RESUMO
ABSTRACT: Pancreas is a vital gland of gastro-intestinal system with exocrine and endocrine secretory functions, interweaved into essential metabolic circuitries of the human body. Pancreatic ductal adenocarcinoma (PDAC) represents one of the most lethal malignancies, with a five-year survival rate of 11%. This poor prognosis is primarily attributed to the absence of early symptoms, rapid metastatic dissemination, and the limited efficacy of current therapeutic interventions. Despite recent advancements in understanding the etiopathogenesis and treatment of PDAC, there remains a pressing need for improved individualized models, the identification of novel molecular targets, and the development of unbiased predictors of disease progression. Here we aim to explore the concept of precision medicine utilizing three-dimensional, patient-specific cellular models of pancreatic tumors and discuss their potential applications in uncovering novel druggable molecular targets and predicting clinical parameters for individual patients.
RESUMO
Introduction: The management of patients with COVID-19 infection has placed great pressure on the healthcare systems around the world. The aim of this study was to investigate the impact of the COVID-19 pandemic on the treatment outcomes of patients with rectal cancer by comparing them to those of patients with the same diagnosis in the pre-pandemic period. Methods: Retrospective data analysis of patients undergoing multimodal treatment for rectal cancer at the four university hospitals during the COVID-19 pandemic (2020-2021) and the 2-year pre-pandemic period (2018-2019). Results: A total of 693 patients (319 in the pre-pandemic period and 374 in the pandemic period) with rectal cancer were included in the study. The demographic and clinical characteristics of patients in both study periods were comparable, as was the spectrum of surgical procedures. Palliative surgery was more common in the pandemic period (18% vs 13%, p=0.084). The proportion of patients undergoing minimally invasive surgery was higher during the COVID-19 pandemic (p=0.025). There were no statistically significant differences between the study periods in the incidence/severity of post-operative complications, 30-day mortality and length of hospital stay. The number of positive resection margins was similar (5% vs 5%). Based on these results, COVID-19 had no effect on the postoperative morbidity and mortality in patients undergoing surgery for rectal cancer. Neoadjuvant treatment was more common in the pre-pandemic period (50% vs 45%). Long-course RT was predominantly offered in the pre-pandemic period, short-course RT during the pandemic. Significantly shorter "diagnosis-surgery" intervals were observed during the pandemic (23 days vs 33 days, p=0.0002). The "surgery-adjuvant therapy" interval was similar in both analysed study periods (p=0.219). Conclusion: Our study showed, that despite concerns about the COVID-19 pandemic, multimodal treatment of rectal cancer was associated with unchanged postoperative morbidity rates, increased frequency of short-course neoadjuvant RT administration and shorter "diagnosis-surgery" intervals.
RESUMO
Colorectal cancer (CRC) is the second most prevalent cancer type worldwide, which highlights the urgent need for non-invasive biomarkers for its early detection and improved prognosis. We aimed to investigate the patterns of long non-coding RNAs (lncRNAs) in small extracellular vesicles (sEVs) collected from low-volume blood serum specimens of CRC patients, focusing on their potential as diagnostic biomarkers. Our research comprised two phases: an initial exploratory phase involving RNA sequencing of sEVs from 76 CRC patients and 29 healthy controls, and a subsequent validation phase with a larger cohort of 159 CRC patients and 138 healthy controls. Techniques such as dynamic light scattering, transmission electron microscopy, and Western blotting were utilized for sEV characterization. Optimized protocol for sEV purification, RNA isolation and preamplification was applied to successfully sequence the RNA content of sEVs and validate the results by RT-qPCR. We successfully isolated sEVs from blood serum and prepared sequencing libraries from a low amount of RNA. High-throughput sequencing identified differential levels of 460 transcripts between CRC patients and healthy controls, including mRNAs, lncRNAs, and pseudogenes, with approximately 20% being lncRNAs, highlighting several tumor-specific lncRNAs that have not been associated with CRC development and progression. The validation phase confirmed the upregulation of three lncRNAs (NALT1, AL096828, and LINC01637) in blood serum of CRC patients. This study not only identified lncRNA profiles in a population of sEVs from low-volume blood serum specimens of CRC patients but also highlights the value of innovative techniques in biomolecular research, particularly for the detection and analysis of low-abundance biomolecules in clinical samples. The identification of specific lncRNAs associated with CRC provides a foundation for future research into their functional roles in cancer development and potential clinical applications.
