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Human satellite II (HSATII), composed of tandem repeats in pericentromeric regions, is aberrantly transcribed in epithelial cancers, particularly pancreatic cancer. Dysregulation of repetitive elements in cancer tissues can facilitate incidental dsRNA formation; however, it remains controversial whether dsRNAs play tumor-promoting or tumor-suppressing roles during cancer progression. Therefore, we focused on the double-stranded formation of HSATII RNA and explored its molecular function. The overexpression of double-stranded HSATII (dsHSATII) RNA promoted mesenchymal-like morphological changes and enhanced the invasiveness of pancreatic cancer cells. We identified an RNA-binding protein, spermatid perinuclear RNA-binding protein (STRBP), which preferentially binds to dsHSATII RNA rather than single-stranded HSATII RNA. The mesenchymal transition of dsHSATII-expressing cells was rescued by STRBP overexpression. Mechanistically, STRBP is involved in the alternative splicing of genes associated with epithelial-mesenchymal transition (EMT). We also confirmed that isoform switching of CLSTN1, driven by dsHSATII overexpression or STRBP depletion, induced EMT-like morphological changes. These findings reveal a novel tumor-promoting function of dsHSATII RNA, inducing EMT-like changes and cell invasiveness, thus enhancing our understanding of the biological significance of aberrant expression of satellite arrays in malignant tumors.
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Empalme Alternativo , ADN Satélite , Transición Epitelial-Mesenquimal , Regulación Neoplásica de la Expresión Génica , Neoplasias Pancreáticas , ARN Bicatenario , Humanos , Empalme Alternativo/genética , Línea Celular Tumoral , Transición Epitelial-Mesenquimal/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , ARN Bicatenario/genética , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Proteínas Asociadas a Microtúbulos/deficiencia , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Proteínas de Unión al Calcio/química , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/metabolismo , Progresión de la Enfermedad , Invasividad Neoplásica/genética , ADN Satélite/genéticaRESUMEN
OBJECTIVE: To examine whether long-term surveillance of intraductal papillary mucinous neoplasms (IPMNs) leads to early diagnosis and better clinical outcomes of pancreatic ductal adenocarcinomas (PDACs) developing concomitantly with IPMNs. SUMMARY BACKGROUND DATA: Long-term image-based surveillance is recommended for patients with low-risk IPMNs. However, it is unknown whether the surveillance can improve surgical and survival outcomes of patients with concomitant PDACs. METHODS: Using a prospective single-institutional cohort of 4,620 patients with pancreatic cysts including 3,638 IPMN patients, we identified 63 patients who developed concomitant PDAC during long-term surveillance. We compared overall survival (OS) of 46 cases with concomitant PDAC to that of 460 matched cases diagnosed with non-IPMN-associated PDAC at the same institution. Multivariable hazard ratios and 95% confidence intervals (CIs) for overall mortality were computed using the Cox regression model with adjustment for potential confounders. RESULTS: Concomitant PDACs were identified at an earlier cancer stage compared to non-IPMN-associated PDACs with 67% and 38% cases identified at stage 2 or earlier, respectively (P<0.001) and 57% and 21% cases with R0 resection, respectively (P<0.001). Compared to non-IPMN-associated PDACs, concomitant PDACs were associated with longer OS (P=0.034) with a multivariable hazard ratio of 0.61 (95% CI, 0.39-0.96). The 5-year survival rate of patients with concomitant PDAC was higher compared to patients with non-IPMN-associated PDAC (34% vs. 18%, respectively; P=0.018). CONCLUSIONS: The surveillance for patients with IPMNs was associated with early identification of concomitant PDACs and longer survival of patients diagnosed with this malignancy.
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BACKGROUND & AIMS: The revised Kyoto guidelines have a new catalog of high-risk stigmata and worrisome features for the risk stratification of intraductal papillary mucinous neoplasms (IPMNs). We aimed to validate the stratification system in terms of short- and long-term risks of pancreatic carcinoma. METHODS: We included 3336 patients diagnosed with IPMNs in 2000-2021 and examined short-term (≤6 months) and long-term risks of pancreatic carcinoma diagnosis. We used the multivariable competing-risks proportional hazards regression model to calculate subdistribution hazard ratios for long-term incidence of pancreatic carcinoma with adjustment for potential confounders. RESULTS: In short-term analyses, pancreatic carcinomas were prevalent predominantly in IPMNs with high-risk stigmata (49% vs 1.3% and 0.05% in IPMNs with worrisome features and no risk factors, respectively). In long-term analyses of worrisome features, the main pancreatic duct diameter of 5-9.9 mm, acute pancreatitis, and IPMN growth rate of 2.5 mm/y were associated with a high incidence with multivariable subdistribution hazard ratios of 3.46 (95% confidence interval [CI], 2.04-5.89), 5.65 (95% CI, 1.86-17.2), and 3.83 (95% CI, 2.14-6.86), respectively. An increasing number of worrisome features at baseline was associated with a higher prevalence and incidence of pancreatic carcinoma (Ptrend < .001). Patients with 1, 2, and 3-4 worrisome features had multivariable subdistribution hazard ratios for pancreatic cancer incidence of 1.43 (95% CI, 0.93-2.19), 2.17 (95% CI, 1.17-4.05), and 10.1 (95% CI, 4.20-24.5), respectively (vs no positive feature). CONCLUSIONS: The revised Kyoto criteria stratify IPMN patients well in terms of the short- and long-term risks of pancreatic carcinoma diagnosis, potentially informing personalized patient management.
