RESUMO
Correlated regions of systemic interindividual variation (CoRSIV) represent a small proportion of the human genome showing DNA methylation patterns that are the same in all human tissues, are different among individuals, and are partially regulated by genetic variants in cis. In this study we aimed at investigating single-nucleotide polymorphisms (SNPs) within CoRSIVs and their involvement with pancreatic ductal adenocarcinoma (PDAC) risk. We analyzed 29,099 CoRSIV-SNPs and 133,615 CoRSIV-mQTLs in 14,394 cases and 247,022 controls of European and Asian descent. We observed that the A allele of the rs2976395 SNP was associated with increased PDAC risk in Europeans (p = 2.81 × 10-5). This SNP lies in the prostate stem cell antigen gene and is in perfect linkage disequilibrium with a variant (rs2294008) that has been reported to be associated with risk of many other cancer types. The A allele is associated with the DNA methylation level of the gene according to the PanCan-meQTL database and with overexpression according to QTLbase. The expression of the gene has been observed to be deregulated in many tumors of the gastrointestinal tract including pancreatic cancer; however, functional studies are needed to elucidate the function relevance of the association.
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Coding sequence variants comprise a small fraction of the germline genetic variability of the human genome. However, they often cause deleterious change in protein function and are therefore associated with pathogenic phenotypes. To identify novel pancreatic ductal adenocarcinoma (PDAC) risk loci, we carried out a complete scan of all common missense and synonymous SNPs and analysed them in a case-control study comprising four different populations, for a total of 14 538 PDAC cases and 190 657 controls. We observed a statistically significant association between 13q12.2-rs9581957-T and PDAC risk (Pâ =â 2.46â ×â 10-9), that is in linkage disequilibrium (LD) with a deleterious missense variant (rs9579139) of the URAD gene. Recent findings suggest that this gene is active in peroxisomes. Considering that peroxisomes have a key role as molecular scavengers, especially in eliminating reactive oxygen species, a malfunctioning URAD protein might expose the cell to a higher load of potentially DNA damaging molecules and therefore increase PDAC risk. The association was observed in individuals of European and Asian ethnicity. We also observed the association of the missense variant 15q24.1-rs2277598-T, that belongs to BBS4 gene, with increased PDAC risk (Pâ =â 1.53â ×â 10-6). rs2277598 is associated with body mass index and is in LD with diabetes susceptibility loci. In conclusion, we identified two missense variants associated with the risk of developing PDAC independently from the ethnicity highlighting the importance of conducting reanalysis of genome-wide association studies (GWASs) in light of functional data.
Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Estudos de Casos e Controles , Genoma Humano , Estudo de Associação Genômica Ampla , Predisposição Genética para Doença , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/genética , DNA , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Genes carrying high-penetrance germline mutations may also be associated with cancer susceptibility through common low-penetrance genetic variants. To increase the knowledge on genetic pancreatic ductal adenocarcinoma (PDAC) aetiology, the common genetic variability of PDAC familial genes was analysed in our study. We conducted a multiphase study analysing 7745 single nucleotide polymorphisms (SNPs) from 29 genes reported to harbour a high-penetrance PDAC-associated mutation in at least one published study. To assess the effect of the SNPs on PDAC risk, a total of 14 666 PDAC cases and 221 897 controls across five different studies were analysed. The T allele of the rs1412832 polymorphism, that is situated in the CDKN2B-AS1/ANRIL, showed a genome-wide significant association with increased risk of developing PDAC (OR = 1.11, 95% CI = 1.07-1.15, P = 5.25 × 10-9 ). CDKN2B-AS1/ANRIL is a long noncoding RNA, situated in 9p21.3, and regulates many target genes, among which CDKN2A (p16) that frequently shows deleterious somatic and germline mutations and deregulation in PDAC. Our results strongly support the role of the genetic variability of the 9p21.3 region in PDAC aetiopathogenesis and highlight the importance of secondary analysis as a tool for discovering new risk loci in complex human diseases.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , RNA Longo não Codificante , Humanos , Carcinoma Ductal Pancreático/genética , Predisposição Genética para Doença , Neoplasias Pancreáticas/genética , Polimorfismo de Nucleotídeo Único , RNA Longo não Codificante/genética , Neoplasias PancreáticasRESUMO
