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1.
Phys Rev Lett ; 125(12): 128103, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-33016731

RESUMO

While many cellular mechanisms leading to chemotherapeutic resistance have been identified, there is an increasing realization that tumor-stroma interactions also play an important role. In particular, mechanical alterations are inherent to solid cancer progression and profoundly impact cell physiology. Here, we explore the influence of compressive stress on the efficacy of chemotherapeutics in pancreatic cancer spheroids. We find that increased compressive stress leads to decreased drug efficacy. Theoretical modeling and experiments suggest that mechanical stress decreases cell proliferation which in turn reduces the efficacy of chemotherapeutics that target proliferating cells. Our work highlights a mechanical form of drug resistance and suggests new strategies for therapy.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Modelos Biológicos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Humanos , Estresse Mecânico
2.
Anticancer Res ; 40(9): 5181-5189, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878806

RESUMO

BACKGROUND/AIM: Mathematical models have long been considered as important tools in cancer biology and therapy. Herein, we present an advanced non-linear mathematical model that can predict accurately the effect of an anticancer agent on the growth of a solid tumor. MATERIALS AND METHODS: Advanced non-linear mathematical optimization techniques and human-to-mouse experimental data were used to develop a tumor growth inhibition (TGI) estimation model. RESULTS: Using this mathematical model, we could accurately predict the tumor mass in a human-to-mouse pancreatic ductal adenocarcinoma (PDAC) xenograft under gemcitabine treatment up to five time periods (points) ahead of the last treatment. CONCLUSION: The ability of the identified TGI dynamic model to perform satisfactory short-term predictions of the tumor growth for up to five time periods ahead was investigated, evaluated and validated for the first time. Such a prediction model could not only assist the pre-clinical testing of putative anticancer agents, but also the early modification of a chemotherapy schedule towards increased efficacy.


Assuntos
Antineoplásicos/farmacologia , Modelos Teóricos , Dinâmica não Linear , Ensaios Antitumorais Modelo de Xenoenxerto , Algoritmos , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Camundongos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia
3.
Anticancer Res ; 40(10): 5765-5776, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988904

RESUMO

BACKGROUND/AIM: We evaluated the safety, feasibility, and preliminary efficacy of Wilms tumor gene 1 (WT1) peptide and Mucin 1 (MUC1)-pulsed dendritic cell (DC) (WT1/MUC1-DC) vaccination as an adjuvant immunotherapy for surgically resectable pancreatic ductal adenocarcinoma (PDA) patients. PATIENTS AND METHODS: Eligible patients were administered WT1/MUC1-DC vaccination at least seven times every 2 weeks with concomitant adjuvant chemotherapy after surgical resection of PDA. RESULTS: Ten patients were enrolled and no Grade 2 or higher toxicities were associated with DC vaccination. The estimated overall survival (OS) and relapse-free survival (RFS) at 3-years from the time of surgical resection were 77.8% and 35.0%, respectively. Immunohistochemical analysis suggested a possible relationship between induction of WT1-specific cytotoxic T lymphocyte after DC vaccination and higher infiltration of CD3/CD4/CD8 lymphocytes in tumor tissues. CONCLUSION: WT1/MUC1-DC vaccination in the adjuvant setting was safe and well-tolerated in PDA patients after tumor resection. A large-scale prospective study is warranted to evaluate the clinical benefit of this modality.


Assuntos
Adenocarcinoma/tratamento farmacológico , Carcinoma Ductal Pancreático/tratamento farmacológico , Mucina-1/genética , Proteínas WT1/genética , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Idoso , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/imunologia , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/cirurgia , Quimioterapia Adjuvante/métodos , Células Dendríticas/imunologia , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Intervalo Livre de Doença , Feminino , Humanos , Imunoterapia/métodos , Masculino , Pessoa de Meia-Idade , Mucina-1/uso terapêutico , Proteínas WT1/uso terapêutico
4.
Nat Commun ; 11(1): 4516, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32908137

RESUMO

Acinar metaplasia is an initial step in a series of events that can lead to pancreatic cancer. Here we perform single-cell RNA-sequencing of mouse pancreas during the progression from preinvasive stages to tumor formation. Using a reporter gene, we identify metaplastic cells that originated from acinar cells and express two transcription factors, Onecut2 and Foxq1. Further analyses of metaplastic acinar cell heterogeneity define six acinar metaplastic cell types and states, including stomach-specific cell types. Localization of metaplastic cell types and mixture of different metaplastic cell types in the same pre-malignant lesion is shown. Finally, single-cell transcriptome analyses of tumor-associated stromal, immune, endothelial and fibroblast cells identify signals that may support tumor development, as well as the recruitment and education of immune cells. Our findings are consistent with the early, premalignant formation of an immunosuppressive environment mediated by interactions between acinar metaplastic cells and other cells in the microenvironment.


