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1.
Int J Clin Oncol ; 26(10): 1784-1792, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34476650

RESUMO

Pancreatic cancer is associated with both family and hereditary cancer syndromes. Multigene panel testing for pancreatic cancer detected the germline variants BRCA1/2, PALB2, ATM, TP53, MLH1, STK11/LKB1, APC, CDKN2A, and SPINK1/PRSS1 as high-risk genes. A latest genome-wide association study revealed the common, but low-risk germline variants in pancreatic cancer patients. Active pancreatic surveillance using magnetic resonance imaging and endoscopic ultrasound is recommended for high-risk individuals who have a family history of pancreatic cancer or harbor these germline pathogenic variants to improve the detection rate and prognosis of pancreatic cancer. Since poly-ADP-ribose polymerase (PARP) inhibitor has been shown to be effective in improving the prognosis of BRCA-positive pancreatic cancer as well as hereditary breast and ovarian cancer syndrome, PARP inhibitor therapy is currently being applied as precision medicine to pancreatic cancer patients harboring the BRCA1/2 germline variant. This review highlights the importance of surveillance for germline pathogenic variants in pancreatic cancer and is expected to lead to improvements in the diagnosis and prevention of pancreatic cancer as well as facilitate the development of effective therapeutic strategies and precision medicine.


Assuntos
Neoplasias da Mama , Neoplasias Pancreáticas , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Mutação em Linhagem Germinativa , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Prognóstico , Inibidor da Tripsina Pancreática de Kazal
2.
Nanoscale ; 13(31): 13328-13343, 2021 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-34477739

RESUMO

Facing the barriers in each step of the in vivo delivery cascade, the low drug delivery efficiency remains problematic in tumor therapy. Although recently the nanofibril drug delivery systems have shown improved circulation and accumulation compared with nanoparticles, the poor deep penetration and cellular internalization hinder their application, especially for pancreatic cancer with dense stroma. To comprehensively address the hurdles in the delivery cascade, a matrix metalloproteinase 2 (MMP-2) responsive transformable beaded nanofibril, which integrates the merits of nanofibril and small-sized nanoparticles, is established. The beaded nanofibril (GD@PPF) is prepared by conjugating gemcitabine-loaded small-sized nanoparticles (GD) with fibrous PEG-PCL (PPF) via GPLGVRG, a substrate peptide of MMP-2. GD@PPF escapes the clearance of the reticuloendothelial system (RES), prolongs the circulation time, and increases the selective accumulation in the tumor as fibrous micelles. Once accumulated in the tumor, small positively-charged GD is released from the beaded nanofibrils in response to MMP-2 overexpression in the stroma of pancreatic cancer, enabling permeation in the dense tumor matrix and cellular internalization, which makes up for the shortcomings of fibrous micelles. Furthermore, the remaining fibrous PPF surround the tumor tightly to impede the efflux of drugs, leading to improved retention. GD@PPF is biocompatible and exhibits excellent antitumor effect in Pan 02 subcutaneous tumor models. Therefore, the MMP-2 responsive transformable beaded nanofibril, which enhances the delivery efficiency in multiple stage of the delivery cascade, presents a promising strategy for pancreatic cancer therapy.


Assuntos
Nanopartículas , Neoplasias Pancreáticas , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Humanos , Metaloproteinase 2 da Matriz , Micelas , Neoplasias Pancreáticas/tratamento farmacológico
3.
World J Gastroenterol ; 27(30): 4963-4984, 2021 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-34497429

RESUMO

Pancreatic cancer is a dismal disease with high incidence and poor survival rates. With the aim to improve overall survival of pancreatic cancer patients, new therapeutic approaches are urgently needed. Protein kinases are key regulatory players in basically all stages of development, maintaining physiologic functions but also being involved in pathogenic processes. c-Jun N-terminal kinases (JNK) and p38 kinases, representatives of the mitogen-activated protein kinases, as well as the casein kinase 1 (CK1) family of protein kinases are important mediators of adequate response to cellular stress following inflammatory and metabolic stressors, DNA damage, and others. In their physiologic roles, they are responsible for the regulation of cell cycle progression, cell proliferation and differentiation, and apoptosis. Dysregulation of the underlying pathways consequently has been identified in various cancer types, including pancreatic cancer. Pharmacological targeting of those pathways has been the field of interest for several years. While success in earlier studies was limited due to lacking specificity and off-target effects, more recent improvements in small molecule inhibitor design against stress-activated protein kinases and their use in combination therapies have shown promising in vitro results. Consequently, targeting of JNK, p38, and CK1 protein kinase family members may actually be of particular interest in the field of precision medicine in patients with highly deregulated kinase pathways related to these kinases. However, further studies are warranted, especially involving in vivo investigation and clinical trials, in order to advance inhibition of stress-activated kinases to the field of translational medicine.