BACKGROUND AND AIMS: Lumen-apposing metal stents (LAMSs) have proven to be effective for drainage of pancreatic walled-off necrosis (WON), although associated adverse events (AEs) have been reported. Anchoring coaxial double-pigtail plastic stents (DPSs) within LAMSs have been proposed to prevent LAMS-related AEs but have not been assessed in prospective studies. We aimed to evaluate the utility of such measures with a randomized controlled trial. METHODS: We randomly assigned consecutive patients with WON indications for drainage to EUS-guided transluminal drainage using LAMSs with (group A) or without (group B) DPSs. All LAMSs were to be removed after 3 weeks had elapsed from the index procedure with a preceding CT to decide whether additional steps needed to be taken (eg, transluminal necrosectomy or placing transluminal plastic stents in patients with incomplete resolution of WON). The main outcomes were failure of the index method, defined as necessity of reintervention (endoscopic, percutaneous, or surgical) before LAMS removal because of LAMS-related AEs and/or clinical deterioration; AE rates; and mortality with the LAMS in place. Variables were evaluated using the Mann-Whitney U test, χ2 test, or Fisher exact test as appropriate. P < .05 was considered significant. RESULTS: Sixty-seven patients (37.3% women; mean age, 54 ± 14.4 years) underwent LAMS placement with (n = 34) or without (n = 33) DPS placement in 2 tertiary centers. Baseline characteristics including demographics, etiology, comorbidity, and clinical presentation (sterile vs infected necrosis) were comparable between both groups. The technical success rate in placing LAMSs and DPSs was 100%. The global rate of AEs was significantly lower in group A versus group B (20.7% vs 51.5%, respectively; P = .008). Stent occlusion was the most frequently observed AE (14.7% vs 36.3%, P = .042). Failure of the index method was lower in group A versus group B (29.4% vs 48.5%, respectively; P = .109); however, the difference did not achieve statistical significance. The same applied to the mortality rate with LAMSs in place (2.9% vs 12.1%, P = .197). CONCLUSIONS: The addition of a coaxial DPS within a LAMS was associated with a significantly lower global rate of AEs and stent occlusion rate in EUS-guided drainage of WON. (Clinical trial registration number: NCT03923686.).
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Pancreatite Necrosante Aguda , Stents , Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Masculino , Estudos Prospectivos , Resultado do Tratamento , Estudos Retrospectivos , Stents/efeitos adversos , Pancreatite Necrosante Aguda/cirurgia , Drenagem/métodos , Plásticos , Necrose/etiologia , EndossonografiaRESUMO
PURPOSE: Bile duct injury (BDI) remains the most serious complication following cholecystectomy. However, the actual incidence of BDI in the Czech Republic remains unknown. Hence, we aimed to identify the incidence of major BDI requiring operative reconstruction after elective cholecystectomy in our region despite the prevailing modern 4 K Ultra HD laparoscopy and Critical View of Safety (CVS) standards implemented in daily surgical practice among the Czech population. METHODS: In the absence of a specific registry for BDI, we analysed data from The Czech National Patient Register of Reimbursed Healthcare Services, where all procedures are mandatorily recorded. We investigated 76,345 patients who were enrolled for at least a year and underwent elective cholecystectomy during the period from 2018-2021. In this cohort, we examined the incidence of major BDI following the reconstruction of the biliary tract and other complications. RESULTS: A total of 76,345 elective cholecystectomies were performed during the study period, and 186 major BDIs were registered (0.24%). Most elective cholecystectomies were performed laparoscopically (84.7%), with the remaining open (15.3%). The incidence of BDI was higher in the open surgery group (150 BDI/11700 cases/1.28%) than in laparoscopic cholecystectomy (36 BDI/64645 cases/0.06%). Furthermore, the total hospital stays with BDI after reconstruction was 13.6 days. However, the majority of laparoscopic elective cholecystectomies (57,914, 89.6%) were safe and standard procedures with no complications. CONCLUSION: Our study corroborates the findings of previous nationwide studies. Therefore, though laparoscopic cholecystectomy is reliable, the risks of BDI cannot be eliminated.
