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BACKGROUND: Recent retrospective studies suggest a role for distinct microbiota in the perioperative morbidity and mortality of pancreatic head resections. OBJECTIVE: We aimed to prospectively investigate the microbial colonization of critical operative sites of pancreatic head resections to identify microbial stratification factors for surgical and long-term oncologic outcomes. METHODS: Prospective biomarker study applying 16S rRNA sequencing and microbial culturing to samples collected from various sites of the GI tract and surgical sites of patients during pancreatic head resections at a German single high-volume pancreatic center. RESULTS: A total of 101 patients were included (38 non-cancer, 63 cancer patients [50 PDAC patients]) in the study. In a first data analysis series, 16S rRNA sequencing data were utilized from 96 patients to assess associations of microbiome profiles with clinical parameters and outcomes. In general, microbiome composition varied according to sampling site, cancer, age or preoperative ERCP intervention, notably for the bile microbiome. In the PDAC subcohort, compositional variance of the bile or periampullary microbiome was significantly associated with postoperative complications such as ICU admission; on a taxonomic level we observed Enterococcus spp. to be significantly more abundant in patients developing deep or organ-space surgical site infections (SSI). Elevated Enterococcus relative abundances in the upper GI tract, in turn, were associated with 6-months mortality rates. In a second step, we focused on microbiological cultures collected from bile aspirates during surgery and investigated associations with perioperative complications and long-term survival. Notably, Enterococcus spp. were among the most prevalent pathobiont isolates observed in cancer patient bile specimens that were associated with severe SSIs, and thereby elevated mortality rates up to 24 months. Clinically relevant postoperative pancreatic fistulas or severe SSI were found as other major variables determining short-term mortality in this cancer patient cohort. In the context of adverse microbiological factors, a preoperative ERCP was also observed to segregate long-term survival, and it appeared to interact with the presence of Enterococcus spp. as highest mortality rates were observed in PDAC patients with both preoperative ERCP and presence of E. faecalis in bile aspirates. CONCLUSIONS: The presence of Enterococcus spp. in bile ducts of PDAC patients undergoing pancreatic surgery represents a significant risk factor for perioperative infections and, thereby, elevated postoperative and long-term mortality. This finding supports previous data on the use of the antibiotic drug piperacillin-tazobactam as appropriate perioperative antibiotic prophylaxis for preventing adverse outcomes after pancreatoduodenectomy.
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BACKGROUND & AIMS: Oncogenic KrasG12D induces neoplastic transformation of pancreatic acinar cells through acinar-to-ductal metaplasia (ADM), an actin-based morphogenetic process, and drives pancreatic ductal adenocarcinoma (PDAC). mTOR (mechanistic target of rapamycin kinase) complex 1 (mTORC1) and 2 (mTORC2) contain Rptor and Rictor, respectively, and are activated downstream of KrasG12D, thereby contributing to PDAC. Yet, whether and how mTORC1 and mTORC2 impact on ADM and the identity of the actin nucleator(s) mediating such actin rearrangements remain unknown. METHODS: A mouse model of inflammation-accelerated KrasG12D-driven early pancreatic carcinogenesis was used. Rptor, Rictor, and Arpc4 (actin-related protein 2/3 complex subunit 4) were conditionally ablated in acinar cells to deactivate the function of mTORC1, mTORC2 and the actin-related protein (Arp) 2/3 complex, respectively. RESULTS: We found that mTORC1 and mTORC2 are markedly activated in human and mouse ADM lesions, and cooperate to promote KrasG12D-driven ADM in mice and in vitro. They use the Arp2/3 complex as a common downstream effector to induce the remodeling the actin cytoskeleton leading to ADM. In particular, mTORC1 regulates the translation of Rac1 (Rac family small GTPase 1) and the Arp2/3-complex subunit Arp3, whereas mTORC2 activates the Arp2/3 complex by promoting Akt/Rac1 signaling. Consistently, genetic ablation of the Arp2/3 complex prevents KrasG12D-driven ADM in vivo. In acinar cells, the Arp2/3 complex and its actin-nucleation activity mediated the formation of a basolateral actin cortex, which is indispensable for ADM and pre-neoplastic transformation. CONCLUSIONS: Here, we show that mTORC1 and mTORC2 attain a dual, yet nonredundant regulatory role in ADM and early pancreatic carcinogenesis by promoting Arp2/3 complex function. The role of Arp2/3 complex as a common effector of mTORC1 and mTORC2 fills the gap between oncogenic signals and actin dynamics underlying PDAC initiation.