Assuntos
Células Acinares/patologia , Carcinoma Ductal Pancreático/genética , Regulação Neoplásica da Expressão Gênica , Pâncreas/patologia , Neoplasias Pancreáticas/genética , Lesões Pré-Cancerosas/genética , Animais , Animais Geneticamente Modificados , Biópsia , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/cirurgia , Diferenciação Celular , Modelos Animais de Doenças , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Heterogeneidade Genética , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Estimativa de Kaplan-Meier , Masculino , Metaplasia/genética , Camundongos , Mutação , Pâncreas/citologia , Pâncreas/cirurgia , Pancreatectomia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Lesões Pré-Cancerosas/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , RNA-Seq , Análise de Célula Única , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Microambiente Tumoral/genética
5.
Medicine (Baltimore) ; 99(37): e22115, 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32925757

RESUMO

Pancreatectomy for pancreatic cancer with arterial invasion is controversial and performed infrequently. As its indication evolves and neoadjuvant chemotherapy also evolves, it is meaningful to identify short- and long-term outcomes of pancreatectomy with arterial resection (AR). This study aimed to retrospectively analyze the clinical outcomes of pancreatectomy with AR for pancreatic ductal adenocarcinoma.Patients with pancreatic ductal adenocarcinoma treated with pancreatectomy with AR at our institute between January 2000 and April 2017 were retrospectively reviewed. Operative outcome and survival were compared according to the presence of neoadjuvant chemotherapy.This study included 109 patients (38 underwent surgery after neoadjuvant chemotherapy, 71 underwent upfront surgery). The median hospital stay was 17 (interquartile range, 12-26.5) days. Clinically relevant postoperative pancreatic fistula (grade B or C) occurred in 14 patients (12.8%). The major morbidity (≥grade III) and mortality rates were 26.6% and 0.9%, respectively. R0 resection was achieved in 80 patients (73.4%). Microscopic actual tumor invasion into the arterial wall was identified in 25 patients (22.9%). The median overall survival (OS) of all patients was 18.4 months. The neoadjuvant chemotherapy group showed better OS than the upfront surgery group, without statistical significance (25.3 vs 16.2 months, P = .06). Progression-free survival was better in patients with neoadjuvant chemotherapy (13.2 vs 7.1 months, P = .01). Patients with partial response to neoadjuvant chemotherapy showed better OS than those with stable disease (33.7 vs 17.5 months, P = .04).Pancreatectomy with AR for advanced pancreatic cancer showed acceptable procedure-related morbidity and mortality. A survival benefit of neoadjuvant chemotherapy was identified, compared to upfront surgery.


Assuntos
Carcinoma Ductal Pancreático/cirurgia , Artéria Celíaca/cirurgia , Artéria Hepática/cirurgia , Artéria Mesentérica Superior/cirurgia , Pancreatectomia , Neoplasias Pancreáticas/cirurgia , Idoso , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Feminino , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Estudos Retrospectivos , Taxa de Sobrevida
6.
AAPS PharmSciTech ; 21(6): 231, 2020 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-32778980