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Traumatismos Abdominais , Colecistectomia Laparoscópica , Humanos , Ductos Biliares/cirurgia , Ductos Biliares/lesões , República Tcheca/epidemiologia , Colecistectomia/efeitos adversos , Colecistectomia Laparoscópica/efeitos adversos , Traumatismos Abdominais/cirurgia , Sistema de Registros , Doença Iatrogênica/epidemiologiaRESUMO
BACKGROUND: The genomes of present-day non-Africans are composed of 1-3% of Neandertal-derived DNA as a consequence of admixture events between Neandertals and anatomically modern humans about 50-60 thousand years ago. Neandertal-introgressed single nucleotide polymorphisms (aSNPs) have been associated with modern human disease-related traits, which are risk factors for pancreatic ductal adenocarcinoma (PDAC), such as obesity, type 2 diabetes, and inflammation. In this study, we aimed at investigating the role of aSNPs in PDAC in three Eurasian populations. RESULTS: The high-coverage Vindija Neandertal genome was used to select aSNPs in non-African populations from 1000 Genomes project phase 3 data. Then, the association between aSNPs and PDAC risk was tested independently in Europeans and East Asians, using existing GWAS data on more than 200 000 individuals. We did not find any significant associations between aSNPs and PDAC in samples of European descent, whereas, in East Asians, we observed that the Chr10p12.1-rs117585753-T allele (MAF = 10%) increased the risk to develop PDAC (OR = 1.35, 95%CI 1.19-1.54, P = 3.59 × 10-6), with a P-value close to a threshold that takes into account multiple testing. CONCLUSIONS: Our results show only a minimal contribution of Neandertal SNPs to PDAC risk.
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Carcinoma Ductal Pancreático , Diabetes Mellitus Tipo 2 , Homem de Neandertal , Neoplasias Pancreáticas , Humanos , Animais , Homem de Neandertal/genética , Polimorfismo de Nucleotídeo Único , Carcinoma Ductal Pancreático/genética , Neoplasias Pancreáticas/genéticaRESUMO
BACKGROUND: Most cases of pancreatic ductal adenocarcinoma (PDAC) are asymptomatic in early stages, and the disease is typically diagnosed in advanced phases, resulting in very high mortality. Tools to identify individuals at high risk of developing PDAC would be useful to improve chances of early detection. OBJECTIVE: We generated a polygenic risk score (PRS) for PDAC risk prediction, combining the effect of known risk SNPs, and carried out an exploratory analysis of a multifactorial score. METHODS: We tested the associations of the individual known risk SNPs on up to 2851 PDAC cases and 4810 controls of European origin from the PANcreatic Disease ReseArch (PANDoRA) consortium. Thirty risk SNPs were included in a PRS, which was computed on the subset of subjects that had 100% call rate, consisting of 839 cases and 2040 controls in PANDoRA and 6420 cases and 4889 controls from the previously published Pancreatic Cancer Cohort Consortium I-III and Pancreatic Cancer Case-Control Consortium genome-wide association studies. Additional exploratory multifactorial scores were constructed by complementing the genetic score with smoking and diabetes. RESULTS: The scores were associated with increased PDAC risk and reached high statistical significance (OR=2.70, 95% CI 1.99 to 3.68, p=2.54×10-10 highest vs lowest quintile of the weighted PRS, and OR=14.37, 95% CI 5.57 to 37.09, p=3.64×10-8, highest vs lowest quintile of the weighted multifactorial score). CONCLUSION: We found a highly significant association between a PRS and PDAC risk, which explains more than individual SNPs and is a step forward in the direction of the construction of a tool for risk stratification in the population.
