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1.
Anticancer Res ; 41(9): 4229-4238, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475042

RESUMO

BACKGROUND/AIM: Pancreatic ductal adenocarcinoma (PDAC) shows poor survival and early systemic dissemination. Cancer associated fibroblasts (CAFs) enhance migration and invasion of cancer cells. We aimed to investigate the role of CAFs in cell migration and their underlying paracrine effects. MATERIALS AND METHODS: Using Transwell® migration assays, PDAC cells (PANC-1) and three distinct types of fibroblasts were analyzed: CAFs, genetically transformed human foreskin-fibroblasts (BJeLR), and non-transformed human foreskin-fibroblasts (VH7). IL6 in the culture supernatant was measured to investigate paracrine communication in monocultures and direct/indirect cocultures. RESULTS: CAFs showed a significantly higher capacity to migrate in vitro when compared to benign fibroblasts (p=0.009). They also facilitated the migration of PDAC cells in coculture (p=0.001). Neither BJeLR, nor VH7 displayed such features. This was accompanied by a significant increase in IL-6 when CAFs were cocultured with PANC-1 (p=0.009). CONCLUSION: CAFs are a key element of intra-tumoral migration and should be further investigated as a potential therapeutic target.


Assuntos
Fibroblastos Associados a Câncer/citologia , Carcinoma Ductal Pancreático/patologia , Prepúcio do Pênis/citologia , Interleucina-6/metabolismo , Neoplasias Pancreáticas/patologia , Fibroblastos Associados a Câncer/imunologia , Fibroblastos Associados a Câncer/patologia , Carcinoma Ductal Pancreático/imunologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Células Cultivadas , Técnicas de Cocultura , Feminino , Prepúcio do Pênis/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/imunologia , Comunicação Parácrina , Microambiente Tumoral
2.
Nat Commun ; 12(1): 4860, 2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34381026

RESUMO

Cancer metabolism is rewired to support cell survival in response to intrinsic and environmental stressors. Identification of strategies to target these adaptions is an area of active research. We previously described a cytosolic aspartate aminotransaminase (GOT1)-driven pathway in pancreatic cancer used to maintain redox balance. Here, we sought to identify metabolic dependencies following GOT1 inhibition to exploit this feature of pancreatic cancer and to provide additional insight into regulation of redox metabolism. Using pharmacological methods, we identify cysteine, glutathione, and lipid antioxidant function as metabolic vulnerabilities following GOT1 withdrawal. We demonstrate that targeting any of these pathways triggers ferroptosis, an oxidative, iron-dependent form of cell death, in GOT1 knockdown cells. Mechanistically, we reveal that GOT1 inhibition represses mitochondrial metabolism and promotes a catabolic state. Consequently, we find that this enhances labile iron availability through autophagy, which potentiates the activity of ferroptotic stimuli. Overall, our study identifies a biochemical connection between GOT1, iron regulation, and ferroptosis.


Assuntos
Aspartato Aminotransferase Citoplasmática/antagonistas & inibidores , Ferroptose , Neoplasias Pancreáticas/metabolismo , Animais , Antioxidantes/farmacologia , Aspartato Aminotransferase Citoplasmática/genética , Aspartato Aminotransferase Citoplasmática/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular/efeitos dos fármacos , Cistina/metabolismo , Ferroptose/efeitos dos fármacos , Glutationa/biossíntese , Humanos , Ferro/metabolismo , Camundongos , Mitocôndrias/metabolismo , Neoplasias Pancreáticas/patologia
3.
Pan Afr Med J ; 39: 18, 2021.
Artigo em Francês | MEDLINE | ID: mdl-34394809

