RESUMO
BACKGROUND: Pain due to pancreatic cancer/PCa or chronic pancreatitis/CP, is notoriously resistant to the strongest pain medications. Here, we aimed at deciphering the specific molecular mediators of pain at surgical-stage pancreatic disease and to discover novel translational targets. METHODS: We performed a systematic, quantitative analysis of the neurotransmitter/neuroenzmye profile within intrapancreatic nerves of CP and PCa patients. Ex vivo neuronal cultures treated with human pancreatic extracts, conditional genetically engineered knockout mouse models of PCa and CP, and the cerulein-induced CP model were employed to explore the therapeutic potential of the identified targets. FINDINGS: We identified a unique enrichment of neuronal nitric-oxide-synthase (nNOS) in the pancreatic nerves of CP patients with increasing pain severity. Employment of ex vivo neuronal cultures treated with pancreatic tissue extracts of CP patients, and brain-derived-neurotrophic-factor-deficient (BDNF+/-) mice revealed neuronal enrichment of nNOS to be a consequence of BDNF loss in the progressively destroyed pancreatic tissue. Mechanistically, nNOS upregulation in sensory neurons was induced by tryptase secreted from perineural mast cells. In a head-to-head comparison of several genetically induced, painless mouse models of PCa (KPC, KC mice) or CP (Ptf1a-Cre;Atg5fl/fl) against the hypersecretion/cerulein-induced, painful CP mouse model, we show that a similar nNOS enrichment is present in the painful cerulein-CP model, but absent in painless genetic models. Consequently, mice afflicted with painful cerulein-induced CP could be significantly relieved upon treatment with the specific nNOS inhibitor NPLA. INTERPRETATION: We propose nNOS inhibition as a novel strategy to treat the unbearable pain in CP. FUND: Deutsche Forschungsgemeinschaft/DFG (DE2428/3-1 and 3-2).
Assuntos
Neuralgia/diagnóstico , Neuralgia/etiologia , Óxido Nítrico Sintase Tipo I/metabolismo , Pancreatite Crônica/complicações , Pancreatite Crônica/metabolismo , Adulto , Animais , Biomarcadores , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Neuralgia/tratamento farmacológico , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/cirurgia , Pancreatite Crônica/cirurgiaRESUMO
BACKGROUND: Although routinely used, the benefit of surgically placed intraperitoneal drains after pancreas resection is still under debate. To assess the true impact of intraperitoneal drains in pancreas resection, a systematic review with meta-analysis was performed. METHODS: For this, the Preferred-Reporting-Items-for-Systematic-review-and-Meta-Analysis/PRISMA-guidelines were conducted and Pubmed/Medline, Embase, Scopus and The Cochrane Library were screened for relevant studies. RESULTS: 8 retrospective and 3 prospective studies were included in the systematic review. No difference was found between patients with or without intraperitoneal drains in mortality (Risk-ratio/RR 0.74, 95%-Confidence-interval/CI: 0.47-1.18, pâ¯=â¯0.20), in Grade B/C-postoperative pancreatic fistulas/POPF (RR 1.31, 95%-CI: 0.74-2.32, pâ¯=â¯0.35), in intraabdominal abscesses (RR 0.92, 95%-CI: 0.65-1.30, pâ¯=â¯0.64), in surgical site infection (RR 1.20, 95%-CI: 0.85-1.70, pâ¯=â¯0.30), in delayed gastric emptying (RR 1.11, 95%-CI: 0.65-1.90, pâ¯=â¯0.71), in postoperative haemorrhages (RR 0.92 95%-CI: 0.63-1.33, pâ¯=â¯0.65), in reoperations (RR 1.15, 95%-CI: 0.87-1.52, pâ¯=â¯0.33), or in radiological reinterventions (RR 0.95, 95%-CI: 0.69-1.31, pâ¯=â¯0.76). The risk for overall morbidity (RR 1.16, 95%-CI: 1.04-1.29, pâ¯=â¯0.008), of any POPF (RR 2.15, 95%-CI: 1.52-3.04, pâ¯<â¯0.0001) and of readmissions (RR 1.23, 95%-CI: 1.04-1.45, pâ¯=â¯0.01) was increased for patients with intraperitoneal drain compared to patients without following pancreatic resection. CONCLUSION: Regarding the controversial results of the recent prospective, randomized trials this meta-analysis revealed no difference in mortality but an increased risk for postoperative morbidity, POPF and readmissions of patients with intraperitoneal drains after pancreatic resection. Therefore, the indication for intraperitoneal drains should be critically weighed in patients undergoing pancreatic resections.