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Herança Multifatorial , Sistema ABO de Grupos Sanguíneos/genética , Alelos , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/genética , Detecção Precoce de Câncer , Feminino , Frequência do Gene , Humanos , Masculino , Neoplasias Pancreáticas/genética , Polimorfismo de Nucleotídeo Único , Medição de RiscoRESUMO
Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers. Its poor prognosis is predominantly due to the fact that most patients remain asymptomatic until the disease reaches an advanced stage, alongside the lack of early markers and screening strategies. A better understanding of PDAC risk factors is essential for the identification of groups at high risk in the population. Genome-wide association studies (GWAS) have been a powerful tool for detecting genetic variants associated with complex traits, including pancreatic cancer. By exploiting functional and GWAS data, we investigated the associations between polymorphisms affecting gene function in the pancreas (expression quantitative trait loci, eQTLs) and PDAC risk. In a two-phase approach, we analysed 13 713 PDAC cases and 43 784 controls and identified a genome-wide significant association between the A allele of the rs2035875 polymorphism and increased PDAC risk (P = 7.14 × 10-10). This allele is known to be associated with increased expression in the pancreas of the keratin genes KRT8 and KRT18, whose increased levels have been reported to correlate with various tumour cell characteristics. Additionally, the A allele of the rs789744 variant was associated with decreased risk of developing PDAC (P = 3.56 × 10-6). This single nucleotide polymorphism is situated in the SRGAP1 gene and the A allele is associated with higher expression of the gene, which in turn inactivates the cyclin-dependent protein 42 (CDC42) gene expression, thus decreasing the risk of PDAC. In conclusion, we present here a functional-based novel PDAC risk locus and an additional strong candidate supported by significant associations and plausible biological mechanisms.
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Carcinoma Ductal Pancreático/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Neoplasias Pancreáticas/genética , Locos de Características Quantitativas , Idoso , Alelos , Estudos de Casos e Controles , Feminino , Proteínas Ativadoras de GTPase/genética , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second cancer-related cause of death by 2030. Identifying novel risk factors, including genetic risk loci, could be instrumental in risk stratification and implementation of prevention strategies. Long noncoding RNAs (lncRNAs) are involved in regulation of key biological processes, and the possible role of their genetic variability has been unexplored so far. Combining genome wide association studies and functional data, we investigated the genetic variability in all lncRNAs. We analyzed 9893 PDAC cases and 9969 controls and identified a genome-wide significant association between the rs7046076 SNP and risk of developing PDAC (P = 9.73 × 10-9 ). This SNP is located in the NONHSAG053086.2 (lnc-SMC2-1) gene and the risk allele is predicted to disrupt the binding of the lncRNA with the micro-RNA (miRNA) hsa-mir-1256 that regulates several genes involved in cell cycle, such as CDKN2B. The CDKN2B region is pleiotropic and its genetic variants have been associated with several human diseases, possibly though an imperfect interaction between lncRNA and miRNA. We present a novel PDAC risk locus, supported by a genome-wide statistical significance and a plausible biological mechanism.
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Carcinoma Ductal Pancreático/genética , Inibidor de Quinase Dependente de Ciclina p15/genética , MicroRNAs/genética , Neoplasias Pancreáticas/genética , Polimorfismo de Nucleotídeo Único , RNA Longo não Codificante/genética , Idoso , Estudos de Casos e Controles , Biologia Computacional/métodos , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis, caused by various factors, such as the aggressiveness of the disease, the limited therapeutic options and the lack of early detection and risk markers. The ATP binding cassette subfamily C member 2 (ABCC2) protein plays a critical role in response to various drugs and is differentially expressed in gemcitabine sensitive and resistant cells. Moreover, single nucleotide polymorphisms (SNPs) in the gene have been associated with differential outcomes and prognosis in several tumour types. The aim of this study was to investigate the possible association between SNPs in the ABCC2 gene and overall survival (OS) in PDAC patients. We analysed 12 polymorphisms, including tagging-SNPs covering all the genetic variability of the ABCC2 gene and genotyped them in 1415 PDAC patients collected within the Pancreatic Disease ReseArch (PANDoRA) consortium. We tested the association between ABCC2 SNPs and PDAC OS using Cox proportional hazard models. We analysed PDAC patients dividing them by stage and observed that the minor alleles of three SNPs showed an association with worse OS [rs3740067: hazard ratio (HR) = 3.29, 95% confidence interval (CI) = 1.56-6.97, P = 0.002; rs3740073: HR = 3.11, 95% CI = 1.52-6.38, P = 0.002 and rs717620: HR = 2.90, 95% CI = 1.41-5.95, P = 0.004, respectively] in stage I patients. In patients with more advanced PDAC, we did not observe any statistically significant association. Our results suggest that rs3740067, rs3740073 and rs717620 could be promising prognostic markers in stage I PDAC patients.