Assuntos
Neoplasias Colorretais , Vesículas Extracelulares , Segunda Neoplasia Primária , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , Soro , Vesículas Extracelulares/genética , Biomarcadores , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genéticaRESUMO
BACKGROUND & AIMS: Autoimmune pancreatitis (AIP) is an immune-mediated disease of the pancreas with distinct pathophysiology and manifestations. Our aims were to characterize type 1 AIP in a large pan-European cohort and study the effectiveness of current treatment regimens. METHODS: We retrospectively analyzed adults diagnosed since 2005 with type 1 or not-otherwise-specified AIP in 42 European university hospitals. Type 1 AIP was uniformly diagnosed using specific diagnostic criteria. Patients with type 2 AIP and those who had undergone pancreatic surgery were excluded. The primary end point was complete remission, defined as the absence of clinical symptoms and resolution of the index radiologic pancreatic abnormalities attributed to AIP. RESULTS: We included 735 individuals with AIP (69% male; median age, 57 years; 85% White). Steroid treatment was started in 634 patients, of whom 9 (1%) were lost to follow-up. The remaining 625 had a 79% (496/625) complete, 18% (111/625) partial, and 97% (607/625) cumulative remission rate, whereas 3% (18/625) did not achieve remission. No treatment was given in 95 patients, who had a 61% complete (58/95), 19% partial (18/95), and 80% cumulative (76/95) spontaneous remission rate. Higher (≥0.4 mg/kg/day) corticosteroid doses were no more effective than lower (<0.4 mg/kg/day) doses (odds ratio, 0.428; 95% confidence interval, 0.054-3.387) and neither was a starting dose duration >2 weeks (odds ratio, 0.908; 95% confidence interval, 0.818-1.009). Elevated IgG4 levels were independently associated with a decreased chance of complete remission (odds ratio, 0.639; 95% confidence interval, 0.427-0.955). Relapse occurred in 30% of patients. Relapses within 6 months of remission induction were independent of the steroid-tapering duration, induction treatment duration, and total cumulative dose. CONCLUSIONS: Patients with type 1 AIP and elevated IgG4 level may need closer monitoring. For remission induction, a starting dose of 0.4 mg/kg/day for 2 weeks followed by a short taper period seems effective. This study provides no evidence to support more aggressive regimens.
Assuntos
Pancreatite Autoimune , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Estudos Retrospectivos , Pancreatite Autoimune/tratamento farmacológico , Pancreatite Autoimune/diagnóstico , Europa (Continente) , Idoso , Resultado do Tratamento , Adulto , Esteroides/uso terapêutico , Esteroides/administração & dosagem , Idoso de 80 Anos ou maisRESUMO
A new utilization of entropy in the context of buckling is presented. The novel concept of connecting the strain energy and entropy for a pin-ended strut is derived. The entropy of the buckling mode is extracted through a surrogate model by decomposing the strain energy into entropy and virtual temperature. This concept rationalizes the ranking of buckling modes based on their strain energy under the assumption of given entropy. By assigning identical entropy to all buckling modes, they can be ranked according to their deformation energy. Conversely, with identical strain energy assigned to all the modes, ranking according to entropy is possible. Decreasing entropy was found to represent the scaling factors of the buckling modes that coincide with the measurement of the initial out-of-straightness imperfections in IPE160 beams. Applied to steel plane frames, scaled buckling modes can be used to model initial imperfections. It is demonstrated that the entropy (scale factor) for a given energy roughly decreases with the inverse square of the mode index. For practical engineering, this study presents the possibility of using scaled buckling modes of steel plane frames to model initial geometric imperfections. Entropy proves to be a valuable complement to strain energy in structural mechanics.