RESUMO

Introduction: cancer is a major cause of death in the world. The purpose of this study is to evaluate the epidemiological, clinical, therapeutic and prognostic features of cancers of the pancreas (CP) at the National Hospital and University Center of Cotonou. Methods: we conducted a cross-sectional descriptive and analytical study with a prospective and retrospective data collection over a period of ten years, from 1 October 2009 to 31 October 2019. Results: out of 15.102 hospitalizations, we identified 72 cases of CP, reflecting a hospitalization rate of 0.5%. The average age of patients was 59 years. The sex-ratio (H/F) was 1.5. The main reason for consultation was abdominal pain. More than half (51.4%) of patients had metastatic tumor at the time of diagnosis. Histological evidence of adenocarcinoma was only reported in 15.1% of cases. The rate of operable patients was 37.5% while the rate of resectable patients was 2.7%. Palliative chemotherapy was given to 13.9% of patients. The average cost of treatment was 955.882,4 FCFA (23.9 times the Guaranteed Interprofessional Minimum Wage in Benin). Median overall survival was 6 months. Mortality rate was 86.9% (53/61), survival rate at one year was 31.4%, and zero at five years. Palliative surgery (p = 0.021) and chemotherapy (p = 0.023) improved patient survival. Conclusion: cancer of the pancreas, due to its non-specific signs and insidious outcome, is often diagnosed at a late stage. A metastatic tumor and the limited individual and institutional therapeutic possibilities lead to more pejorative prognosis.


Assuntos
Adenocarcinoma/epidemiologia , Hospitalização/estatística & dados numéricos , Cuidados Paliativos/métodos , Neoplasias Pancreáticas/epidemiologia , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Benin , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/terapia , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Taxa de Sobrevida
4.
Medicine (Baltimore) ; 100(29): e26737, 2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34398051

RESUMO

ABSTRACT: Cutaneous metastasis (CM) occurs infrequently and usually presents during the later stages of cancer, and has a poor prognosis. Although there are insufficient current data, cancer treatment changes could have a positive impact on the outcome. This retrospective study aimed to review the pattern and prognosis of CM in patients with solid malignancy in a tertiary cancer center in Thailand.We reviewed the medical records of cancer patients diagnosed with CM between October 2009 and August 2015 at Chulabhorn Hospital, a tertiary cancer center in Thailand. Patients with primary skin cancer and hematological malignancies were excluded. We collected and analyzed data, including the time of cancer diagnosis and CM, type of cancer, clinical characteristics, and survival outcome.Of 11,418 patients, there were 33 (0.3%) were diagnosed with CM. Breast cancer was the most common primary cancer (12 cases, 36%). Skin nodules were commonly detected on the anterior chest wall. Also, 79% of CM patients had concomitant visceral metastasis. The median overall survival of those with CM was 9.21 months (95% confidence interval 4.75-83.38 months) regardless of presentation either at onset or disease recurrence (P = .083). However, the change of management was affected in 78% diagnosed with a later stage of CM. No statistical difference in survival was observed between breast cancer and non-breast cancer patients (8.79 vs 9.21 months, P = .613).Despite CM being a sign of poor prognosis, it may still be an indicator for changing cancer patients' treatment. Hence, early CM diagnosis and prompt novel therapy may positively affect outcomes for cancer patients.


Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias Pancreáticas/epidemiologia , Neoplasias Cutâneas/epidemiologia , Adulto , Idoso , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Feminino , Humanos , Masculino , Registros Médicos , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Prognóstico , Estudos Retrospectivos , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/secundário , Análise de Sobrevida , Centros de Atenção Terciária , Tailândia/epidemiologia
6.
Theranostics ; 11(16): 7700-7714, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335959