Assuntos
Procedimentos Cirúrgicos do Sistema Digestório/efeitos adversos , Drenagem , Pâncreas/cirurgia , Cavidade Peritoneal , Complicações Pós-Operatórias/epidemiologia , Procedimentos Cirúrgicos do Sistema Digestório/mortalidade , Humanos , Complicações Pós-Operatórias/mortalidade , ReoperaçãoRESUMO
BACKGROUND: Malignant potential of small (≤20 mm) nonfunctional pancreatic neuroendocrine tumors (sNF-PNET) is difficult to predict and management remain controversial. The aim of this study was to assess the prognosis of sporadic nonmetastatic sNF-PNETs. METHODS: Patients were identified from databases of 16 centers. Outcomes and risk factors for recurrence were identified by uni- and multivariate analyses. RESULTS: sNF-PNET was resected in 210 patients, and 66% (n = 138) were asymptomatic. Median age was 60 years, median tumor size was 15 mm, parenchyma-sparing surgery was performed in 42%. Postoperative mortality was 0.5% (n = 1), severe morbidity rate was 14.3% (n = 30), and 14 of 132 patients (10.6%) with harvested lymph nodes had metastatic lymph nodes. Tumor size, presence of biliary or pancreatic duct dilatation, and WHO grade 2-3 were independently associated with recurrence. Patients with tumors sized ≤10 mm were disease free at last follow-up. The 1-, 3- and 5-year disease-free survival rates for patients with tumors sized 11-20 mm on preoperative imaging were 95.1%, 91.0%, and 87.3%, respectively. CONCLUSIONS: In sNF-PNETs, the presence of biliary or pancreatic duct dilatation or WHO grade 2-3 advocate for surgical treatment. In the remaining patients, a wait-and-see policy might be considered.
Assuntos
Tumores Neuroendócrinos/cirurgia , Pancreatectomia , Neoplasias Pancreáticas/cirurgia , Pancreaticoduodenectomia , Idoso , Ductos Biliares/patologia , Bases de Dados Factuais , Dilatação Patológica , Intervalo Livre de Doença , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/mortalidade , Tumores Neuroendócrinos/patologia , Pancreatectomia/efeitos adversos , Pancreatectomia/mortalidade , Ductos Pancreáticos/patologia , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Pancreaticoduodenectomia/efeitos adversos , Pancreaticoduodenectomia/mortalidade , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Carga TumoralRESUMO
OBJECTIVE: The aim of this study was to decipher the true importance of R0 versus R1 resection for survival in pancreatic ductal adenocarcinoma (PDAC). SUMMARY OF BACKGROUND DATA: PDAC is characterized by poor survival, even after curative resection. In many studies, R0 versus R1 does not result in different prognosis and does not affect the postoperative management. METHODS: Pubmed, Embase, and Cochrane databases were screened for prognostic studies on the association between resection status and survival. Hazard ratios (HRs) were pooled in a meta-analysis. Furthermore, our prospective database was retrospectively screened for curative PDAC resections according to inclusion criteria (n = 254 patients) between July 2007 and October 2014. RESULTS: In the meta-analysis, R1 was associated with a decreased overall survival [HR 1.45 (95% confidence interval, 95% CI 1.37-1.52)] and disease-free survival [HR 1.44 (1.30-1.59)] in PDAC when compared with R0. Importantly, this effect held true only for pancreatic head resection both in the meta-analysis [R0 ≥0âmm: HR 1.21 (1.05-1.39) vs R0 ≥1âmm: HR 1.66 (1.46-1.89)] and in our cohort (R0 ≥0âmm: 31.8 vs 14.5 months, P < 0.001; R0 ≥1âmm, 41.2 vs 16.8 months; P < 0.001). Moreover, R1 resections were associated with advanced tumor disease, that is, larger tumor size, lymph node metastases, and extended resections. Multivariable Cox proportional hazard model suggested G3, pN1, tumor size, and R1 (0âmm/1âmm) as independent predictors of overall survival. CONCLUSION: Resection margin is not a valid prognostic marker in publications before 2010 due to heterogeneity of cohorts and lack of standardized histopathological examination. Within standardized pathology protocols, R-status' prognostic validity may be primarily confined to pancreatic head cancers.