RESUMO
BACKGROUND: The aim of this prospective study was to evaluate the role of serum IL-6 as a potential predictive biomarker of postoperative complications (POC) in elective colorectal surgery. METHOD: A total of 115 patients underwent colorectal surgery for malignancy. IL-6 was measured on the first and third postoperative days (POD1, POD3), and C-reactive protein (CRP) was measured on the POD3. POC was analysed in subgroups according to ClavienâDindo (CD), antibiotic (ATB) treatment, intensive care unit (ICU) and hospital length of stay. The predictive power of variables for evaluated endpoints was analysed using receiver-operating characteristic (ROC) analysis and described by area under the curve (AUC). ROC analysis was adopted for the identification of optimal cut-offs. Histological analysis was performed to verify IL-6 production by the tumour. RESULTS: Out of 115 patients who were analysed, 42% had POC. Patients with POC had significantly higher serum levels of IL-6 on POD1 (p < 0.001) and POD3 (p < 0.001). IL-6 early on POD1 as a predictor of antibiotic treatment, ICU stay and hospital stay (AUC 0.818; 0.811; 0.771) did not significantly differ from the AUC of CRP late on POD3 (0.879; 0.838, 0.752). A cut-off IL-6 value of 113 pg/ml on POD1 and 180.5 pg/ml on POD3 in severe complications (CD > 3a) resulted in 75% and 72% sensitivity, 78.6% and 99% specificity, negative predictive value 96.4% and 97% and positive predictive value 29% and 88.9%. CONCLUSION: The serum level of interleukin-6 can predict severe (CD > 3a) POC early on POD1. On POD3, IL-6 is superior to CRP in terms of high positive predictive power of severe POC. Interestingly, the advantage of IL-6 on POD1 is early prediction of the need for antibiotic treatment, ICU stay and hospital stay, which is comparable to the CRP serum level late on the third POD.
Assuntos
Cirurgia Colorretal , Interleucina-6 , Humanos , Antibacterianos , Biomarcadores , Proteína C-Reativa/análise , Complicações Pós-Operatórias/etiologia , Estudos Prospectivos , Curva ROCRESUMO
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.
RESUMO
16S rRNA amplicon sequencing or, more recently, metatranscriptomic analysis are currently the only preferred methods for microbial profiling of samples containing a predominant ratio of human to bacterial DNA. However, due to the off-target amplification of human DNA, current protocols are inadequate for bioptic samples. Here we present an efficient, reliable, and affordable method for the bacteriome analysis of clinical samples human DNA content predominates. We determined the microbiota profile in a total of 40 human biopsies of the esophagus, stomach, and duodenum using 16S rRNA amplicon sequencing with the widely used 515F-806R (V4) primers targeting the V4 region, 68F-338R primers and a modified set of 68F-338R (V1-V2M) primers targeting the V1-V2 region. With the V4 primers, on average 70% of amplicon sequence variants (ASV) mapped to the human genome. On the other hand, this off-target amplification was absent when using the V1-V2M primers. Moreover, the V1-V2M primers provided significantly higher taxonomic richness and reproducibility of analysis compared to the V4 primers. We conclude that the V1-V2M 16S rRNA sequencing method is reliable, cost-effective, and applicable for low-bacterial abundant human samples in medical research.
Assuntos
Microbiota , Humanos , RNA Ribossômico 16S/genética , Genes de RNAr , Reprodutibilidade dos Testes , Análise de Sequência de DNA/métodos , Microbiota/genética , Trato Gastrointestinal , Biópsia , Sequenciamento de Nucleotídeos em Larga Escala/métodosRESUMO
Pheochromocytomas (PCCs) are rare neuroendocrine tumors derived from the chromaffin cells of the adrenal medulla. When these tumors have an extra-adrenal location, they are called paragangliomas (PGLs) and arise from sympathetic and parasympathetic ganglia, particularly of the para-aortic location. Up to 25% of PCCs/PGLs are associated with inherited genetic disorders. The majority of PCCs/PGLs exhibit indolent behavior. However, according to their affiliation to molecular clusters based on underlying genetic aberrations, their tumorigenesis, location, clinical symptomatology, and potential to metastasize are heterogenous. Thus, PCCs/PGLs are often associated with diagnostic difficulties. In recent years, extensive research revealed a broad genetic background and multiple signaling pathways leading to tumor development. Along with this, the diagnostic and therapeutic options were also expanded. In this review, we focus on the current knowledge and recent advancements in the diagnosis and treatment of PCCs/PGLs with respect to the underlying gene alterations while also discussing future perspectives in this field.
