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PURPOSE: Laparoscopic pancreatoduodenectomy (LPD) has emerged as an alternative to open technique in treating periampullary tumors. However, the safety and efficacy of LPD compared to open pancreatoduodenectomy (OPD) remain unclear. Thus, we conducted an updated meta-analysis to evaluate the efficacy and safety of LPD versus OPD in patients with periampullary tumors, with a particular focus on the pancreatic ductal adenocarcinoma patient subgroup. METHODS: According to PRISMA guidelines, we searched PubMed, Embase, and Cochrane Library in December 2023 for randomized controlled trials (RCTs) that directly compare LPD versus OPD in patients with periampullary tumors. Endpoints and sensitive analysis were conducted for short-term endpoints. All statistical analysis was performed using R software version 4.3.1 with a random-effects model. RESULTS: Five RCTs yielding 1018 patients with periampullary tumors were included, of whom 511 (50.2%) were randomized to the LPD group. Total follow-up time was 90 days. LPD was associated with a longer operation time (MD 66.75; 95% CI 26.59 to 106.92; p = 0.001; I2 = 87%; Fig. 1A), lower intraoperative blood loss (MD - 124.05; 95% CI - 178.56 to - 69.53; p < 0.001; I2 = 86%; Fig. 1B), and shorter length of stay (MD - 1.37; 95% IC - 2.31 to - 0.43; p = 0.004; I2 = 14%; Fig. 1C) as compared with OPD. In terms of 90-day mortality rates and number of lymph nodes yield, no significant differences were found between both groups. CONCLUSION: Our meta-analysis of RCTs suggests that LPD is an effective and safe alternative for patients with periampullary tumors, with lower intraoperative blood loss and shorter length of stay.
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Carcinoma Ductal Pancreático , Laparoscopia , Neoplasias Pancreáticas , Pancreaticoduodenectomia , Humanos , Ampola Hepatopancreática/cirurgia , Ampola Hepatopancreática/patologia , Carcinoma Ductal Pancreático/cirurgia , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/mortalidade , Laparoscopia/efeitos adversos , Laparoscopia/métodos , Tempo de Internação/estatística & dados numéricos , Duração da Cirurgia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Pancreaticoduodenectomia/métodos , Pancreaticoduodenectomia/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy about 50% of PDAC are metastatic at presentation. In this study, we evaluated PDAC demographics, annual trend analysis, racial disparities, survival rate, and the role of different treatment modalities in localized and metastatic disease. METHODS: A total of 144,824 cases of PDAC were obtained from the SEER database from 2000 to 2018. RESULTS: The median age was 69 years, with a slightly higher incidence in males (52%) and 80% of all cases were white. Among cases with available data, 43% were grade III tumors and 57% were metastatic. The most common site of metastasis was the liver (15.7%). The annual incidence has increased steadily from 2000 to 2018. The overall observed (OS) 5-year survival rate was 4.4% (95% CI 4.3-4.6%), and 5 years cause-specific survival (CSS) was 5% (95% CI 5.1-5.4%). The 5-year survival with multimodal therapy (chemotherapy, surgery, and radiation) was 22% (95% CI 20.5-22.8%). 5-year CSS for the blacks was lower at 4.7% (95% CI 4.2-5.1%) compared to the whites at 5.3% (95% CI 5.1-5.4%). Multivariate analysis found male gender and black race associated with worse prognosis. Kaplan-Meier survival analysis found multimodal therapy to have the best outcomes in all three stages. CONCLUSION: PDAC is an aggressive malignancy with male gender and black race are associated with a poor prognosis. Surgery with chemoradiation was associated with the best overall survival. With steadily increasing rates of PDAC, improved treatment modalities are paramount to improving survival in these patients.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Programa de SEER , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Negro ou Afro-Americano/estatística & dados numéricos , Carcinoma Ductal Pancreático/etnologia , Carcinoma Ductal Pancreático/mortalidade , Terapia Combinada , Disparidades em Assistência à Saúde , Incidência , Neoplasias Hepáticas/etnologia , Neoplasias Hepáticas/mortalidade , Neoplasias Pancreáticas/etnologia , Neoplasias Pancreáticas/mortalidade , Taxa de Sobrevida , Estados Unidos/epidemiologia , BrancosRESUMO