Assuntos
Pancreatectomia/métodos , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Pancreaticoduodenectomia , Humanos , Metástase Linfática/patologia , Margens de Excisão , Estadiamento de Neoplasias , PrognósticoRESUMO
BACKGROUND: Non-functional pancreatic neuroendocrine tumors (NF-PNET) are rare neoplasms being increasingly diagnosed. Surgical treatment or expectant management are both suggested for small NF-PNETs. The aim of this study was to evaluate the outcome of surveillance strategy for small NF-PNETs. METHODS: A systematic search was performed up to March 2016 in MEDLINE, EMBASE and the Cochrane Library according to the PRISMA guidelines. Data was pooled using the random-effects model. RESULTS: Nine articles including 344 patients with sporadic and 64 patients with MEN1 related NF-PNET were selected. Tumor growth was observed in 22% and 52%, development of metastases were reported on 0% and 9%, and rate of secondary surgical resection was 12% and 25% in patients with sporadic or MEN1 related NF-PNETs, respectively. All metastases (1 distant, 4 nodal) were reported by a single study in patients with MEN1. Reason for secondary surgery was tumor growth in half of patients undergoing surgery. DISCUSSION: Expectant management of small asymptomatic, sporadic, NF-PNETs could be a reasonable option in highly selected patients. However, the level of evidence is low and longer follow-up is needed to identify patients could benefit from upfront surgery instead of expectant treatment.
Assuntos
Tumores Neuroendócrinos/terapia , Neoplasias Pancreáticas/terapia , Conduta Expectante , Adulto , Idoso , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/secundário , Tumores Neuroendócrinos/cirurgia , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Seleção de Pacientes , Valor Preditivo dos Testes , Prognóstico , Medição de Risco , Fatores de Risco , Fatores de Tempo , Carga TumoralRESUMO
OBJECTIVES: To assess the impact of neural invasion/NI on overall survival/OS and tumor recurrence in pancreatic ductal adenocarcinoma/PDAC. SUMMARY BACKGROUND DATA: NI is a histopathological hallmark of PDAC. Although some studies suggested an important role for NI on OS, disease-free/DFS and progression-free survival/PFS in PDAC, there is still no consensus on the actual role of NI on survival and local recurrence in PDAC. METHODS: Pubmed, Cochrane library, Ovid and Google Scholar were screened for the terms "pancreatic ductal adenocarcinoma", "pancreatic cancer", "survival", "tumor recurrence" and "perineural invasion". The Preferred-Reporting-Items-for-Systematic-review-and-Meta-Analysis/PRISMA-guidelines were used for systematic review and meta-analysis. Articles meeting predefined criteria were critically analysed on relevance, and meta-analyses were performed by pooling univariate and multivariate hazard ratios/HR. RESULTS: A total number of 25 studies on the influence of NI on tumor recurrence, and 121 studies analysing the influence of NI on survival were identified by systematic review. The HR of the univariate (HR 1.88; 95%-CI 1.71-2.07; p < 0.00001) and multivariate meta-analysis (HR 1.68; 95%-CI 1.47-1.92; p < 0.00001) showed a major impact of NI on OS. Likewise, NI was associated with decreased DFS (HR 2.53; 95%-CI: 1.67-3.83; p = 0.0001) and PFS (HR 2.41; 95%-CI: 1.73-3.37: p < 0.00001) multivariate meta-analysis. CONCLUSIONS: Although the power of this study is limited by missing pathological procedures to assess the true incidence of NI, NI appears to be an independent prognostic factor for OS, DFS and PFS in PDAC. Therefore, NI should be increasingly considered in patient stratification and in the development of novel therapeutic algorithms.
