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1.
Cancer Med ; 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32017404

RESUMO

PURPOSE: Kras mutation and abnormal immune status are associated with pancreatic cancer development and progression. In this study, we evaluated the Kras mutation status in circulating tumor DNA and circulating T cell subsets in a cohort of advanced pancreatic cancer patients. METHODS: Samples were retrospectively obtained from a series of 210 pathological advanced pancreatic cancer patients between 2012 and 2014. The Kras mutation status was detected in cell-free circulating tumor DNA (ctDNA) by ddPCR and circulating T cell subsets were analyzed by flow cytometry. RESULTS: Univariate analysis found that tumor node metastasis (TNM) stage, chemotherapy, circulating regulatory T cells, CA19-9 levels, CA125 levels, and KrasG12D and KrasG12V mutations were significantly related to overall survival in advanced pancreatic cancer patients. Multivariate analysis identified that TNM stage (P = .03, HR:1.422), Tregs (P = .004, HR:1.522), CA19-9 levels (P = .009, HR:1.488), KrasG12D mutation (P = .044, HR:1.353), and KrasG12V mutation (P = .001, HR:1.667) were independent prognostic markers. Furthermore, we found that KrasG12V mutation in ctDNA was correlated with high circulating proportion of Tregs, and patients with both KrasG12V mutation and high levels of Tregs were associated with extremely poor survival in advanced pancreatic cancer. CONCLUSION: KrasG12V mutation was associated with high circulating regulatory T cell levels, and both of them predicted worse prognosis in advanced pancreatic cancer patients.

2.
Oncologist ; 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31784489

RESUMO

BACKGROUND: The objective of this study was to develop and validate a nomogram to predict 1-year overall survival (OS) and 2-year OS in patients with high-grade digestive neuroendocrine neoplasms (NENs) as well as to guide selection of subgroups that could benefit from systemic chemotherapy. SUBJECTS, MATERIALS, AND METHODS: We performed a retrospective analysis of 223 patients with NENs of the gut and hepato-biliary-pancreatic system from four centers included in the development cohort. The nomogram was externally validated in a cohort of 90 patients from another one. RESULTS: The final model included lactate dehydrogenase, performance status, stage, Ki67, and site of primary tumor, all of which had a significant effect on OS. The uncorrected C-index was 0.761 for OS, and the bias-corrected C-index was 0.744. Predictions correlated well with observed 1-year and 2-year outcomes (judged by eye). The area under the time-dependent receiver operating characteristic curve at 12 months and 24 months was 0.876 and 0.838, respectively. The nomogram performed well in terms of both discrimination and calibration when applied to the validation cohort, and OS was significantly different between the two groups classified by nomogram score (log-rank p < .001). CONCLUSION: The validated nomogram provided useful prediction of OS, which can be offered for clinicians to improve their abilities to assess patient prognosis, to create clinical risk groups for informing treatment or for patient stratification by disease severity in clinical trials. IMPLICATIONS FOR PRACTICE: The high-grade neuroendocrine neoplasms of the digestive system are rare malignancies with great heterogeneity. An overall survival nomogram was developed and externally validated in this study. Two subgroups were classified by the nomogram score, and platinum-based chemotherapy may not bring clinical benefit for the low-risk patients.

3.
Cancer Manag Res ; 11: 8781-8788, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31632137

RESUMO

Purpose: The CRP/albumin (Alb) ratio, a recently reported predictor, has shown value for prognosis in various human cancers. This study aimed to determine the prognostic value of baseline CRP/Alb and to explore the relevance between postchemotherapy CRP/Alb and the efficacy of chemotherapy in advanced pancreatic cancer patients. Patients and methods: Five hundred and ninety-five patients diagnosed with locally advanced or metastatic adenocarcinoma of the pancreas were enrolled. Cut-off Finder was used to calculate the best cut­off value for baseline CRP/Alb. The primary endpoint was overall survival, which was analyzed by Kaplan-Meier survival curves with 95% confidence intervals. The log rank test and Cox proportional hazard model were used to evaluate the univariate and multivariate analyses. Results: The optimal cut-off value for baseline CRP/Alb was determined to be 0.18. Both the baseline CRP/Alb (CRP/Alb≥0.18 vs. CRP/Alb<0.18, hazard ratio [HR] = 2.506; p<0.001) and postchemotherapy CRP/Alb (CRP/Alb≥0.18 vs. CRP/Alb<0.18, HR = 1.854; p =0.002) were significant predictors of overall survival according to multivariate analysis and were independent of other factors. Patients with a baseline and postchemotherapy CRP/Alb ≥0.18 had the worst prognosis. Conclusion: CRP/Alb is a strong and useful indicator of prognosis for advanced pancreatic cancer. Both baseline and postchemotherapy CRP/Alb can be used in predicting the survival of patients and monitoring the effectiveness of chemotherapy in clinical practice.