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Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/mortalidade , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Neoplasias Pancreáticas/mortalidade , Polimorfismo de Nucleotídeo Único , Idoso , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/terapia , Estudos de Casos e Controles , Terapia Combinada , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Proteína 2 Associada à Farmacorresistência Múltipla , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/terapia , Prognóstico , Taxa de SobrevidaRESUMO
Telomere deregulation is a hallmark of cancer. Telomere length measured in lymphocytes (LTL) has been shown to be a risk marker for several cancers. For pancreatic ductal adenocarcinoma (PDAC) consensus is lacking whether risk is associated with long or short telomeres. Mendelian randomization approaches have shown that a score built from SNPs associated with LTL could be used as a robust risk marker. We explored this approach in a large scale study within the PANcreatic Disease ReseArch (PANDoRA) consortium. We analyzed 10 SNPs (ZNF676-rs409627, TERT-rs2736100, CTC1-rs3027234, DHX35-rs6028466, PXK-rs6772228, NAF1-rs7675998, ZNF208-rs8105767, OBFC1-rs9420907, ACYP2-rs11125529 and TERC-rs10936599) alone and combined in a LTL genetic score ("teloscore", which explains 2.2% of the telomere variability) in relation to PDAC risk in 2,374 cases and 4,326 controls. We identified several associations with PDAC risk, among which the strongest were with the TERT-rs2736100 SNP (OR = 1.54; 95%CI 1.35-1.76; p = 1.54 × 10-10 ) and a novel one with the NAF1-rs7675998 SNP (OR = 0.80; 95%CI 0.73-0.88; p = 1.87 × 10-6 , ptrend = 3.27 × 10-7 ). The association of short LTL, measured by the teloscore, with PDAC risk reached genome-wide significance (p = 2.98 × 10-9 for highest vs. lowest quintile; p = 1.82 × 10-10 as a continuous variable). In conclusion, we present a novel genome-wide candidate SNP for PDAC risk (TERT-rs2736100), a completely new signal (NAF1-rs7675998) approaching genome-wide significance and we report a strong association between the teloscore and risk of pancreatic cancer, suggesting that telomeres are a potential risk factor for pancreatic cancer.
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Carcinoma Ductal Pancreático/genética , Neoplasias Pancreáticas/genética , Ribonucleoproteínas/genética , Telomerase/genética , Encurtamento do Telômero/genética , Telômero/metabolismo , Idoso , Estudos de Casos e Controles , Europa (Continente) , Feminino , Estudo de Associação Genômica Ampla , Humanos , Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Telomerase/metabolismoRESUMO
BACKGROUND: The aim of this study is to identify the incidence trends of primary and secondary peritoneal surface malignancies in a representative Czech population. METHODS: Data were obtained from patients registered in the Czech National Cancer Registry between 1979 and 2016. The incidence rates were analyzed between 2012 and 2016. To observe the incidence trends, we analyzed the data from two time periods, 1979-2005 and 2006-2016. The analyzed data included age, sex, and the histological types and primary origins of the malignancies. The Cochrane-Armitage test for linear trends was used for verification of the null hypothesis. The significance level established for hypothesis testing was p = 0.05. RESULTS: Between 2012 and 2016, 230 patients with primary peritoneal tumors were identified and divided into the following groups according to their "International Statistical Classification of Diseases and Related Health Problems, 10th revision" codes: malignant neoplasm of specified parts of the peritoneum (C48.1); malignant neoplasm of the peritoneum, unspecified (C48.2); and malignant neoplasm of overlapping sites of the retroperitoneum and peritoneum (C48.8). Moreover, 549 primary tumors of the appendix (C18.1, encompassing all appendiceal malignancies) and 3137 secondary synchronous peritoneal carcinomatoses of other primary origins were documented. The age-adjusted incidence of primary peritoneal tumors in 2012-2016 was 4.36/year/1,000,000 inhabitants. The age-adjusted incidence of synchronous secondary peritoneal malignancies in 2014-2016 was 99.0/year/1,000,000 inhabitants. The diagnoses of primary peritoneal malignancies followed a stable trend between 1979 and 2016. However, the incidences of primary tumors of the appendix increased by 76.7%. CONCLUSIONS: The data produced in our study ought to clarify the status of peritoneal surface malignancies in the Czech Republic, which can lead to improved planning and development of therapeutic interventions as well as physician training.