Assuntos
Carcinoma Ductal Pancreático/mortalidade , Recidiva Local de Neoplasia/mortalidade , Neurônios/patologia , Neoplasias Pancreáticas/mortalidade , Carcinoma Ductal Pancreático/patologia , Humanos , Invasividade Neoplásica , Recidiva Local de Neoplasia/patologia , Neoplasias Pancreáticas/patologia , Prognóstico , Taxa de SobrevidaRESUMO
BACKGROUND: Due to increased rates of curative tumor resections exceeding 60% after FOLFIRINOX-treatment, neoadjuvant therapy/NTx is increasingly recognized as an effective therapy option for downstaging borderline or locally advanced pancreatic ductal adenocarcinoma/PDAC. Yet, the effects of NTx on the common histopathological features of PDAC have not been systematically analysed. Therefore, the aim of the current study was to assess the impact of NTx on relevant histopathological features of PDAC. PATIENTS AND METHODS: Biomedical databases were systematically screened for predefined searching terms related to NTx and PDAC. The Preferred-Reporting-Items-for-Systematic-review-and-Meta-Analysis/PRISMA-guidelines were used to perform a systematic review and meta-analysis. Articles meeting the predefined criteria were analysed on relevance, and a meta-analysis was performed. RESULTS: A total of 9031 studies could be identified that analysed the effect of NTx on PDAC. Only 35 studies presented comparative data on the histological features of neoadjuvantly treated vs. upfront resected PDAC patients. In meta-analyses, the beneficial effect of NTx was reflected by reduced tumor size (T1/2: RR 2.87, 95%-CI: 1.52-5.42, P=0.001, T3/4: RR 0.78, 95%-CI: 0.69-0.89, P=0.0002), lower N-Stage (N0: RR 2.14, 95%-CI: 1.85-2.46, P<0.00001, N1: RR 0.59, 95%-CI: 0.53-0.65, P<0.00001), higher R0-rates (R0: RR 1.13, 95%-CI: 1.08-1.18, P<0.00001, R1: RR 0.66, 95%-CI: 0.58-0.76, P<0.00001), less perineural invasion (Pn1: RR 0.78, 95%-CI: 0.73-0.83, P<0.00001), less lymphatic vessel invasion (RR: 0.50, 95%-CI: 0.36-0.70, P<0.0001) and fewer G3-tumors (RR 0.82, 95%-CI: 0.71-0.94, P=0.005). CONCLUSIONS: NTx in PDAC seems to exert its beneficial effect in borderline or locally advanced PDAC over genuine tumor downstaging. Thus, although at least 40% of all NTx treated patients remain unresectable even with modern NTx regimes, neoadjuvantly treated PDAC showed not only increasing resectability rates especially after FOLFIRINOX, but even reach a lower tumor stage than primarily resected PDAC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/secundário , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/cirurgia , Humanos , Metástase Linfática , Vasos Linfáticos/patologia , Terapia Neoadjuvante , Invasividade Neoplásica , Estadiamento de Neoplasias , Neoplasia Residual , Neoplasias Pancreáticas/cirurgia , Nervos Periféricos/patologia , Carga TumoralRESUMO
BACKGROUND: Obstructive jaundice is a common presenting symptom among patients with pancreatic cancer. While benefits of preoperative biliary drainage have been suggested by previous studies, recent evidence has shown no significant improvements of preoperative biliary drainage on the postoperative outcome but rather an increase of complications. There is no clear consensus on whether to treat malignant obstructive jaundice with preoperative biliary drainage prior to operative intervention or to proceed directly to resection. Thus, our aim was to elucidate the impact of preoperative biliary drainage of obstructive jaundice due to malignant pancreatic head tumors on postoperative morbidity and mortality. METHODS: We conducted a meta-analysis in accordance with the PRISMA guidelines and carried out a systematic search of medical databases. The results were analyzed according to predefined criteria. We pooled the incidence of overall complications, wound infection, pancreatic fistula, intra-abdominal abscess, and death within the perioperative time period. RESULTS: We initially identified 1,816 studies, and 25 of these (22 retrospective studies, 3 randomized controlled trials) were finally included in the analysis with a total number of 6,214 patients. Analysis revealed an increased incidence of overall complications (odds ratio: 1.40; 95% confidence interval: 1.14-1.72; P = .002) and wound infections (odds ratio: 1.94; 95% confidence interval: 1.48-2.53; P < .00001) in patients receiving preoperative biliary drainage compared to operative intervention first. Mortality, incidence of pancreatic fistula, or intra-abdominal abscess formation were not affected by preoperative biliary drainage. CONCLUSION: Preoperative biliary drainage does not have a beneficial effect on postoperative outcome. The increase of postoperative overall complications and wound infections urges for precise indications for preoperative biliary drainage and against routine preoperative biliary decompression.