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INTRODUCTION: Aging has been implicated in the development of various cancer types. No study has specifically investigated age at intraductal papillary mucinous neoplasm (IPMN) diagnosis in relation to the long-term risk of pancreatic carcinogenesis. METHODS: Within a prospective cohort of 4,104 patients diagnosed with pancreatic cysts, we identified 3,142 patients with IPMNs and examined an association of age at IPMN diagnosis with the incidence of pancreatic carcinoma. Using the multivariable competing-risks proportional hazards regression model, we estimated subdistribution hazard ratios (SHRs) and 95% confidence intervals (CIs) for pancreatic carcinoma incidence according to age at IPMN diagnosis. RESULTS: During 22,187 person-years of follow-up, we documented 130 patients diagnosed with pancreatic carcinoma (64 with IPMN-derived carcinoma and 66 with concomitant ductal adenocarcinoma). Older age at IPMN diagnosis was associated with a higher risk of pancreatic cancer incidence ( Ptrend = 0.002). Compared with patients younger than 55 years, patients aged 55-64, 65-74, and ≥ 75 years had adjusted SHRs of 1.80 (95% CI, 0.75-4.32), 2.56 (95% CI, 1.10-5.98), and 3.31 (95% CI, 1.40-7.83), respectively. Patients aged 70 years and older had a numerically similar adjusted SHR compared with patients younger than 70 years with worrisome features defined by the international consensus guidelines (1.73 [95% CI, 1.01-2.97] and 1.66 [95% CI, 0.89-3.10], respectively). DISCUSSION: Older patients with IPMNs were at a higher risk of developing pancreatic carcinoma during surveillance. Surgically fit elderly patients may be good candidates for periodic surveillance aimed at a reduction of pancreatic cancer-related deaths.
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BACKGROUND AND AIM: Balloon endoscopy-assisted endoscopic retrograde cholangiopancreatography (BE-ERCP) is an emerging procedure for pancreatobiliary diseases in patients with surgically altered anatomy. However, data on BE-ERCP for hepatolithiasis after hepaticojejunostomy (HJS) are still limited. METHODS: Stone removal success, adverse events and recurrence were retrospectively studied in consecutive patients who underwent BE-ERCP for hepatolithiasis after HJS between January 2011 and October 2022. Subgroup analysis was performed to compare clinical outcomes between patients who had undergone HJS over 10 years before (past HJS group) and within 10 years (recent HJS group). RESULTS: A total of 131 patients were included; 39% had undergone HJS for malignancy and 32% for congenital biliary dilation. Scope insertion and complete stone removal were successful in 89% and 73%, respectively. Early adverse events were observed in 9.9%. Four patients (3.1%) developed gastrointestinal perforation but could be managed conservatively. Hepatolithiasis recurrence rate was 17%, 20% and 31% in 1-year, 3-year, and 5-year after complete stone removal. The past HJS group was the only risk factor for failed stone removal (odds ratio 10.4, 95% confidence interval 2.99-36.5) in the multivariable analysis. Failed scope insertion (20%) and failed guidewire or device insertion to the bile duct (22%) were two major reasons for failed stone removal in the past HJS group. CONCLUSIONS: BE-ERCP for hepatolithiasis was effective and safe in cases with HJS but the complete stone removal rate was low in the past HJS group. Recurrent hepatolithiasis was common and careful follow up study is needed even after complete stone removal.