Assuntos
Neoplasias Pancreáticas , Proteínas Quinases p38 Ativadas por Mitógeno , Apoptose , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno , Proteínas Quinases Ativadas por Mitógeno , Neoplasias Pancreáticas/tratamento farmacológico
4.
BMJ Case Rep ; 14(9)2021 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-34511423

RESUMO

We report a case of a frail 68-year-old woman with stage 4 pancreatic carcinoma harbouring a fibroblastic growth factor receptor 2 (FGFR2) fusion who achieved a durable complete response after treatment with erdafitinib a pan-FGFR inhibitor. The FGFR2-TACC2 fusion was detected on comprehensive tumour somatic mutation profiling. There is ongoing complete response at 10 months after initiation of erdafitinib. Transient central serous retinopathy, grade 2 hyperphosphataemia and diarrhoea were the adverse events encountered.


Assuntos
Adenocarcinoma , Neoplasias Pancreáticas , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Idoso , Proteínas de Transporte , Feminino , Humanos , Mutação , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Pirazóis , Quinoxalinas , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Proteínas Supressoras de Tumor
6.
Acta Oncol ; 60(9): 1146-1153, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34338111

RESUMO

BACKGROUND: The prognosis of pancreatic cancer is poor and new treatment strategies are urgently needed. To identify non-cancer drugs that could be re-purposed for cancer, we investigated the association between the use of selected drugs and cancer-specific mortality in a nationwide cohort of pancreatic cancer patients. MATERIAL AND METHODS: The study is based on linkage between the Cancer Registry of Norway and the Norwegian Prescription Database, comprising 2614 pancreatic cancer patients diagnosed between 2007 and 2014. We evaluated the association between use at diagnosis of a pre-defined list of non-cancer drugs, including metformin, antihypertensives, and statins, and pancreatic cancer-specific mortality, using Cox regression. Patients were defined as users of a particular drug if it was prescribed before diagnosis, and the prescription covered the date of diagnosis. RESULTS: In total, 2096 (80.2%) patients died from pancreatic cancer; median survival was 6 months. Statin users (n = 621) had lower mortality (hazard ratio (HR): 0.86; 95% confidence interval (CI) 0.76-0.97) compared to non-users (n = 1993). This association was more pronounced (P-heterogeneity 0.062) in users of hydrophilic (n = 37, HR: 0.61; 95% CI 0.42-0.90) than lipophilic (n = 587, HR: 0.87; 95% CI 0.78-0.98) statins. An indication for lower mortality (HR: 0.85; 95% CI 0.69-1.05) was observed in users of non-selective beta-blockers (n = 113) compared to non-users (n = 2501). Notably, when compared to users of other antihypertensives (n = 643), users of non-selective beta-blockers (n = 40) had lower mortality (HR 0.67; 95% CI 0.47-0.96). The use of other drugs, including selective beta-blockers and metformin, was not associated with mortality. CONCLUSION: The findings suggest an association between the use of statins and non-selective beta-blockers and reduced pancreatic cancer mortality, and add to the literature supporting the design of randomised clinical trials to evaluate those drugs in the management of pancreatic cancer.


Assuntos
Adenocarcinoma , Inibidores de Hidroximetilglutaril-CoA Redutases , Metformina , Neoplasias Pancreáticas , Adenocarcinoma/tratamento farmacológico , Estudos de Coortes , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Metformina/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Sistema de Registros
7.
Adv Exp Med Biol ; 1301: 7-24, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34370285

