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OBJECTIVE: The aim of the present study was to compare long-term post-resection oncological outcomes between A-IPMN and PDAC. SUMMARY BACKGROUND DATA: Knowledge of long term oncological outcomes (e.g recurrence and survival data) comparing between adenocarcinoma arising from intraductal papillary mucinous neoplasms (A-IPMN) and pancreatic ductal adenocarcinoma (PDAC) is scarce. METHODS: Patients undergoing pancreatic resection (2010-2020) for A-IPMN were identified retrospectively from 18 academic pancreatic centres and compared with PDAC patients from the same time-period. Propensity-score matching (PSM) was performed and survival and recurrence were compared between A-IPMN and PDAC. RESULTS: 459 A-IPMN patients (median age,70; M:F,250:209) were compared with 476 PDAC patients (median age,69; M:F,262:214). A-IPMN patients had lower T-stage, lymphovascular invasion (51.4%vs. 75.6%), perineural invasion (55.8%vs. 71.2%), lymph node positivity (47.3vs. 72.3%) and R1 resection (38.6%vs. 56.3%) compared to PDAC(P<0.001). The median survival and time-to-recurrence for A-IPMN versus PDAC were 39.0 versus19.5months (P<0.001) and 33.1 versus 14.8months (P<0.001), respectively (median follow-up,78 vs.73 months). Ten-year overall survival for A-IPMN was 34.6%(27/78) and PDAC was 9%(6/67). A-IPMN had higher rates of peritoneal (23.0 vs. 9.1%, P<0.001) and lung recurrence (27.8% vs. 15.6%, P<0.001) but lower rates of locoregional recurrence (39.7% vs. 57.8%; P<0.001). Matched analysis demonstrated inferior overall survival (P=0.005), inferior disease-free survival (P=0.003) and higher locoregional recurrence (P<0.001) in PDAC compared to A-IPMN but no significant difference in systemic recurrence rates (P=0.695). CONCLUSIONS: PDACs have inferior survival and higher recurrence rates compared to A-IPMN in matched cohorts. Locoregional recurrence is higher in PDAC but systemic recurrence rates are comparable and constituted by their own distinctive site-specific recurrence patterns.
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BACKGROUND: The clinico-oncological outcomes of precursor epithelial subtypes of adenocarcinoma arising from intraductal papillary mucinous neoplasms (A-IPMN) are limited to small cohort studies. Differences in recurrence patterns and response to adjuvant chemotherapy between A-IPMN subtypes are unknown. METHODS: Clincopathological features, recurrence patterns and long-term outcomes of patients undergoing pancreatic resection (2010-2020) for A-IPMN were reported from 18 academic pancreatic centres worldwide. Precursor epithelial subtype groups were compared using uni- and multivariate analysis. RESULTS: In total, 297 patients were included (median age, 70 years; male, 78.9%), including 54 (18.2%) gastric, 111 (37.3%) pancreatobiliary, 80 (26.9%) intestinal and 52 (17.5%) mixed subtypes. Gastric, pancreaticobiliary and mixed subtypes had comparable clinicopathological features, yet the outcomes were significantly less favourable than the intestinal subtype. The median time to recurrence in gastric, pancreatobiliary, intestinal and mixed subtypes were 32, 30, 61 and 33 months. Gastric and pancreatobiliary subtypes had worse overall recurrence (p = 0.048 and p = 0.049, respectively) compared with the intestinal subtype but gastric and pancreatobiliary subtypes had comparable outcomes. Adjuvant chemotherapy was associated with improved survival in the pancreatobiliary subtype (p = 0.049) but not gastric (p = 0.992), intestinal (p = 0.852) or mixed subtypes (p = 0.723). In multivariate survival analysis, adjuvant chemotherapy was associated with a lower likelihood of death in pancreatobiliary subtype, albeit with borderline significance [hazard ratio (HR) 0.56; 95% confidence interval (CI) 0.31-1.01; p = 0.058]. CONCLUSIONS: Gastric, pancreatobiliary and mixed subtypes have comparable recurrence and survival outcomes, which are inferior to the more indolent intestinal subtype. Pancreatobiliary subtype may respond to adjuvant chemotherapy and further research is warranted to determine the most appropriate adjuvant chemotherapy regimens for each subtype.