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Colangiopancreatografia Retrógrada Endoscópica , Litiasis , Hepatopatías , Humanos , Masculino , Femenino , Estudios Retrospectivos , Colangiopancreatografia Retrógrada Endoscópica/métodos , Persona de Mediana Edad , Anciano , Hepatopatías/cirugía , Litiasis/cirugía , Adulto , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Recurrencia , Yeyunostomía/métodos , Anciano de 80 o más Años , Resultado del TratamientoRESUMEN
BACKGROUND: Studies have demonstrated a prognostic role of sarcopenia (i.e., loss of skeletal muscle volume and functionality) in patients with various cancer types. In patients with biliary tract cancer, the quantity and quality of skeletal muscles and their serial changes have not been fully investigated in relation to survival outcomes. METHODS: We identified 386 patients with unresectable or recurrent biliary tract cancer and calculated skeletal muscle index (SMI) and skeletal muscle density (SMD) to estimate muscular quantity and quality, respectively, based on computed tomography images. Using the Cox regression model with adjustment for potential confounders, we calculated hazard ratios (HRs) and 95% confidence intervals (CIs) for progression-free survival (PFS) and overall survival (OS) according to skeletal muscle status and its serial change. RESULTS: Compared to patients without sarcopenia, patients with sarcopenia were associated with shorter PFS (multivariable HR, 1.60; 95% CI, 1.15-2.22; P = 0.005), but not with OS (P = 0.027) at the adjusted α level of 0.013. SMD at baseline was associated with OS (multivariable HR comparing the extreme quartiles, 1.52; 95% CI, 1.07-2.14; Ptrend = 0.012), but not with PFS (Ptrend = 0.13). A reduction in SMI rather than that in SMD was associated with OS. Progressive disease was a risk factor for reductions in SMI and SMD. CONCLUSIONS: Skeletal muscle quantity and quality and their serial changes were associated with survival outcomes in patients with advanced biliary tract cancer. Our data highlight the importance of designing nutritional and physical interventions for improvements in skeletal muscle status.
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Neoplasias de los Conductos Biliares , Neoplasias del Sistema Biliar , Sarcopenia , Humanos , Sarcopenia/etiología , Estudios Retrospectivos , Recurrencia Local de Neoplasia/patología , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/patología , Pronóstico , Neoplasias de los Conductos Biliares/patología , Neoplasias del Sistema Biliar/patologíaRESUMEN
OBJECTIVES: Endoscopic management of unresectable hilar malignant biliary obstruction (HMBO) is technically challenging, and effectiveness of stent-in-stent using large-cell, metal stents was reported. A new, large-cell stent with a 6F tapered delivery system was recently developed. The aim of this study was to compare clinical outcomes of slim-delivery and conventional large-cell stents. METHODS: This was a multicenter retrospective comparative study of stent-in-stent methods using slim-delivery stents (Niti-S Large Cell SR Slim Delivery [LC slim-delivery]) and conventional stents (Niti-S large-cell D-type; LCD) for unresectable HMBO. RESULTS: Eighty-three patients with HMBO were included; 31 LC slim-delivery and 52 LCD. Overall technical and clinical success rates were 100% and 90% in LC slim-delivery group and 98% and 88% in LCD group. Use of the LC slim-delivery was associated with shorter stent placement time in the multiple regression analysis, with a stent placement time of 18 and 23 min in LC slim-delivery and LCD groups, respectively. The early adverse event (AE) rate of LC slim-delivery was 10%, with no cholangitis or cholecystitis as compared to 23% in the LCD group. Recurrent biliary obstruction (RBO) rates and time to RBO were comparable between the two groups: 35% and 44%, and 8.5 and 8.0 months in LC slim-delivery and LCD groups, respectively. The major cause of RBO was tumor ingrowth (82%) in the LC slim-delivery group and sludge (43%) and ingrowth (48%) in LCD group. CONCLUSION: Stent-in-stent methods using LC slim-delivery shortened stent placement time with low early AE rates and comparable time to RBO in patients with HMBO.
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Neoplasias de los Conductos Biliares , Colangitis , Colestasis , Humanos , Estudios Retrospectivos , Neoplasias de los Conductos Biliares/complicaciones , Neoplasias de los Conductos Biliares/cirugía , Stents/efectos adversos , Colestasis/cirugía , Colestasis/complicaciones , Colangitis/complicaciones , Resultado del TratamientoRESUMEN
BACKGROUND & AIMS: Dilatation of the main pancreatic duct (MPD) has been a surgical indication for intraductal papillary mucinous neoplasms (IPMNs). Few studies have investigated long-term outcomes of IPMNs with MPD dilatation. METHODS: Among 3610 patients diagnosed with pancreatic cysts between 1994 and 2021, we identified 2829 IPMN patients, including 282 patients with MPD ≥5 mm, and examined short-term (≤6 months) and long-term risks of pancreatic carcinoma. Utilizing competing risks proportional hazards models, we estimated subdistribution hazard ratios for incidence of pancreatic carcinoma with adjustment for potential confounders. RESULTS: In analyses of short-term outcomes of the 282 patients with MPD dilatation, 72 (26%) patients were diagnosed with pancreatic carcinoma based on surgical or nonsurgical exploration. During long-term follow-up of 168 patients, we documented 24 (14%) patients diagnosed with pancreatic carcinoma (18 with IPMN-derived carcinoma and 6 with concomitant ductal adenocarcinoma). The patients with the MPD = 5-9.9 mm had cumulative incidence rates of pancreatic carcinoma diagnosis of 8.1% (95% confidence interval [CI], 4.3%-13.5%) and 10.0% (95% CI, 5.5%-15.9%) at 2 and 5 years, respectively; and the patients with the MPD ≥10 mm had the corresponding rates of 16.0% (95% CI, 3.6-36.5%) and 33.3% (95% CI, 10.3%-58.8%). The multivariable subdistribution hazard ratios were 2.78 (95% CI, 1.57-4.90) and 7.00 (95% CI, 2.58-19.0) for the MPD = 5-9.9 mm and ≥10 mm (vs <5 mm), respectively. CONCLUSIONS: IPMNs with MPD dilatation at baseline were associated with higher prevalence and incidence of pancreatic carcinoma compared with IPMNs with no MPD dilatation.