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal cancers with a dismal 5-year survival rate of 5% and very limited efficacy of the current therapeutic regimens. The lethality of PDAC stems from asymptomatic early stage of the disease, its propensity to rapidly disseminate, as well as unusual, dense and highly active surrounding stroma. Fortunately, promising literature data suggests that exploiting newly contextualized type of cell death, termed "ferroptosis", has great potential for overcoming the major problems regarding PDAC treatment. A major player in this type of cell death is Glutamate/Cystine antiporter - xCT, which is responsible for the uptake of oxidized form of cysteine, and thus maintenance of intracellular amino acid and redox homeostasis. xCT seems to fulfill all requirements of the solid and specific molecular target for ferroptosis-based anti-cancer therapy. In this chapter we summarized mounting literature data supporting this hypothesis, but also, we pointed out some of the underexamined aspects of xCT-dependent (patho)physiology of the cancer cell, which have to be addressed in future studies. The abstract could be used as "informative abstract" for the online version.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/tratamento farmacológico , Morte Celular , Cistina/metabolismo , Humanos , Oxirredução , Neoplasias Pancreáticas/tratamento farmacológico
8.
Trials ; 22(1): 568, 2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34446057

RESUMO

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease, and multimodal strategies, such as surgery plus neoadjuvant chemotherapy (NAC)/adjuvant chemotherapy, have been attempted to improve survival in patients with localized PDAC. To date, there is one prospective study providing evidence for the superiority of a neoadjuvant strategy over upfront surgery for localized PDAC. However, which NAC regimen is optimal remains unclear. METHODS: A randomized, exploratory trial is performed to examine the clinical benefits of two chemotherapy regimens, gemcitabine plus S-1 (GS) and gemcitabine plus nab-paclitaxel (GA), as NAC for patients with planned PDAC resection. Patients are enrolled after the diagnosis of resectable or borderline resectable PDAC. They are randomly assigned to either NAC regimen. Adjuvant chemotherapy after curative resection is highly recommended for 6 months in both arms. The primary endpoint is tumor progression-free survival time, and secondary endpoints include the rate of curative resection, the completion rate of protocol therapy, the recurrence type, the overall survival time, and safety. The target sample size is set as at least 100. DISCUSSION: This study is the first randomized phase II study comparing GS combination therapy with GA combination therapy as NAC for localized pancreatic cancer. TRIAL REGISTRATION: UMIN Clinical Trials Registry UMIN000021484 . This trial began in April 2016.


Assuntos
Adenocarcinoma , Nanopartículas , Neoplasias Pancreáticas , Paclitaxel Ligado a Albumina/uso terapêutico , Albuminas , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Desoxicitidina/análogos & derivados , Proteínas de Ligação ao GTP/uso terapêutico , Humanos , Proteínas de Membrana , Terapia Neoadjuvante/efeitos adversos , Paclitaxel , Neoplasias Pancreáticas/tratamento farmacológico , Estudos Prospectivos
9.
J Biomed Nanotechnol ; 17(7): 1453-1458, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34446148

RESUMO

MMEO (3'-methoxy-3',4″(methylenedioxy)-2,5-epoksilignan-4'ol-6-on) is a derivative of DMEO (3'-methoxy-3″,4″(methylenedioxy)-2,5-epoksilignan-4',6-diol) synthesized through demethylation using dimethylsulfoxide-acetic anhydride reagent. MMEO inhibits Hedgehog signaling at a concentration of 4.1 µM. The current study aimed to formulate MMEO as solid dispersed nanoparticles and determine their physicochemical properties and inhibitory activities. XRD (X-ray diffraction) analysis showed that the crystalline particles of the pure compound MMEO was smaller than MMEO nanoparticles. Image J software showed that at concentrations of 25 mg/mL and 50 mg/mL, the average nanoparticle sizes were 852.26 nm and 178.65 nm, respectively. Therefore, the MMEO solid dispersion system with the PEG 4000 polymer increases the solubility of MMEO. The higher the concentration of PEG 4000 the greater the solubility of MMEO. Treating pancreatic cancer cell lines with MMEO silenced the smoothened function by downregulating mRNA Ptch expression. This study suggests that MMEO may inhibit pancreatic cancer disease.


Assuntos
Antineoplásicos , Nanopartículas , Neoplasias Pancreáticas , Antineoplásicos/farmacologia , Proteínas Hedgehog , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Solubilidade , Difração de Raios X
10.
ACS Biomater Sci Eng ; 7(9): 4439-4445, 2021 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-34351746

RESUMO

Phosphorylcholine (PC) has been used to improve the water solubility and biocompatibility of biomaterials. Here, we show that PC can also work as a ligand for targeting cancer cells based on their increased phospholipid metabolism. PC-installed multiarm poly(ethylene glycol)s and polymeric micelles achieved high and rapid internalization in pancreatic cancer cells. This enhanced cellular uptake was drastically reduced when the cells were incubated with excess free PC or at 4 °C, as well as by inhibiting the phospholipid transfer protein (PLTP) on the surface of cancer cells, indicating an energy dependent active transport mediated by PLTP.