RESUMO

CD4+ T helper cells are capable of mediating long-term antitumoral immune responses. We developed a combined immunotherapy (COMBO) using tumor antigen-specific T helper 1 cells (Tag-Th1), dual PD-L1/LAG-3 immune checkpoint blockade, and a low-dose total body irradiation (TBI) of 2 Gy, that was highly efficient in controlling the tumor burden of non-immunogenic RIP1-Tag2 mice with late-stage endogenous pancreatic islet carcinomas. In this study, we aimed to explore the impact of 2 Gy TBI on the treatment efficacy and the underlying mechanisms to boost CD4+ T cell-based immunotherapies. Methods: Heavily progressed RIP1-Tag2 mice underwent COMBO treatment and their survival was compared to a cohort without 2 Gy TBI. Positron emission tomography/computed tomography (PET/CT) with radiolabeled anti-CD3 monoclonal antibodies and flow cytometry were applied to investigate 2 Gy TBI-induced alterations in the biodistribution of endogenous T cells of healthy C3H mice. Migration and homing properties of Cy5-labeled adoptive Tag-Th1 cells were monitored by optical imaging and flow cytometric analyses in C3H and tumor-bearing RIP1-Tag2 mice. Splenectomy or sham-surgery of late-stage RIP1-Tag2 mice was performed before onset of COMBO treatment to elucidate the impact of the spleen on the therapy response. Results: First, we determined a significant longer survival of RIP1-Tag2 mice and an increased CD4+ T cell tumor infiltrate when 2 Gy TBI was applied in addition to Tag-Th1 cell PD-L1/LAG-3 treatment. In non-tumor-bearing C3H mice, TBI induced a moderate host lymphodepletion and a tumor antigen-independent accumulation of Tag-Th1 cells in lymphoid and non-lymphoid organs. In RIP1-Tag2, we found increased numbers of effector memory-like Tag-Th1 and endogenous CD4+ T cells in the pancreatic tumor tissue after TBI, accompanied by a tumor-specific Th1-driven immune response. Furthermore, the spleen negatively regulated T cell effector function by upregulation PD-1/LAG-3/TIM-3 immune checkpoints, providing a further rationale for this combined treatment approach. Conclusion: Low-dose TBI represents a powerful tool to foster CD4+ T cell-based cancer immunotherapies by favoring Th1-driven antitumoral immunity. As TBI is a clinically approved and well-established technique it might be an ideal addition for adoptive cell therapy with CD4+ T cells in the clinical setting.


Assuntos
Imunoterapia/métodos , Células Th1/metabolismo , Irradiação Corporal Total/métodos , Animais , Anticorpos Monoclonais/farmacologia , Antígenos CD/imunologia , Antígenos CD/metabolismo , Antígenos de Neoplasias , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Feminino , Imunidade/efeitos dos fármacos , Imunoterapia Adotiva/métodos , Camundongos , Camundongos Endogâmicos C3H , Imagem Óptica , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Células Th1/imunologia , Distribuição Tecidual
7.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201897

RESUMO

Intraductal papillary mucinous neoplasms (IPMN) are common and one of the main precursor lesions of pancreatic ductal adenocarcinoma (PDAC). PDAC derived from an IPMN is called intraductal papillary mucinous carcinoma (IPMC) and defines a subgroup of patients with ill-defined specificities. As compared to conventional PDAC, IPMCs have been associated to clinical particularities and favorable pathological features, as well as debated outcomes. However, IPMNs and IPMCs include distinct subtypes of precursor (gastric, pancreato-biliary, intestinal) and invasive (tubular, colloid) lesions, also associated to specific characteristics. Notably, consistent data have shown intestinal IPMNs and associated colloid carcinomas, defining the "intestinal pathway", to be associated with less aggressive features. Genomic specificities have also been uncovered, such as mutations of the GNAS gene, and recent data provide more insights into the mechanisms involved in IPMCs carcinogenesis. This review synthetizes available data on clinical-pathological features and outcomes associated with IPMCs and their subtypes. We also describe known genomic hallmarks of these lesions and summarize the latest data about molecular processes involved in IPMNs initiation and progression to IPMCs. Finally, potential implications for clinical practice and future research strategies are discussed.


Assuntos
Carcinoma Ductal Pancreático/patologia , Neoplasias Intraductais Pancreáticas/patologia , Neoplasias Pancreáticas/patologia , Animais , Carcinoma Ductal Pancreático/classificação , Carcinoma Ductal Pancreático/genética , Cromograninas/genética , Progressão da Doença , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Humanos , Camundongos , Modelos Biológicos , Mutação , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Neoplasias Intraductais Pancreáticas/classificação , Neoplasias Intraductais Pancreáticas/genética , Neoplasias Pancreáticas/classificação , Neoplasias Pancreáticas/genética , Prognóstico , Proteínas Proto-Oncogênicas p21(ras)/genética
8.
Anticancer Res ; 41(8): 4047-4052, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34281873