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Neoplasias Primárias Múltiplas/epidemiologia , Neoplasias Peritoneais/epidemiologia , Peritônio/patologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , República Tcheca/epidemiologia , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/patologia , Neoplasias Peritoneais/patologia , Neoplasias Peritoneais/secundário , Sistema de Registros/estatística & dados numéricos , Estudos Retrospectivos , Fatores Sexuais , Adulto JovemRESUMO
OBJECTIVES: Biliary strictures frequently present a diagnostic challenge. The aim of this study was to evaluate the impact of digital single-operator cholangioscopy (DSOC) on subsequent treatment of patients with biliary stricture. METHODS: Consecutive patients undergoing DSOC for biliary stricture were enrolled. Gold standard for final diagnosis included histology from surgical resection. In patients without surgery, clinical evaluation methods and repeated imaging studies were used for comparison of DSOC findings and final diagnosis. Patients were followed-up prospectively focusing on subsequent treatment. RESULTS: Among 30 enrolled patients, final diagnosis was malignant in 13 (43%) and benign in 17 (57%). The sensitivity and specificity of visual impression in diagnosing malignant stricture were 100% (95% CI: 75 - 100) and 76% (95% CI: 50 - 93), respectively. The sensitivity and specificity for biopsy were 92% (95% CI: 62 - 100) and 100% (95% CI: 78 - 100), respectively. One (3%) case of complicating cholangitis with fatal outcome occurred. Final treatment included surgery in 7 (23%), endoscopy in 18 (60%) and chemotherapy in 3 (10%) of patients. CONCLUSIONS: In this study, favorable operating characteristics of DSOC were confirmed. Absolute negative predictive value of visual impression provided reassurance to patients with benign strictures who avoided unnecessary surgery in 53%. One (3%) case of cholangitis with fatal outcome occurred.
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Doenças dos Ductos Biliares/diagnóstico , Doenças dos Ductos Biliares/cirurgia , Ductos Biliares Intra-Hepáticos , Procedimentos Cirúrgicos do Sistema Biliar/instrumentação , Colangiografia/instrumentação , Adulto , Idoso , Idoso de 80 Anos ou mais , Procedimentos Cirúrgicos do Sistema Biliar/métodos , Biópsia , Colangiografia/métodos , Constrição Patológica/diagnóstico , Constrição Patológica/etiologia , República Tcheca , Desenho de Equipamento , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Resultado do TratamentoRESUMO
The tumors of the peritoneal surface, both primary and secondary, are associated with a very poor prognosis and rapid progression through conventional oncology treatment including systemic chemotherapy, targeted treatment, radiotherapy, surgery, and symptomatic treatment. Until recently, most of them were considered incurable. In the 1980s, the first cytoreductive surgery ("CRS") combined with intraperitoneal hyperthermic chemotherapy ("HIPEC") became the standard of treatment for selected tumor peritoneal tumor (pseudomyxoma peritonei and primary peritoneal malignant mesothelioma). In some cases of other peritoneal carcinomatosis associated with colorectal cancer, gastric cancer and ovarian cancer in the subgroup of well selected patients, this treatment can lead to a significant prolongation of overall survival and good standard of quality of life. This method is safe in specialized centers with an acceptable rate of morbidity and mortality comparable to foreign workplaces and is also available for patients in the Czech Republic. Key words surgery, oncology, cytoreduction, intraperitoneal chemotherapy, hyperthermia.
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Protocolos de Quimioterapia Combinada Antineoplásica , Hipertermia Induzida , Neoplasias Peritoneais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada , Procedimentos Cirúrgicos de Citorredução , República Tcheca , Humanos , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/cirurgia , Qualidade de VidaRESUMO
The aim of our study was to analyse the mitochondrial ultrastructure in primary ductal adenocarcinomas of the pancreas and to compare it with normal pancreatic cells. 52 samples of adenocarcinoma of the pancreas obtained by surgical resection or by endosonographic biopsy were examined. Compared to normal mitochondrial ultrastructure in non-tumorous cells, the mitochondria in cancer cells had a dense matrix and condensed configuration or with lucent-swelling matrix associated with disarrangement and distortion of cristae and partial or total cristolysis. Functionally, these structural alterations presume the presence of hypoxia-tolerant and hypoxia-sensitive cancer cells.
