of OC by combining multiple modalities, which enables to determine the appropriate location for resection, anastomosis, and construction of a covering stoma.
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Colitis , Neoplasias Colorrectales , Obstrucción Intestinal , Stents Metálicos Autoexpandibles , Humanos , Obstrucción Intestinal/diagnóstico por imagen , Obstrucción Intestinal/etiología , Obstrucción Intestinal/cirugía , Estudios Retrospectivos , Neoplasias Colorrectales/complicaciones , Neoplasias Colorrectales/cirugía , Colitis/diagnóstico por imagen , Colitis/cirugía , Edema , Resultado del Tratamiento , Stents/efectos adversosRESUMEN
Mutational activation of the KRAS gene occurs in almost all pancreatic ductal adenocarcinoma (PDAC) and is the earliest molecular event in their carcinogenesis. Evidence has accumulated of the metabolic reprogramming in PDAC, such as amino acid homeostasis and autophagic flux. However, the biological effects of KRAS mutation on metabolic reprogramming at the earlier stages of PDAC carcinogenesis are unclear. Here we report dynamic metabolic reprogramming in immortalized human non-cancerous pancreatic ductal epithelial cells, in which a KRAS mutation was induced by gene-editing, which may mimic early pancreatic carcinogenesis. Similar to the cases of PDAC, KRAS gene mutation increased the dependency on glucose and glutamine for maintaining the intracellular redox balance. In addition, the intracellular levels of amino acids were significantly decreased because of active protein synthesis, and the cells required greater autophagic flux to maintain their viability. The lysosomal inhibitor chloroquine significantly inhibited cell proliferation. Therefore, metabolic reprogramming is an early event in carcinogenesis initiated by KRAS gene mutation, suggesting a rationale for the development of nutritional interventions that suppress or delay the development of PDAC.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Proteínas Proto-Oncogénicas p21(ras) , Carcinogénesis , Carcinoma Ductal Pancreático/metabolismo , Humanos , Mutación , Neoplasias Pancreáticas/patología , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Neoplasias PancreáticasRESUMEN
BACKGROUND & AIMS: Hepatitis B virus (HBV) infection is a major health concern worldwide. Although currently used nucleos(t)ide analogs efficiently inhibit viral replication, viral proteins transcribed from the episomal viral covalently closed circular DNA (cccDNA) minichromosome continue to be expressed long-term. Because high viral RNA or antigen loads may play a biological role during this chronicity, the elimination of viral products is an ultimate goal of HBV treatment. HBV regulatory protein X (HBx) was recently found to promote transcription of cccDNA with degradation of Smc5/6 through the interaction of HBx with the host protein DDB1. Here, this protein-protein interaction was considered as a new molecular target of HBV treatment. METHODS: To identify candidate compounds that target the HBx-DDB1 interaction, a newly constructed split luciferase assay system was applied to comprehensive compound screening. The effects of the identified compounds on HBV transcription and cccDNA maintenance were determined using HBV minicircle DNA, which mimics HBV cccDNA, and the natural HBV infection model of human primary hepatocytes. RESULTS: We show that nitazoxanide (NTZ), a thiazolide anti-infective agent that has been approved by the FDA for protozoan enteritis, efficiently inhibits the HBx-DDB1 protein interaction. NTZ significantly restores Smc5 protein levels and suppresses viral transcription and viral protein production in the HBV minicircle system and in human primary hepatocytes naturally infected with HBV. CONCLUSIONS: These results indicate that NTZ, which targets an HBV-related viral-host protein interaction, may be a promising new therapeutic agent and a step toward a functional HBV cure.
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ADN Circular/genética , Proteínas de Unión al ADN/metabolismo , Virus de la Hepatitis B/genética , Tiazoles/farmacología , Transactivadores/metabolismo , Transcripción Genética/efectos de los fármacos , ADN Viral/genética , Células HEK293 , Células Hep G2 , Virus de la Hepatitis B/efectos de los fármacos , Hepatocitos/metabolismo , Hepatocitos/virología , Ensayos Analíticos de Alto Rendimiento , Humanos , Nitrocompuestos , Unión Proteica/efectos de los fármacos , Proteolisis/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Viral/genética , Proteínas Reguladoras y Accesorias ViralesRESUMEN
Although the detection of circulating tumor cells (CTCs) should be crucial for future personalized medicine, no efficient and flexible methods have been established. The current study established a polymeric custom-made chip for capturing CTCs with a high efficiency and flexibility. As an example of clinical application, the effects of self-expandable metallic stent (SEMS) placement on the release of cancer cells into the blood of patients with colorectal cancer and bowel obstruction were analyzed. This was assessed as the placement of SEMS may cause mechanical damage and physical force to malignant tissue, increasing the risk of cancer cell release into the bloodstream. The present study examined the number of CTCs using a custom-made chip, before, at 24 h after and at 4 days after SEMS placement in patients with colorectal cancer. The results revealed that, among the 13 patients examined, the number of CTCs was increased in three cases at 24 h after SEMS placement. However, this increase was temporary. The number of CTCs also decreased at 4 days after stent placement in most cases. The CTC chip of the current study detected the number of CD133-positive cancer stem-like cells, which did not change, even in the patient whose total number of CTCs temporarily increased. The results indicated that this custom-made microfluid system can efficiently and flexibly detect CTCs, demonstrating its potential for obtaining information during the management of patients with cancer.