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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: 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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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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Recurrencia Local de Neoplasia , Pancreatectomía , Neoplasias Pancreáticas , Humanos , Masculino , Femenino , Anciano , Neoplasias Pancreáticas/cirugía , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Persona de Mediana Edad , Pronóstico , Pancreatectomía/mortalidad , Supervivencia sin Enfermedad , Recurrencia Local de Neoplasia/epidemiología , Estudios Retrospectivos , Carcinoma Ductal Pancreático/cirugía , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/patología , Adenocarcinoma Mucinoso/cirugía , Adenocarcinoma Mucinoso/patología , Adenocarcinoma Mucinoso/mortalidad , Modelos de Riesgos Proporcionales , Neoplasias Intraductales Pancreáticas/cirugía , Neoplasias Intraductales Pancreáticas/patología , Neoplasias Intraductales Pancreáticas/mortalidad , Estudios de Seguimiento , Europa (Continente)/epidemiología , Adenocarcinoma/cirugía , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Tasa de Supervivencia , Anciano de 80 o más AñosRESUMEN
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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Recurrencia Local de Neoplasia , Pancreatectomía , Neoplasias Pancreáticas , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adenocarcinoma/patología , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/mortalidad , Adenocarcinoma/terapia , Adenocarcinoma Mucinoso/patología , Adenocarcinoma Mucinoso/tratamiento farmacológico , Adenocarcinoma Mucinoso/terapia , Adenocarcinoma Mucinoso/mortalidad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Capecitabina/administración & dosificación , Capecitabina/uso terapéutico , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/terapia , Carcinoma Ductal Pancreático/cirugía , Quimioterapia Adyuvante , Gemcitabina , Recurrencia Local de Neoplasia/epidemiología , Neoplasias Intraductales Pancreáticas/patología , Neoplasias Intraductales Pancreáticas/terapia , Neoplasias Intraductales Pancreáticas/mortalidad , Neoplasias Intraductales Pancreáticas/cirugía , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/cirugía , Puntaje de Propensión , Estudios RetrospectivosRESUMEN
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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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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Management of liver metastases from uveal melanoma (LMUM) requires multimodal approach. This study describes evolution of liver resection for LMUM, reviewing current literature and institutional outcomes. Records of patients referred to the Melanoma Multi-Disciplinary Team between February 2005 and August 2018 were reviewed. All publications describing surgery for LMUM were identified from PubMed, Embase, and Google Scholar. Thirty-one of 147 patients with LMUM underwent laparoscopic liver biopsy, and 29 (14 females) had liver resections. Nineteen liver resections were performed locally [7 major (≥3 seg), 14 laparoscopic] without major complications or mortality. Overall survival positively correlated with the time from uveal melanoma to LMUM (Spearman's rho rs = 0.859, P < 0.0001). Overall and recurrence-free survivals were comparable following R1 or R0 resections (OS 25 vs. 28 months, P = 0.404; RFS 13 vs. 6 months, P = 0.596). R1 resection cohort had longer lead-time (median 100 vs. 24 months, P = 0.0408). Eleven publications describing liver resection for LMUM were identified and included in the narrative review. Surgery for LMUM is safe and complements multidisciplinary management. Despite heterogeneity in literature, time from diagnosis of uveal melanoma to LMUM remains a key factor affecting survival after liver resection.
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Neoplasias Hepáticas , Melanoma , Neoplasias Primarias Secundarias , Neoplasias Cutáneas , Neoplasias de la Úvea , Femenino , Humanos , Melanoma/patología , Neoplasias Cutáneas/cirugía , Neoplasias de la Úvea/cirugía , Neoplasias de la Úvea/patología , Hepatectomía , Neoplasias Hepáticas/cirugía , Neoplasias Hepáticas/secundarioRESUMEN
PURPOSE: A preoperative estimate of the risk of malignancy for intraductal papillary mucinous neoplasms (IPMN) is important. The present study carries out an external validation of the Shin score in a European multicenter cohort. METHODS: An observational multicenter European study from 2010 to 2015. All consecutive patients undergoing surgery for IPMN at 35 hospitals with histological-confirmed IPMN were included. RESULTS: A total of 567 patients were included. The score was significantly associated with the presence of malignancy (p < 0.001). In all, 64% of the patients with benign IPMN had a Shin score < 3 and 57% of those with a diagnosis of malignancy had a score ≥ 3. The relative risk (RR) with a Shin score of 3 was 1.37 (95% CI: 1.07-1.77), with a sensitivity of 57.1% and specificity of 64.4%. CONCLUSION: Patients with a Shin score ≤ 1 should undergo surveillance, while patients with a score ≥ 4 should undergo surgery. Treatment of patients with Shin scores of 2 or 3 should be individualized because these scores cannot accurately predict malignancy of IPMNs. This score should not be the only criterion and should be applied in accordance with agreed clinical guidelines.