4.
Cancer Med ; 8(13): 5903-5915, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31426130

RESUMO

Gemcitabine (GEM) is the standard chemotherapy drug for pancreatic cancer. Because of widespread drug resistance, the effect is limited. Therefore, it is urgent to reveal the underlying mechanism. Glycolysis is the most remarkable character of tumor aberrant metabolism, which plays vital roles on tumor drug resistance. Hexokinase 2 (HK2), as the key enzyme regulating the first-step reaction of glycolysis, is overexpressed in many kinds of tumors. The putative role of HK2 resisting GEM therapy was investigated in this study. We found that HK2 was overexpressed in pancreatic cancer and associated with poor prognosis. HK2 knockdown decreased pancreatic cancer cell proliferation, migration viability, and promoted cell apoptosis in vitro. HK2 high expression in pancreatic cancer showed GEM resistance. HK2 knockdown increased the sensitivity of pancreatic cancer cell to GEM, the growth of xenograft tumor with HK2 knockdown was also further decreased with the GEM treatment compared with control in vivo. GEM-resistant pancreatic cancer showed the increase of HK2 dimer rather than HK2 mRNA or protein. Our study revealed that the ROS derived from GEM promoted HK2 dimerization combining with voltage-dependent anion channel, which resulted in the resistance to GEM. Meanwhile, our study established a new sight for GEM resistance in pancreatic cancer.

5.
World J Surg Oncol ; 17(1): 137, 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31387646

RESUMO

BACKGROUND: Both the 7th and 8th editions of the American Joint Committee on Cancer (AJCC) staging systems have been introduced for pancreatic adenocarcinoma. However, the applicability of these classifications for invasive intraductal papillary mucinous neoplasms (IPMN) has not been systematically examined. METHODS: Patients with invasive IPMN were retrieved from a cohort of 18 geographical sites (1973-2014 varying) in the Surveillance, Epidemiology, and End Results (SEER) cancer registry. The 7th and 8th editions of the AJCC staging were compared. Survival rates and multivariate analyses were computed. RESULTS: In total, 1216 patients with resected invasive IPMN were included. A major difference between the 7th and 8th systems is the definition of stage IIA (7th, beyond the pancreas without involvement of major arteries; 8th, maximum tumor diameter > 4 cm). The hazard ratio (HR) of stage IIA disease (versus stage IA, HR = 2.33, P < 0.001) was higher than that of stage IB disease (HR = 1.48, P = 0.087) by the 7th edition classification, whereas the HR of stage IIA disease (HR = 1.26, P = 0.232) was even lower than that of stage IB disease (HR = 1.48, P = 0.040) by the 8th edition classification. In addition, for the 8th edition staging system, tumor size was not a predictor of survival in patients with resectable tumor > 2 cm (size > 4 cm versus > 2 ≤ 4 cm, HR = 0.91, P = 0.420). CONCLUSIONS: The AJCC 7th edition staging classification is more applicable than the 8th edition classification for invasive IPMN.

6.
Cancer Med ; 8(11): 5000-5011, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31293053

RESUMO

PURPOSE: This study aimed to investigate the characteristics of colonic neuroendocrine neoplasms (NENs) and to validate the prognostic value of the European Neuroendocrine Tumor Society (ENETS) and American Joint Committee on Cancer (AJCC) 8th staging systems. METHODS: A total of 167 and 1248 patients with colonic NENs from 12 medical centers across China and from the Surveillance, Epidemiology, and End Results (SEER) cancer registry in the United States, respectively, were reviewed. Patients were staged according to the ENETS and AJCC 8th staging systems. RESULTS: Clinicopathological features of colonic NENs in the Chinese cohort and SEER cohort were significantly distinct. In both the Chinese cohort and the SEER cohort, colonic neuroendocrine carcinoma (NEC) and mixed adeno-neuroendocrine carcinoma (MANEC) were more frequent in the midgut than in the hindgut. Tumors originating from the midgut tended to be larger and at a more advanced stage than those from the hindgut. The AJCC 8th staging system and the ENETS system appeared to have similar prognostic ability for colonic NEC/MANEC. CONCLUSIONS: Our study revealed that tumors originating from the midgut and the hindgut shared different clinicopathological features. The AJCC 8th staging system and the ENETS system appeared to have similar prognostic ability for colonic NEC/MANEC.