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Células Acinares/enzimología , Complejo 2-3 Proteico Relacionado con la Actina/metabolismo , Carcinoma Ductal Pancreático/enzimología , Transformación Celular Neoplásica/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Diana Mecanicista del Complejo 2 de la Rapamicina/metabolismo , Mutación , Conductos Pancreáticos/enzimología , Neoplasias Pancreáticas/enzimología , Proteínas Proto-Oncogénicas p21(ras)/genética , Células Acinares/patología , Complejo 2-3 Proteico Relacionado con la Actina/genética , Animales , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Modelos Animales de Enfermedad , Regulación Neoplásica de la Expresión Génica , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina/genética , Diana Mecanicista del Complejo 2 de la Rapamicina/genética , Metaplasia , Ratones Endogámicos C57BL , Ratones Noqueados , Conductos Pancreáticos/patología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Proteína Asociada al mTOR Insensible a la Rapamicina/genética , Proteína Asociada al mTOR Insensible a la Rapamicina/metabolismo , Proteína Reguladora Asociada a mTOR/genética , Proteína Reguladora Asociada a mTOR/metabolismo , Transducción de SeñalRESUMEN
BACKGROUND: Non-resectability is common in patients with pancreatic ductal adenocarcinoma (PDAC) due to local invasion or distant metastases. Then, biliary or gastroenteric bypasses or both are often established despite associated morbidity and mortality. The current study explores outcomes after palliative bypass surgery in patients with non-resectable PDAC. METHODS: From the prospectively maintained German StuDoQ|Pancreas registry, all patients with histopathologically confirmed PDAC who underwent non-resective pancreatic surgery between 2013 and 2018 were retrospectively identified, and the influence of the surgical procedure on morbidity and mortality was analyzed. RESULTS: Of 389 included patients, 127 (32.6%) underwent explorative surgery only, and a biliary, gastroenteric or double bypass was established in 92 (23.7%), 65 (16.7%) and 105 (27.0%). After exploration only, patients had a significantly shorter stay in the intensive care unit (mean 0.5 days [SD 1.7] vs. 1.9 [3.6], 2.0 [2.8] or 2.1 [2.8]; P < 0.0001) and in the hospital (median 7 days [IQR 4-11] vs. 12 [10-18], 12 [8-19] or 12 [9-17]; P < 0.0001), and complications occurred less frequently (22/127 [17.3%] vs. 37/92 [40.2%], 29/65 [44.6%] or 48/105 [45.7%]; P < 0.0001). In multivariable logistic regression, biliary stents were associated with less major (Clavien-Dindo grade ≥ IIIa) complications (OR 0.49 [95% CI 0.25-0.96], P = 0.037), whereas-compared to exploration only-biliary, gastroenteric, and double bypass were associated with more major complications (OR 3.58 [1.48-8.64], P = 0.005; 3.50 [1.39-8.81], P = 0.008; 4.96 [2.15-11.43], P < 0.001). CONCLUSIONS: In patients with non-resectable PDAC, biliary, gastroenteric or double bypass surgery is associated with relevant morbidity and mortality. Although surgical palliation is indicated if interventional alternatives are inapplicable, or life expectancy is high, less invasive options should be considered.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Estudios Retrospectivos , Neoplasias Pancreáticas/patología , Carcinoma Ductal Pancreático/cirugía , Páncreas/patología , Cuidados Paliativos , Sistema de Registros , Neoplasias PancreáticasRESUMEN
The cardinal symptom of chronic pancreatitis is severe belt-like upper abdominal pain, which requires immediate and adequate treatment. Furthermore, advanced stage chronic pancreatitis is often associated with complications, such as pancreatic pseudocysts, pancreatic duct stones and stenosis as well as biliary stenosis. The various endoscopic and surgical treatment options for chronic pancreatitis patients have been controversially discussed for decades. The new German S3 guidelines on pancreatitis now clearly define the best treatment options depending on the indications for treatment. For the treatment of pain in chronic pancreatitis it has been known for a long time that a surgical intervention is superior to endoscopic intervention concerning long-term pain relief. The recently published ESCAPE study has further underlined this by showing that early surgical intervention was superior to a step-up approach with initial endoscopic treatment. For the treatment of pancreatic pain, an initial endoscopic treatment attempt is therefore justified for short-term pain relief but in the midterm and long term, surgical intervention is the treatment of choice. In contrast, pancreatic pseudocysts, solitary proximally situated pancreatic duct stones and benign biliary strictures (except in calcifying pancreatitis) can nowadays generally be managed endoscopically. For distal pancreatic duct stones and symptomatic pancreatic duct stenosis surgical treatment is again the method of choice. This review article discusses these indication-related procedures in detail and explains them in relation to the recently published S3 guidelines on pancreatitis of the German Society for Gastroenterology, Digestive and Metabolic Diseases (DGVS).