Assuntos
Neoplasias Pancreáticas , Fosforilcolina , Humanos , Micelas , Neoplasias Pancreáticas/tratamento farmacológico , Proteínas de Transferência de Fosfolipídeos , Polietilenoglicóis
11.
Free Radic Biol Med ; 174: 202-210, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34364982

RESUMO

The intrinsic chemoresistance of pancreatic ductal adenocarcinoma (PDAC) represents the main obstacle in treating this aggressive malignancy. It has been observed that high antioxidant levels and upregulated Nrf2 and the YAP protein expression can be involved in PDAC chemoresistance. The mechanisms of Nrf2 and YAP increase need to be clarified. We chose a panel of PDAC cell lines with diverse sensitivity to cisplatin and gemcitabine. In PANC-1 chemoresistant cells, we found a low level of oxidative stress and high levels of Nrf2 and YAP protein expressions and their respective targets. On the contrary, in CFPAC-1 chemosensitive cells, we found high levels of oxidative stress and low level of these two proteins, as well as their respective targets. In MiaPaCa-2 cells with a middle chemoresistance, we observed intermediate features. When Nrf2 and YAP were inhibited in PANC-1 cells by Ailanthone, a plant extract, we observed a reduction of viability, thus sustaining the role of these two proteins in maintaining the PDAC chemoresistance. We then delved into the mechanisms of the Nrf2 and YAP protein upregulation in chemoresistance, discovering that it was at a post-translational level since the mRNA expressions did not match the protein levels. Treatments of PANC-1 cells with the proteasome inhibitor MG-132 and the protein synthesis inhibitor cycloheximide further confirmed this observation. The expression of DUB3 and OTUD1 deubiquitinases, involved in the control of Nrf2 and YAP protein level, respectively, was also investigated. Both protein expressions were higher in PANC-1 cells, intermediate in MiaPaCa-2 cells, and lower in CFPAC-1 cells. When DUB3 or OTUD1 were silenced, both Nrf2 and YAP expressions were downregulated. Importantly, in deubiquitinase-silenced cells, we observed a great reduction of proliferation and a higher sensitivity to gemcitabine treatment, suggesting that DUB3 and OTUD1 can represent a suitable target to overcome chemoresistance in PDAC cells.


Assuntos
Fator 2 Relacionado a NF-E2 , Neoplasias Pancreáticas , Linhagem Celular Tumoral , Enzimas Desubiquitinantes , Regulação para Baixo , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Proteases Específicas de Ubiquitina
12.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360896

RESUMO

Despite the improved overall survival rates in most cancers, pancreatic cancer remains one of the deadliest cancers in this decade. The rigid microenvironment, which majorly comprises cancer-associated fibroblasts (CAFs), plays an important role in the obstruction of pancreatic cancer therapy. To overcome this predicament, the signaling of receptor tyrosine kinases (RTKs) and TGF beta receptor (TGFßR) in both pancreatic cancer cell and supporting CAF should be considered as the therapeutic target. The activation of receptors has been reported to be aberrant to cell cycle regulation, and signal transduction pathways, such as growth-factor induced proliferation, and can also influence the apoptotic sensitivity of tumor cells. In this article, the regulation of RTKs/TGFßR between pancreatic ductal adenocarcinoma (PDAC) and CAFs, as well as the RTKs/TGFßR inhibitor-based clinical trials on pancreatic cancer are reviewed.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Fibroblastos Associados a Câncer/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Neoplasias Pancreáticas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacos
13.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360829

RESUMO

Pancreatic cancer (PC), one of the most lethal solid tumors in humans, has a five-year survival rate of only 4%. Surgical treatment is the only accepted therapy with curative intent because the vast majority of these tumors are chemoresistant. Unfortunately, due to the aggressive nature of these tumors, fewer than 20% are resectable when the first symptoms occur. Novel therapies are required to overcome all these therapeutic issues, and the development of active nanocarriers represents an exciting opportunity to improve PC outcomes. The present review focuses on recent advances in the field of nanotechnology with application in PC treatment.