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Carcinoma Ductal Pancreático , Neoplasias Quísticas, Mucinosas y Serosas , Neoplasias Intraductales Pancreáticas , Neoplasias Pancreáticas , Humanos , Carcinoma Ductal Pancreático/epidemiología , Carcinoma Ductal Pancreático/cirugía , Carcinoma Ductal Pancreático/diagnóstico , Neoplasias Intraductales Pancreáticas/patología , Dilatación , Neoplasias Pancreáticas/epidemiología , Neoplasias Pancreáticas/cirugía , Neoplasias Pancreáticas/diagnóstico , Conductos Pancreáticos/patología , Neoplasias Quísticas, Mucinosas y Serosas/patología , Estudios Retrospectivos , Neoplasias PancreáticasRESUMEN
BACKGROUND & AIMS: Chromatin architecture governs cell lineages by regulating the specific gene expression; however, its role in the diversity of cancer development remains unknown. Among pancreatic cancers, pancreatic ductal adenocarcinoma (PDAC) and intraductal papillary mucinous neoplasms (IPMN) with an associated invasive carcinoma (IPMNinv) arise from 2 distinct precursors, and their fundamental differences remain obscure. Here, we aimed to assess the difference of chromatin architecture regulating the transcriptional signatures or biological features in pancreatic cancers. METHODS: We established 28 human organoids from distinct subtypes of pancreatic tumors, including IPMN, IPMNinv, and PDAC. We performed exome sequencing (seq), RNA-seq, assay for transposase-accessible chromatin-seq, chromatin immunoprecipitation-seq, high-throughput chromosome conformation capture, and phenotypic analyses with short hairpin RNA or clustered regularly interspaced short palindromic repeats interference. RESULTS: Established organoids successfully reproduced the histology of primary tumors. IPMN and IPMNinv organoids harbored GNAS, RNF43, or KLF4 mutations and showed the distinct expression profiles compared with PDAC. Chromatin accessibility profiles revealed the gain of stomach-specific open regions in IPMN and the pattern of diverse gastrointestinal tissues in IPMNinv. In contrast, PDAC presented an impressive loss of accessible regions compared with normal pancreatic ducts. Transcription factor footprint analysis and functional assays identified that MNX1 and HNF1B were biologically indispensable for IPMN lineages. The upregulation of MNX1 was specifically marked in the human IPMN lineage tissues. The MNX1-HNF1B axis governed a set of genes, including MYC, SOX9, and OLFM4, which are known to be essential for gastrointestinal stem cells. High-throughput chromosome conformation capture analysis suggested the HNF1B target genes to be 3-dimensionally connected in the genome of IPMNinv. CONCLUSIONS: Our organoid analyses identified the MNX1-HNF1B axis to be biologically significant in IPMN lineages.
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Adenocarcinoma Mucinoso , Carcinoma Ductal Pancreático , Factor Nuclear 1-beta del Hepatocito , Proteínas de Homeodominio , Neoplasias Intraductales Pancreáticas , Factores de Transcripción , Adenocarcinoma Mucinoso/genética , Carcinoma Ductal Pancreático/patología , Cromatina , Factor Nuclear 1-beta del Hepatocito/genética , Proteínas de Homeodominio/genética , Humanos , Neoplasias Intraductales Pancreáticas/genética , Factores de Transcripción/genética , Neoplasias PancreáticasRESUMEN
BACKGROUND AND AIMS: Endoscopic retrograde cholangiopancreatography (ERCP) is widely performed for management of pancreatobiliary diseases; however, post-ERCP pancreatitis (PEP) remains as an unsolved problem. Although various risk factors for PEP have been reported, the prediction of PEP remains controversial. This study aimed to develop a predictive model for PEP. METHODS: Consecutive patients undergoing ERCP for biliary indications at two centers were retrospectively studied. Using data from a training cohort, we utilized a multivariable model to select five variables to construct a nomogram. The predictive model was internally and externally validated. Based on the nomogram, the patients were categorized into low-, moderate-, and high-risk groups. RESULTS: Using the data of 2224 patients in the training cohort, five variables were selected to generate a nomogram: 1) sex, 2) indication for ERCP, 3) difficult cannulation, 4) guidewire insertion into the pancreatic duct, and 5) endoscopic sphincterotomy or sphincteroplasty. The most significant risk factor was endoscopic papillary balloon dilation such as endoscopic sphincterotomy or sphincteroplasty. The bias-corrected concordance index was 0.72 in the training cohort and 0.72 in the validation cohort. Calibration curves for both cohorts demonstrated good agreement between the predicted and observed frequencies of the actual outcome. In the validation cohort, PEP developed in 5.0% and 14% of patients in the moderate- and high-risk groups, respectively. CONCLUSIONS: We successfully developed a good predictive model for PEP. The prevention of PEP in high risk patients should be investigated further.