Assuntos
Neoplasias das Glândulas Suprarrenais , Paraganglioma , Feocromocitoma , Humanos , Feocromocitoma/diagnóstico , Feocromocitoma/genética , Feocromocitoma/terapia , Paraganglioma/diagnóstico , Paraganglioma/genética , Paraganglioma/terapia , Carcinogênese , Transformação Celular Neoplásica , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/terapiaRESUMO
PURPOSE: It is still unclear if pathological complete response (pCR) after neoadjuvant chemoradiotherapy (CRT) in patients treated for rectal cancer causes worse postoperative outcomes, especially after transanal total mesorectal excision (TaTME). Worse postoperative outcomes might be an argument for an organ preserving watch and wait strategy in fragile patients and patients with comorbidities. The aim of this study is to evaluate whether patients treated for rectal cancer who had pCR to neoadjuvant therapy develop worse postoperative outcomes after TaTME than patients without complete response. METHODS: Comparative retrospective analysis (with nearest neighbor matching algorithm) of postoperative outcomes in two groups of patients, with pCR, n = 15 and without pCR (non-pCR), n = 57. All patients were operated on only by one surgical approach, TaTME, for middle and distal rectal tumors. All procedures were performed by one surgical team between 2014 and 2020 at the University Hospital Brno in Czech Republic. RESULTS: Overall morbidity was comparable between the groups (pCR group - 53.8% vs. non-pCR - 38.6%, p = 0.381). Anastomotic leak (AL) was observed in 33.3% of patients with pCR and in 17.5% of patients in the non-pCR group without statistical significance (p = 0.281). CONCLUSION: In conclusion, pathological complete response after neoadjuvant therapy does not appear to affect postoperative morbidity in rectal cancer after TaTME. Therefore, in patients with complete response who are not adherent to W&W surveillance, surgical resection can be perform without increased postoperative complications.
Assuntos
Laparoscopia , Neoplasias Retais , Humanos , Reto/cirurgia , Reto/patologia , Terapia Neoadjuvante , Estudos Retrospectivos , Neoplasias Retais/cirurgia , Neoplasias Retais/patologia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Morbidade , Laparoscopia/métodos , Resultado do TratamentoRESUMO
BACKGROUND: Periampullary tumours (PAT) may cause obstruction of distal choledochus. The bile stasis is a risk factor for microbial colonisation of bile (bacteriobilia), cholangitis, hepatic insufficiency and coagulopathy. PAT obstruction can be managed surgically or non-operatively - by inserting a biliary drain or stent (BDS). Although BDS allows for adequate bile drainage, liver function restitution and coagulopathy, increased bacteriobilia has been reported and this is associated with an increased incidence of postoperative complications. METHODS: A monocentric, prospective, comparative study including 100 patients operated with PAT. The effects of bacteriobilia and the presence of a drain in the biliary tract on the development of postoperative complications were evaluated. RESULTS: Positive microbial findings in bile were found in 67% of patients. It was 98% in the biliary drain group vs. 36% in non-drained patients (p = 0.0001). In 68% 2 or more different bacterial strains were simultaneously present (p = 0.0001). Patients with a positive microbial finding in bile had more frequent incidence of infectious complications 40.2% (27) vs. 9.1% (3); p = 0.0011. The most frequent infectious complication was wound infection 29.8% (20) vs. 3.03% (1); p = 0.0014. Similarly, a higher incidence of postoperative infectious complications occurred in patients with BDS - 36% (18) vs. 24% (12); p = 0.2752. CONCLUSION: The presence of a drain or stent in the biliary tract significantly increases the microbial colonisation of bile. It is associated with a significant increase in infectious complications, especially infections in the wound.