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Adenocarcinoma Mucinoso , Carcinoma Ductal Pancreático , Neoplasias Intraductales Pancreáticas , Neoplasias Pancreáticas , Humanos , Neoplasias Intraductales Pancreáticas/cirugía , Neoplasias Intraductales Pancreáticas/patología , Adenocarcinoma Mucinoso/cirugía , Adenocarcinoma Mucinoso/patología , Neoplasias Pancreáticas/cirugía , Neoplasias Pancreáticas/patología , Páncreas/cirugía , Carcinoma Ductal Pancreático/cirugía , Carcinoma Ductal Pancreático/patología , Estudios RetrospectivosRESUMEN
AIM: Hepatocellular carcinoma (HCC) is a common cause a cancer-related death. Focal adhesions (FAs) represent multiprotein complexes at integrin-mediated cell-extracellular matrix adhesion sites that orchestrate vital cellular functions. The heterotrimeric ILK-PINCH-PARVB (IPP) complex, RSU1, a PINCH binding protein and CTEN, a member of the tensin family of proteins exert a critical role in FAs, where they regulate important cancer related functions such as cell adhesion, migration, proliferation and survival. Previous studies implicate these FA proteins in liver pathophysiology but their detailed role in human HCC is not fully understood. Here in we investigated expression and function of IPP, RSU1 and CTEN in human HCC. METHODS: The expression of focal adhesion proteins was studied in human HCC by immunohistochemistry in relation to clinicopathological parameters, previous studied genomic instability markers and patient's survival. Effects on cell proliferation and FA proteins expression upon ILK inhibition and RSU1 silencing were also investigated in HCC in vitro. RESULTS: IPP complex and CTEN proteins are overexpressed while RSU1 expression is decreased in human HCC. CTEN expression correlates with reduced patients' survival while RSU1 represents an independent favorable prognostic indicator in human HCC. Nuclear ILK expression correlates with markers of genomic instability. Pharmacological targeting of ILK suppresses, while RSU1 silencing promotes cell growth of HCC cells in vitro, while in both experimental conditions expression and/or localization of focal adhesion proteins is deregulated. CONCLUSION: Our results suggest that FA signaling is implicated in hepatocellular carcinogenesis with prognostic significance. RSU1 seems to exert tumor suppressive functions in HCC and represents a novel favorable prognostic indicator.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Factores de Transcripción , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Adhesiones Focales/genética , Adhesiones Focales/metabolismo , Inestabilidad Genómica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Pronóstico , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
BACKGROUNDS/AIMS: Post-operative pancreatic fistulas (POPF) and fluid collections (POPFC) remain significant sources of morbidity and mortality after pancreatic resections. There remains a paucity of literature describing endoscopic ultrasound (EUS) guided drainage of POPFC using a Hot AXIOS™ lumen apposing metal stent (LAMS). METHODS: We conducted a retrospective study, encompassing all consecutive patients with POPFC managed using Hot AXIOS™ LAMS at our institution between January 2017 and December 2019. Primary outcome measures were technical and clinical success. Secondary outcome measures were adverse events and recurrence rates. RESULTS: Five patients underwent EUS guided drainage using Hot AXIOS™ LAMS during the study period. Mean age of patients was 67.8 ± 2.16 years. The majority (60.0%) of patients were males. Median duration of symptom onset after surgery was 9 days. All patients presented with abdominal pain. Median size of the collection measured on computed tomography was 91 mm. Median interval time between symptom onset and EUS drainage was 30 days. Two patients required percutaneous drainage prior to EUS guided drainage. Technical and clinical success were achieved for all patients. No adverse events were observed. Median duration of follow-up was 90 days. No recurrence of collection occurred during the follow-up period. CONCLUSIONS: EUS guided drainage of POPFC using Hot AXIOS™ LAMS is a safe and effective treatment modality with technical and clinical success rates of 100% in our experience.