Assuntos
Nanopartículas/uso terapêutico , Nanotecnologia/métodos , Neoplasias Pancreáticas , Animais , Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Humanos , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/tratamento farmacológico
14.
J Transl Med ; 19(1): 373, 2021 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-34461940

RESUMO

BACKGROUND: Pancreatic cancer is one of the most serious digestive malignancies. At present, there is an extreme lack of effective strategies in clinical treatment. The purpose of this study is to identify key genes and pathways in the development of pancreatic cancer and provide targets for the treatment of pancreatic cancer. METHODS: GSE15471 and GSE62165 were used to screen differentially expressed genes by GEO2R tool. Hub genes prognostic potential assessed using the GEPIA and Kaplan-Meier plotter databases. The drug susceptibility data of pan-cancer cell lines is provided by The Genomics of Drug Sensitivity in Cancer Project (GDSC). Finally, the effects of PI3K-Akt signaling pathway inhibitors on cell viability of pancreatic cancer cells were detected by cell proliferation and invasion assays. RESULTS: A total of 609 differentially expressed genes were screened and enriched in the focal adhesion, phagosome and PI3K-Akt signaling pathway. Of the 15 hub genes we found, four were primarily associated with the PI3K-Akt signaling pathway, including COL3A1, EGF, FN1 and ITGA2. GDSC analysis showed that mTOR inhibitors are very sensitive to pancreatic cancer cells with mutations in EWSR1.FLI1 and RNF43. Cell proliferation and invasion results showed that mTOR inhibitors (GSK2126458) can inhibit the proliferation of pancreatic cancer cells. CONCLUSIONS: This study suggested that the PI3K-Akt signaling pathway may be a key pathway for pancreatic cancer, our study uncovered the potential therapeutic potential of GSK2126458, a specific mTOR inhibitor, for pancreatic cancer.


Assuntos
Biologia Computacional , Neoplasias Pancreáticas , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Fosfatidilinositol 3-Quinases , Piridazinas , Quinolinas , Sulfonamidas
15.
Gan To Kagaku Ryoho ; 48(8): 1061-1063, 2021 Aug.
Artigo em Japonês | MEDLINE | ID: mdl-34404077

RESUMO

A 70s woman with pancreatic metastases of HER2-negative breast cancer was being treated with bevacizumab plus paclitaxel. Tumor markers decreased after treatment initiation. After 8 months of treatment, the patient developed abdominal pain and distention, along with loss of appetite. Contrast-enhanced abdominal CT scan images showed the presence of a large 25 cm pseudopancreatic cyst and disappearance of the pancreatic metastatic lesions. Endoscopic ultrasound-guided cystogastrostomy was performed and an AXIOS stent was placed in the lower part of the gastric body. Subsequently, the cyst disappeared and her abdominal symptoms improved. The patient was able to resume treatment with other drugs and did not experience any recurrence of pancreatitis. Four months later, the AXIOS stent was removed. Bevacizumab plus paclitaxel is reportedly effective against HER2-negative metastatic breast cancer. Bevacizumab is a molecular targeted therapy against vascular endothelial growth factor, and the mechanism of its antitumor effect and complications are different from those of conventional drugs. Paclitaxel has also been reported to cause pancreatitis in rare cases. In this case, the mechanism of response to bevacizumab plus paclitaxel for metastatic pancreatic lesions or the development of drug-induced pancreatitis was considered to be the cause of pseudopancreatic cyst formation.


Assuntos
Neoplasias da Mama , Cistos , Neoplasias Pancreáticas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Feminino , Humanos , Metástase Neoplásica , Recidiva Local de Neoplasia/tratamento farmacológico , Paclitaxel/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/cirurgia , Fator A de Crescimento do Endotélio Vascular
16.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 50(3): 375-382, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34402250