RESUMO

BACKGROUND/AIM: Tropomyosin-related kinase B (TrkB)/brain-derived neurotrophic factor (BDNF) signaling plays a role in inducing malignant phenotypes in several aggressive types of cancers. To create a conclusive therapy targeting TrkB/BDNF signaling in solid refractory cancers, the biological significance of TrkB/BDNF signaling was analyzed in pancreatic ductal adenocarcinoma (PDAC) cells. MATERIALS AND METHODS: Three PDAC cell lines were used as target cells to investigate proliferation and invasiveness. Small interfering RNA (siRNA) and the TrkB tyrosine kinase inhibitor k252a were used as TrkB/BDNF signaling inhibitors. RESULTS: All PDAC cell lines expressed TrkB and BDNF. When TrkB and BDNF were inhibited by siRNA or k252a, the invasiveness of PANC-1 and SUIT-2 cells significantly decreased. When TrkB was inhibited by siRNA or k252a, proliferation was significantly inhibited in PDAC cells. CONCLUSION: TrkB/BDNF signaling may be a new therapeutic target for PDAC. Therapies targeting TrkB/BDNF signaling may be a conclusive cancer therapy for refractory solid cancer.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Glicoproteínas de Membrana/metabolismo , Neoplasias Pancreáticas/metabolismo , Receptor trkB/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Carbazóis/farmacologia , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Alcaloides Indólicos/farmacologia , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/genética , Neoplasias Pancreáticas/patologia , Inibidores de Proteínas Quinases/farmacologia , Interferência de RNA , RNA Interferente Pequeno/genética , Receptor trkB/antagonistas & inibidores , Receptor trkB/genética , Transdução de Sinais/efeitos dos fármacos
9.
Int J Clin Oncol ; 26(10): 1929-1937, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34232427

RESUMO

INTRODUCTION: Osteopenia, which is defined as a decrease in bone mineral density, has been recently recognized as a metabolic and an oncological biomarker for surgery in patients with malignancy. We aimed to study the prognostic impact of osteopenia in patients with pancreatic cancer (PC) after resection. METHODS: A total of 56 patients who underwent curative resection of PC were retrospectively investigated. The skeletal muscle index at the third lumbar spine and bone mineral density at the 11th thoracic vertebra were measured using computed tomography. RESULTS: Sarcopenia and osteopenia were identified in 24 (43%) and 27 (48%) patients, respectively. The overall and disease-free survival rates were significantly lower in the sarcopenia group than in the non-sarcopenia group (p < 0.01 and p < 0.01, respectively) and in the osteopenia group than in the non-osteopenia group (p < 0.01 and p < 0.01, respectively). In multivariate analysis, sarcopenia (odds ratio [OR] 4.05; 95% confidence interval [CI] 1.23-13.38; p = 0.02) was a significant independent predictor of 1-year disease-free survival. Further, sarcopenia (OR 6.00; 95% CI 1.46-24.6; p = 0.01) and osteopenia (OR 4.66; 95% CI 1.15-18.82; p = 0.03) were significant independent predictors of 2-year overall survival. CONCLUSION: Osteopenia is a significant negative factor for 2-year overall survival after curative resection of PC.


Assuntos
Doenças Ósseas Metabólicas , Neoplasias Pancreáticas , Sarcopenia , Doenças Ósseas Metabólicas/patologia , Humanos , Músculo Esquelético/patologia , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Prognóstico , Estudos Retrospectivos , Sarcopenia/complicações , Sarcopenia/patologia
10.
Cell Death Dis ; 12(7): 693, 2021 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-34247201

RESUMO

Nuclear factor erythroid 2-related factor 2 (NRF2) is aberrantly activated in about 93% of pancreatic cancers. Activated NRF2 regulates multiple downstream molecules involved in cancer cell metabolic reprogramming, translational control, and treatment resistance; however, targeting NRF2 for pancreatic cancer therapy remains largely unexplored. In this study, we used the online computational tool CellMinerTM to explore the NCI-60 drug databases for compounds with anticancer activities correlating most closely with the mRNA expression of NQO1, a marker for NRF2 pathway activity. Among the >100,000 compounds analyzed, NSC84167, termed herein as NRF2 synthetic lethality compound-01 (NSLC01), was one of the top hits (r = 0.71, P < 0.001) and selected for functional characterization. NSLC01 selectively inhibited the viabilities of four out of seven conventional pancreatic cancer cell lines and induced dramatic apoptosis in the cells with high NRF2 activation. The selective anticancer activity of NSLC01 was further validated with a panel of nine low-passage pancreatic patient-derived cell lines, and a significant reverse correlation between log(IC50) of NSLC01 and NQO1 expression was confirmed (r = -0.5563, P = 0.024). Notably, screening of a panel of nine patient-derived xenografts (PDXs) revealed six PDXs with high NQO1/NRF2 activation, and NSLC01 dramatically inhibited the viabilities and induced apoptosis in ex vivo cultures of PDX tumors. Consistent with the ex vivo results, NSLC01 inhibited the tumor growth of two NRF2-activated PDX models in vivo (P < 0.01, n = 7-8) but had no effects on the NRF2-low counterpart. To characterize the mechanism of action, we employed a metabolomic isotope tracer assay that demonstrated that NSLC01-mediated inhibition of de novo synthesis of multiple amino acids, including asparagine and methionine. Importantly, we further found that NSLC01 suppresses the eEF2K/eEF2 translation elongation cascade and protein translation of asparagine synthetase. In summary, this study identified a novel compound that selectively targets protein translation and induces synthetic lethal effects in NRF2-activated pancreatic cancers.