BACKGROUND: Patients with pancreatic cancer have a dismal prognosis due to tumor cell infiltration and metastasis. Many reports have documented that EMT and PI3K-AKT-mTOR axis control pancreatic cancer cell infiltration and metastasis. Chloroxine is an artificially synthesized antibacterial compound that demonstrated anti-pancreatic cancer effects in our previous drug-screening trial. We have explored the impact of chloroxine on pancreatic cancer growth, infiltration, migration, and apoptosis. METHODS: The proliferation of pancreatic cancer cell lines (PCCs) treated with chloroxine was assessed through real-time cell analysis (RTCA), colony formation assay, CCK-8 assay, as well as immunofluorescence. Chloroxine effects on the infiltrative and migratory capacities of PCCs were assessed via Transwell invasion and scratch experiments. To assess the contents of EMT- and apoptosis-associated proteins in tumor cells, we adopted Western immunoblotting as well as immunofluorescence assays, and flow cytometry to determine chloroxine effects on PCCs apoptosis. The in vivo chloroxine antineoplastic effects were explored in nude mice xenografts. RESULTS: Chloroxine repressed pancreatic cancer cell growth, migration, and infiltration in vitro, as well as in vivo, and stimulated apoptosis of the PCCs. Chloroxine appeared to inhibit PCC growth by Ki67 downregulation; this targeted and inhibited aberrant stimulation of the PI3K-AKT-mTOR signaling cascade, triggered apoptosis in PCC via mitochondria-dependent apoptosis, and modulated the EMT to inhibit PCC infiltration and migration. CONCLUSIONS: Chloroxine targeted and inhibited the PI3K-AKT-mTOR cascade to repress PCCs growth, migration, as well as invasion, and triggered cellular apoptosis. Therefore, chloroxine may constitute a potential antineoplastic drug for the treatment of pancreatic cancer.
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Antineoplásicos , Cloroquinolinóis , Neoplasias Pancreáticas , Animais , Humanos , Camundongos , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Cloroquinolinóis/farmacologia , Cloroquinolinóis/uso terapêutico , Camundongos Nus , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismoRESUMO
Background and Objective: Pancreatic adenocarcinoma remains a dismal disease and is expected to become an even greater burden in the near future. This review focuses on the different surgical aspects for pancreaticoduodenectomy (PD), distal and total pancreatectomy (TP), incorporating lessons from both the western and eastern visions in treating pancreatic cancer. Methods: We conducted an extensive literature review through PubMed, prioritizing papers published in the last 5 years, but older emblematic papers were also included. We included articles that explored the treatment of pancreatic adenocarcinoma, with focus on the surgical aspect and strategies to improve outcomes. References of selected articles were also reviewed to identify any missed studies. Only papers in English were included. Key Content and Findings: As evidence continues to build, it is clear that both systemic and surgical therapies have a fundamental and complementary role. State of art surgical treatment encompasses complete mesopancreas excision for radical lymphadenectomy. Preoperative planning of dissection planes, extensive knowledge of vascular anatomic variations, oncological principles and expertise for vascular resections are mandatory to perform a more radical operation, in pursuit of improved outcomes. Conclusions: Based on current data, patient selection remains key and a more radical surgical approach brings more accomplishing results bringing as to believe that more is better.
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PURPOSE: This study aimed to evaluate the role of NADPH in pancreatic ductal adenocarcinoma using bioinformatic analyses and experimental validations. METHODS: We compared the expression levels, performed GO and KEGG analysis of NADPH oxidase family and its regulatory subunits, and determined the survival of patients with pancreatic ductal adenocarcinoma by GEPIA, David and KM plotter. The relationship between their expression with immune infiltration levels, phagocytotic/NK cell immune checkpoints, recruitment-related molecules were detected by Timer 2.0 and TISIDB, respectively. Subsequently, their correlation with NK cell infiltration level was verified by immunohistochemistry. RESULTS: The expression of some members of the NADPH oxidase family and its regulatory subunits was significantly increased in pancreatic ductal adenocarcinoma tissues compared to that in normal tissues and was positively correlated with natural killer (NK) cell infiltration. Furthermore, the NADPH oxidase family and its regulatory subunits were associated with survival and immune status in patients with pancreatic ductal adenocarcinoma, including chemokines, immune checkpoints, and immune infiltration levels of NK cells, monocytes, and myeloid-derived suppressor cells. CONCLUSIONS: These results suggest the NADPH oxidase family and its regulatory subunits might serve as indicators for predicting the responsiveness to immunotherapy and outcome of patients with pancreatic ductal adenocarcinoma, providing a new perspective or strategy for immunotherapy in pancreatic ductal adenocarcinoma.