Assuntos
Causas de Morte , Drenagem/métodos , Icterícia Obstrutiva/patologia , Neoplasias Pancreáticas/cirurgia , Pancreaticoduodenectomia/métodos , Intervalo Livre de Doença , Drenagem/instrumentação , Feminino , Humanos , Icterícia Obstrutiva/etiologia , Icterícia Obstrutiva/cirurgia , Masculino , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Pancreaticoduodenectomia/efeitos adversos , Pancreaticoduodenectomia/mortalidade , Guias de Prática Clínica como Assunto , Cuidados Pré-Operatórios/métodos , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Medição de Risco , Stents , Infecção da Ferida Cirúrgica/mortalidade , Infecção da Ferida Cirúrgica/fisiopatologia , Infecção da Ferida Cirúrgica/terapia , Taxa de SobrevidaRESUMO
Pancreatic ductal adenocarcinoma (PDAC) cells (PCC) have an exceptional propensity to metastasize early into intratumoral, chemokine-secreting nerves. However, we hypothesized the opposite process, that precancerous pancreatic cells secrete chemokines that chemoattract Schwann cells (SC) of nerves and thus induce ready-to-use routes of dissemination in early carcinogenesis. Here we show a peculiar role for the chemokine CXCL12 secreted in early PDAC and for its receptors CXCR4/CXCR7 on SC in the initiation of neural invasion in the cancer precursor stage and the resulting delay in the onset of PDAC-associated pain. SC exhibited cancer- or hypoxia-induced CXCR4/CXCR7 expression in vivo and in vitro and migrated toward CXCL12-expressing PCC. Glia-specific depletion of CXCR4/CXCR7 in mice abrogated the chemoattraction of SC to PCC. PDAC mice with pancreas-specific CXCL12 depletion exhibited diminished SC chemoattraction to pancreatic intraepithelial neoplasia and increased abdominal hypersensitivity caused by augmented spinal astroglial and microglial activity. In PDAC patients, reduced CXCR4/CXCR7 expression in nerves correlated with increased pain. Mechanistically, upon CXCL12 exposure, SC down-regulated the expression of several pain-associated targets. Therefore, PDAC-derived CXCL12 seems to induce tumor infiltration by SC during early carcinogenesis and to attenuate pain, possibly resulting in delayed diagnosis in PDAC.
Assuntos
Carcinoma Ductal Pancreático/patologia , Quimiocina CXCL12/metabolismo , Quimiotaxia/fisiologia , Dor/prevenção & controle , Neoplasias Pancreáticas/patologia , Receptores CXCR4/metabolismo , Receptores CXCR/metabolismo , Células de Schwann/fisiologia , Animais , Linhagem Celular Tumoral , Camundongos , Camundongos TransgênicosRESUMO
In the past 20years, nerve growth factor (NGF) and its receptors TrkA & p75NTR were recognized to be overexpressed in the overwhelming majority of human solid cancers. Recent studies discovered the presence of overactive TrkA signaling due to TrkA rearrangements or TrkA fusion products in frequent cancers like colorectal cancer, thyroid cancer, or acute myeloid leukemia. Thus, targeting TrkA/NGF via selective small-molecule-inhibitors or antibodies has gained enormous attention in the drug discovery sector. Clinical studies on the anti-cancer impact of NGF-blocking antibodies are likely to be accelerated after the recent removal of clinical holds on these agents by regulatory authorities. Based on these current developments, the present review provides not only a broad overview of the biological effects of NGF-TrkA-p75NTR on cancer cells and their microenvironment, but also explains why NGF and its receptors are going to evoke major interest as promising therapeutic anti-cancer targets in the coming decade.