Assuntos
Colangite , Colestase , Neoplasias , Humanos , Estudos Prospectivos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Colangite/epidemiologia , Colangite/etiologia , Colangite/cirurgiaRESUMO
The epidermal growth factor (EGF) and its receptor (EGFR) gene-gene interactions were shown to increase the susceptibility to esophageal cancer. However, the role of the EGF/EGFR pathway in the development of gastroesophageal reflux disease (GERD) and its complications (reflux esophagitis (RE), Barrett's esophagus (BE), and esophageal adenocarcinoma (EAC)) remains unclear. This association study is aimed at investigating functional EGF and EGFR gene polymorphisms, their mRNA expression in esophageal tissues, and EGF plasma levels in relation to RE, BE, and EAC development in the Central European population. 301 patients with RE/BE/EAC (cases) as well as 98 patients with nonerosive reflux disease (NERD) and 8 healthy individuals (controls) were genotyped for +61 A>G EGF (rs4444903) and +142285 G>A EGFR (rs2227983) polymorphisms using the TaqMan quantitative polymerase chain reaction (qPCR). In random subgroups, the EGF and EGFR mRNA expressions were analyzed by reverse transcription qPCR in esophageal tissue with and without endoscopically visible pathological changes; and the EGF plasma levels were determined by enzyme-linked immunosorbent assay. None of the genotyped SNPs nor EGF-EGFR genotype interactions were associated with RE, BE, or EAC development (p > 0.05). Moreover, mRNA expression of neither EGF nor EGFR differed between samples of the esophageal tissue with and without endoscopically visible pathology (p > 0.05) nor between samples from patients with different diagnoses, i.e., RE, BE, or EAC (p > 0.05). Nevertheless, the lower EGF mRNA expression in carriers of combined genotypes AA +61 EGF (rs4444903) and GG +142285 EGFR (rs2227983; p < 0.05) suggests a possible direct/indirect effect of EGF-EGFR gene interactions on EGF gene expression. In conclusion, EGF and EGFR gene variants and their mRNA/protein expression were not associated with RE, BE or EAC development in the Central European population.
Assuntos
Adenocarcinoma , Esôfago de Barrett , Neoplasias Esofágicas , Esofagite Péptica , Refluxo Gastroesofágico , Adenocarcinoma/patologia , Esôfago de Barrett/metabolismo , Proteínas de Transporte/genética , Estudos de Casos e Controles , Fator de Crescimento Epidérmico/genética , Receptores ErbB/genética , Receptores ErbB/metabolismo , Neoplasias Esofágicas/patologia , Esofagite Péptica/genética , Refluxo Gastroesofágico/genética , Humanos , Polimorfismo de Nucleotídeo Único , RNA MensageiroRESUMO
Background: A new silver-based dressing has been designed to reduce surgical sited infections. Patients and Methods: A prospective multicenter observational study was conducted from January 2020 to October 2021. Patients with and without silver-based dressing after surgical incision were observed and their data analyzed. The study aimed to assess the incidence of incisional surgical site infection and primary healing after general surgery procedures. Results: Overall, 218 patients with silver-based (n = 109) and conventional silver-free dressing (n = 109) were analyzed. Surgical site infection (SSI) and primary incision healing were reported in 10 (9.2%) versus 21 (19.3%) (p = 0.037) and in 95 (87.2%) versus 86 (78.9%) (p = 0.107) patients treated with and without silver-based dressing, respectively. Conclusions: Silver-based dressing demonstrated a lower incidence of incisional SSI and improved primary healing in comparison with patients in whom conventional non-silver-based dressing has been used.