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Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Prognóstico , NADPH Oxidases/uso terapêutico , Adenocarcinoma/patologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Imunoterapia , BiomarcadoresRESUMO
Pancreatic ductal adenocarcinoma remains a global health challenge and is predicted to soon become the second leading cause of cancer death in developed countries. Currently, surgical resection in combination with systemic chemotherapy offers the only chance of cure or long-term survival. However, only 20% of cases are diagnosed with anatomically resectable disease. Neoadjuvant treatment followed by highly complex surgical procedures has been studied over the last decade with promising short- and long-term results in patients with locally advanced pancreatic ductal adenocarcinoma (LAPC). In recent years, a wide variety of complex surgical techniques that involve extended pancreatectomies, including portomesenteric venous resection, arterial resection, or multi-organ resection, have emerged to optimize local control of the disease and improve postoperative outcomes. Although there are multiple surgical techniques described in the literature to improve outcomes in LAPC, the comprehensive view of these strategies remains underdeveloped. We aim to describe the preoperative surgical planning as well different surgical resections strategies in LAPC after neoadjuvant treatment in an integrated way for selected patients with no other potentially curative option other than surgery.
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As one of the most aggressive malignant tumors, pancreatic ductal adenocarcinoma (PDAC) ranks as the fourth cancer-related mortality in the world. The extremely low survival rate is closely related to early invasion and distant metastasis. However, effective target therapy for weakening its malignant behavior remains limited. Over the past decades, many proteins correlating with invasion and metastasis of PDAC have been discovered using proteomics. The discovery of these proteins gives us a deeper understanding of the invasive and migratory processes of PDAC. This review is a systemic integration of these proteomics findings over the past 10 years. The discovered proteins were typically associated with the glycolytic process, hypoxic microenvironment, post-translational modification, extracellular matrix, exosomes, cancer stem cells, and immune escape. Some proteins were found to have multiple functions, and, cooperation between different proteins in the invasive and metastatic processes was found. This cooperation, and not just single protein function, may play a more significant role in the poor prognosis of PDAC. Therefore, multi-target therapy against these cooperative networks should be a primary choice in the future.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Proteômica , Neoplasias Pancreáticas/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Regulação Neoplásica da Expressão Gênica , Linhagem Celular Tumoral , Microambiente Tumoral , Neoplasias PancreáticasRESUMO
Background: Despite being rare in domestic animals, pancreatic adenocarcinoma is the most common malignant tumor of the feline pancreas. Due non-specificity of clinical signs in cats and the late diagnosis of the neoplasm, it is necessary to understand this disease better, to contribute for the knowledge of its early recognition and treatment. Thus, this study aims to report a case of metastatic pancreatic ductal adenocarcinoma in a cat, focusing on the main clinical aspects, diagnosis, and prognosis of this disease, in addition to the description of the presentation of peritoneal carcinomatosis. Case: A 14-year-old male neutered mixed breed cat, was referred to the Feline Medicine Service (MedFel) of the Hospital de Clínicas Veterinárias (HCV) - Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, with a history of hyporexia, constipation and increased abdominal volume for 3 days, besides mild difficulty in locomotion and progressive weight loss in the last 6 months. On the physical examination, the patient was alert, with a body condition score of 6/9; muscle condition score 1/4 and moderate dehydration of 7%. Popliteal lymph nodes were enlarged, and abdominal distension was evident. Around 200 mL of a slightly cloudy, straw-yellow liquid were drained from the abdominal cavity. After draining the fluid, a new abdominal palpation was performed, and there were fecal retention and a palpable mass in the right hypogastric region. The result of the cytological analysis of the fluid was consistent with a protein-rich transudate, suggesting neoplastic effusion of epithelial origin. Hematological and biochemical changes included leukocytosis due to neutrophilia, monocytosis, lymphopenia, thrombocytosis and azotemia. On abdominal ultrasound, the patient had free fluid in the abdominal cavity, and the gallbladder had discreet of biliary sludge. The intestines showed some corrugated segments with other segments lacking definition of its layers, and without peristaltic movements, suggesting intestinal neoplasia. Pancreas and adrenals were not visualized. On the chest X-ray, moderate opacification of lung fields with a diffuse interstitial pattern was observed, suggesting lung metastasis. The patient presented an acute worsening of the clinical condition and the owner requested euthanasia. The patient was referred for necropsy and based on the macroscopic and microscopic changes, the post-mortem diagnosis was metastatic pancreatic ductal adenocarcinoma with peritoneal carcinomatosis. Discussion: The clinical presentation of cats with exocrine pancreatic neoplasia is nonspecific, as clinical signs are common to several diseases, such as anorexia, vomiting, abdominal pain, weight loss with normal appetite, jaundice, depression, and lethargy. Complementary blood tests also do not provide data that could lead to the suspicion of pancreatic neoplastic disease. In the present case, the diagnosis of metastatic pancreatic ductal adenocarcinoma with peritoneal carcinomatosis was only possible post mortem. The pancreas is a difficult organ to assess adequately using most diagnostic imaging methods, so histopathology is still the method of choice for differentiating pancreatic tissue comorbidities. Therefore, exploratory laparotomy should be instituted to provide tissue samples from the pancreas and its metastases for histopathological diagnosis, whenever ultrasound or other imaging methods indicate suspicious abdominal changes. The literature reports that less than 10% of affected cats treated with complete surgical removal of the mass and chemotherapy alone will survive more than a year, and the average time for untreated cats is only 6 days. The prognosis of this disease is bad and most cats are euthanized, due to rapid clinical worsening. Therefore, diagnosis is essential to determine an adequate prognosis in advanced cases and to support therapeutic decisions or euthanasia.