Assuntos
Antineoplásicos/farmacologia , Asparagina/biossíntese , Aspartato-Amônia Ligase/metabolismo , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinase do Fator 2 de Elongação/metabolismo , Humanos , Camundongos Endogâmicos NOD , Camundongos SCID , NAD(P)H Desidrogenase (Quinona)/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Cell Death Dis ; 12(7): 705, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34262021

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is an extremely lethal cancer with limited treatment options. Cisplatin (DDP) is used as a mainstay of chemotherapeutic agents in combination with other drugs or radiotherapy for PDAC therapy. However, DDP exhibits severe side-effects that can lead to discontinuation of therapy, and the acquired drug resistance of tumor cells presents serious clinical obstacles. Therefore, it is imperative to develop a more effective and less toxic therapeutic strategy. We and others have previously discovered that dihydroartemisinin (DHA) represents a safe and promising therapeutic agent to preferentially induce cancer cell ferroptosis. In the present study, we find that DHA could intensively strengthen the cytotoxicity of DDP and significantly reduce its effective concentrations both in vitro and in vivo. Combination of DHA and DDP synergistically inhibits the proliferation and induces DNA damage of PDAC cells. Mechanically, the combinative treatment impairs mitochondrial homeostasis, characterized by destroyed mitochondrial morphology, decreased respiratory capacity, reduced ATP production, and accumulated mitochondria-derived ROS. Further studies show that ferroptosis contributes to the cytotoxic effects in PDAC cells under the challenge of DHA and DDP, together with catastrophic accumulation of free iron and unrestricted lipid peroxidation. Moreover, pharmacologic depleting of the free iron reservoir or reconstituted expression of FTH contributes to the tolerance of DHA/DDP-induced ferroptosis, while iron addition accelerates the ferroptotic cell death. In summary, these results provide experimental evidence that DHA acts synergistically with DDP and renders PDAC cells vulnerable to ferroptosis, which may act as a promising therapeutic strategy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Artemisininas/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Cisplatino/farmacologia , Ferroptose/efeitos dos fármacos , Ferro/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Trifosfato de Adenosina/metabolismo , Animais , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Dano ao DNA , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Invasividade Neoplásica , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Espécies Reativas de Oxigênio/metabolismo , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
12.
J Surg Oncol ; 124(5): 801-809, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34231222

RESUMO

INTRODUCTION: Neoadjuvant therapy (NAT) is an emerging strategy for operable pancreatic ductal adenocarcinoma (PDAC). While NAT increases multimodal therapy completion, it risks functional decline and treatment dropout. We used decision analysis to determine optimal management of localized PDAC and consider risks faced by elderly patients. METHODS: A Markov cohort decision analysis model evaluated treatment options for a 60-year-old patient with resectable PDAC: (1) upfront pancreaticoduodenectomy or (2) NAT. One-way and probabilistic sensitivity analyses were performed. A subanalysis considered the scenario of a 75-year-old patient. RESULTS: For the base case, NAT offered an incremental survival gain of 4.6 months compared with SF (overall survival: 26.3 vs. 21.7 months). In one-way sensitivity analyses, findings were sensitive to recurrence-free survival for NAT patients undergoing adjuvant, probability of completing NAT, and probability of being resectable at exploration after NAT. On probabilistic analysis, NAT was favored in a majority of trials (97%) with a median survival benefit of 5.1 months. In altering the base case for the 75-year-old scenario, NAT had a survival benefit of 3.8 months. CONCLUSIONS: This analysis demonstrates a significant benefit to NAT in patients with localized PDAC. This benefit persists even in the elderly cohort.