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Colangiopancreatografia Retrógrada Endoscópica , Pancreatitis , Humanos , Colangiopancreatografia Retrógrada Endoscópica/efectos adversos , Estudios Retrospectivos , Nomogramas , Cateterismo , Pancreatitis/epidemiología , Pancreatitis/etiología , Pancreatitis/prevención & control , Factores de RiesgoRESUMEN
PURPOSE: Patients with pancreatic cancer often have cancer cachexia at diagnosis. Recent studies suggested that loss of skeletal muscle mass was related to cancer cachexia, which hindered continuance of chemotherapy and could be one of prognostic factors in pancreatic cancer, however the association remains unclear in patients receiving gemcitabine and nab-paclitaxel (GnP). METHODS: We retrospectively studied 138 patients with unresectable pancreatic cancer receiving first-line GnP at the University of Tokyo from January 2015 to September 2020. We calculated body composition in CT images before chemotherapy and at initial evaluation, and evaluated the association of both body composition before chemotherapy and its changes at initial evaluation. RESULTS: Compared by skeletal muscle mass index (SMI) change rate between pre-chemotherapy and initial evaluation, there were statistically significantly differences in the median OS: 16.3 months (95%CI 12.3-22.7) and 10.3 months (95%CI 8.3-18.1) between SMI change rate ≥ -3.5% and < -3.5% groups (P = 0.01). By multivariate analysis for OS, CA19-9 (HR 3.34, 95%CI 2.00-5.57, P < 0.01), PLR (HR 1.68, 95%CI 1.01-2.78, P = 0.04), mGPS (HR 2.32, 95%CI 1.47-3.65, P < 0.01) and relative dose intensity (HR 2.21, 95%CI 1.42-3.46, P < 0.01) were significantly poor prognostic factors. SMI change rate (HR 1.47, 95%CI 0.95-2.28, P = 0.08) showed a trend to poor prognosis. Sarcopenia before chemotherapy was not significantly associated with PFS or OS. CONCLUSION: Early skeletal muscle mass decline was associated with poor OS. Further investigation is warranted whether the maintenance of skeletal muscle mass by nutritional support would improve prognosis.
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Gemcitabina , Neoplasias Pancreáticas , Humanos , Caquexia , Pronóstico , Estudios Retrospectivos , Neoplasias Pancreáticas/complicaciones , Neoplasias Pancreáticas/tratamiento farmacológico , Músculo Esquelético/diagnóstico por imagen , Neoplasias PancreáticasRESUMEN
KRAS mutation is a major driver of pancreatic carcinogenesis and will likely be a therapeutic target. Due to lack of sensitive assays for clinical samples of pancreatic cancer with low cellularity, KRAS mutations and their prognostic association have not been fully examined in large populations. In a multi-institutional cohort of 1162 pancreatic cancer patients with formalin-fixed paraffin-embedded tumor samples, we undertook droplet digital PCR (ddPCR) for KRAS codons 12/13/61. We examined detection rates of KRAS mutations by clinicopathological parameters and survival associations of KRAS mutation status. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for disease-free survival (DFS) and overall survival (OS) were computed using the Cox regression model with adjustment for potential confounders. KRAS mutations were detected in 1139 (98%) patients. The detection rate did not differ by age of tissue blocks, tumor cellularity, or receipt of neoadjuvant chemotherapy. KRAS mutations were not associated with DFS or OS (multivariable HR comparing KRAS-mutant to KRAS-wild-type tumors, 1.04 [95% CI, 0.62-1.75] and 1.05 [95% CI, 0.60-1.84], respectively). Among KRAS-mutant tumors, KRAS variant allele frequency (VAF) was inversely associated with DFS and OS with HRs per 20% VAF increase of 1.27 (95% CI, 1.13-1.42; ptrend <0.001) and 1.31 (95% CI, 1.16-1.48; ptrend <0.001), respectively. In summary, ddPCR detected KRAS mutations in clinical specimens of pancreatic cancer with high sensitivity irrespective of parameters potentially affecting mutation detections. KRAS VAF, but not mutation positivity, was associated with survival of pancreatic cancer patients.