RESUMO

The classically used nontargeted chemotherapeutic approach to pancreatic cancer has a dual drawback of suboptimal drug delivery at the target site and the systemic side effects produced by the unfettered exposure of the drug to healthy tissue. This study has the objective of developing novel poly(2-ethyl-2-oxazoline) (PETOX)-based long circulating liposomes loaded with gemcitabine and irinotecan for the treatment of pancreatic ductal adenocarcinoma, with a juxtaposition to PEGylated and uncoated liposomes. A PETOX-cholesteryl chloroformate lipopolymer conjugate (PETOX-ChC) with a carbonate linkage was prepared and characterized by 1H NMR, FTIR, and DSC. Liposomes were prepared using the thin film hydration technique followed by freeze-thaw and membrane extrusion methods. Liposome characterization includes particle size determination, zeta potential determination using a zetameter, and structural elucidation using 31P NMR and cryo-TEM. The PETOXylated liposomes showed a particle size of 180.1 ± 2.2 nm and a zeta potential of - 33.63 ± 1.23 mV. The liposomal combination therapy of gemcitabine and irinotecan was found to have an IC50 value 39 times lower in comparison to the drug combination in solution, while the PEGylated and PETOXylated liposomes showed IC50 values 1.6 times lower and 2 times lower than that of uncoated liposomes, respectively, against Mia PaCa II pancreatic cancer cell line. The PEGylated and PETOXylated liposomes showed 4.1 and 5.4 times slower macrophagial uptake in vitro in comparison to the uncoated liposomes respectively. The PEGylated liposomes showed 11% higher in vitro macrophagial uptake in comparison to PETOXylated liposomes.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Ductal Pancreático/tratamento farmacológico , Desoxicitidina/análogos & derivados , Irinotecano/administração & dosagem , Lipossomos , Neoplasias Pancreáticas/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Desoxicitidina/administração & dosagem , Sistemas de Liberação de Medicamentos , Humanos , Neoplasias Pancreáticas/patologia , Tamanho da Partícula , Polietilenoglicóis/química
7.
Nat Commun ; 11(1): 3409, 2020 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-32641778

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is associated with high mortality and therapy resistance. Here, we show that low expression of κB-Ras GTPases is frequently detected in PDAC and correlates with higher histologic grade. In a model of KRasG12D-driven PDAC, loss of κB-Ras accelerates tumour development and shortens median survival. κB-Ras deficiency promotes acinar-to-ductal metaplasia (ADM) during tumour initiation as well as tumour progression through intrinsic effects on proliferation and invasion. κB-Ras proteins are also required for acinar regeneration after pancreatitis, demonstrating a general role in control of plasticity. Molecularly, upregulation of Ral GTPase activity and Sox9 expression underlies the observed phenotypes, identifying a previously unrecognized function of Ral signalling in ADM. Our results provide evidence for a tumour suppressive role of κB-Ras proteins and highlight low κB-Ras levels and consequent loss of Ral control as risk factors, thus emphasizing the necessity for therapeutic options that allow interference with Ral-driven signalling.


Assuntos
Células Acinares/metabolismo , Carcinoma Ductal Pancreático/genética , GTP Fosfo-Hidrolases/genética , Neoplasias Pancreáticas/genética , Pancreatite/genética , Proteínas/genética , Células Acinares/patologia , Idoso , Animais , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Feminino , GTP Fosfo-Hidrolases/metabolismo , Regulação da Expressão Gênica , Humanos , Proteínas I-kappa B/genética , Proteínas I-kappa B/metabolismo , Estimativa de Kaplan-Meier , Masculino , Metaplasia/genética , Metaplasia/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Pancreatite/metabolismo , Proteínas/metabolismo , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismo , Proteínas ral de Ligação ao GTP/genética , Proteínas ral de Ligação ao GTP/metabolismo , Proteínas ras/genética , Proteínas ras/metabolismo
8.
Ann Surg ; 272(2): 357-365, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32675550

RESUMO

OBJECTIVE: Our aim was to evaluate recurrence patterns of surgically resected PDAC patients with negative (pN0) or positive (pN1) lymph nodes. SUMMARY BACKGROUND DATA: Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second leading cause of cancer death by 2030. This is mostly due to early local and distant metastasis, even after surgical resection. Knowledge about patterns of recurrence in different patient populations could offer new therapeutic avenues. METHODS: Clinicopathologic data were collected for 546 patients who underwent resection of their PDAC between 2005 and 2016 from 2 tertiary university centers. Patients were divided into an upfront resection group (n = 394) and a neoadjuvant group (n = 152). RESULTS: Tumor recurrence was significantly less common in pN0 patients as compared with pN1 patients, (upfront surgery: 55% vs. 77%, P < 0.001 and 64% vs. 78%, P = 0.040 in the neoadjuvant group). In addition, time to recurrence was significantly longer in pN0 versus pN1 patients in the upfront resected patients (median 16 mo pN0 vs. 10 mo pN1 P < 0.001), and the neoadjuvant group (pN0 21 mo vs. 11 mo pN1, P < 0.001). Of the patients who recurred, 62% presented with distant metastases (63% of pN0 and 62% of pN1, P = 0.553), 24% with local disease (27% of pN0 and 23% of pN1, P = 0.672) and 14% with synchronous local and distant disease (10% of pN0 and 15% of pN1, P = 0.292). Similarly, there was no difference in recurrence patterns between pN0 and pN1 in the neoadjuvant group, in which 68% recurred with distant metastases (76% of pN0 and 64% of pN1, P = 0.326) and 18% recurred with local disease (pN0: 22% and pN1: 15%, P = 0.435). CONCLUSION: Time to recurrence was significantly longer for pN0 patients. However, patterns of recurrence for pN0 vs. pN1 patients were identical. Lymph node status was predictive of time to recurrence, but not location of recurrence.