Assuntos
Bandagens , Infecção da Ferida Cirúrgica , Bandagens/efeitos adversos , Humanos , Estudos Prospectivos , Infecção da Ferida Cirúrgica/epidemiologia , Infecção da Ferida Cirúrgica/etiologia , Infecção da Ferida Cirúrgica/prevenção & controleRESUMO
Confocal laser endomicroscopy (CLE) is a diagnostic technique that enables real-time microscopic imaging during microscopic examination and evaluation of epithelial structures with 1000-fold magnification. CLE can be used in the diagnosis of various pathologies, in pneumology, and in urology, and it is very widely utilized in gastroenterology, most importantly in the diagnosis of Barrett's esophagus (BE), esophageal adenocarcinoma (EAC), biliary strictures, and cystic pancreatic lesions. A literature search was made in MEDLINE/PubMed and Google Scholar databases while focusing on diagnostics using CLE of BE and EAC. We then examined randomized and observational studies, systematic reviews, and meta-analyses relating to the utilization of CLE in BE and EAC diagnostics. Here, we discuss whether CLE can be a suitable diagnostic method for surveillance of BE. Even though many studies have proven that CLE increases diagnostic accuracy in detecting neoplastic transformation of BE, CLE is still not used as a standard diagnostic tool in BE surveillance due to a deficiency of scientific evidence. More studies and data are needed if CLE is to find a place as a new technique in BE surveillance.
RESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) is a major contributor to the worldwide cancer burden. Recent studies on HCC have demonstrated dramatic alterations in expression of several cytochrome P450 (CYP) family members that play a crucial role in biotransformation of many drugs and other xenobiotics; however, the mechanisms responsible for their deregulation remain unclear. METHODS: We investigated a potential involvement of miRNAs in downregulation of expression of CYPs observed in HCC tumors. We compared miRNA expression profiles (TaqMan Array Human MicroRNA v3.0 TLDA qPCR) between HCC human patient tumors with strong (CYP-) and weak/no (CYP+) downregulation of drug-metabolizing CYPs. The role of significantly deregulated miRNAs in modulation of expression of the CYPs and associated xenobiotic receptors was then investigated in human liver HepaRG cells transfected with relevant miRNA mimics or inhibitors. RESULTS: We identified five differentially expressed miRNAs in CYP- versus CYP+ tumors, namely miR-29c, miR-125b1, miR-505, miR-653 and miR-675. The two most-upregulated miRNAs found in CYP- tumor samples, miR-29c and miR-653, were found to act as efficient suppressors of CYP1A2 or AHR expression. CONCLUSIONS: Our results revealed a novel role of miR-653 and miR-29c in regulation of expresion of CYPs involved in crucial biotransformation processes in liver, which are often deregulated during liver cancer progression.
Assuntos
Carcinoma Hepatocelular , Citocromo P-450 CYP1A2/metabolismo , Neoplasias Hepáticas , MicroRNAs/metabolismo , Biotransformação , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Hepatócitos/metabolismo , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Xenobióticos/metabolismoRESUMO
BACKGROUND: Acromegaly is a disorder associated with hypersecretion of growth hormone, most usually caused by a pituitary adenoma. Dysmotility of the gastrointestinal tract has been reported in acromegalic patients. Achalasia is a disorder characterized by aperistalsis of the oesophagus with incomplete lower oesophageal sphincter relaxation and whose aetiology remains unknown. Mutations in some genes have previously been associated with the development of acromegaly or achalasia. The study aims were to analyse mutations in selected genes in a woman having both of these diseases, to identify their aetiological factors, and to suggest explanations for the co-incidence of acromegaly and achalasia. METHODS AND RESULTS: A female patient with acromegaly, achalasia, and a multinodular thyroid gland with hyperplastic colloid nodules underwent successful treatment of achalasia via laparoscopic Heller myotomy, a thyroidectomy was performed, and the pituitary macroadenoma was surgically excised via transnasal endoscopic extirpation. Germline DNA from the leukocytes was analysed by sequencing methods for a panel of genes. No pathogenic mutation in AAAS, AIP, MEN1, CDKN1B, PRKAR1A, SDHB, GPR101, and GNAS genes was found in germline DNA. The somatic mutation c.601C>T/p.R201C in the GNAS gene was identified in DNA extracted from a tissue sample of the pituitary macroadenoma. CONCLUSIONS: We here describe the first case report to our knowledge of a patient with both acromegaly and achalasia. Association of acromegaly and soft muscle tissue hypertrophy may contribute to achalasia's development. If one of these diagnoses is determined, the other also should be considered along with increased risk of oesophageal and colorectal malignancy.