Assuntos
Neoplasias/tratamento farmacológico , Fator de Crescimento Neural/genética , Proteínas do Tecido Nervoso/genética , Receptor trkA/genética , Receptores de Fator de Crescimento Neural/genética , Humanos , Neoplasias/genética , Fator de Crescimento Neural/antagonistas & inibidores , Proteínas do Tecido Nervoso/antagonistas & inibidores , Receptor trkA/antagonistas & inibidores , Receptores de Fator de Crescimento Neural/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/uso terapêutico , Microambiente Tumoral/efeitos dos fármacosRESUMO
OBJECTIVE: The impact of glia cells during GI carcinogenesis and in cancer pain is unknown. Here, we demonstrate a novel mechanism how Schwann cells (SCs) become activated in the pancreatic cancer (PCa) microenvironment and influence spinal activity and pain sensation. DESIGN: Human SCs were exposed to hypoxia, to pancreatic cancer cells (PCCs) and/or to T-lymphocytes. Both SC and intrapancreatic nerves of patients with PCa with known pain severity were assessed for glial intermediate filament and hypoxia marker expression, proliferation and for transcriptional alterations of pain-related targets. In conditional PCa mouse models with selective in vivo blockade of interleukin (IL)-6 signalling (Ptf1a-Cre;LSL-Kras(G12D)/KC interbred with IL6(-/-) or sgp130(tg) mice), SC reactivity, abdominal mechanosensitivity and spinal glial/neuronal activity were quantified. RESULTS: Tumour hypoxia, PCC and/or T-lymphocytes activated SC via IL-6-signalling in vitro. Blockade of the IL-6-signalling suppressed SC activation around PCa precursor lesions (pancreatic intraepithelial neoplasia (PanIN)) in KC;IL6(-/-) (32.06%±5.25% of PanINs) and KC;sgp130(tg) (55.84%±5.51%) mouse models compared with KC mice (78.27%±3.91%). Activated SCs were associated with less pain in human PCa and with decreased abdominal mechanosensitivity in KC mice (von Frey score of KC: 3.9±0.5 vs KC;IL6(-/-) mice: 5.9±0.9; and KC;sgp130(tg): 10.21±1.4) parallel to attenuation of spinal astroglial and/or microglial activity. Activated SC exhibited a transcriptomic profile with anti-inflammatory and anti-nociceptive features. CONCLUSIONS: Activated SC in PCa recapitulate the hallmarks of 'reactive gliosis' and contribute to analgesia due to suppression of spinal glia. Our findings propose a mechanism for how cancer might remain pain-free via the SC-central glia interplay during cancer progression.
Assuntos
Analgesia , Astrócitos , Microglia , Neoplasias Pancreáticas/genética , Células de Schwann/metabolismo , Hipóxia Tumoral/genética , Animais , Astrócitos/metabolismo , Modelos Animais de Doenças , Humanos , Técnicas In Vitro , Interleucina-6/genética , Camundongos , Camundongos Transgênicos , Microglia/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Linfócitos T/metabolismoRESUMO
Neural invasion (NI) and severe pain are common features in patients with pancreatic cancer (PCa). Here, we present the case of a 67-year-old patient with PCa whose pre- and postoperative physical situation was clearly dominated by severe pain sensation. The resected pancreas specimen revealed severe and frequent NI by cancer cells. Seven months after R1 resection and additive chemotherapy, the patient presented with severe lumbar back pain. The CT scan showed liver metastasis and local recurrence around the celiac trunk. Yet 1 month after palliative chemotherapy, the patient presented again in poor general condition and lumbar pain requiring constant morphine intake, and died 2 days after hospitalization. Postmortem histological analysis showed local recurrence with an extensive invasion by cancer cells along almost all nerves of the celiac plexus. Hence, new-onset or recurrent back and/or abdominal pain, as in this case, should raise the clinician's suspicion for local recurrence in PCa.
RESUMO
Neuroplasticity is an inherent feature of the enteric nervous system and gastrointestinal (GI) innervation under pathological conditions. However, the pathophysiological role of neuroplasticity in GI disorders remains unknown. Novel experimental models which allow simulation and modulation of GI neuroplasticity may enable enhanced appreciation of the contribution of neuroplasticity in particular GI diseases such as pancreatic cancer (PCa) and chronic pancreatitis (CP). Here, we present a protocol for simulation of pancreatic neuroplasticity under in vitro conditions using newborn rat dorsal root ganglia (DRG) and myenteric plexus (MP) neurons. This dual-neuron approach not only permits monitoring of both organ-intrinsic and -extrinsic neuroplasticity, but also represents a valuable tool to assess neuronal and glial morphology and electrophysiology. Moreover, it allows functional modulation of supplied microenvironmental contents for studying their impact on neuroplasticity. Once established, the present neuroplasticity assay bears the potential of being applicable to the study of neuroplasticity in any GI organ.
Assuntos
Gânglios Espinais/citologia , Plexo Mientérico/citologia , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Pâncreas/inervação , Animais , Gânglios Espinais/fisiologia , Trato Gastrointestinal/inervação , Plexo Mientérico/fisiologia , Pâncreas/citologia , RatosRESUMO
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.