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Carcinoma Ductal Pancreático/ultraestrutura , Mitocôndrias/ultraestrutura , Neoplasias Pancreáticas/ultraestrutura , Biópsia , Endossonografia , Humanos , Microscopia EletrônicaRESUMO
Background: This study aimed to validate the accuracy of the Preoperative Pancreatic Resection (PREPARE) risk score in pancreatic resection patients. Patients and methods: This prospective study included 216 patients who underwent pancreatic resection between January 2015 and December 2018. All patients in our cohort with weight loss or lack of appetite received dietary advice and preoperative oral nutritional supplementation (600â kcal/day). Demographic, clinicopathological, operative, and postoperative data were collected prospectively. The PREPARE score and the predicted risk of major complications were computed for each patient. Differences in major postoperative complications were analyzed using a multivariate Cox proportional hazards regression model. The predicted and observed risks of major complications were tested using the C-statistic. Results: The study included 216 patients [117 men (54.2%)] with a median age of 65.0 (30.0-83.0) years. The majority of patients were classified as American Society of Anesthesiologists (ASA)' Physical Status score II (N = 164/216; 75.9%) and as "low risk" PREPARE score (N = 185/216; 85.6%) before the surgery. Only 4 (1.9%) patients were malnourished, with albumin levels of less than 3.5â g/dl. The most common type of pancreatic resection was a pylorus-preserving pancreaticoduodenectomy (N = 122/216; 56.5%). Major morbidity and 30-day mortality rates were 11.1% and 1.9%, respectively. The type of surgical procedure (hazard ratio [HR]: 3.849; 95% confidence interval [CI]: 1.208-12.264) and ASA score (HR: 3.089; 95% CI: 1.067-8.947) were significantly associated with the incidence of major postoperative complications in multivariate analysis. The receiver operating characteristic curve was 0.657 for incremental values and 0.559 for risk categories, indicating a weak predictive model. Conclusion: The results of the present study suggest that the PREPARE risk score has low accuracy in predicting the risk of major complications in patients with consistent preoperative nutritional support. This limits the use of PREPARE risk score in future preoperative clinical routines.
RESUMO
BACKGROUND: The painless form of chronic pancreatitis is one of the rarer forms of the disease. While 80% to 90% of all chronic pancreatitis cases have abdominal pain as their clinical symptom, a smaller proportion of persons with chronic pancreatitis do not report typical pain. This form of the disease is often associated with exocrine and endocrine pancreatic insufficiency and weight loss, but the absence of pain symptoms may initially lead to misdiagnosis. METHODS: In a cohort of 257 people with chronic pancreatitis, the painless form was diagnosed in 30 individuals (11.6%), with an average age of 56 years and a predominance of men (71.4%). Thirty-eight percent were non-smokers and 47.6% of patients smoked up to 10 cigarettes per day. Alcohol intake of less than 40 g per day was reported by 61.9% of subjects. A quarter were moderately overweight, with a mean BMI of 26.5. Newly diagnosed diabetes mellitus had 25.7% of the subjects. RESULTS: A frequent finding was the demonstration of morphological changes, with calcifications found in 85,7% and dilatation of the pancreatic duct greater than 6.0 mm in 66%. A surprising finding was the presence of metabolic syndrome in 42.8% and the most frequent finding was the demonstration of decreased external pancreatic secretion (90%). CONCLUSION: Painless chronic pancreatitis is usually treated conservatively. We demonstrate a subset of 28 patients with painless chronic pancreatitis treated surgically. Most frequent indications were benign stenosis of the intrapancreatic bile duct and stenosis of the pancreatic duct. Although approximately 1 in 10 people with chronic pancreatitis present with a painless form of it, so that the form of the disease is described as rare, this does not change the fact that management of these people is still not optimal.