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Seudoquiste Pancreático , Pancreatitis Crónica , Enfermedad Crónica , Humanos , Dolor , Manejo del Dolor , Seudoquiste Pancreático/diagnóstico , Seudoquiste Pancreático/cirugía , Pancreatitis Crónica/diagnóstico , Pancreatitis Crónica/cirugíaRESUMEN
BACKGROUND & AIMS: Changes to the microenvironment of pancreatic ductal adenocarcinomas (PDACs) have been associated with poor outcomes of patients. We studied the associations between composition of the pancreatic stroma (fibrogenic, inert, dormant, or fibrolytic stroma) and infiltration by inflammatory cells and times of progression-free survival (PFS) of patients with PDACs after resection. METHODS: We obtained 1824 tissue microarray specimens from 385 patients included in the European Study Group for Pancreatic Cancer trial 1 and 3 and performed immunohistochemistry to detect alpha smooth muscle actin, type 1 collagen, CD3, CD4, CD8, CD68, CD206, and neutrophils. Tumors that expressed high and low levels of these markers were compared with patient outcomes using Kaplan-Meier curves and multivariable recursive partitioning for discrete-time survival tree analysis. Prognostic index was delineated by a multivariable Cox proportional hazards model of immune cell and stromal markers and PFS. Findings were validated using 279 tissue microarray specimens from 93 patients in a separate cohort. RESULTS: Levels of CD3, CD4, CD8, CD68, and CD206 were independently associated with tumor recurrence. Recursive partitioning for discrete-time survival tree analysis identified a high level of CD3 as the strongest independent predictor for longer PFS. Tumors with levels of CD3 and high levels of CD206 associated with a median PFS time of 16.6 months and a median prognostic index of -0.32 (95% confidence interval [CI] -0.35 to -0.31), whereas tumors with low level of CD3 cell and low level of CD8 and high level of CD68 associated with a median PFS time of 7.9 months and a prognostic index of 0.32 (95% CI 0.050-0.32); we called these patterns histologic signatures. Stroma composition, when unassociated with inflammatory cell markers, did not associate significantly with PFS. In the validation cohort, the histologic signature resulted in an error matrix accuracy of predicted response of 0.75 (95% CI 0.64-0.83; accuracy P < .001). CONCLUSIONS: In an analysis of PDAC tissue microarray specimens, we identified and validated a histologic signature, based on leukocyte and stromal factors, that associates with PFS times of patients with resected PDACs. Immune cells might affect the composition of the pancreatic stroma to affect progression of PDAC. These findings provide new insights into the immune response to PDAC.
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Adenocarcinoma/inmunología , Carcinoma Ductal Pancreático/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Neoplasias Pancreáticas/inmunología , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adenocarcinoma/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD/análisis , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/cirugía , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/cirugíaRESUMEN
BACKGROUND/OBJECTIVE: The impact of preoperative biliary stenting (PBS) before pancreatoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC) is controversial. METHODS: Patients undergoing PD with or without PBS for PDAC were identified from the German DGAV-StuDoQlPancreas registry. The impact of PBS on perioperative complications was analyzed. RESULTS: 1133 patients undergoing PD for PDAC were identified from the registry. After matching, 480 PBS patients vs. 480 patients without PBS were analyzed. Postoperative complications Clavien-Dindo classification (CDC) grade IIIa-IVb were higher in PBS patients (PBS 27% vs. no PBS 22%, pâ¯=â¯0.027). 320 PBS patients (66%) had no history of jaundice. In these patients, PBS was associated with higher morbidity. In contrast, PBS was not associated with higher complication rates in patients with history of jaundice. Serum bilirubin levels of 15â¯mg/dl and higher lead to more CDC IIIa-IVb (24% vs. 28%, pâ¯=â¯0.053) and higher mortality (3% vs. 7%, pâ¯<â¯0.001). PBS in patients with serum bilirubin levels of >15â¯mg/dl increased CDC IIa-IVb complications (21% vs. 50%, pâ¯=â¯0.001), mortality was equivalent. CONCLUSION: Most PBS procedures were performed in patients with no history of jaundice and increased morbidity. Serum bilirubin levels >15â¯mg/dl lead to higher morbidity and mortality. PBS correlated with higher complication rates in these patients.
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Procedimientos Quirúrgicos del Sistema Biliar , Carcinoma Ductal Pancreático/cirugía , Neoplasias Pancreáticas/cirugía , Pancreaticoduodenectomía , Sistema de Registros , Stents , Anciano , Estudios de Casos y Controles , Femenino , Alemania/epidemiología , Humanos , Masculino , Oportunidad Relativa , Complicaciones Posoperatorias , Cuidados PreoperatoriosRESUMEN
One of the main reasons for the dismal prognosis of pancreatic ductal adenocarcinoma (PDAC) is its late diagnosis. At the time of presentation, only approximately 15-20% of all patients with PDAC are considered resectable and around 30% are considered borderline resectable. A surgical approach, which is the only curative option, is limited in borderline resectable patients by local involvement of surrounding structures. In borderline resectable pancreatic cancer (BRPC), neoadjuvant treatment regimens have been introduced with the rationale to downstage and downsize the tumor in order to enable resection and eliminate -microscopic distant metastases. However, there are no official guidelines for the preoperative treatment of BRPC. In the majority of cases, patients are administered -Gemcitabine-based or FOLFIRINOX-based chemotherapy regimens with or without radiation. Radiologic restaging after neoadjuvant therapy has to be judged with caution when it comes to predict tumor response and resectability, since inflammation induced by neoadjuvant therapy may mimic solid tumor. Patients who do not show any disease progression during neoadjuvant therapy should be offered surgical exploration, since a high percentage is likely to undergo resection with negative margins (R0) and, thus, achieve improved overall survival although imaging judged it unlikely. Despite the promising new approaches of neoadjuvant treatment regimens during the last 2 decades, surgery remains the first choice if the tumor appears to be primary resectable at the time of diagnosis. At present, there are no international guidelines regarding the preoperative treatment of BRPC. Therefore, in order to standardize and adjust neoadjuvant treatment in the future, new guidelines have to be determined on the basis of upcoming prospective randomized studies.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/cirugía , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/cirugía , Carcinoma Ductal Pancreático/patología , Quimioterapia Adyuvante , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Fluorouracilo/uso terapéutico , Humanos , Irinotecán/uso terapéutico , Leucovorina/uso terapéutico , Terapia Neoadyuvante , Estadificación de Neoplasias , Oxaliplatino/uso terapéutico , Pancreatectomía , Neoplasias Pancreáticas/patología , Carga Tumoral , GemcitabinaRESUMEN