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Animais , Masculino , Gatos , Neoplasias Pancreáticas/veterinária , Carcinoma Ductal Pancreático/veterinária , Neoplasias Abdominais/veterinária , Ultrassonografia/veterináriaRESUMO
El adenocarcinoma pancreático ductal (APD) es la cuarta causa de muerte por cáncer y se proyecta que para el 2030 ocupe el segundo lugar. El pronóstico es sombrío, siendo la sobrevida menor a 9% en 5 años. Se consideró durante mucho tiempo a la resección quirúrgica como el único tratamiento curativo, sin embargo, sólo el 15 a 20% de los pacientes pueden ser beneficiados con la misma. La clasificación pre terapéutica más utilizada es la del National Comprehensive Cáncer Network (NCCN), basada en la relación del tumor con estructuras vasculares, clasificándolos en tumores "resecables", de resección límite "Borderlines" y "localmente avanzados". Se presenta el primer caso registrado en Paraguay de APD con infiltración de la Vena Mesentérica Superior (VMS) tratado con duodenopancreatectomía cefálica (DPC) asociada a resección vascular mayor.
Pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of cancer death and is projected to rank second by 2030. The prognosis is bleak, with survival being less than 9% in 5 years. For a long time, surgical resection was considered the only curative treatment, however, only 15 to 20% of patients can benefit from it. The most widely used pre-therapeutic classification is that of the National Comprehensive Cancer Network (NCCN), based on the relationship of the tumor with vascular structures, classifying them into "resectable", "borderline" and "locally advanced" tumors. We present the first registered case in Paraguay of PDA with infiltration of the Superior Mesenteric Vein (SMV) treated with cephalic duodenopancreatectomy (CPD) associated with major vascular resection.
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Adenocarcinoma , Pancreaticoduodenectomia , Protectomia/métodosRESUMO
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease which confers to patients a poor prognosis at short term. PDAC is the fourth leading cause of death among cancers in the Western world. The rate of new cases of pancreatic cancer (incidence) is 10 per 100,000 but present a 5-year survival of less than 10%, highlighting the poor prognosis of this pathology. Furthermore, 90% of advanced PDAC tumor present KRAS mutations impacting in several oncogenic signaling pathways, many of them associated with cell proliferation and tumor progression. Different combinations of chemotherapeutic agents have been tested over the years without an improvement of significance in its treatment. PDAC remains as one the more challenging biomedical topics thus far. The lack of a proper early diagnosis, the notable mortality statistics and the poor outcome with the available therapies urge the entire scientific community to find novel approaches against PDAC with real improvements in patients' survival and life quality. Natural compounds have played an important role in the process of discovery and development of new drugs. Among them, terpenoids, such as sesquiterpene lactones, stand out due to their biological activities and pharmacological potential as antitumor agents. In this review, we will describe the sesquiterpene lactones with in vitro and in vivo activity against pancreatic tumor cells. We will also discuss the mechanism of action of the compounds as well as the signaling pathways associated with their activity.