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Neoplasias Pancreáticas , Proteínas Proto-Oncogénicas p21(ras) , Biomarcadores de Tumor/genética , Frecuencia de los Genes , Humanos , Mutación , Neoplasias Pancreáticas/patología , Pronóstico , Proteínas Proto-Oncogénicas p21(ras)/genética , Neoplasias PancreáticasRESUMEN
In Japan, the Pharmaceutical and Medical Device Act was amended in December 2019 and now requires pharmacists to follow-up patients continuously during treatment to ensure proper use of medicines. According to some reports on patients with type 2 diabetes mellitus (T2DM), follow-up by doctors is effective for improving treatment. Enhanced face-to-face medication counseling by pharmacists leads to good glycemic control in patients with diabetes. However, the effects of information and communication technology (ICT)-based follow-up during the medication period are not well-understood. We determined the efficacy of pharmacists' follow-up using FollowNavi, a patient compliance instruction support system, and using our developed LINE tool for patients with T2DM. Through a before-after study, changes in glycemic control and medication adherence after 6 months of follow-up were investigated, and multiple regression analysis was performed to investigate the factors associated with changes in hemoglobin A1c (HbA1c) levels. Questionnaire surveys related to usability were completed by patients and pharmacists. In the 35 patients with T2DM, HbA1c levels decreased significantly after 6 months, although fasting blood glucose levels and medication adherence showed no significant differences. Changes in HbA1c levels were significantly associated with age (p = 0.044), baseline HbA1c levels (p < 0.001), and diabetes duration (p = 0.004). In the questionnaire, 81.8% of patients responded that they would prefer to continue using FollowNavi. These results suggest that follow-up using FollowNavi is useful for glycemic control in patients with T2DM.
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Diabetes Mellitus Tipo 2 , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hemoglobina Glucada/análisis , Humanos , Hipoglucemiantes/uso terapéutico , Cumplimiento de la Medicación , FarmacéuticosRESUMEN
Remyelination is a regenerative process that restores the lost neurological function and partially depends on oligodendrocyte differentiation. Differentiation of oligodendrocytes spontaneously occurs after demyelination, depending on the cell intrinsic mechanisms. By combining a loss-of-function genomic screen with a web-resource-based candidate gene identification approach, we identified that dimethylarginine dimethylaminohydrolase 1 (DDAH1) is a novel regulator of oligodendrocyte differentiation. Silencing DDAH1 in oligodendrocytes prevented the expression of myelin basic protein in mouse oligodendrocyte culture with the change in expression of genes annotated with oligodendrocyte development. DDAH1 inhibition attenuated spontaneous remyelination in a cuprizone-induced demyelinated mouse model. Conversely, increased DDAH1 expression enhanced remyelination capacity in experimental autoimmune encephalomyelitis. These results provide a novel therapeutic option for demyelinating diseases by modulating DDAH1 activity.
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Remielinización , Amidohidrolasas , Animales , Diferenciación Celular , Sistema Nervioso Central , Cuprizona/toxicidad , Ratones , Ratones Endogámicos C57BL , Vaina de Mielina/metabolismo , Oligodendroglía/metabolismo , Remielinización/fisiologíaRESUMEN
BACKGROUND & AIMS: Long-term outcomes of patients with branch-duct intraductal papillary mucinous neoplasms (IPMNs), particularly those after 5 years of surveillance, have not been fully evaluated in large studies. We analyzed incidences of IPMN-derived carcinoma and concomitant ductal adenocarcinoma (pancreatic ductal adenocarcinoma [PDAC]) over 20 years in a large population of patients. METHODS: We identified 1404 consecutive patients (52% women; mean age, 67.5 years) with a diagnosis of branch-duct IPMN, from 1994 through 2017, at the University of Tokyo in Japan. Using a competing risk analysis, we estimated cumulative incidence of pancreatic carcinoma, overall and by carcinoma type. We used competing risks proportional hazards models to estimate subdistribution hazard ratios (SHRs) for incidences of carcinomas. To differentiate IPMN-derived and concomitant carcinomas, we collected genomic DNA from available paired samples of IPMNs and carcinomas and detected mutations in GNAS and KRAS by polymerase chain reaction and pyrosequencing. RESULTS: During 9231 person-years of follow-up, we identified 68 patients with pancreatic carcinomas (38 patients with IPMN-derived carcinomas and 30 patients with concomitant PDACs); the overall incidence rates were 3.3%, 6.6%, and 15.0% at 5, 10, and 15 years, respectively. Among 804 patients followed more than 5 years, overall cumulative incidence rates of pancreatic carcinoma were 3.5% at 10 years and 12.0% at 15 years from the initial diagnosis. The size of the IPMN and the diameter of the main pancreatic duct associated with incidence of IPMN-derived carcinoma (SHR 1.85; 95% confidence interval 1.38-2.48 for a 10-mm increase in the IPMN size and SHR 1.56; 95% confidence interval 1.33-1.83 for a 1-mm increase in the main pancreatic duct diameter) but not with incidence of concomitant PDAC. CONCLUSIONS: In a large long-term study of patients with branch-duct IPMNs, we found the 5-year incidence rate of pancreatic malignancy to be 3.3%, reaching 15.0% at 15 years after IPMN diagnosis. We observed heterogeneous risk factor profiles between IPMN-derived and concomitant carcinomas.