Mitochondria are indispensable for energy metabolism, apoptosis regulation, and cell signaling. Mitochondria in malignant cells differ structurally and functionally from those in normal cells and participate actively in metabolic reprogramming. Mitochondria in cancer cells are characterized by reactive oxygen species (ROS) overproduction, which promotes cancer development by inducing genomic instability, modifying gene expression, and participating in signaling pathways. Mitochondrial and nuclear DNA mutations caused by oxidative damage that impair the oxidative phosphorylation process will result in further mitochondrial ROS production, completing the "vicious cycle" between mitochondria, ROS, genomic instability, and cancer development. The multiple essential roles of mitochondria have been utilized for designing novel mitochondria-targeted anticancer agents. Selective drug delivery to mitochondria helps to increase specificity and reduce toxicity of these agents. In order to reduce mitochondrial ROS production, mitochondria-targeted antioxidants can specifically accumulate in mitochondria by affiliating to a lipophilic penetrating cation and prevent mitochondria from oxidative damage. In consistence with the oncogenic role of ROS, mitochondria-targeted antioxidants are found to be effective in cancer prevention and anticancer therapy. A better understanding of the role played by mitochondria in cancer development will help to reveal more therapeutic targets, and will help to increase the activity and selectivity of mitochondria-targeted anticancer drugs. In this review we summarized the impact of mitochondria on cancer and gave summary about the possibilities to target mitochondria for anticancer therapies. J. Cell. Physiol. 231: 2570-2581, 2016. © 2016 Wiley Periodicals, Inc.
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Antineoplásicos/uso terapéutico , Mitocondrias/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Antineoplásicos/farmacología , ADN Mitocondrial/genética , Sistemas de Liberación de Medicamentos , Humanos , Mitocondrias/efectos de los fármacosRESUMEN
Our understanding in the last few years about reactive oxygen species (ROS) has changed from being harmful substances to crucial intra- and extracellular messengers as well as important regulators controlling a wide spectrum of signaling pathways, including those in cancer immunology. Therefore, these multiple essential roles of ROS and especially of mitochondria-derived ROS in malignant transformation and cancer progression make them a promising target for anticancer therapy. Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers in the world. A link between ROS, antioxidants and the PDAC development and progression has been recently established. Therefore, usage of specific highly efficient antioxidants could bring an option for treatment and/or prevention of PDAC. 10-(6'-plastoquinonyl) decyltriphenylphosphonium (SkQ1) is a new antioxidant with the highest mitochondrion membrane penetrating ability and potent antioxidant capability. In this work, we investigated an impact of SkQ1 on tumor angiogenesis, immune micromilieu, and oncological parameters in the orthotopic Panc02 murine model of PDAC. We showed that in this model SkQ1 treatment leads to the elevation of pro-angiogenic factors and to building of mainly an anti-inflammatory cytokine milieu. On the cellular level we showed an increase in a percentage of memory T cells and a decrease in frequency on natural killer T (NKT) cells. At the same time, SkQ1 was ineffective in the improvement of oncological parameters of PDAC-bearing mice. New studies are needed to clarify the absence of therapeutic and/or prophylactic benefits of the antioxidant.
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Adenocarcinoma/tratamiento farmacológico , Carcinoma Ductal Pancreático/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Neovascularización Patológica/tratamiento farmacológico , Plastoquinona/análogos & derivados , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Animales , Antioxidantes/administración & dosificación , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Humanos , Inflamación/metabolismo , Inflamación/patología , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/patología , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Plastoquinona/administración & dosificación , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND & AIMS: The association between pancreatic intraductal papillary mucinous neoplasms (IPMNs) and extrapancreatic neoplasms (EPNs) is controversial. We performed a multicenter observational study to assess the incidence of EPNs after an IPMN diagnosis. METHODS: 1340 patients with IPMNs were evaluated from 2000 through 2013 at 4 academic institutions in Europe for development of EPN. To estimate the actual incidence of EPN, we excluded patients with an EPN previous or synchronous to the IPMN, and patients who had been followed for less than 12 months, resulting in a study population of 816 patients. The incidence of EPN was compared with sex-specific, age-adjusted European cancer statistics; the standardized incidence ratio (SIR), and the 5- and 10-year cumulative incidence rates were calculated. RESULTS: A total of 290/1340 patients had a history of EPN (prevalence of 21.6%). In this subgroup of patients, the IPMN was discovered incidentally in 241. Among the 816 patients included in the incidence analysis, 50 developed an EPN after a median time of 46 months from study enrollment. The incidence of any EPN was not greater in patients with than without IPMN with a SIR of 1.48 (95% confidence interval, 0.94-2.22) in males and of 1.39 (95% CI 0.90-2.05) in females. The 5- and 10-year cumulative incidence rates for development of EPN in patients with IPMN were 7.9% and 16.6% in men, and 3.4% and 23.1% in women. CONCLUSIONS: Patients with IPMN do not have a significantly higher incidence of EPNs than the general European population. It might not be necessary to screen patients with IPMN for EPN.