Assuntos
Carcinoma Ductal Pancreático/patologia , Causas de Morte , Linfonodos/patologia , Recidiva Local de Neoplasia/patologia , Neoplasias Pancreáticas/patologia , Idoso , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/cirurgia , Estudos de Coortes , Bases de Dados Factuais , Intervalo Livre de Doença , Feminino , Alemanha , Humanos , Linfonodos/cirurgia , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/cirurgia , Prognóstico , Pontuação de Propensão , Estudos Retrospectivos , Medição de Risco , Análise de Sobrevida , Resultado do Tratamento , Estados Unidos
9.
PLoS One ; 15(7): e0235904, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32663208

RESUMO

Pancreatic ductal adenocarcinoma is one of the most aggressive types of cancer. Certain proteins in the tumor microenvironment have attracted considerable attention owing to their association with tumor invasion and metastasis. Here, we used proteomics to identify proteins associated with lymph-node metastasis, which is one of the prognostic factors. We selected lymph node metastasis-positive and -negative patients (n = 5 each) who underwent pancreatectomy between 2005 and 2015 and subjected to comprehensive proteomic profiling of tumor stroma. A total of 490 proteins were detected by mass spectrometry. Software analysis revealed that nine of these proteins were differentially expressed between the two patient groups. We focused on hemopexin and ferritin light chain based on immunohistochemistry results. We assessed the clinicopathological data of 163 patients and found that hemopexin expression was associated with UICC N2 (p = 0.0399), lymph node ratio (p = 0.0252), venous invasion (p = 0.0096), and lymphatic invasion (p = 0.0232). Notably, in vitro assays showed that hemopexin promotes invasion of the pancreatic cancer cells. Our findings suggest that hemopexin is a lymph node metastasis-associated protein that could potentially serve as a useful therapeutic target or biomarker of pancreatic ductal adenocarcinoma.


Assuntos
Carcinoma Ductal Pancreático/patologia , Hemopexina/metabolismo , Neoplasias Pancreáticas/patologia , Idoso , Apoferritinas/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Imuno-Histoquímica , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias Pancreáticas/metabolismo , Prognóstico , Proteoma/análise , Proteômica/métodos , Espectrometria de Massas em Tandem
10.
Anticancer Res ; 40(8): 4401-4404, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32727769

RESUMO

BACKGROUND: The occurrence of lung adenocarcinoma metastasizing to the pancreas is overall rare and can histologically imitate primary pancreatic ductal carcinoma (PDAC). CASE REPORT: This is a case report of a 70-year-old female with a history of surgically resected right lung adenocarcinoma presenting for routine follow up without symptoms. CT scans revealed a pancreatic cystic mass with ductal dilatation that was sampled via endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) and thought to be a primary pancreatic mucinous neoplasm with high grade dysplasia suspicious for carcinoma based on smear cytology. On repeat EUS-FNA and biopsy (FNB) with additional immunohistochemical testing for lung adenocarcinoma markers thyroid transcription factor (TTF1) and Napsin A and molecular testing, the lesion was identified as a metastasis of lung adenocarcinoma with an epidermal growth factor receptor (EGFR L858R) mutation; subsequently, the patient underwent targeted therapy that yielded an almost complete response. CONCLUSION: To the best of our knowledge, this is the first documented case in English literature of a lung adenocarcinoma metastasis to the pancreas mimicking a pancreatic primary neoplasm and highlights the potential pitfalls of EUS-FNA for the diagnosis of certain metastases to the pancreas.