RESUMO

To investigate whether chemotherapy could prolong the postoperative survival time in patients with early stages pancreatic ductal adenocarcinoma (PDAC). A total of 5280 stage ⅠA -ⅡB PDAC patients diagnosed from 2010 to 2015 were selected from surveillance,epidemiology,and end results (SEER) database. Propensity score matching (PSM) analysis was adopted to reduce the baseline differences between the groups. Univariate survival analysis was conducted with the Kaplan-Meier method. Multivariate survival analysis was performed with the Cox proportional hazards model. Univariate and multivariate survival analyses showed that age, differentiation, stage, chemotherapy were independent risk factors for the survival of PDAC patients. After PSM, it is found that adjuvant chemotherapy could prolong the median overall survival time (mOS) for stage ⅠB, ⅡA and ⅡB patients. However, for stage ⅠA patients, there were no significant differences in 3-year survival rate and mOS between patients with chemotherapy (=283) and without chemotherapy (=229) (57.4% vs 55.6%, vs all >0.05). Further analyses show that among 101 patients with well differentiated PDAC and 294 patients with moderately differentiated PDAC, there were no significant differences in survival rate and mOS between patients with and without chemotherapy (all >0.05). Among 117 patients with low-differentiated + undifferentiated PDAC, 3-year survival rate and mOS in patients with chemotherapy were significantly better than those without chemotherapy (48.5% vs 34.1%, vs all <0.05). Chemotherapy regimen used currently is not beneficial for patients with moderately and well differentiated stage ⅠA PDAC, but it is an independent prognostic factor for low-differentiated + undifferentiated PDAC patients.


Assuntos
Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Adenocarcinoma/patologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/cirurgia , Quimioterapia Adjuvante , Humanos , Estadiamento de Neoplasias , Neoplasias Pancreáticas/tratamento farmacológico , Prognóstico , Pontuação de Propensão
17.
J Transl Med ; 19(1): 301, 2021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-34247626

RESUMO

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with molecular heterogeneity, inducing differences in biological behavior, and therapeutic strategy. NGS profiles of pathogenic alterations in the Chinese PDAC population are limited. We conducted a retrospective study to investigate the predictive role of DNA damage repair (DDR) mutations in precision medicine. METHODS: The NGS profiles were performed on resected tissues from 195 Chinese PDAC patients. Baseline clinical or genetic characteristics and survival status were collected. The Kaplan-Meier survival analyses were performed by the R version 3.6.1. RESULTS: The main driver genes were KRAS, TP53, CDKN2A, and SMAD4. Advanced patients with KRAS mutation showed a worse OS than KRAS wild-type (p = 0.048). DDR pathogenic deficiency was identified in 30 (15.38%) of overall patients, mainly involving BRCA2 (n = 9, 4.62%), ATM (n = 8, 4.10%) and RAD50 genes (n = 3, 1.54%). No significance of OS between patients with or without DDR mutations (p = 0.88). But DDR mutation was an independent prognostic factor for survival analysis of advanced PDAC patients (p = 0.032). For DDR mutant patients, treatment with platinum-based chemotherapy (p = 0.0096) or olaparib (p = 0.018) respectively improved the overall survival. No statistical difference between tumor mutation burden (TMB) and DDR mutations was identified. Treatment of PD-1 blockades did not bring significantly improved OS to DDR-mutated patients than the naive DDR group (p = 0.14). CONCLUSIONS: In this retrospective study, we showed the role of germline and somatic DDR mutation in predicting the efficacy of olaparib and platinum-based chemotherapy in Chinese patients. However, the value of DDR mutation in the prediction of hypermutation status and the sensitivity to the PD-1 blockade needed further investigation.


Assuntos
Adenocarcinoma , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , China , Dano ao DNA/genética , Células Germinativas , Humanos , Mutação/genética , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Estudos Retrospectivos
18.
J R Soc Interface ; 18(180): 20210266, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34229458

RESUMO

Pulsed high-intensity focused ultrasound (pHIFU) uses acoustic pressure to physically disrupt tumours. The aim of this study was to investigate whether pHIFU can be used in combination with immune checkpoint inhibitors (ICIs) to enhance survival of tumour-bearing animals. Murine orthotopic pancreatic KPC tumours were exposed both to a grid of pHIFU lesions (peak negative pressure = 17 MPa, frequency = 1.5 MHz, duty cycle = 1%, 1 pulse s-1, duration = 25 s) and to anti-CTLA-4/anti-PD-1 antibodies. Acoustic cavitation was detected using a weakly focused passive sensor. Tumour dimensions were measured with B-mode ultrasound before treatment and with callipers post-mortem. Immune cell subtypes were quantified with immunohistochemistry and flow cytometry. pHIFU treatment of pancreatic tumours resulted in detectable acoustic cavitation and increased infiltration of CD8+ T cells in the tumours of pHIFU and pHIFU + ICI-treated subjects compared with sham-exposed subjects. Survival of subjects treated with pHIFU + ICI was extended relative to both control untreated subjects and those treated with either pHIFU or ICI alone. Subjects treated with pHIFU + ICI had increased levels of CD8+IFNγ+ T cells, increased ratios of CD8+IFNγ+ to CD3+CD4+FoxP3+ and CD11b+Ly6G+ cells, and decreased CD11chigh cells in their tumours compared with controls. These results provide evidence that pHIFU combined with ICI may have potential for use in pancreatic cancer therapy.