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Carcinoma Ductal Pancreático/complicaciones , Carcinoma Papilar/complicaciones , Neoplasias Primarias Múltiples/epidemiología , Neoplasias Pancreáticas/complicaciones , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Europa (Continente)/epidemiología , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Prevalencia , Adulto JovenRESUMEN
BACKGROUND: To identify potential associations between intraductal papillary mucinous neoplasm of the pancreas (IPMN) and extrapancreatic neoplasms (EPN), a systematic review of the literature has been performed. METHODS: A systematic search of Medline/Pubmed was performed according to the PRISMA guidelines for reporting systematic reviews and meta-analysis for the following search terms: "extrapancreatic", "non pancreatic", "additional pancreatic", "additional primary" and alternatively matched with "neoplasms/tumours/cancers/malignancies/lesions". The results obtained specifically for IPMN were examined one by one by two independent investigators for further data selection and extraction. RESULTS: Fifteen studies were identified to be suitable and included for systematic review. Fourteen reported an elevated risk for extrapancreatic malignancy, particularly gastric and colon cancer, while the largest and only prospective study did not find any association. Most studies were retrospective with a weak level of evidence that was not substantially enhanced even by a recent multicentre case series. CONCLUSIONS: The available data on this clinically relevant question remain inconclusive. Due to lacking evidence on extrapancreatic neoplasms in IPMN patients, only a standard surveillance can be advised.
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Adenocarcinoma Mucinoso/epidemiología , Carcinoma Ductal Pancreático/epidemiología , Carcinoma Papilar/epidemiología , Neoplasias Primarias Múltiples/epidemiología , Neoplasias Pancreáticas/epidemiología , Adenocarcinoma Mucinoso/diagnóstico , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Papilar/diagnóstico , Salud Global , Humanos , Neoplasias Primarias Múltiples/diagnóstico , Neoplasias Pancreáticas/diagnóstico , PronósticoRESUMEN
UNLABELLED: Neurotrophic factors possess an emerging role in the pathophysiology of several gastrointestinal disorders, regulating innervation, pain sensation and disease-associated neuroplasticity. Here, we aimed at characterizing the role of the neurotrophic factor neurturin (NRTN) and its receptor glial-cell-line-derived neurotrophic factor receptor alpha-2 (GFRα-2) in pancreatic cancer (PCa) and pancreatic neuropathy. For this purpose, NRTN and GFRα-2 were studied in normal human pancreas and PCa tissues via immunohistochemistry, quantitative reverse transcription-polymerase chain reaction, immunoblotting and correlated to abdominal pain. The impact of NRTN/GFRα-2 on PCa cell (PCC) biology was investigated via exposure to hypoxia, 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide viability and matrigel invasion assays in native and specific small interfering RNA-silenced PCCs. To assess the influence of NRTN on pancreatic neuroplasticity and neural invasion (NI), its impact was explored via an in vitro 'neuroplasticity assay' and a 3D neural migration assay. NRTN and GFRα-2 demonstrated a site-specific upregulation in PCa, predominantly in nerves, PCCs and extracellular matrix. Patients with severe pain demonstrated higher intraneural GFRα-2 immunoreactivity than patients with no pain. PCa tissue and PCCs contained increased amounts of NRTN, which was suppressed under hypoxia. NRTN promoted PCC invasiveness, and silencing of NRTN limited both PCC proliferation and invasion. Depletion of NRTN from PCa tissue extracts and PCC supernatants decreased axonal sprouting in neuronal cultures but did not influence glial density. Silencing of NRTN in PCCs boosted NI. We conclude that increased NRTN/GFRα-2 in PCa seems to promote an aggressive PCC phenotype and neuroplasticity in PCa. Accelerated NI following NRTN suppression constitutes a novel explanation for the attraction of PCC to nerves in the hypoxic PCa tumor microenvironment. SUMMARY: PCa is characterized by intrapancreatic neuroplasticity and NI. Here, we show that PCC produce the neurotrophic factor NRTN, which reinforces their biological properties, triggers neuroplastic alterations, NI and influences pain sensation via the GFRα-2 receptor.