Assuntos
Adenocarcinoma de Pulmão/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pancreáticas/secundário , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Idoso , Biomarcadores/metabolismo , Carcinoma Ductal Pancreático/diagnóstico por imagem , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Diagnóstico Diferencial , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Mutação , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Tomografia Computadorizada por Raios X
11.
Anticancer Res ; 40(7): 4029-4032, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620648

RESUMO

The synchronous diagnosis of two or more primary malignancies in a patient is overall rare. This is a case report of a 70-year-old female with a history of skin squamous cell carcinoma presenting with occult hematochezia. Colonoscopy and biopsy results confirmed a microsatellite stable (MMS) adenocarcinoma in the ascending colon, and subsequent computed tomography (CT) scans identified a 3.2 cm right colonic mass and a 5.0 cm mass in the pancreatic body. Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) confirmed the presence of pancreatic ductal adenocarcinoma (PDAC). The patient underwent neo-adjuvant FOLFIRINOX (folinic acid, fluorouracil, irinotecan and oxaliplatin) chemotherapy prior to the simultaneous distal pancreatectomy and right hemicolectomy for both pancreatic and colonic tumors. The pathology diagnoses included moderately differentiated pancreatic ductal carcinoma (PDAC) with histiocyte-like features (tumor stage: ypT3N1M0) and moderately differentiated colonic adenocarcinoma, intestinal type (tumor stage: ypT3N0M0). To the best of our knowledge, this is the first documented case of synchronous primary colonic adenocarcinoma and PDAC in the English literature.


Assuntos
Adenocarcinoma/diagnóstico , Carcinoma Ductal Pancreático/diagnóstico , Neoplasias do Colo/diagnóstico , Neoplasias Primárias Múltiplas/diagnóstico , Neoplasias Pancreáticas/diagnóstico , Adenocarcinoma/patologia , Idoso , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/patologia , Carcinoma de Células Escamosas , Neoplasias do Colo/patologia , Feminino , Fluoruracila/uso terapêutico , Humanos , Irinotecano/uso terapêutico , Leucovorina/uso terapêutico , Neoplasias Primárias Múltiplas/patologia , Oxaliplatina/uso terapêutico , Neoplasias Pancreáticas/patologia , Neoplasias Cutâneas
12.
PLoS One ; 15(7): e0234568, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32658932

RESUMO

INTRODUCTION: The aim of this study was to define histo-morphological stroma characteristics by analyzing stromal components, and to evaluate their impact on local and systemic tumor spread and overall survival in pancreatic ductal adenocarcinoma (PDAC). METHODS AND MATERIALS: Patients who underwent oncologic resections with curative intent for PDAC were identified from a prospectively maintained database. Histological specimens were re-evaluated for morphological stroma features as stromal fibers, fibroblast morphology, stroma matrix density, microvessel density and distribution of immune cell populations. RESULTS: A total of 108 patients were identified undergoing curative resection for PDAC in the period from 2011-2016. 33 (30.6%) patients showed parallel alignment of stroma fibers while 75 (69.4%) had randomly oriented stroma fibers. As compared to parallel alignment, random orientation of stroma fibers was associated with larger tumor size (median 3.62 cm vs. median 2.87cm, p = 0.037), nodal positive disease (76.0% vs. 54.5%, p = 0.040), higher margin positive resection rates (41.9% vs. 15.2%, p = 0.008) and a trend for higher rates of T3/4 tumors (33.3% vs. 15.2%, p = 0.064). In univariate analysis, patients with parallel alignment of stroma fibers had improved overall survival rates as compared to patients with random orientation of stroma fibers (42 months vs. 22 months, p = 0.046). The combination of random orientation of stroma fibers and low microvessel density was associated with impaired overall survival rates (16 months vs. 36 months, p = 0.019). A high CD4/CD3 ratio (16 months vs. 33 months, p = 0.040) and high stromal density of CD163 positive cells were associated with reduced overall survival (27 months vs. 34 months, p = 0.039). In multivariable analysis, the combination of random orientation of stroma fibers and low microvessel density (HR 1.592, 95%CI 1.098-2.733, p = 0.029), high CD4/CD3 ratio (HR 2.044, 95%CI 1.203-3.508, p = 0.028) and high density of CD163 positive cells (HR 1.596, 95%CI 1.367-1.968, p = 0.036) remained independent prognostic factors. CONCLUSION: Alignment of stroma fibers and microvessel density are simple histomorphological features serving as surrogate markers of local tumor progression dissemination and surgical resectability and determine prognosis in PDAC patients. High CD4/CD3 ratio and CD163 positive cell counts determine poor prognosis.