Assuntos
Dor Abdominal/metabolismo , Plasticidade Neuronal , Neurturina/metabolismo , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/fisiopatologia , Animais , Hipóxia Celular , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/patologia , Regulação Neoplásica da Expressão Gênica , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Plasticidade Neuronal/fisiologia , Neurturina/genética , Neurturina/farmacologia , Isoformas de Proteínas/metabolismo , RatosRESUMO
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.
Assuntos
Endoscopia , Manejo da Dor , Dor/prevenção & controle , Pancreatectomia , Pancreatite Crônica/terapia , Endoscopia/efeitos adversos , Humanos , Dor/diagnóstico , Dor/etiologia , Manejo da Dor/efeitos adversos , Manejo da Dor/métodos , Pancreatectomia/efeitos adversos , Pancreatite Crônica/complicações , Pancreatite Crônica/diagnóstico , Qualidade de Vida , Resultado do TratamentoRESUMO
Neural plasticity is not only the adaptive response of the central nervous system to learning, structural damage or sensory deprivation, but also an increasingly recognized common feature of the gastrointestinal (GI) nervous system during pathological states. Indeed, nearly all chronic GI disorders exhibit a disease-stage-dependent, structural and functional neuroplasticity. At structural level, GI neuroplasticity usually comprises local tissue hyperinnervation (neural sprouting, neural, and ganglionic hypertrophy) next to hypoinnervated areas, a switch in the neurochemical (neurotransmitter/neuropeptide) code toward preferential expression of neuropeptides which are frequently present in nociceptive neurons (e.g., substance P/SP, calcitonin-gene-related-peptide/CGRP) and of ion channels (TRPV1, TRPA1, PAR2), and concomitant activation of peripheral neural glia. The functional counterpart of these structural alterations is altered neuronal electric activity, leading to organ dysfunction (e.g., impaired motility and secretion), together with reduced sensory thresholds, resulting in hypersensitivity and pain. The present review underlines that neural plasticity in all GI organs, starting from esophagus, stomach, small and large intestine to liver, gallbladder, and pancreas, actually exhibits common phenotypes and mechanisms. Careful appraisal of these GI neuroplastic alterations reveals that--no matter which etiology, i.e., inflammatory, infectious, neoplastic/malignant, or degenerative--neural plasticity in the GI tract primarily occurs in the presence of chronic tissue- and neuro-inflammation. It seems that studying the abundant trophic and activating signals which are generated during this neuro-immune-crosstalk represents the key to understand the remarkable neuroplasticity of the GI tract.
Assuntos
Trato Gastrointestinal/metabolismo , Plasticidade Neuronal/fisiologia , Peptídeo Relacionado com Gene de Calcitonina/genética , Humanos , Inflamação/metabolismo , Inflamação/fisiopatologia , Neurônios/metabolismo , Nociceptores/metabolismo , Canais de Cátion TRPV/metabolismoRESUMO
BACKGROUND: Unraveling the mechanisms of pain in chronic pancreatitis (CP) remains a true challenge. The rapid development of pancreatic surgery in the twentieth century, usage of advanced molecular biological techniques, and emergence of clinician-scientists have enabled the elucidation of several mechanisms that lead to the chronic, complicated neuropathic pain syndrome in CP. However, the proper analysis of pain in CP should include three main arms of mechanisms: "peripheral nociception," "peripheral/pancreatic neuropathy and neuroplasticity," and "central neuropathy and neuroplasticity." DISCUSSION: According to our current knowledge, pain in CP involves sustained sensitization of pancreatic peripheral nociceptors by neurotransmitters and neurotrophic factors following neural damage. This peripheral pancreatic neuropathy leads to intrapancreatic neuroplastic alterations that involve a profound switch in the autonomic innervation of the human pancreas via "neural remodeling." Furthermore, this neuropathy entails a hyperexcitability of spinal sensory second-order neurons, which are subject to modulation from the brainstem via descending facilitation. Finally, viscerosensory cortical areas react to this central sensitization via spatial reorganization and thus a central neuroplasticity. The present review summarizes the current findings in these arms of mechanisms and introduces a novel concept to consistently describe pain in CP as a "predominantly neuropathic," "mixed-type" pain.