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BACKGROUND: The clinical impact of adjuvant chemotherapy after resection for adenocarcinoma arising from intraductal papillary mucinous neoplasia is unclear. The aim of this study was to identify factors related to receipt of adjuvant chemotherapy and its impact on recurrence and survival. METHODS: This was a multicentre retrospective study of patients undergoing pancreatic resection for adenocarcinoma arising from intraductal papillary mucinous neoplasia between January 2010 and December 2020 at 18 centres. Recurrence and survival outcomes for patients who did and did not receive adjuvant chemotherapy were compared using propensity score matching. RESULTS: Of 459 patients who underwent pancreatic resection, 275 (59.9%) received adjuvant chemotherapy (gemcitabine 51.3%, gemcitabine-capecitabine 21.8%, FOLFIRINOX 8.0%, other 18.9%). Median follow-up was 78 months. The overall recurrence rate was 45.5% and the median time to recurrence was 33 months. In univariable analysis in the matched cohort, adjuvant chemotherapy was not associated with reduced overall (P = 0.713), locoregional (P = 0.283) or systemic (P = 0.592) recurrence, disease-free survival (P = 0.284) or overall survival (P = 0.455). Adjuvant chemotherapy was not associated with reduced site-specific recurrence. In multivariable analysis, there was no association between adjuvant chemotherapy and overall recurrence (HR 0.89, 95% c.i. 0.57 to 1.40), disease-free survival (HR 0.86, 0.59 to 1.30) or overall survival (HR 0.77, 0.50 to 1.20). Adjuvant chemotherapy was not associated with reduced recurrence in any high-risk subgroup (for example, lymph node-positive, higher AJCC stage, poor differentiation). No particular chemotherapy regimen resulted in superior outcomes. CONCLUSION: Chemotherapy following resection of adenocarcinoma arising from intraductal papillary mucinous neoplasia does not appear to influence recurrence rates, recurrence patterns or survival.
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Recidiva Local de Neoplasia , Pancreatectomia , Neoplasias Pancreáticas , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adenocarcinoma/patologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/mortalidade , Adenocarcinoma/terapia , Adenocarcinoma Mucinoso/patologia , Adenocarcinoma Mucinoso/tratamento farmacológico , Adenocarcinoma Mucinoso/terapia , Adenocarcinoma Mucinoso/mortalidade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Capecitabina/administração & dosagem , Capecitabina/uso terapêutico , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/terapia , Carcinoma Ductal Pancreático/cirurgia , Quimioterapia Adjuvante , Gencitabina , Recidiva Local de Neoplasia/epidemiologia , Neoplasias Intraductais Pancreáticas/patologia , Neoplasias Intraductais Pancreáticas/terapia , Neoplasias Intraductais Pancreáticas/mortalidade , Neoplasias Intraductais Pancreáticas/cirurgia , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/cirurgia , Pontuação de Propensão , Estudos RetrospectivosRESUMO
BACKGROUND: Intraductal oncocytic papillary neoplasms (IOPNs) of the pancreas are now considered a separate entity to intraductal papillary mucinous neoplasms (IPMN). Invasive IOPNs are extremely rare, and their recurrence patterns, response to adjuvant chemotherapy and long-term survival outcomes are unknown. METHODS: Consecutive patients undergoing pancreatic resection (2010-2020) for invasive IOPNs or adenocarcinoma arising from IPMN (A-IPMN) from 18 academic pancreatic centers worldwide were included. Outcomes of invasive IOPNs were compared with A-IPMN invasive subtypes (ductal and colloid A-IPMN). RESULTS: 415 patients were included: 20 invasive IOPN, 331 ductal A-IPMN and 64 colloid A-IPMN. After a median follow-up of 6-years, 45% and 60% of invasive IOPNs had developed recurrence and died, respectively. There was no significant difference in recurrence or overall survival between invasive IOPN and ductal A-IPMN. Overall survival of invasive IOPNs was inferior to colloid A-IPMNs (median time of survival 24.4 months vs. 86.7, months, p = 0.013), but the difference in recurrence only showed borderline significance (median time to recurrence, 22.5 months vs. 78.5 months, p = 0.132). Adjuvant chemotherapy, after accounting for high-risk features, did not reduce rates of recurrence in invasive IOPN (p = 0.443), ductal carcinoma (p = 0.192) or colloid carcinoma (p = 0.574). CONCLUSIONS: Invasive IOPNs should be considered an aggressive cancer with a recurrence rate and prognosis consistent with ductal type A-IPMN.