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Antineoplásicos , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Sesquiterpenos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Lactonas/farmacologia , Lactonas/uso terapêutico , Neoplasias Pancreáticas/patologia , Sesquiterpenos/farmacologia , Sesquiterpenos/uso terapêutico , Neoplasias PancreáticasRESUMO
PURPOSE: OX40 signaling pathway occupies a vital place in anti-tumor immunity; however, the role of tumor-infiltrating OX40+ lymphocytes in pancreatic ductal adenocarcinoma (PDAC) remains to be identified. METHODS: A total of 325 sequential PDAC patients who received curative tumor resection between January 2014 and December 2016 were enrolled. Tissues of these patients were immunohistochemically assessed for tumor infiltration of CD4+ T cells, CD8+ cytotoxic T cells (CTLs), and OX40+ lymphocytes. The frequency of OX40+ tumor-infiltrating lymphocytes (TILs) was then analyzed to various clinicopathological features, densities of tumor infiltration of CD4+ T cells and CTLs, and survival analysis was conducted using Kaplan-Meier (KM) curves. The risk scores of associated markers were calculated by the Cox proportional-hazards model. RESULTS: Our results showed that higher OX40+ lymphocytes infiltration was significantly correlated with superior median overall survival (OS) (25.8 vs 13.4 months, P < 0.001). Additionally, using univariate and multivariate Cox proportional hazards analyses, this study revealed that together with tumor differentiation, tumor size, serum CA199 levels, serum CA125 levels, and the infiltration of intratumoral CD8+ T cells. The abundance of OX40+ lymphocytes within the tumor was continued to be an independent predictor for OS (P = 0.023, HR = 0.713, 95% CI: 0.532-0.954). CONCLUSIONS: This study demonstrated that intratumoral infiltration by a high number of OX40+ lymphocytes is a novel biomarker for favorable prognosis in resected PDAC patients, which implies that OX40-agonist-based immunotherapy might be a potential target in PDAC patients.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Linfócitos T CD8-Positivos , Humanos , Linfócitos do Interstício Tumoral , Prognóstico , Neoplasias PancreáticasRESUMO
PURPOSE: Transcriptome analysis of pancreatic ductal adenocarcinoma (PDAC) has been useful to identify gene expression changes that sustain malignant phenotypes. Yet, most studies examined only tumor tissues and focused on protein-coding genes, leaving long non-coding RNAs (lncRNAs) largely underexplored. METHODS: We generated total RNA-Seq data from patient-matched tumor and nonmalignant pancreatic tissues and implemented a computational pipeline to survey known and novel lncRNAs. siRNA-mediated knockdown in tumor cell lines was performed to assess the contribution of PDAC-associated lncRNAs to malignant phenotypes. Gene co-expression network and functional enrichment analyses were used to assign deregulated lncRNAs to biological processes and molecular pathways. RESULTS: We detected 9,032 GENCODE lncRNAs as well as 523 unannotated lncRNAs, including transcripts significantly associated with patient outcome. Aberrant expression of a subset of novel and known lncRNAs was confirmed in patient samples and cell lines. siRNA-mediated knockdown of a subset of these lncRNAs (LINC01559, LINC01133, CCAT1, LINC00920 and UCA1) reduced cell proliferation, migration and invasion. Gene co-expression network analysis associated PDAC-deregulated lncRNAs with diverse biological processes, such as cell adhesion, protein glycosylation and DNA repair. Furthermore, UCA1 knockdown was shown to specifically deregulate co-expressed genes involved in DNA repair and to negatively impact DNA repair following damage induced by ionizing radiation. CONCLUSIONS: Our study expands the repertoire of lncRNAs deregulated in PDAC, thereby revealing novel candidate biomarkers for patient risk stratification. It also provides a roadmap for functional assays aimed to characterize novel mechanisms of action of lncRNAs in pancreatic cancer, which could be explored for therapeutic development.
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Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , RNA Longo não Codificante , Adenocarcinoma/genética , Adenocarcinoma/patologia , Carcinoma Ductal Pancreático/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Neoplasias Pancreáticas/patologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Interferente Pequeno , Neoplasias PancreáticasRESUMO
Although there are currently several factors that allow measuring the risk of having breast cancer or predicting its progression, the underlying causes of this malignancy have remained unknown. Several molecular studies have described some mechanisms involved in the progress of breast cancer. These have helped in identifying new targets with therapeutic potential. However, despite the therapeutic strategies implemented from the advances achieved in breast cancer research, a large percentage of patients with breast cancer die due to the spread of malignant cells to other tissues or organs, such as bones and lungs. Therefore, determining the processes that promote the migration of malignant cells remains one of the greatest challenges for oncological research. Several research groups have reported evidence on how the dedifferentiation of tumor cells leads to the acquisition of stemness characteristics, such as invasion, metastasis, the capability to evade the immunological response, and resistance to several cytotoxic drugs. These phenotypic changes have been associated with a complex reprogramming of gene expression in tumor cells during the Epithelial- Mesenchymal Transition (EMT). Considering the determining role that the transcriptional regulation plays in the expression of the specific characteristics and attributes of breast cancer during ETM, in the present work, we reviewed and analyzed several transcriptional mechanisms that support the mesenchymal phenotype. In the same way, we established the importance of transcription factors with a therapeutic perspective in the progress of breast cancer.