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Dolor Abdominal/metabolismo , Plasticidad Neuronal , Neurturina/metabolismo , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/fisiopatología , Animales , Hipoxia de la Célula , Línea Celular Tumoral , Proliferación Celular , Femenino , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/patología , Regulación Neoplásica de la Expresión Génica , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Plasticidad Neuronal/fisiología , Neurturina/genética , Neurturina/farmacología , Isoformas de Proteínas/metabolismo , RatasRESUMEN
BACKGROUND: Longlasting and unbearable pain is the most common and striking symptom of chronic pancreatitis. Accordingly, pain relief and improvement in patients' quality of life are the primary goals in the treatment of this disease. This systematic review aims to summarize the available data on treatment options. METHODS: A systematic search of MEDLINE/PubMed and the Cochrane Library was performed according to the PRISMA statement for reporting systematic reviews and meta-analysis. The search was limited to randomized controlled trials and meta-analyses. Reference lists were then hand-searched for additional relevant titles. The results obtained were examined individually by two independent investigators for further selection and data extraction. RESULTS: A total of 416 abstracts were reviewed, of which 367 were excluded because they were obviously irrelevant or represented overlapping studies. Consequently, 49 full-text articles were systematically reviewed. CONCLUSIONS: First-line medical options include the provision of pain medication, adjunctive agents and pancreatic enzymes, and abstinence from alcohol and tobacco. If medical treatment fails, endoscopic treatment offers pain relief in the majority of patients in the short term. However, current data suggest that surgical treatment seems to be superior to endoscopic intervention because it is significantly more effective and, especially, lasts longer.
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Endoscopía , Manejo del Dolor , Dolor/prevención & control , Pancreatectomía , Pancreatitis Crónica/terapia , Endoscopía/efectos adversos , Humanos , Dolor/diagnóstico , Dolor/etiología , Manejo del Dolor/efectos adversos , Manejo del Dolor/métodos , Pancreatectomía/efectos adversos , Pancreatitis Crónica/complicaciones , Pancreatitis Crónica/diagnóstico , Calidad de Vida , Resultado del TratamientoRESUMEN
BACKGROUND: Colorectal surgery still experiences high rates of infectious complications, such as anastomotic leakage (AL) and surgical site infections (SSIs). Therefore, oral antibiotic bowel decontamination (OABD) has experienced a renaissance. However, data on perioperative selective digestive tract decontamination (SDD)-based regimens or combined bowel preparation are inconsistent. Nonetheless, with widespread use of Enhanced Recovery After Surgery concepts, the ideal length for perioperative SDD treatment has to be reconsidered. METHODS: Perioperative outcome was analyzed in a cohort of patients undergoing minimally invasive surgery for left-sided colorectal cancer in a retrospective study. Additional to usual perioperative outcome measures, including AL, SSIs, and overall infectious complications, the efficacy of a shortened 3-day perioperative OABD treatment was compared with the efficacy of a 7-day perioperative OABD treatment based on a noninferiority analysis. RESULTS: Overall, 256 patients were included into analysis, of whom 84 and 172 patients were treated by 3-day and 7-day perioperative OABD regimens, respectively. AL occurred in 1.2% of patients in the 3-day group and 5.2% of patients in the 7-day group, and SSIs occurred in 3.6% of patients in the 3-day group and 5.8% of patients in the 7-day group, without significant difference. The shortened 3-day perioperative SDD-based regimen was noninferior to the regular 7-day perioperative SDD-based regimen concerning the rates of AL, SSIs, and infectious complications. CONCLUSION: Our data demonstrated noninferiority of a shortened 3-day SDD-based treatment vs a 7-day SDD-based treatment for AL, SSIs, and overall infectious complications.
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BACKGROUND: The glycoprotein MFG-E8 mediates phagocytic clearance of apoptotic cells and influences the pathogenesis and progression of inflammatory diseases. MFG-E8 was shown to attenuate the progression of inflammation and to improve survival in septic rats. Accumulating evidence suggests an immunomodulatory link between MFG-E8 and the pro-inflammatory chemokine fractalkine, which may determine the severity of pain, fibrosis, and inflammation in chronic pancreatitis (CP). METHODS: The expression and localization of MFG-E8 was investigated in CP (n=62), and normal pancreas (NP; n=34) by QRT-PCR, Western-blot and immunohistochemistry analyses. Results were correlated with mRNA expression of fractalkine, CX3CR1, and with the presence and degree of pain and fibrosis. Human pancreatic stellate cells (hPSCs) were isolated from CP tissues and evaluated for MFG-E8 mRNA expression after fractalkine stimulation. RESULTS: MFG-E8-mRNA was significantly overexpressed in CP and isolated hPSCs when compared to NP. Western-blot and immunohistochemistry analysis confirmed accumulation of MFG-E8 in CP, with noticeably increased MFG-E8 immunoreactivity in tubular complexes. MFG-E8 expression correlated significantly with fractalkine expression, severe fibrosis, and the presence of pain in CP patients. Stimulation of hPSCs with fractalkine led to a significant increase in MFG-E8 expression. CONCLUSIONS: In the present study, we demonstrated for the first time that MFG-E8 is significantly up-regulated in CP patients and together with fractalkine correlated noticeably with severe fibrosis and the presence of pain. hPSCs overexpress MFG-E8 upon fractalkine stimulation in vitro, which underlines the suggested immunmodulatory link in CP and may be a key mechanism in CP fibrogenesis and pain generation. Taken together, these novel findings suggest that MFG-E8 blockade may be a promising tool for future immunotherapy in CP to attenuate both fibrosis and pain sensation.