Assuntos
Adenocarcinoma/terapia , Carcinoma Ductal Pancreático/terapia , Técnicas de Apoio para a Decisão , Cadeias de Markov , Terapia Neoadjuvante/mortalidade , Pancreatectomia/mortalidade , Neoplasias Pancreáticas/terapia , Adenocarcinoma/patologia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/patologia , Terapia Combinada , Seguimentos , Humanos , Pessoa de Meia-Idade , Neoplasias Pancreáticas/patologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
13.
Eur J Radiol ; 142: 109834, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34252866

RESUMO

BACKGROUND: Body composition is associated with mortality; however its routine assessment is too time-consuming. PURPOSE: To demonstrate the value of artificial intelligence (AI) to extract body composition measures from routine studies, we aimed to develop a fully automated AI approach to measure fat and muscles masses, to validate its clinical discriminatory value, and to provide the code, training data and workflow solutions to facilitate its integration into local practice. METHODS: We developed a neural network that quantified the tissue components at the L3 vertebral body level using data from the Liver Tumor Challenge (LiTS) and a pancreatic cancer cohort. We classified sarcopenia using accepted skeletal muscle index cut-offs and visceral fat based its median value. We used Kaplan Meier curves and Cox regression analysis to assess the association between these measures and mortality. RESULTS: Applying the algorithm trained on LiTS data to the local cohort yielded good agreement [>0.8 intraclass correlation (ICC)]; when trained on both datasets, it had excellent agreement (>0.9 ICC). The pancreatic cancer cohort had 136 patients (mean age: 67 ± 11 years; 54% women); 15% had sarcopenia; mean visceral fat was 142 cm2. Concurrent with prior research, we found a significant association between sarcopenia and mortality [mean survival of 15 ± 12 vs. 22 ± 12 (p < 0.05), adjusted HR of 1.58 (95% CI: 1.03-3.33)] but no association between visceral fat and mortality. The detector analysis took 1 ± 0.5 s. CONCLUSIONS: AI body composition analysis can provide meaningful imaging biomarkers from routine exams demonstrating AI's ability to further enhance the clinical value of radiology reports.


Assuntos
Neoplasias Pancreáticas , Sarcopenia , Idoso , Inteligência Artificial , Composição Corporal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/patologia , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/patologia , Sarcopenia/patologia , Tomografia Computadorizada por Raios X
14.
Int J Mol Sci ; 22(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203589

RESUMO

Pancreatic ductal adenocarcinoma is one of the deadliest tumors. This neoplasia is characterized by an important cellular and phenotypic heterogeneity. In particular, it has been shown that at least two subtypes can be found: basal-like, which presents stem-like properties, and classical. Cancer stem cells have been isolated and characterized from these tumors, showing their dependance on general and tissue-specific stem transcription factors and signaling pathways. Nevertheless, little is known about their tissue microenvironment and cell non-autonomous regulators, such as long-non-coding RNAs. (lncRNAs). In this review, we summarize the current knowledge about the positive and negative effects of lncRNAs in the stemness phenotype of pancreatic ductal adenocarcinoma cancer (PDAC).


Assuntos
Adenocarcinoma/genética , Carcinoma Ductal Pancreático/genética , Células-Tronco Neoplásicas/patologia , Neoplasias Pancreáticas/genética , RNA Longo não Codificante/metabolismo , Adenocarcinoma/patologia , Animais , Carcinoma Ductal Pancreático/patologia , Humanos , Células-Tronco Neoplásicas/metabolismo , Neoplasias Pancreáticas/patologia , Fenótipo , RNA Longo não Codificante/genética
15.
Int J Mol Sci ; 22(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203923

RESUMO

Pancreatic ductal adenocarcinoma (PDAC), accounting for 90-95% of all pancreatic tumors, is a highly devastating disease associated with poor prognosis. The lack of accurate diagnostic tests and failure of conventional therapies contribute to this pejorative issue. Over the last decade, the advent of theranostics in nuclear medicine has opened great opportunities for the diagnosis and treatment of several solid tumors. Several radiotracers dedicated to PDAC imaging or internal vectorized radiotherapy have been developed and some of them are currently under clinical consideration. The functional information provided by Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) could indeed provide an additive diagnostic value and thus help in the selection of patients for targeted therapies. Moreover, the therapeutic potential of ß-- and α-emitter-radiolabeled agents could also overcome the resistance to conventional therapies. This review summarizes the current knowledge concerning the recent developments in the nuclear medicine field for the management of PDAC patients.