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OBJECTIVE: There is emerging evidence that the pancreas may be a target organ of SARS-CoV-2 infection. This aim of this study was to investigate the outcome of patients with acute pancreatitis (AP) and coexistent SARS-CoV-2 infection. DESIGN: A prospective international multicentre cohort study including consecutive patients admitted with AP during the current pandemic was undertaken. Primary outcome measure was severity of AP. Secondary outcome measures were aetiology of AP, intensive care unit (ICU) admission, length of hospital stay, local complications, acute respiratory distress syndrome (ARDS), persistent organ failure and 30-day mortality. Multilevel logistic regression was used to compare the two groups. RESULTS: 1777 patients with AP were included during the study period from 1 March to 23 July 2020. 149 patients (8.3%) had concomitant SARS-CoV-2 infection. Overall, SARS-CoV-2-positive patients were older male patients and more likely to develop severe AP and ARDS (p<0.001). Unadjusted analysis showed that SARS-CoV-2-positive patients with AP were more likely to require ICU admission (OR 5.21, p<0.001), local complications (OR 2.91, p<0.001), persistent organ failure (OR 7.32, p<0.001), prolonged hospital stay (OR 1.89, p<0.001) and a higher 30-day mortality (OR 6.56, p<0.001). Adjusted analysis showed length of stay (OR 1.32, p<0.001), persistent organ failure (OR 2.77, p<0.003) and 30-day mortality (OR 2.41, p<0.04) were significantly higher in SARS-CoV-2 co-infection. CONCLUSION: Patients with AP and coexistent SARS-CoV-2 infection are at increased risk of severe AP, worse clinical outcomes, prolonged length of hospital stay and high 30-day mortality.
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COVID-19 , Pancreatitis , COVID-19/diagnóstico , COVID-19/epidemiología , Estudios de Cohortes , Comorbilidad , Progresión de la Enfermedad , Femenino , Humanos , Unidades de Cuidados Intensivos/estadística & datos numéricos , Cooperación Internacional , Tiempo de Internación/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Mortalidad , Puntuaciones en la Disfunción de Órganos , Evaluación de Resultado en la Atención de Salud , Pancreatitis/diagnóstico , Pancreatitis/mortalidad , Pancreatitis/fisiopatología , Síndrome de Dificultad Respiratoria/diagnóstico , Síndrome de Dificultad Respiratoria/etiología , SARS-CoV-2/aislamiento & purificación , Índice de Severidad de la EnfermedadAsunto(s)
Hernia Inguinal , Obstrucción Intestinal , Hernia Inguinal/diagnóstico por imagen , Hernia Inguinal/cirugía , Herniorrafia , Humanos , Obstrucción Intestinal/diagnóstico por imagen , Obstrucción Intestinal/etiología , Obstrucción Intestinal/cirugía , Masculino , Escroto/diagnóstico por imagen , Escroto/cirugíaRESUMEN
BACKGROUND: Recently, statins have been associated with improved survival in certain cancers. The aim of this study was to evaluate the impact of statins on the outcome of patients undergoing surgery for pancreatic cancer. In addition, the effect of statins on the histopathological characteristics of the disease was assessed. METHODS: A retrospective review of the prospectively maintained hepato-pancreatico-biliary database was performed and patients with pancreatic cancer who underwent surgery between January 2014 and December 2017 were included. Statistical analysis was performed to assess the impact of statins on histopathological characteristics and survival outcome. RESULTS: A total of 151 patients were included, of whom 71 underwent pancreatic resections and 80 underwent trial dissection and bypass procedures. In the operated group, 20 patients were on statin therapy preoperatively. With respect to disease-free survival, tumour size (P = 0.023) and lymphatic invasion (P = 0.015) were significant variables on univariate analysis. Gender (P = 0.022), adjuvant chemotherapy (P < 0.001), lymphatic invasion (P = 0.021) and tumour size (P = 0.041) were significant variables on univariate analysis with respect to overall survival. Multivariate analysis identified adjuvant chemotherapy as the only independent predictor of overall survival (P < 0.001). No correlations between the use of statins and the histopathological characteristics were identified. CONCLUSION: Adjuvant chemotherapy is an independent predictor of overall survival in patients undergoing surgery for pancreatic cancer. Statin therapy does not influence survival outcomes and histopathological characteristics following surgery for pancreatic cancer.