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Antígenos de Superficie/metabolismo , Inmunoterapia , Proteínas de la Leche/metabolismo , Páncreas/metabolismo , Pancreatitis Crónica/metabolismo , Adulto , Estudios de Casos y Controles , Células Cultivadas , Quimiocina CX3CL1/metabolismo , Quimiocina CX3CL1/farmacología , Femenino , Humanos , Técnicas In Vitro , Masculino , Persona de Mediana Edad , Dimensión del Dolor , Páncreas/patología , Células Estrelladas Pancreáticas/efectos de los fármacos , Células Estrelladas Pancreáticas/metabolismo , Células Estrelladas Pancreáticas/patología , Pancreatitis Crónica/patología , Pancreatitis Crónica/terapia , Índice de Severidad de la EnfermedadRESUMEN
The revision of the medical device regulation (MDR) legislation by the European Union and supplementations by the member states has been implemented for good reasons but causes dramatic side effects. It is no longer allowed to produce some rarely used medical devices by various manufacturers that have been successfully used for decades. Before production, a new application to the MDR would be necessary, which is not a realistic business case for companies producing rarely used devices. This problem currently relates to the Kehr Tdrain made from soft rubber or latex that has been in use since the late nineteenth century. A surgically placed Tdrain, although rarely necessary nowadays, is still in use worldwide for special indications in an attempt to avoid severe complications. These special indications include complex hepato-pancreato-biliary (HPB) procedures and perforations of the upper gastrointestinal (GI) tract where Tdrains may be used to secure the hepatojejunostomy or to create a stable fistula. The HPB working group (CALGP) of the German Society of General and Visceral Surgery (DGAV) provides a statement from a surgical perspective on this matter after a survey of all its members. Politics should be very careful not to generalize when implementing useful new regulations at a European and national level. Established and comprehensible treatment concepts should not be restricted and exemption permits should be quickly granted in these cases because the discontinuation of these niche products may lead to potential patient safety issues and even fatalities.
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Vesícula Biliar , Enfermedades Pancreáticas , Humanos , Seguridad del Paciente , Hígado , Sociedades Médicas , AlemaniaRESUMEN
OBJECTIVES: Pancreatic ductal adenocarcinoma (PDAC) represents a widespread form of malignant pancreatic neoplasms and a leading oncologic cause of death in Europe and the USA. Despite advances in understanding its molecular biology, the 5-year survival rate remains low at 10%. The extracellular matrix in PDAC contains proteins, including SPOCK2, which are essential for tumorigenicity and drug resistance. The present study aims to explore the possible role of SPOCK2 in the pathogenesis of PDAC. MATERIALS AND METHODS: Expression of SPOCK2 was evaluated in 7 PDAC cell lines and 1 normal pancreatic cell line using quantitative RT-PCR. Demethylation of the gene was carried out using 5-aza-2'-deoxycytidine (5-aza-dC) treatment with subsequent validation Western Blot analysis. In vitro downregulation of SPOCK2 gene was performed using siRNA transfection. MTT and transwell assays were employed to evaluate the impact of the SPOK2 demethylation on the proliferation and migration of PDAC cells. KM Plotter was applied to analyze a correlation between SPOCK2 mRNA expression and the survival of PDAC patients. RESULTS: In contrast to the normal pancreatic cell line, SPOCK2 expression was significantly downregulated in PDAC cell lines. Treatment with 5-aza-dC, led to increase in SPOCK2 expression in the cell lines tested. Importantly, compared with control cells, transfected with SPOCK2 siRNA cells exhibited increased growth rates and more migration ability. Finally, we demonstrated that a high SPOCK2 expression level correlated with longer overall survival of patients with PDAC. CONCLUSION: The expression of SPOCK2 is downregulated in PDAC as a result of hypermethylation of its corresponding gene. SPOCK2 expression as well as the demethylation of its gene could be a potential marker for PDAC.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Línea Celular Tumoral , Proliferación Celular , Carcinoma Ductal Pancreático/patología , Neoplasias Pancreáticas/patología , Pronóstico , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/uso terapéutico , Expresión Génica , Regulación Neoplásica de la Expresión Génica , Movimiento Celular/genética , Proteoglicanos/genética , Proteoglicanos/metabolismo , Proteoglicanos/uso terapéutico , Neoplasias PancreáticasRESUMEN
BACKGROUND: In pancreatic cancer, systemic treatment options in addition to chemotherapy remain scarce, and so far only a small proportion of patients benefit from targeted therapies. OBJECTIVE: The patients with pancreatic cancer discussed in the CCCMunichLMU Molecular Tumor Board were reviewed to gain a better real-world understanding of the challenges and chances of precision oncology in this hard-to-treat cancer. METHODS: Patients with pancreatic cancer who received comprehensive genomic profiling and were discussed in the interdisciplinary Molecular Tumor Board between May 2017 and July 2022 were included. These patients' medical charts, comprehensive genomic profiling results, and Molecular Tumor Board recommendations were analyzed in this retrospective cohort study. RESULTS: Molecular profiles of 165 patients with pancreatic cancer were discussed in the Molecular Tumor Board. In the 149 cases where comprehensive genomic profiling was successful, KRAS mutations were detected in 87.9%, TP53 in 53.0%, and CDKN2A in 14.1%. 33.3% of KRAS wild-type patients harbored targetable mutations, while these were only found in 19.1% of patients with the KRAS mutation; however, this difference was not statistically significant. 63.8% of patients with successful testing received a targeted treatment recommendation by the Molecular Tumor Board; however, only 3.2% of these were put into practice. Compared to a historic cohort of patients with pancreatic cancer with synchronous metastatic disease diagnosed between 2010 and 2017, the patients from the pancreatic cancer cohort with synchronous metastatic disease had a longer survival. CONCLUSIONS: This single-center experience emphasizes the challenges of targeted treatment in pancreatic cancer. Very few patients ultimately received the recommended therapies, highlighting the need for more and better targeted treatment options in pancreatic cancer, early comprehensive genomic profiling to allow sufficient time to put Molecular Tumor Board recommendations into practice, and close cooperation with clinical trial units to give patients access to otherwise not available targeted treatments.