Assuntos
Adenocarcinoma/patologia , Carcinoma Ductal Pancreático/patologia , Medicina Nuclear , Neoplasias Pancreáticas/patologia , Adenocarcinoma/diagnóstico , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/terapia , Animais , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/diagnóstico por imagem , Carcinoma Ductal Pancreático/terapia , Diagnóstico por Imagem , Humanos , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/terapia , Compostos Radiofarmacêuticos/química
16.
Int J Mol Sci ; 22(12)2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34198548

RESUMO

Inflammation in the tumor microenvironment has been shown to promote disease progression in pancreatic ductal adenocarcinoma (PDAC); however, the role of macrophage metabolism in promoting inflammation is unclear. Using an orthotopic mouse model of PDAC, we demonstrate that macrophages from tumor-bearing mice exhibit elevated glycolysis. Macrophage-specific deletion of Glucose Transporter 1 (GLUT1) significantly reduced tumor burden, which was accompanied by increased Natural Killer and CD8+ T cell activity and suppression of the NLRP3-IL1ß inflammasome axis. Administration of mice with a GLUT1-specific inhibitor reduced tumor burden, comparable with gemcitabine, the current standard-of-care. In addition, we observe that intra-tumoral macrophages from human PDAC patients exhibit a pronounced glycolytic signature, which reliably predicts poor survival. Our data support a key role for macrophage metabolism in tumor immunity, which could be exploited to improve patient outcomes.


Assuntos
Adenocarcinoma/patologia , Carcinoma Ductal Pancreático/patologia , Citoproteção , Glicólise , Macrófagos/metabolismo , Neoplasias Pancreáticas/patologia , Adenocarcinoma/imunologia , Animais , Carcinoma Ductal Pancreático/imunologia , Proliferação de Células/efeitos dos fármacos , Citoproteção/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Transportador de Glucose Tipo 1/metabolismo , Glicólise/efeitos dos fármacos , Humanos , Hidroxibenzoatos/farmacologia , Inflamação/patologia , Interleucina-1beta/metabolismo , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Macrófagos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neoplasias Pancreáticas/imunologia , Análise de Sobrevida , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Carga Tumoral/efeitos dos fármacos
17.
Anticancer Res ; 41(8): 3933-3940, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34281856

RESUMO

BACKGROUND: Oligometastatic cancer (OM) is possibly associated with relatively better survival outcomes. We attempted to identify cases in line with this OM concept. PATIENTS AND METHODS: A total of 130 cases with unresectable metastatic pancreatic cancer underwent non-curative surgery from April 2001 to December 2019. Sites of metastasis, clinicopathological information, and surgical outcomes were collected to formulate a better definition of OM. RESULTS: OM criteria were defined as having metastasis to a single organ, few countable lesions and low serum cancer antigen 19-9 level. The median overall survival after non-curative surgery of OM cases was 13.0 months and was significantly better than that of non-OM cases (8.4 months, p=0.003). CONCLUSION: We propose single-organ metastasis of limited tumor volume (H1 or P1/2 by the Japanese Society of Cancer of the Colon and Rectum classification) and low serum cancer antigen 19-9 level (<2,000 U/ml) as new criteria for defining OM pancreatic cancer.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Idoso , Antígeno CA-19-9/sangue , Carcinoma Ductal Pancreático/sangue , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/terapia , Feminino , Humanos , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Masculino , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/terapia , Neoplasias Peritoneais/sangue , Neoplasias Peritoneais/mortalidade , Neoplasias Peritoneais/secundário , Neoplasias Peritoneais/terapia , Carga Tumoral
18.
Int J Mol Sci ; 22(14)2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34299067