Assuntos
Pancreatite Crônica , Masculino , Humanos , Pessoa de Meia-Idade , Feminino , Constrição Patológica , Doença Crônica , Pancreatite Crônica/complicações , Pancreatite Crônica/diagnóstico , DorRESUMO
Background and aims: Diagnosis of the biliary stricture remains a challenge. In view of the low sensitivity of brush cytology (BC), fluorescence in situ hybridization (FISH) has been reported as a useful adjunctive test in patients with biliary strictures. We aimed to determine performance characteristics of BC and FISH individually and in combination (BC + FISH) in the primary diagnosis of biliary strictures. Methods: This single-center prospective study was conducted between April 2019 and January 2021. Consecutive patients with unsampled biliary strictures undergoing first endoscopic retrograde cholangiopancreatography in our institution were included. Tissue specimens from two standardized transpapillary brushings from the strictures were examined by routine cytology and FISH. Histopathological confirmation after surgery or 12-month follow-up was regarded as the reference standard for final diagnosis. Results: Of 109 enrolled patients, six were excluded and one lost from the final analysis. In the remaining 102 patients (60.8% males, mean age 67.4, range 25-92 years), the proportions of benign and malignant strictures were 28 (27.5%) and 74 (72.5%), respectively. The proportions of proximal and distal strictures were 26 (25.5%) and 76 (74.5%), respectively. In comparison to BC alone, FISH increased the sensitivity from 36.1% to 50.7% (p = 0.076) while maintaining similar specificity (p = 0.311). Conclusions: Dual-modality tissue evaluation using BC + FISH showed an improving trend in sensitivity for the primary diagnosis of biliary strictures when compared with BC alone.
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Pancreatic cancer (PDAC) has a poor prognosis despite surgical removal and adjuvant therapy. Additionally, the effects of postoperative analgesia with morphine and piritramide on survival among PDAC patients are unknown, as are their interactions with opioid/cannabinoid receptor gene expressions in PDAC tissue. Cancer-specific survival data for 71 PDAC patients who underwent radical surgery followed by postoperative analgesia with morphine (n = 48) or piritramide (n = 23) were therefore analyzed in conjunction with opioid/cannabinoid receptor gene expressions in the patients' tumors. Receptor gene expressions were determined using the quantitative real-time polymerase chain reaction. Patients receiving morphine had significantly longer cancer-specific survival (CSS) than those receiving piritramide postoperative analgesia (median 22.4 vs. 15 months; p = 0.038). This finding was supported by multivariate modelling (p < 0.001). The morphine and piritramide groups had similar morphine equipotent doses, receptor expression, and baseline characteristics. The opioid/cannabinoid receptor gene expression was analyzed in a group of 130 pancreatic cancer patients. Of the studied receptors, high cannabinoid receptor 2 (CB2) and opioid growth factor receptor (OGFR) gene expressions have a positive influence on the length of overall survival (OS; p = 0.029, resp. p = 0.01). Conversely, high delta opioid receptor gene expression shortened OS (p = 0.043). Multivariate modelling indicated that high CB2 and OGFR expression improved OS (HR = 0.538, p = 0.011, resp. HR = 0.435, p = 0.001), while high OPRD receptor expression shortened OS (HR = 2.264, p = 0.002). Morphine analgesia, CB2, and OGFR cancer tissue gene expression thus improved CSS resp. OS after radical PDAC surgery, whereas delta opioid receptor expression shortened OS.
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BACKGROUND: Early-onset pancreatic cancer (EOPC) represents 5-10% of all pancreatic ductal adenocarcinoma (PDAC) cases, and the etiology of this form is poorly understood. It is not clear if established PDAC risk factors have the same relevance for younger patients. This study aims to identify genetic and non-genetic risk factors specific to EOPC. METHODS: A genome-wide association study was performed, analysing 912 EOPC cases and 10 222 controls, divided into discovery and replication phases. Furthermore, the associations between a polygenic risk score (PRS), smoking, alcohol consumption, type 2 diabetes and PDAC risk were also assessed. RESULTS: Six novel SNPs were associated with EOPC risk in the discovery phase, but not in the replication phase. The PRS, smoking, and diabetes affected EOPC risk. The OR comparing current smokers to never-smokers was 2.92 (95% CI 1.69-5.04, P = 1.44 × 10-4). For diabetes, the corresponding OR was 14.95 (95% CI 3.41-65.50, P = 3.58 × 10-4). CONCLUSION: In conclusion, we did not identify novel genetic variants associated specifically with EOPC, and we found that established PDAC risk variants do not have a strong age-dependent effect. Furthermore, we add to the evidence pointing to the role of smoking and diabetes in EOPC.