Assuntos
Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Microvasos/patologia , Células Estromais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Prognóstico , Taxa de Sobrevida
13.
Anticancer Res ; 40(6): 3109-3118, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487605

RESUMO

BACKGROUND/AIM: Pancreatic cancer is one of the deadliest forms of cancer and ranks among the leading causes of cancer-related death worldwide. The most common histological type is ductal adenocarcinoma (PDAC), accounting for approximately 95% of cases. Deregulation of protein synthesis has been found to be closely related to cancer. The rate-limiting step of translation is initiation, which is regulated by a broad range of eukaryotic translation initiation factors (eIFs). PATIENTS AND METHODS: Human PDAC samples were biochemically analyzed for the expression of various eIF subunits on the protein level (immunohistochemistry, immunoblot analyses) in 174 cases of PDAC in comparison with non-neoplastic pancreatic tissue (n=10). RESULTS: Our investigation revealed a significant down-regulation of four specific eIF subunits, namely eIF1, eIF2D, eIF3C and eIF6. Concomitantly, the protein (immunoblot) levels of eIF1, eIF2D, eIF3C and eIF6 were reduced in PDAC samples as compared with non-neoplastic pancreatic tissue. CONCLUSION: Members of the eIF family are of relevance in pancreatic tumor biology and may play a major role in translational control in PDAC. Consequently, they might be useful as potential new biomarkers and therapeutic targets in PDAC.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/genética , Fatores de Iniciação em Eucariotos/genética , Neoplasias Pancreáticas/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Regulação para Baixo , Fatores de Iniciação em Eucariotos/biossíntese , Fatores de Iniciação em Eucariotos/metabolismo , Humanos , Imuno-Histoquímica , Neoplasias Pancreáticas/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Taxa de Sobrevida , Serina-Treonina Quinases TOR/metabolismo , Análise Serial de Tecidos
15.
Tech Vasc Interv Radiol ; 23(2): 100675, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32591191

RESUMO

Several minimally invasive image guided tumor ablation techniques have been added to the treatment spectrum for locally advanced pancreatic cancer (LAPC). Irreversible electroporation (IRE) might have a significant additive value in the management of this difficult-to-treat disease. As opposed to thermal ablative techniques, IRE induces cell death by the delivery of high-voltage electrical pulses. The electrical energy disrupts the cellular membrane integrity, causes loss of cellular homeostasis and ultimately results in cell death. The extracellular matrix of connective tissue in surrounding delicate structures such as bile ducts, bowel wall, and larger blood vessels is spared. The preservation of these structures makes IRE attractive for the treatment of pancreatic cancers that are unresectable due to their anatomical location (ie, LAPC and local recurrence after surgical resection). In addition to its cytoreductive abilities, evidence is emerging on IRE's capability to induce systemic immunomodulation through active in vivo vaccination against pancreatic cancer cells. These effects in combination with immunotherapy may offer a new treatment paradigm for tumors with low immunogenic potential like pancreatic ductal adenocarcinoma (PDAC). This review discusses several practical and technical issues of IRE for LAPC: clinical evaluation, indications, patient preparations, procedural steps, imaging characteristics, clinical results, and "tricks of the trade" used to improve the safety and efficacy of the treatment. Future directions such as the combination of IRE with immunotherapy will be shortly addressed.


Assuntos
Técnicas de Ablação , Carcinoma Ductal Pancreático/cirurgia , Eletroporação , Neoplasias Pancreáticas/cirurgia , Cirurgia Assistida por Computador , Técnicas de Ablação/efeitos adversos , Carcinoma Ductal Pancreático/diagnóstico por imagem , Carcinoma Ductal Pancreático/patologia , Tomada de Decisão Clínica , Humanos , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/patologia , Seleção de Pacientes , Complicações Pós-Operatórias/etiologia , Fatores de Risco , Cirurgia Assistida por Computador/efeitos adversos , Resultado do Tratamento
16.
Tumour Biol ; 42(6): 1010428320936410, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32586207