Assuntos
Ablação por Ultrassom Focalizado de Alta Intensidade , Neoplasias Pancreáticas , Animais , Linfócitos T CD8-Positivos , Humanos , Inibidores de Checkpoint Imunológico , Camundongos , Pâncreas , Neoplasias Pancreáticas/tratamento farmacológico
19.
Biomater Sci ; 9(16): 5599-5611, 2021 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-34250995

RESUMO

Pancreatic carcinoma elevates quickly and thus has a high mortality rate. Therefore, early treatment is essential for treating pancreatic carcinoma. KRAS is the most frequently identified and one of the earliest mutations in pancreatic tumorigenesis. Thus, the KRAS-mutant cell is an ideal target for the treatment of pancreatic carcinoma, especially at the early stage. KRAS mutation increases macropinocytosis in pancreatic cancer cells, enhancing the internalization of exosomes. Because acquiring natural exosomes could be laborious and their encapsulation efficiency is often unsatisfactory, we aimed to develop a delivery system that mimics the Kras-mutant cell targeting capability of exosomes but is easier to generate and has better loading efficiency. For this purpose, we constructed a hybrid nanoplatform by fusing CLT (Celastrol)-Loaded PEGylated lipids with the DC2.4 cell membrane (M-LIP-CLT) to achieve targeted treatment of Kras-mutant pancreatic cancer. This hybrid nanoplatform improved CLT tumor accumulation and showed excellent anti-cancer efficiency both in vitro and in vivo with increased safety. These results suggest that M-LIP-CLT is an effective drug delivery system for targeted therapy against pancreatic carcinoma, and the fusion strategy showed attractive potential for further development.


Assuntos
Exossomos , Neoplasias Pancreáticas , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Exossomos/genética , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogênicas p21(ras)/genética
20.
Acta Oncol ; 60(9): 1114-1121, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34197269

RESUMO

BACKGROUND: Neoadjuvant treatment (NAT) is debated for borderline resectable pancreatic cancer (BRPC). This retrospective study assessed the impact of NAT on R0 rate and survival for BRPC patients in comparison with upfront surgery (US). MATERIAL AND METHODS: Between 2010 and 2017 patient records for all consecutive patients treated for BRPC according to NCCN 2017 were reviewed. The endpoints analysed were R0 rate, recurrence-free-survival (RFS) and overall survival (OS). RESULTS: Seventy-nine patients were included: 63 (79.7%) patients received NAT and 16 (20.3%) were upfront operated. NAT consisted in FOLFIRINOX (median cycles: 5, range 4-8) followed by chemoradiation (n = 55, 87.3%, median dose: 54 Gy). Thirty-nine (61.9%) patients had resection. R0 rate was higher in the NAT group considering a margin clearance of 0 mm (94.9%) or 1 mm (89.7%) compared to the US group (68.8% and 43.8% respectively). In the whole population, median RFS was 12.6 [95%CI: 10.5-22.1] in the NAT group vs 7.7 [95%CI: 4.4-14] months in the US group (p < 0.01). Median OS was 29.0 [95%CI: 23.5-63.1] and 27.2 [95%CI: 11.6-38.8] months in the NAT and US groups respectively (p = 0.06). In operated patients the NAT group achieved better RFS and OS than the US group (p < 0.01 for both). In multivariate analysis NAT, surgical resection and age <65 (p < 0.01 for both) were prognostic of RFS. NAT, surgical resection and adjuvant chemotherapy were prognostic of OS (p < 0.05 for all). In operated patients (n = 55) multivariate analysis showed that N1 status was associated with decreased RFS; age < 65 and NAT were associated with a longer RFS. Receiving a NAT, an adjuvant chemotherapy and achieving a ypT0-1N0 status were associated with better OS. NAT was well tolerated with 14.3% grade ≥ 3 toxicities. CONCLUSION: NAT permitted a high R0 rate with a 0- or 1-mm clearance margin and was associated with better RFS and OS for patients with BRPC.


Assuntos
Adenocarcinoma , Neoplasias Pancreáticas , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/cirurgia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Humanos , Terapia Neoadjuvante , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/cirurgia , Estudos Retrospectivos
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