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OBJECTIVE: This international multicentre cohort study aims to identify recurrence patterns and treatment of first and second recurrence in a large cohort of patients after pancreatic resection for adenocarcinoma arising from IPMN. SUMMARY BACKGROUND DATA: Recurrence patterns and treatment of recurrence post resection of adenocarcinoma arising from IPMN are poorly explored. METHOD: Patients undergoing pancreatic resection for adenocarcinoma from IPMN between January 2010 to December 2020 at 18 pancreatic centres were identified. Survival analysis was performed by the Kaplan-Meier log rank test and multivariable logistic regression by Cox-Proportional Hazards modelling. Endpoints were recurrence (time-to, location, and pattern of recurrence) and survival (overall survival and adjusted for treatment provided). RESULTS: Four hundred and fifty-nine patients were included (median, 70 y; IQR, 64-76; male, 54 percent) with a median follow-up of 26.3 months (IQR, 13.0-48.1 mo). Recurrence occurred in 209 patients (45.5 percent; median time to recurrence, 32.8 months, early recurrence [within 1 y], 23.2 percent). Eighty-three (18.1 percent) patients experienced a local regional recurrence and 164 (35.7 percent) patients experienced distant recurrence. Adjuvant chemotherapy was not associated with reduction in recurrence (HR 1.09;P=0.669) One hundred and twenty patients with recurrence received further treatment. The median survival with and without additional treatment was 27.0 and 14.6 months (P<0.001), with no significant difference between treatment modalities. There was no significant difference in survival between location of recurrence (P=0.401). CONCLUSION: Recurrence after pancreatic resection for adenocarcinoma arising from IPMN is frequent with a quarter of patients recurring within 12 months. Treatment of recurrence is associated with improved overall survival and should be considered.
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BACKGROUND: The overall poor prognosis in pancreatic cancer is related to late clinical detection. Early diagnosis remains a considerable challenge in pancreatic cancer. Unfortunately, the onset of clinical symptoms in patients usually indicate advanced disease or presence of metastasis. ANALYSIS AND RESULTS: Currently, there are no designated diagnostic or screening tests for pancreatic cancer in clinical use. Thus, identifying risk groups, preclinical risk factors or surveillance strategies to facilitate early detection is a target for ongoing research. Hereditary genetic syndromes are a obvious, but small group at risk, and warrants close surveillance as suggested by society guidelines. Screening for pancreatic cancer in asymptomatic individuals is currently associated with the risk of false positive tests and, thus, risk of harms that outweigh benefits. The promise of cancer biomarkers and use of 'omics' technology (genomic, transcriptomics, metabolomics etc.) has yet to see a clinical breakthrough. Several proposed biomarker studies for early cancer detection lack external validation or, when externally validated, have shown considerably lower accuracy than in the original data. Biopsies or tissues are often taken at the time of diagnosis in research studies, hence invalidating the value of a time-dependent lag of the biomarker to detect a pre-clinical, asymptomatic yet operable cancer. New technologies will be essential for early diagnosis, with emerging data from image-based radiomics approaches, artificial intelligence and machine learning suggesting avenues for improved detection. CONCLUSIONS: Early detection may come from analytics of various body fluids (eg 'liquid biopsies' from blood or urine). In this review we present some the technological platforms that are explored for their ability to detect pancreatic cancer, some of which may eventually change the prospects and outcomes of patients with pancreatic cancer.
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Detecção Precoce de Câncer , Neoplasias Pancreáticas , Humanos , Inteligência Artificial , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/cirurgia , Neoplasias Pancreáticas/genética , Fatores de Risco , Neoplasias PancreáticasRESUMO
A young man was hospitalised with acute abdomen and signs of pancreatitis. He became seriously ill and required surgery to address the underlying cause.
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Abdome Agudo , Anemia , Pancreatite , Masculino , Humanos , Abdome Agudo/etiologia , Pancreatite/diagnóstico , Pancreatite/diagnóstico por imagem , Anemia/diagnóstico , Anemia/etiologia , Abdome , Doença AgudaRESUMO
BACKGROUND: Predictors of long-term survival after resection of adenocarcinoma arising from intraductal papillary mucinous neoplasms are unknown. This study determines predictors of long-term (>5 years) disease-free survival and recurrence in adenocarcinoma arising from intraductal papillary mucinous neoplasms and derives a prognostic model for disease-free survival. METHODS: Consecutive patients who underwent pancreatic resection for adenocarcinoma arising from intraductal papillary mucinous neoplasms in 18 academic pancreatic centers in Europe and Asia between 2010 to 2017 with at least 5-year follow-up were identified. Factors associated with disease-free survival were determined using Cox proportional hazards model. Internal validation was performed, and discrimination and calibration indices were assessed. RESULTS: In the study, 288 patients (median age, 70 years; 52% male) were identified; 140 (48%) patients developed recurrence after a median follow-up of 98 months (interquartile range, 78.4-123), 57 patients (19.8%) developed locoregional recurrence, and 109 patients (37.8%) systemic recurrence. At 5 years after resection, the overall and disease-free survival was 46.5% (134/288) and 35.0% (101/288), respectively. On Cox proportional hazards model analysis, multivisceral resection (hazard ratio, 2.20; 95% confidence interval, 1.06-4.60), pancreatic tail location (hazard ratio, 2.34; 95% confidence interval, 1.22-4.50), poor tumor differentiation (hazard ratio, 2.48; 95% confidence interval, 1.10-5.30), lymphovascular invasion (hazard ratio, 1.74; 95% confidence interval, 1.06-2.88), and perineural invasion (hazard ratio, 1.83; 95% confidence interval, 1.09-3.10) were negatively associated with long-term disease-free survival. The final predictive model incorporated 8 predictors and demonstrated good predictive ability for disease-free survival (C-index, 0.74; calibration, slope 1.00). CONCLUSION: A third of patients achieve long-term disease-free survival (>5 years) after pancreatic resection for adenocarcinoma arising from intraductal papillary mucinous neoplasms. The predictive model developed in the current study can be used to estimate the probability of long-term disease-free survival.