RESUMO

Pancreatic ductal adenocarcinoma is the most common and aggressive type of pancreatic cancer, with a 5-year survival rate that is less than 10%. New biomarkers to aid in predicting the prognosis of pancreatic ductal adenocarcinoma patients are needed. Previous proteomic studies have to a great extent focused on finding proteins of value for the diagnosis of pancreatic ductal adenocarcinoma. There is a lack of studies that have profiled the serum or plasma proteome in order to discover candidates for new prognostic biomarkers. In this study, we have used ultra-performance liquid chromatography-ultra-definition mass spectrometry to analyze the serum samples of 21 pancreatic ductal adenocarcinoma patients with short or long survival. Statistical analysis discovered 31 proteins whose expression differed significantly between pancreatic ductal adenocarcinoma patients with short or long survival. Pathway analysis discovered multiple canonical pathways enriched in this data set, with several pathways having roles in inflammation and lipid metabolism. The serum proteins identified here, which include complement components and several enzymes, could be of value as candidates for new noninvasive prognostic markers.


Assuntos
Adenocarcinoma/mortalidade , Biomarcadores Tumorais/metabolismo , Proteínas Sanguíneas/metabolismo , Carcinoma Ductal Pancreático/mortalidade , Neoplasias Pancreáticas/mortalidade , Proteoma/metabolismo , Proteômica/métodos , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Idoso , Biomarcadores Tumorais/análise , Proteínas Sanguíneas/análise , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Projetos Piloto , Prognóstico , Mapas de Interação de Proteínas , Proteoma/análise , Taxa de Sobrevida
17.
Medicine (Baltimore) ; 99(25): e20564, 2020 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-32569179

RESUMO

INTRODUCTION: Surgical management is not a standard treatment option for metastatic recurrence of pancreatic adenocarcinoma. However, the surgical management of a solitary metastasis is useful in selected cases. PATIENT CONCERNS: A 42-year-old woman was referred to our hospital on account of epigastric pain associated with a mass in the pancreatic body. The patient had a family history of branch duct-type intraductal papillary mucinous neoplasm of the pancreas. DIAGNOSIS: The patient was diagnosed with pancreatic ductal adenocarcinoma (PDA) complicated with pancreatitis due to pancreatic duct involvement. INTERVENTIONS: The patient underwent distal pancreatectomy, and pathological examination revealed a tubular adenocarcinoma. Solitary liver and lung metastatic tumors were found 6 and 43 months after the initial presentation, respectively, and sequential metastasectomies were performed. OUTCOMES: The patient survived until 8 years after her initial presentation. The genetic profiles of the resected specimens, primary PDA, and recurrent tumors in the liver and lung possessed identical KRAS mutations at codon 12, whereas there were no mutations in the main tumor suppressor genes, such as TP53, CDKN2A, and SMAD4. Multiplex polymerase chain reaction-based microsatellite instability assay demonstrated microsatellite stability. CONCLUSION: In our case, the patient with pancreatic adenocarcinoma survived for over 8 years following the resection of the primary tumor and resections of metachronous metastatic tumors. The outcome of PDA may be associated with the genetic profile that regulates its biological behavior. Operative management of solitary metastatic tumors may be a therapeutic options for selected patients with pancreatic cancer.


Assuntos
Carcinoma Ductal Pancreático/cirurgia , Neoplasias Pancreáticas/cirurgia , Adulto , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Feminino , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/cirurgia , Pancreatectomia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas p21(ras)
18.
Am J Pathol ; 190(9): 1931-1942, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32526166

RESUMO

Pancreatic cancer has a dismal prognosis, and there is no targeted therapy against this malignancy. The neuronal membrane protein sortilin is emerging as a regulator of cancer cell development, but its expression and impact in pancreatic cancer are unknown. This study found that sortilin expression was higher in pancreatic cell lines versus normal pancreatic ductal epithelial cells, as shown by Western blot analysis and mass spectrometry. The increased sortilin level in pancreatic cancer cells was confirmed by immunohistochemistry in a series of 99 human pancreatic adenocarcinomas versus 48 normal pancreatic tissues (P = 0.0014). Sortilin inhibition by siRNA and the pharmacologic inhibitor AF38469 strongly reduced the adhesion and invasion of pancreatic cancer cells without affecting cell survival and viability. Sortilin inhibition also decreased the phosphorylation of the focal adhesion kinase in Tyr925. Together, these data show that sortilin contributes to pancreatic cancer invasion and could eventually be targeted in therapy.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Neoplasias Pancreáticas/patologia , Adesão Celular/fisiologia , Movimento Celular/fisiologia , Humanos , Invasividade Neoplásica/patologia , Neoplasias Pancreáticas/metabolismo
19.
J Surg Oncol ; 122(2): 234-242, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32350882