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Antineoplásicos , Neoplasias da Mama , Antineoplásicos/farmacologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Fatores de Transcrição/genéticaRESUMO
PURPOSE: Distal cholangiocarcinoma and pancreatic ductal adenocarcinoma are malignancies with poor prognoses that can be difficult to distinguish preoperatively. Thrombospondin-2 has been proposed as a novel diagnostic biomarker for early pancreatic ductal adenocarcinoma. The aim of the present study was to evaluate thrombospondin-2 as a diagnostic and prognostic biomarker in combination with current biomarker CA 19-9 for distal cholangiocarcinoma and pancreatic ductal adenocarcinoma. METHODS: Thrombospondin-2 was measured in prospectively collected serum samples from patients who underwent surgery with a histopathological diagnosis of distal cholangiocarcinoma (N = 51), pancreatic ductal adenocarcinoma (N = 52) and benign pancreatic diseases (N = 27) as well as healthy blood donors (N = 52) using an enzyme-linked immunosorbent assay. RESULTS: Thrombospondin-2 levels (ng/ml) were similar in distal cholangiocarcinoma 55 (41-77) and pancreatic ductal adenocarcinoma 48 (35-80) (P = 0.221). Thrombospondin-2 + CA 19-9 had an area under the curve of 0.92 (95% CI 0.88-0.97) in differentiating distal cholangiocarcinoma and pancreatic ductal adenocarcinoma from healthy donors which was superior to CA 19-9 alone (P < 0.001). The diagnostic value of adding thrombospondin-2 to CA 19-9 was larger in early disease stages. Thrombospondin-2 did not provide additional value to CA 19-9 in differentiating the benign disease group; however, heterogeneity was notable in the benign cohort. Three of five patients with autoimmune pancreatitis patients had greatly elevated thrombospondin-2 levels. Thrombospondin-2 levels had no correlation with prognoses. CONCLUSIONS: Serum thrombospondin-2 in combination with CA 19-9 has potential as a biomarker for distal cholangiocarcinoma and pancreatic cancer.
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Biomarcadores Tumorais/sangue , Antígeno CA-19-9/sangue , Carcinoma Ductal Pancreático/sangue , Carcinoma Ductal Pancreático/diagnóstico , Colangiocarcinoma/sangue , Colangiocarcinoma/diagnóstico , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/diagnóstico , Trombospondinas/sangue , Idoso , Colangiocarcinoma/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/patologia , Estudos ProspectivosRESUMO
Malignant cells are commonly characterised by being capable of invading tissue, growing self-sufficiently and uncontrollably, being insensitive to apoptosis induction and controlling their environment, for example inducing angiogenesis. Amongst them, a subpopulation of cancer cells, called cancer stem cells (CSCs) shows sustained replicative potential, tumor-initiating properties and chemoresistance. These characteristics make CSCs responsible for therapy resistance, tumor relapse and growth in distant organs, causing metastatic dissemination. For these reasons, eliminating CSCs is necessary in order to achieve long-term survival of cancer patients. New insights in cancer metabolism have revealed that cellular metabolism in tumors is highly heterogeneous and that CSCs show specific metabolic traits supporting their unique functionality. Indeed, CSCs adapt differently to the deprivation of specific nutrients that represent potentially targetable vulnerabilities. This review focuses on three of the most aggressive tumor types: pancreatic ductal adenocarcinoma (PDAC), hepatocellular carcinoma (HCC) and glioblastoma (GBM). The aim is to prove whether CSCs from different tumour types share common metabolic requirements and responses to nutrient starvation, by outlining the diverse roles of glucose and amino acids within tumour cells and in the tumour microenvironment, as well as the consequences of their deprivation. Beyond their role in biosynthesis, they serve as energy sources and help maintain redox balance. In addition, glucose and amino acid derivatives contribute to immune responses linked to tumourigenesis and metastasis. Furthermore, potential metabolic liabilities are identified and discussed as targets for therapeutic intervention.