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Recidiva Local de Neoplasia , Pancreatectomia , Neoplasias Pancreáticas , Humanos , Masculino , Feminino , Idoso , Neoplasias Pancreáticas/cirurgia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Pessoa de Meia-Idade , Prognóstico , Pancreatectomia/mortalidade , Intervalo Livre de Doença , Recidiva Local de Neoplasia/epidemiologia , Estudos Retrospectivos , Carcinoma Ductal Pancreático/cirurgia , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Adenocarcinoma Mucinoso/cirurgia , Adenocarcinoma Mucinoso/patologia , Adenocarcinoma Mucinoso/mortalidade , Modelos de Riscos Proporcionais , Neoplasias Intraductais Pancreáticas/cirurgia , Neoplasias Intraductais Pancreáticas/patologia , Neoplasias Intraductais Pancreáticas/mortalidade , Seguimentos , Europa (Continente)/epidemiologia , Adenocarcinoma/cirurgia , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Taxa de Sobrevida , Idoso de 80 Anos ou maisRESUMO
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited treatment options. Emerging evidence shows that epigenetic alterations are present in PDAC. The changes are potentially reversible and therefore promising therapeutic targets. Epigenetic aberrations also influence the tumor microenvironment with the potential to modulate and possibly enhance immune-based treatments. Epigenetic marks can also serve as diagnostic screening tools, as epigenetic changes occur at early stages of the disease. Further, epigenetics can be used in prognostication. The field is evolving, and this review seeks to provide an updated overview of the emerging role of epigenetics in the diagnosis, treatment, and prognostication of PDAC.
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Purpose: Pancreatic cancer is one of the most lethal of solid tumors and is associated with aggressive cancer biology. The purpose is to review the role of trypsin and effect on molecular and cellular processes potentially explaining the aggressive biology in pancreatic cancer. Methods: A narrative literature review of studies investigating trypsin and its effect on protease systems in cancer, with special reference to pancreatic cancer biology. Results: Proteases, such as trypsin, provides a significant advantage to developing tumors through the ability to remodel the extracellular matrix, promote cell invasion and migration, and facilitate angiogenesis. Trypsin is a digestive enzyme produced by the exocrine pancreas that is also related to mechanisms of proliferation, invasion and metastasis. Several of these mechanisms may be co-regulated or influenced by activation of proteinase-activated receptor 2 (PAR-2). The current role in pancreatic cancer is not clear but emerging data suggest several potential mechanisms. Trypsin may act as a Trojan horse in the pancreatic gland, facilitating several molecular pathways from the onset, which leads to rapid progression of the disease. Pancreatic cancer cell lines containing PAR-2 proliferate upon exposure to trypsin, whereas cancer cell lines not containing PAR-2 fail to proliferate upon trypsin expression. Several mechanisms of action include a proinflammatory environment, signals inducing proliferation and migration, and direct and indirect evidence for mechanisms promoting invasion and metastasis. Novel techniques (such as organoid models) and increased understanding of mechanisms (such as the microbiome) may yield improved understanding into the role of trypsin in pancreatic carcinogenesis. Conclusion: Trypsin is naturally present in the pancreatic gland and may experience pathological activation intracellularly and in the neoplastic environment, which speeds up molecular mechanisms of proliferation, invasion, and metastasis. Further investigation of these processes will provide important insights into how pancreatic cancer evolves, and suggest new ways for treatment.
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In order to provide optimal cancer care and prognostication, it is necessary to stage the disease. The 8th edition of the TNM-staging for exocrine pancreatic ductal adenocarcinoma (PDAC) system has refined size-based T-stages and number-based N-categories. However, several impediments to the value of this may exist. For one, even at small size (e.g. <0.5 cm), PDACs readily metastasize, making size unreliable to predict behavior. The increasing shift towards neoadjuvant treatments for both resectable and borderline PDAC, and use of conversion therapy for locally advanced disease, suggest the need for additional biological predictors. Here we discuss whether recent changes in the TNM system for PDAC are along the lines of changes seen in contemporary management. Also, with the particular aggressive biology seen in PDAC, it is questioned whether the minute details in TNM refinement represents true progress or merely shuffles the cards.