Assuntos
Acromegalia , Acalasia Esofágica , Neoplasias Hipofisárias , Acromegalia/complicações , Acromegalia/genética , DNA , Acalasia Esofágica/complicações , Acalasia Esofágica/genética , Feminino , Humanos , Incidência , Neoplasias Hipofisárias/genéticaRESUMO
Although 21 pancreatic cancer susceptibility loci have been identified in individuals of European ancestry through genome-wide association studies (GWASs), much of the heritability of pancreatic cancer risk remains unidentified. A recessive genetic model could be a powerful tool for identifying additional risk variants. To discover recessively inherited pancreatic cancer risk loci, we performed a re-analysis of the largest pancreatic cancer GWAS, the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4), including 8,769 cases and 7,055 controls of European ancestry. Six single nucleotide polymorphisms (SNPs) showed associations with pancreatic cancer risk according to a recessive model of inheritance. We replicated these variants in 3,212 cases and 3,470 controls collected from the PANcreatic Disease ReseArch (PANDoRA) consortium. The results of the meta-analyses confirmed that rs4626538 (7q32.2), rs7008921 (8p23.2) and rs147904962 (17q21.31) showed specific recessive effects (p<10-5) compared with the additive effects (p>10-3), although none of the six SNPs reached the conventional threshold for genome-wide significance (p < 5×10-8). Additional bioinformatic analysis explored the functional annotations of the SNPs and indicated a possible relationship between rs36018702 and expression of the BCL2L11 and BUB1 genes, which are known to be involved in pancreatic biology. Our findings, while not conclusive, indicate the importance of considering non-additive genetic models when performing GWAS analysis. The SNPs associated with pancreatic cancer in this study could be used for further meta-analysis for recessive association of SNPs and pancreatic cancer risk and might be a useful addiction to improve the performance of polygenic risk scores.
RESUMO
Exocrine pancreatic insufficiency (EPI), an important cause of maldigestion and malnutrition, results from primary pancreatic disease or is secondary to impaired exocrine pancreatic function. Although chronic pancreatitis is the most common cause of EPI, several additional causes exist. These include pancreatic tumors, pancreatic resection procedures, and cystic fibrosis. Other diseases and conditions, such as diabetes mellitus, celiac disease, inflammatory bowel disease, and advanced patient age, have also been shown to be associated with EPI, but the exact etiology of EPI has not been clearly elucidated in these cases. The causes of EPI can be divided into loss of pancreatic parenchyma, inhibition or inactivation of pancreatic secretion, and postcibal pancreatic asynchrony. Pancreatic enzyme replacement therapy (PERT) is indicated for the conditions described above presenting with clinically clear steatorrhea, weight loss, or symptoms related to maldigestion and malabsorption. This review summarizes the current literature concerning those etiologies of EPI less common than chronic pancreatitis, the pathophysiology of the mechanisms of EPI associated with each diagnosis, and treatment recommendations.
RESUMO
It is well known that some pathological conditions, especially of autoimmune etiology, are associated with the HLA (human leukocyte antigen) phenotype. Among these diseases, we include celiac disease, inflammatory bowel disease, autoimmune enteropathy, autoimmune hepatitis, primary sclerosing cholangitis and primary biliary cholangitis. Immunoglobulin G4-related diseases (IgG4-related diseases) constitute a second group of autoimmune gastrointestinal, hepatobiliary and pancreatic illnesses. IgG4-related diseases are systemic and rare autoimmune illnesses. They often are connected with chronic inflammation and fibrotic reaction that can occur in any organ of the body. The most typical feature of these diseases is a mononuclear infiltrate with IgG4-positive plasma cells and self-sustaining inflammatory response. In this review, we focus especially upon the hepatopancreatobiliary system, autoimmune pancreatitis and IgG4-related sclerosing cholangitis. The cooperation of the gastroenterologist, radiologist, surgeon and histopathologist is crucial for establishing correct diagnoses and appropriate treatment, especially in IgG4 hepatopancreatobiliary diseases.