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BACKGROUND: Second-line (2L) treatments for advanced pancreatic ductal adenocarcinoma (PDAC) achieve a modest benefit at the expense of potential toxicity. In the absence of predictive factors of response, the identification of prognostic factors could help in the therapeutic decisions-making. The purpose of this study was to assess the prognostic factors associated with shorter survival in patients with advanced PDAC who received 2L treatment. METHODS: We conducted a single institution retrospective study, which included all patients with advanced PDAC who received 2L treatment between September 2006 and February 2020 at La Paz University Hospital, Madrid (Spain). Significant variables in the logistic regression model were used to create a prognostic score. RESULTS: We included 108 patients. The median overall survival (OS) was 5.10 months (95%CI 4.02-6.17). In the multivariate analysis, time to progression (TTP) shorter than 4 months after first-line treatment (OR 4.53 [95%CI 1.28-16.00] p = 0.01), neutrophil-to-lymphocyte ratio (NLR) greater than 3 at the beginning of 2L (OR 9.07 [95%CI 1.82-45.16] p = 0.01) and CA-19.9 level higher than the upper limit of normal at the beginning of 2L (OR 7.83 [95%CI 1.30-49.97] p = 0.02) were independently associated with OS shorter than 3 months. The prognostic score classified patients into three prognostic groups (good, intermediate and poor) with significant differences in OS (p < 0.001). CONCLUSIONS: TTP shorter than 4 months after first-line treatment, NLR greater than 3 and CA-19.9 level higher than the upper limit of normal at the beginning of 2L were associated with shorter overall survival. We developed a prognostic score that classifies patients with advanced PDAC into three prognostic groups after progression to the first-line. This score could help in the decision-making for 2L treatment.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos Glicosídicos Associados a Tumores/sangue , Capecitabina/uso terapêutico , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Tomada de Decisão Clínica , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Progressão da Doença , Feminino , Fluoruracila/uso terapêutico , Humanos , Irinotecano/uso terapêutico , Leucovorina/uso terapêutico , Modelos Logísticos , Linfócitos/citologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/citologia , Oxaliplatina/uso terapêutico , Oxaloacetatos/uso terapêutico , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Prognóstico , Estudos Retrospectivos , Fatores de Tempo , GencitabinaRESUMO
Introducción: la diabetes mellitus (DM) se considera un factor de riesgo para el desarrollo de adenocarcinoma ductal de páncreas (ACDP). Objetivos: describir la prevalencia de DM y glucemia en ayuno alterada (GAA) al diagnóstico de ACDP en pacientes asistidos en un centro de referencia gastroenterológico; analizar las diferencias en las características personales y nutricionales en pacientes con ACDP y DM, ACDP y GAA, y ACDP sin DM ni GAA; establecer el tiempo transcurrido desde el diagnóstico de DM hasta diagnosticar ACDP. Materiales y métodos: de octubre de 2019 a marzo de 2020 se revisaron 465 historias clínicas de las Secciones Oncología y Nutrición de pacientes >18 años con diagnóstico de ACDP. Resultados: se registraron 171 historias clínicas (36,7%) con ACDP y DM, y 294 (63,2%) con ACDP sin DM. En el 45,1% de las primeras, el intervalo entre el diagnóstico de DM y el de ACDP fue <1 año, y en el 17,65%, 15,69% y 21,57% los lapsos correspondieron a 1 y 5 años, entre 5 y 10 años y >10 años respectivamente. Conclusiones: la prevalencia de DM en ACDP fue superior a la registrada en la población general (37% vs 12,7%), siendo del 45,10% cuando se presentó dentro del primer año del diagnóstico oncológico. Nuestros resultados concuerdan con la bibliografía internacional que relaciona la DM de reciente diagnóstico como factor asociado a la presencia de ACDP por factores de riesgo compartidos, variables fisiopatológicas de la DM o a consecuencia de la terapéutica farmacológica de la misma.