RESUMO

BACKGROUND: Robotic pancreatectomy is gaining momentum; however, limited data exist on the long-term survival of this approach for pancreatic ductal adenocarcinoma (PDAC). The objective of this study is to compare the long-term oncologic outcomes of robotic pancreaticoduodenectomy (RPD) and robotic distal pancreatectomy (RDP) to open surgery in patients with PDAC. STUDY DESIGN: Robotic and open pancreatectomy for stages I-III PDAC were obtained from the 2010 to 2016 National Cancer Database. RESULTS: We identified 17 831 pancreaticoduodenectomies and 2718 distal pancreatectomies of which 626 (4%) and 332 (12%) were robotic, respectively. There was no difference in median overall survival between RPD (22.0 months) and open pancreatoduodenectomy (21.8 months; logrank P = .755). The adjusted hazard ratio [HR] was 1.014 (95% confidence interval [CI]: 0.903-1.139). The median overall survival for RDP (35.3 months) was higher than open distal pancreatectomy (ODP) (24.9 months; logrank P = .001). The adjusted HR suggests a benefit to RDP compared to ODP (HR, 0.744; 95% CI: 0.632-0.868) CONCLUSION: In a national cohort of resected pancreatic adenocarcinoma, the robotic platform was associated with similar long-term survival for pancreaticoduodenectomy, but improved survival for distal pancreatectomy.


Assuntos
Carcinoma Ductal Pancreático/cirurgia , Neoplasias Pancreáticas/cirurgia , Idoso , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Estudos de Coortes , Feminino , Humanos , Masculino , Estadiamento de Neoplasias , Pancreatectomia/métodos , Pancreatectomia/estatística & dados numéricos , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Pancreaticoduodenectomia/métodos , Pancreaticoduodenectomia/estatística & dados numéricos , Sistema de Registros , Estudos Retrospectivos , Procedimentos Cirúrgicos Robóticos/métodos , Resultado do Tratamento , Estados Unidos/epidemiologia
20.
Nat Commun ; 11(1): 2682, 2020 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-32472071

RESUMO

Pancreatic cancer stem cells (PaCSCs) drive pancreatic cancer tumorigenesis, chemoresistance and metastasis. While eliminating this subpopulation of cells would theoretically result in tumor eradication, PaCSCs are extremely plastic and can successfully adapt to targeted therapies. In this study, we demonstrate that PaCSCs increase expression of interferon-stimulated gene 15 (ISG15) and protein ISGylation, which are essential for maintaining their metabolic plasticity. CRISPR-mediated ISG15 genomic editing reduces overall ISGylation, impairing PaCSCs self-renewal and their in vivo tumorigenic capacity. At the molecular level, ISG15 loss results in decreased mitochondrial ISGylation concomitant with increased accumulation of dysfunctional mitochondria, reduced oxidative phosphorylation (OXPHOS) and impaired mitophagy. Importantly, disruption in mitochondrial metabolism affects PaCSC metabolic plasticity, making them susceptible to prolonged inhibition with metformin in vivo. Thus, ISGylation is critical for optimal and efficient OXPHOS by ensuring the recycling of dysfunctional mitochondria, and when absent, a dysregulation in mitophagy occurs that negatively impacts PaCSC stemness.


Assuntos
Carcinoma Ductal Pancreático/patologia , Transformação Celular Neoplásica/genética , Citocinas/metabolismo , Mitofagia/genética , Células-Tronco Neoplásicas/patologia , Neoplasias Pancreáticas/patologia , Ubiquitinas/metabolismo , Linhagem Celular , Plasticidade Celular/fisiologia , Transformação Celular Neoplásica/patologia , Citocinas/genética , Humanos , Metformina/farmacologia , Mitocôndrias/genética , Mitocôndrias/metabolismo , Fosforilação Oxidativa , Neoplasias Pancreáticas/mortalidade , Edição de RNA/genética , Ubiquitinas/genética
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