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Inhibidores de Hidroximetilglutaril-CoA Reductasas , Neoplasias Pancreáticas , Quimioterapia Adyuvante , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Pancreatectomía , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/cirugía , Pancreaticoduodenectomía , Estudios RetrospectivosRESUMEN
OBJECTIVE: Despite advances in the identification of epigenetic alterations in pancreatic cancer, their biological roles in the pathobiology of this dismal neoplasm remain elusive. Here, we aimed to characterise the functional significance of histone lysine methyltransferases (KMTs) and demethylases (KDMs) in pancreatic tumourigenesis. DESIGN: DNA methylation sequencing and gene expression microarrays were employed to investigate CpG methylation and expression patterns of KMTs and KDMs in pancreatic cancer tissues versus normal tissues. Gene expression was assessed in five cohorts of patients by reverse transcription quantitative-PCR. Molecular analysis and functional assays were conducted in genetically modified cell lines. Cellular metabolic rates were measured using an XF24-3 Analyzer, while quantitative evaluation of lipids was performed by liquid chromatography-mass spectrometry (LC-MS) analysis. Subcutaneous xenograft mouse models were used to evaluate pancreatic tumour growth in vivo. RESULTS: We define a new antitumorous function of the histone lysine (K)-specific methyltransferase 2D (KMT2D) in pancreatic cancer. KMT2D is transcriptionally repressed in human pancreatic tumours through DNA methylation. Clinically, lower levels of this methyltransferase associate with poor prognosis and significant weight alterations. RNAi-based genetic inactivation of KMT2D promotes tumour growth and results in loss of H3K4me3 mark. In addition, KMT2D inhibition increases aerobic glycolysis and alters the lipidomic profiles of pancreatic cancer cells. Further analysis of this phenomenon identified the glucose transporter SLC2A3 as a mediator of KMT2D-induced changes in cellular, metabolic and proliferative rates. CONCLUSION: Together our findings define a new tumour suppressor function of KMT2D through the regulation of glucose/fatty acid metabolism in pancreatic cancer.
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Carcinoma/enzimología , Carcinoma/patología , Histona Demetilasas/metabolismo , N-Metiltransferasa de Histona-Lisina/metabolismo , Neoplasias Pancreáticas/enzimología , Neoplasias Pancreáticas/patología , Animales , Estudios de Casos y Controles , Técnicas de Cultivo de Célula , Modelos Animales de Enfermedad , Humanos , Ratones , Trasplante de NeoplasiasAsunto(s)
Brazo/irrigación sanguínea , Derivación Arteriovenosa Quirúrgica/efectos adversos , Isquemia/etiología , Enfermedades Vasculares Periféricas/etiología , Diálisis Renal , Brazo/diagnóstico por imagen , Brazo/cirugía , Constricción Patológica , Diagnóstico Diferencial , Humanos , Isquemia/diagnóstico por imagen , Isquemia/cirugía , Masculino , Persona de Mediana Edad , Enfermedades Vasculares Periféricas/diagnóstico por imagen , Enfermedades Vasculares Periféricas/cirugía , Síndrome , UltrasonografíaRESUMEN
We developed a medical image segmentation and preoperative planning application which implements a semiautomatic and a hybrid semiautomatic liver segmentation algorithm. The aim of this study was to evaluate the feasibility of computer-assisted liver tumor surgery using these algorithms which are based on thresholding by pixel intensity value from initial seed points. A random sample of 12 patients undergoing elective high-risk hepatectomies at our institution was prospectively selected to undergo computer-assisted surgery using our algorithms (June 2013-July 2014). Quantitative and qualitative evaluation was performed. The average computer analysis time (segmentation, resection planning, volumetry, visualization) was 45 min/dataset. The runtime for the semiautomatic algorithm was <0.2 s/slice. Liver volumetric segmentation using the hybrid method was achieved in 12.9 s/dataset (SD ± 6.14). Mean similarity index was 96.2 % (SD ± 1.6). The future liver remnant volume calculated by the application showed a correlation of 0.99 to that calculated using manual boundary tracing. The 3D liver models and the virtual liver resections had an acceptable coincidence with the real intraoperative findings. The patient-specific 3D models produced using our semiautomatic and hybrid semiautomatic segmentation algorithms proved to be accurate for the preoperative planning in liver tumor surgery and effectively enhanced the intraoperative medical image guidance.