RESUMO

Pancreatic cancer is a fatal disease, and thus its chemoprevention is an important issue. Based on the recent report that patients with allergic diseases have a low risk for pancreatic cancer, we examined the potential chemopreventive effect of anti-allergic agents using a hamster pancreatic carcinogenesis model. Among the three anti-allergic drugs administered, montelukast showed a tendency to suppress the incidence of pancreatic cancer. Further animal study revealed a significantly decreased incidence of pancreatic cancer in the high-dose montelukast group compared with controls. The development of the pancreatic intraepithelial neoplasia lesions was also significantly suppressed. The Ki-67 labeling index was significantly lower in pancreatic carcinomas in the high-dose montelukast group than in controls. In vitro experiments revealed that montelukast suppressed proliferation of pancreatic cancer cells in a dose-dependent manner with decreased expression of phospho-ERK1/2. Montelukast induced G1 phase arrest. Conversely, leukotriene D4 (LTD4), an agonist of CYSLTR1, increased cellular proliferation of pancreatic cancer cells with an accumulation of phospho-ERK1/2. In our cohort, pancreatic ductal adenocarcinoma patients with high CYSLTR1 expression showed a significantly unfavorable clinical outcome compared with those with low expression. Our results indicate that montelukast exerts a chemopreventive effect on pancreatic cancer via the LTD4-CYSLTR1 axis and has potential for treatment of pancreatic carcinogenesis.


Assuntos
Acetatos/farmacologia , Antiasmáticos/farmacologia , Proliferação de Células , Ciclopropanos/farmacologia , Leucotrieno D4/metabolismo , Nitrosaminas/toxicidade , Neoplasias Pancreáticas/tratamento farmacológico , Quinolinas/farmacologia , Receptores de Leucotrienos/metabolismo , Sulfetos/farmacologia , Animais , Carcinógenos/toxicidade , Cricetinae , Humanos , Masculino , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Células Tumorais Cultivadas
19.
Molecules ; 26(12)2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207699

RESUMO

Pancreatic cancer is an aggressive disease that progresses in a relatively symptom-free manner; thus, is difficult to detect and treat. Essential oil is reported to exhibit pharmacological properties, besides its common and well-known function as aromatherapy. Therefore, this study herein aimed to investigate the anti-proliferative effect of essential oil extracted from leaves of Garcinia atroviridis (EO-L) against PANC-1 human pancreatic cancer cell line. The cell growth inhibitory concentration at 50% (IC50) and selective index (SI) values of EO-L analyses were determined as 78 µg/mL and 1.23, respectively. Combination index (CI) analysis revealed moderate synergism (CI values of 0.36 to 0.75) between EO-L and 2 deoxy-d-glucose (2-DG) treatments. The treatments of PANC-1 cells with EO-L, 2-DG and EOL+2DG showed evidence of depolarization of mitochondrial membrane potential, cell growth arrest and apoptosis. The molecular mechanism causing the anti-proliferative effect between EO-L and 2-DG is potentially through pronounced up-regulation of P53 (4.40-fold), HIF1α (1.92-fold), HK2 (2.88-fold) and down-regulation of CYP3A5 (0.11-fold), as supported by quantitative mRNA expression analysis. Collectively, the current data suggest that the combination of two anti-proliferative agents, EO-L and 2-DG, can potentially be explored as therapeutic treatments and as potentiating agents to conventional therapy against human pancreatic cancer.


Assuntos
Desoxiglucose/farmacologia , Garcinia/química , Óleos Voláteis/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Apoptose/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Potencial da Membrana Mitocondrial , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Folhas de Planta/química
20.
Molecules ; 26(12)2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207840

RESUMO

Statins have been widely used for the treatment of hypercholesterolemia due to their ability to inhibit HMG-CoA reductase, the rate-limiting enzyme of de novo cholesterol synthesis, via the so-called mevalonate pathway. However, their inhibitory action also causes depletion of downstream intermediates of the pathway, resulting in the pleiotropic effects of statins, including the beneficial impact in the treatment of cancer. In our study, we compared the effect of all eight existing statins on the expression of genes, the products of which are implicated in cancer inhibition and suggested the molecular mechanisms of their action in epigenetic and posttranslational regulation, and in cell-cycle arrest, death, migration, or invasion of the cancer cells.


Assuntos
Antineoplásicos/farmacologia , Biologia Computacional/métodos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Ácido Mevalônico/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Transcriptoma/efeitos dos fármacos , Morte Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Epigênese Genética , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia
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