Introduction: diabetes mellitus (DM) is considered to be a risk factor for the development of pancreatic ductal adenocarcinoma (PDAC). Objectives: describe the prevalence of DM and of impaired fasting glucose (IFG) at the diagnosis of PDAC, among patients assisted in a gastroenterological reference center. Analyze differences in personal and nutritional characteristics in patients with both PDAC and DM; with both PDAC and IFG; and with PDAC but neither DM nor IFG. Determine the time lapse between the diagnosis of DM and the diagnosis of PDAC. Materials and methods: between October 2019 and March 2020, we analyzed 465 clinical records of PDAC-diagnosed patients over 18 years, from Oncology and Nutrition Sections. Results: 171 clinical records (36.7%) showed both PDAC and DM; 294 clinical records (63.2%) showed PDAC but not DM. In 45.1% of the former, the interval between the diagnosis of DM and that of PDAC was <1 year, and in 17.65%, 15.69% and 21.57%, the lapses corresponded to 1 and 5 years, between 5 and 10 years y >10 years, respectively. Conclusions: the prevalence of DM in PDAC patients (37%) is higher than that registered in the overall population (12.7%), reaching a 45.10% when detected during the first year of oncological diagnosis. Our results match the international literature relating recently-diagnosed DM with the presence of PDAC, as effect of shared risk factors between both diseases, or DM pathophysiology factors, or DM pharmacological therapeutic
Assuntos
Humanos , Diabetes Mellitus , Pâncreas , Neoplasias Pancreáticas , Glicemia , Glucose , OncologiaRESUMO
Pancreatic Ductal Adenocarcinoma (PDA) is a highly metastatic tumor, and the liver is its first target, which restricts the use of medications. PDA is considered one of the most aggressive types of cancer in the world, with an extremely short survival time, depending on the stage of diagnosis. In non-surgical cases, chemotherapy alternatives are only effective in 40% to 60% of patients. The low efficiency of treatments occurs mainly due to the complex microenvironment in PDA, leading to chemoresistance to treatments and making it difficult to reach the affected tissue. A very important histological characteristic of PDA is the extremely dense stroma, which leads to low vascularization of tumor tissue. Consequently, the stroma environment causes less drug accumulation in tumor cells, even of selective and/or targeted drugs. Overcoming the stroma's microenvironment is a major challenge for therapies. Moreover, specific genes lead to direct chemoresistance in PDA due to their high progression. In this scenario, nanotechnology appears as an alternative to overcome these clinical challenges concerning two distinct ways: acting on the stroma or/and acting directly on the pancreatic tumor cells. Thus, this review aimed to highlight advances in the application of nanotechnology aiming to open up new landscapes against PDA. There are a huge number of nanoparticles carrying drugs in preclinical and clinical trials for the effective treatment of PDA. These works have been discussed, and based on the current scenario, the future prospects for an efficient treatment of PDA have been proposed.
Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Humanos , Pâncreas , Neoplasias Pancreáticas/tratamento farmacológico , Microambiente TumoralRESUMO
Hypoxia and nutrient deprivation are responsible for inducing malignant behavior in neoplastic cells. In these conditions, metabolic stress leads the cells to enhance their autophagic flux and to activate key molecules for homeostasis maintenance. Galectin-3 (Gal-3) is upregulated in pancreatic cancer and it is activated under the hypoxic atmosphere. We aimed to analyze the most effective autophagic-inducing conditions in pancreatic ductal adenocarcinoma cells and the effect exerted under these conditions in association with hypoxia on the Gal-3 expression. Gal-3 and the microtubule-associated protein light chain 3 beta (LC3) were accessed through western blot and immunofluorescence. Degradative vacuole quantification was analyzed by transmission electronic microscopy, and inhibition of Gal-3 was performed using siRNA. According to the analyses, the most effective conditions in the inducement of autophagy for PANC-1 and MIA PaCa-2 cells were nutritional deprivation and complete amino acid/glucose deprivation, respectively. PANC-1 cells presented higher Gal-3 when they were submitted to 24 h of nutritional deprivation alone and simultaneously nutritional and oxygen deprivation. Inhibition of Gal-3 causes a decrease of LC3 levels in all experimental conditions. These results confirm that Gal-3 is modulated by microenvironment factors and the possibility of Gal-3 participating in an adaptive response from PDAC cells to extreme conditions.
Assuntos
Neoplasias Pancreáticas , Autofagia , Linhagem Celular Tumoral , Galectina 3 , Humanos , Pâncreas , Microambiente TumoralRESUMO
Pancreatic ductal adenocarcinoma is one of the most aggressive tumors with a microenvironment marked by hypoxia and starvation. Galectin-3 has been evaluated in solid tumors and seems to present both pro/anti-tumor effects. So, this study aims to characterize the expression of Galectin-3 from pancreatic tumor cells and analyze its influence for cell survive and motility in mimetic microenvironment. For this, cell cycle and cell death were accessed through flow cytometry. Characterization of inside and outside Galectin-3 was performed through Real-Time Quantitative Reverse Transcription PCR (qRT-PCR), immunofluorescence, Western blot, and ELISA. Consequences of Galectin-3 extracellular inhibition were investigated using cell death and scratch assays. PANC-1 showed increased Galectin-3 mRNA expression when cultivated in hypoxia for 24 and 48 h. After 24 h in simultaneously hypoxic/deprived incubation, PANC-1 shows increased Galectin-3 protein and secreted levels. For Mia PaCa-2, cultivation in deprivation was determinant for the increasing in Galectin-3 mRNA expression. When cultivated in simultaneously hypoxic/deprived condition, Mia PaCa-2 also presented increasing for the Galectin-3 secreted levels. Treatment of PANC-1 cells with lactose increased the death rate when cells were incubated simultaneously hypoxic/deprived condition. Therefore, it is possible to conclude that the microenvironmental conditions modulate the Galectin-3 expression on the transcriptional and translational levels for pancreatic cancer cells.