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Neoplasias Pancreáticas , Proteínas Proto-Oncogénicas p21(ras) , Humanos , Estudios Retrospectivos , Proteínas Proto-Oncogénicas p21(ras)/genética , Medicina de Precisión/métodos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/tratamiento farmacológico , Mutación , Terapia Molecular Dirigida/métodos , Neoplasias PancreáticasRESUMEN
BACKGROUND AND OBJECTIVE: With the rising importance of precision oncology in biliary tract cancer (BTC), the aim of this retrospective single-center analysis was to describe the clinical and molecular characteristics of patients with BTC who underwent comprehensive genomic profiling (CGP) and were discussed in the CCCMunichLMU molecular tumor board (MTB). PATIENTS AND METHODS: In this single-center observational study, we included BTC patients with intrahepatic cholangiocarcinoma (iCCA), extrahepatic CCA (eCCA), and gallbladder cancer (GB), who had been discussed in the institutional MTB from May 29, 2017, to July 25, 2022. Patients were followed up until 31 January 2023. Data were retrospectively collected by review of medical charts, and MTB recommendation. RESULTS: In total, 153 cases were registered to the MTB with a median follow-up of 15 months. Testing was successful in 81.7% of the patients. CGP detected targetable alterations in 35.3% of our BTC patients (most commonly ARID1A/ERBB2/IDH1/PIK3CA/BRAF-mutations and FGFR2-fusions). Recommendations for molecularly guided therapy were given in 46.4%. Of those, treatment implementation of targeted therapy followed in 19.4%. In patients receiving the recommended treatment, response rate was 57% and median overall survival was 19 months (vs 8 months in the untreated cohort). The progression-free survival ratio of 1.45 suggest a clinical benefit of molecularly guided treatment. CONCLUSIONS: In line with previous work, our series demonstrates feasibility and clinical utility of comprehensive genomic profiling in BTC patients. With the growing number of targeted agents with clinical activity in BTC, CGP should become standard of care in the management of this group of patients.
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Neoplasias de los Conductos Biliares , Neoplasias del Sistema Biliar , Humanos , Estudios Retrospectivos , Medicina de Precisión , Neoplasias del Sistema Biliar/genética , Neoplasias del Sistema Biliar/terapia , Neoplasias del Sistema Biliar/patología , Neoplasias de los Conductos Biliares/patología , Conductos Biliares Intrahepáticos/patologíaRESUMEN
OBJECTIVES: Early patient disposition is crucial to prevent crowding in emergency departments (EDs). Our study aimed to characterise the need of in-house resources for patients treated in the ED according to the Emergency Severity Index (ESI) and the presenting complaint at the timepoint of triage. DESIGN: A retrospective single-centre study was conducted. SETTING: Data of all patients who presented to the interdisciplinary ED of a tertiary care hospital in Munich, Germany, from 2014 to 2017 were analysed. PARTICIPANTS: n=113 694 patients were included. MEASURES: ESI Score, medical speciality according to the chief complaint, mode of arrival, admission rates and discharge destination from the ED were evaluated. RESULTS: Patient disposition varied according to ESI scores in combination with the chief complaint. Patients with low ESI scores were more likely to be admitted after treatment in the ED than patients with high ESI scores. Highly prioritised patients (ESI 1) mainly required admission to an intensive care unit (ICU, 27%), intermediate care unit (IMC, 37%) or immediate intervention (11%). In this critical patient group, 30% of patients with neurological or medical symptoms required immediate intensive care, whereas only 17% of patients with surgical problems were admitted to an ICU. A significant number of patients (particularly with neurological or medical problems) required hospital (and in some cases even ICU or IMC) admission despite high ESI scores. CONCLUSIONS: Overall, ESI seems to be a useful tool to anticipate the need for specialised in-hospital resources on arrival. Patients with symptoms pointing at neurological or medical problems need particular attention as ESI may fail to sufficiently predict the care facility level for this patient group.