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Algoritmos , Neoplasias Hepáticas/cirugía , Cirugía Asistida por Computador , Adulto , Anciano , Femenino , Humanos , Imagenología Tridimensional , Hígado/patología , Hígado/cirugía , Neoplasias Hepáticas/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Tamaño de los Órganos , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: Genomic instability is a common feature in hepatocellular carcinoma. Deregulation of replication licensing factors has been shown to trigger DNA damage response contributing to genomic instability. Overexpression of DNA replication licensing factors chromatin licensing and DNA replication factor 1 (CDT1) and minichromosome maintenance complex component 7 (MCM7) has been previously reported in several human cancers. The aim of the present study was to evaluate the expression and prognostic significance of CDT1 and MCM7 in association with DNA damage response markers and p53 in patients with hepatocellular carcinoma. METHODS: Expression of CDT1, MCM7, p-H2A histone family member X (H2AX), phospho-ataxia telangiectasia-mutated (ATM)/ataxia telangiectasia rad3-related (ATR) substrate, and p53 was evaluated by immunohistochemistry on formalin-fixed paraffin-embedded surgical specimens from 111 patients who underwent hepatectomy for hepatocellular carcinoma. Statistical analysis was performed to evaluate associations between the studied proteins, clinicopathological parameters, and patient survival. RESULTS: CDT1 expression correlated with p-H2AX (p = 0.038), while MCM7 correlated with p-H2AX and phospho-ATM/ATR substrate (p < 0.001). Increased CDT1 expression was associated with higher tumor grade (p = 0.006) and tumor-node-metastasis (TNM) stage (p = 0.033). High CDT1 expression correlated significantly with reduced overall survival (60.8 and 26.5 % vs 82.8 and 53.0 %, for low CDT1 expression, at 2 and 5 years, respectively, p = 0.012) and was identified by multivariate analysis as an independent predictor of poor overall survival (p = 0.049). CONCLUSIONS: Overexpression of CDT1 and MCM7 in hepatocellular carcinoma correlates with DNA damage response, and CDT1 overexpression is a significant prognostic biomarker in hepatocellular carcinoma.
Asunto(s)
Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidad , Proteínas de Ciclo Celular/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/microbiología , Componente 7 del Complejo de Mantenimiento de Minicromosoma/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Carcinoma Hepatocelular/cirugía , Estudios de Cohortes , Femenino , Humanos , Neoplasias Hepáticas/cirugía , Masculino , Persona de Mediana Edad , PronósticoRESUMEN
A 69-year-old male with a history of hepatitis B-induced cirrhosis underwent segmental liver resection for hepatocellular carcinoma. At his 12-month follow-up, local recurrence in segment VII was diagnosed, measuring 7.8 by 6.2 cm, with irregular margins and the presence of a tumor thrombus in the portal vein. After evaluation by the multidisciplinary liver team, the patient underwent transcatheter arterial chemoembolization with drug-eluting beads. Forty-eight hours after his discharge, the patient presented with gangrenous cholecystitis and he underwent an uneventful cholecystectomy. Cholecystitis is a well-documented complication of transcatheter arterial chemoembolization due to inadvertent reflux of the embolic material into the cystic artery. However, super selective embolization significantly reduces the risk of cholecystitis. In most cases, management is conservative and only severe cases require further intervention.