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Adenocarcinoma Mucinoso/epidemiología , Carcinoma Ductal Pancreático/epidemiología , Neoplasias Primarias Múltiples/epidemiología , Neoplasias Intraductales Pancreáticas/patología , Neoplasias Pancreáticas/epidemiología , Adenocarcinoma Mucinoso/genética , Adenocarcinoma Mucinoso/patología , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Cromograninas/genética , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Subunidades alfa de la Proteína de Unión al GTP Gs/genética , Humanos , Incidencia , Japón/epidemiología , Masculino , Persona de Mediana Edad , Mutación , Neoplasias Primarias Múltiples/genética , Neoplasias Primarias Múltiples/patología , Conductos Pancreáticos/patología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Proteínas Proto-Oncogénicas p21(ras)/genética , Factores de RiesgoRESUMEN
Oral anticoagulants (OACs) pose a major bleeding risk, which may be increased or decreased by concomitant medications. To explore medications that affect the bleeding risk of OACs, we conducted a nested case-control study including 554 bleeding cases (warfarin, n = 327; direct OACs [DOACs], n = 227) and 1337 non-bleeding controls (warfarin, n = 814; DOACs, n = 523), using a Japanese health insurance database from January 2005 to June 2017. Major bleeding risk associated with exposure to concomitant medications within 30 d of the event/index date was evaluated, and adjusted odds ratios (aORs) were calculated using logistic regression analysis. Several antihypertensive drugs, such as amlodipine and bisoprolol, were associated with a decreased risk of bleeding (warfarin + amlodipine [aOR, 0.64; 95% confidence interval (CI): 0.41-0.98], DOACs + bisoprolol [aOR, 0.51; 95% CI, 0.33-0.80]). As hypertension is considered a significant risk factor for intracranial bleeding in antithrombotic therapy, antihypertensive drugs may suppress intracranial bleeding. In contrast, telmisartan, a widely used antihypertensive drug, was associated with an increased risk of bleeding [DOACs + telmisartan (aOR, 4.87; 95% CI, 1.84-12.91)]. Since telmisartan is an inhibitor of P-glycoprotein (P-gp), the elimination of rivaroxaban and apixaban, which are substrates of P-gp, is hindered, resulting in increased blood levels of both drugs, thereby increasing the risk of hemorrhage. In conclusion, antihypertensive drugs may improve the safety of OACs, and the pharmacokinetic-based drug interactions of DOACs must be considered.
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Anticoagulantes/efectos adversos , Antihipertensivos/farmacocinética , Hemorragia/epidemiología , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Administración Oral , Reclamos Administrativos en el Cuidado de la Salud/estadística & datos numéricos , Amlodipino/administración & dosificación , Amlodipino/farmacocinética , Anticoagulantes/administración & dosificación , Anticoagulantes/farmacocinética , Antihipertensivos/administración & dosificación , Bisoprolol/administración & dosificación , Bisoprolol/farmacocinética , Estudios de Casos y Controles , Interacciones Farmacológicas , Femenino , Hemorragia/inducido químicamente , Hemorragia/prevención & control , Humanos , Japón/epidemiología , Masculino , Persona de Mediana Edad , Pirazoles/administración & dosificación , Pirazoles/efectos adversos , Pirazoles/farmacocinética , Piridonas/administración & dosificación , Piridonas/efectos adversos , Piridonas/farmacocinética , Medición de Riesgo/estadística & datos numéricos , Rivaroxabán/administración & dosificación , Rivaroxabán/efectos adversos , Rivaroxabán/farmacocinética , Telmisartán/administración & dosificación , Telmisartán/farmacocinética , Warfarina/administración & dosificación , Warfarina/efectos adversos , Warfarina/farmacocinéticaRESUMEN
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: Limited data are available on age and comorbidity assessment in patients with biliary tract cancer (BTC). This study aimed to evaluate the association of age and comorbidity burden with clinical outcomes of chemotherapy for BTC. METHODS: Consecutive 197 BTC patients undergoing first-line chemotherapy between 2007 and 2017 were retrospectively studied. Patients were classified to three groups according to the age-adjusted Charlson comorbidity index (ACCI) excluding the score about BTC and progression-free survival, overall survival (OS), and safety were compared. RESULTS: Fifty-one patients (26%) were elderly (≥ 75 years), and ACCI was 0-2 in 73 patients (37%), 3-4 in 98 (50%), and ≥ 5 in 26 (13%). ACCI was associated with the administration of first-line combination chemotherapy (89% in 0-2, 80% in 3-4, and 64% in ≥ 5, P < 0.01) and second-line chemotherapy (67% in 0-2, 51% in 3-4, and 35% in ≥ 5, P = 0.01). ACCI was prognostic for OS in addition to performance status, disease status, and CA19-9: The hazard ratios in ACCI of 3-4 and ≥ 5 were 1.39 and 1.79, compared with ACCI of 0-2 (P = 0.04). While overall safety profile did not differ by ACCI, higher ACCI score group developed Grade 3-4 neutropenia more frequently (26% in 0-2, 42% in 3-4, and 46% in ≥ 5, P = 0.04). CONCLUSION: Age and comorbidity burden did affect OS and safety profile in BTC patients undergoing first-line palliative chemotherapy. ACCI can be a simple and useful tool to evaluate the age and comorbidity burden in these patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Sistema Biliar/tratamiento farmacológico , Cuidados Paliativos , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Neoplasias del Sistema Biliar/epidemiología , Neoplasias del Sistema Biliar/mortalidad , Comorbilidad , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Estudios Retrospectivos , Seguridad , Tasa de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
Purpose The survival benefit of first-line chemotherapy (CT1) for biliary tract cancer (BTC) is now established but the role of second-line chemotherapy (CT2) has not been fully elucidated yet. Methods Consecutive advanced BTC patients receiving CT1 between 2000 and 2016 were retrospectively studied. We investigated the safety and efficacy of CT2, prognostic factors for residual survival after CT1, and explored subgroups who would benefit from CT2. Results Among 294 patients receiving CT1 for advanced BTC, CT2 was given in 139 patients (47%). CT2 provided a response rate of 4%, a disease control rate of 52%, a median progression-free survival of 2.8 and overall survival of 7.7 months, respectively. CT2 was associated with longer residual survival after CT1 (hazard ratio [HR] 0.61, p < 0.01), as well as PS of 0-1 (HR 0.53, p < 0.01), best response to CT1 of PD (HR 1.46, p = 0.01), and CEA ≥5.0 ng/mL (HR 1.69, p < 0.01). The effects of CT2 were homogeneous across almost all subgroups but were more prominent in patients with age ≥ 70 years (HR 0.32, p for interaction =0.02), CA19-9 ≥ 200 IU/mL (HR 0.41, p for interaction = 0.08) and CEA ≥5.0 ng/mL (HR 0.41, p for interaction = 0.06). Conclusions The introduction rate of CT2 was 47%. Although the efficacy of CT2 was modest in terms of tumor response, it was associated with better survival. Further investigations are necessary both to develop more effective regimens and to select patients who will benefit from CT2.
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Antineoplásicos/uso terapéutico , Neoplasias del Sistema Biliar/tratamiento farmacológico , Neoplasias del Sistema Biliar/patología , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Pronóstico , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Biliary drainage via endoscopic retrograde cholangiopancreatography (ERCP) is the first-line treatment for acute cholangitis. Despite the established effectiveness of urgent biliary drainage in patients with severe acute cholangitis, the indication of this procedure for non-severe acute cholangitis is controversial. AIMS: To assess the safety of elective drainage (≥ 12 h of admission) for non-severe acute cholangitis. METHODS: We retrospectively identified 461 patients with non-severe acute cholangitis who underwent endoscopic biliary drainage. Using linear regression models with adjustment for a variety of potential confounders, we compared elective versus urgent biliary drainage (< 12 h of admission) in terms of clinical outcomes. The primary outcome was the length of stay. RESULTS: There were 98 and 201 patients who underwent elective and urgent biliary drainage, respectively. The median length of stay was 11 days in both groups (P = 0.52). The timing of ERCP was not associated with length of stay in the multivariable model (P = 0.52). Secondary outcomes including in-hospital mortality and recurrence of cholangitis were not different between the groups. CONCLUSIONS: Elective biliary drainage was not associated with worse clinical outcomes of non-severe acute cholangitis as compared to urgent drainage. Further investigation is warranted to justify the elective drainage for non-severe cholangitis.