7.
Pancreas ; 48(6): 817-822, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31210663

RESUMO

OBJECTIVES: Except pancreatic adenocarcinoma, pancreatic cancer has several uncommon histological subtypes, including invasive intraductal papillary mucinous neoplasm (IPMN), pancreatic neuroendocrine tumor (pNET), adenosquamous carcinoma, invasive mucinous cystic neoplasm (MCN), acinar cell carcinoma (ACC), squamous cell carcinoma (SCC), and invasive solid pseudopapillary tumor (SPT). However, features of theses uncommon subtypes are not systematically analyzed. METHODS: Subjects with different histological subtypes of pancreatic cancers were retrieved from the Surveillance, Epidemiology, and End Results registry. Characteristics and behaviors of uncommon subtypes were compared. RESULTS: Pancreatic adenocarcinoma (85.8%) represented most primary pancreatic cancers, and other subtypes were rare (14.2%). Features of uncommon subtypes included females with SPT and MCN, located at the pancreatic body/tail of pNET, SPT, and MCN; poor differentiation of adenosquamous carcinoma and SCC; and large size of MCN, SPT, ACC, and SCC. In addition, IPMN, pNET, MCN, ACC, and SPT were indolent. For indolent subtypes, patients with locoregional tumor had prominent prognosis compared with patients with distant disease, especially for invasive IPMN (median survival, localized, 30.0 months; regional, 11.0 months; distant, 4.0 months). CONCLUSIONS: The study systematically summarizes characteristics and behaviors of primary pancreatic cancer by histological subtypes, which can facilitate the management of pancreatic cancer.

8.
Mol Cancer ; 18(1): 100, 2019 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-31122251

RESUMO

Apoptosis resistance is to a large extent a major obstacle leading to chemotherapy failure during cancer treatment. Bypassing the apoptotic pathway to induce cancer cell death is considered to be a promising approach to overcoming this problem. Necroptosis is a regulated necrotic cell death modality in a caspase-independent fashion and is mainly mediated by Receptor-Interacting Protein 1 (RIP1), RIP3, and Mixed Lineage Kinase Domain-Like (MLKL). Necroptosis serves as an alternative mode of programmed cell death overcoming apoptosis resistance and may trigger and amplify antitumor immunity in cancer therapy.The role of necroptosis in cancer is complicated. The expression of key regulators of the necroptotic pathway is generally downregulated in cancer cells, suggesting that cancer cells may also evade necroptosis to survive; however, in certain types of cancer, the expression level of key mediators is elevated. Necroptosis can elicit strong adaptive immune responses that may defend against tumor progression; however, the recruited inflammatory response may also promote tumorigenesis and cancer metastasis, and necroptosis may generate an immunosuppressive tumor microenvironment. Necroptosis also reportedly promotes oncogenesis and cancer metastasis despite evidence demonstrating its antimetastatic role in cancer. In addition, necroptotic microenvironments can direct lineage commitment to determine cancer subtype development in liver cancer. A plethora of compounds and drugs targeting necroptosis exhibit potential antitumor efficacy, but their clinical feasibility must be validated.Better knowledge of the necroptotic pathway mechanism and its physiological and pathological functions is urgently required to solve the remaining mysteries surrounding the role of necroptosis in cancer. In this review, we briefly introduce the molecular mechanism and characteristics of necroptosis, the interplay between necroptosis and other cell death mechanisms, crosstalk of necroptosis and metabolic signaling and detection methods. We also summarize the intricate role of necroptosis in tumor progression, cancer metastasis, prognosis of cancer patients, cancer immunity regulation, cancer subtype determination and cancer therapeutics.

9.
Ann Surg Oncol ; 26(6): 1649-1656, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30924017

RESUMO

BACKGROUND: Metastatic lesion to the pancreas accounts for approximately 2% of pancreatic neoplasms. There is no prospective, randomized or case-controlled study evaluating the role of pancreatic metastasectomy. METHODS: The PubMed, EMBASE, and Cochrane Library electronic databases were searched for studies published between January 1, 2001 and December 31, 2017. Studies with five or more patients who received pancreatic metastasectomy and data from our institution (29 patients) were included. The Kaplan-Meier method was used for survival analysis. RESULTS: A total of 414 patients from 20 institutions who underwent pancreatic resections were included. Of the reported 31 kinds of primary neoplasms, renal-cell carcinoma (RCC) comprised the most (54.3%). At the time of diagnosis, although 40.3% patients were asymptomatic, abdominal pain (34.8%) and jaundice (20.6%) were relatively common. As for surgical type, pancreatoduodenectomy, total pancreatectomy, distal pancreatectomy, and enucleation took up 37.9%, 11.4%, 43.5%, and 7.2% respectively. The mortality and morbidity rates were 1.4% and 48.3% respectively. Patients with symptoms at the time of diagnosis had significantly shorter survival compared with asymptomatic patients (p = 0.017). Those with RCC as primary tumor had significantly longer survival compared with non-RCC patients (p < 0.001). Positive margin also predicts worse prognosis (p = 0.035). CONCLUSIONS: Pancreatic metastasectomy is safe and associated with acceptable short- and intermediate-term results. In the conditions of RCC as the primary tumor, being asymptomatic, or negative resection margin, a better prognosis after resection can be achieved.


Assuntos
Metastasectomia/mortalidade , Neoplasias Pancreáticas/cirurgia , Humanos , Metástase Neoplásica , Neoplasias Pancreáticas/patologia , Prognóstico , Taxa de Sobrevida
10.
Cancer Lett ; 446: 103-111, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30664964

RESUMO

Genetic alterations have been attributed to the abnormal immune microenvironment in cancer. However, the relationship between the KrasG12D mutation and regulatory T cells (Tregs) in pancreatic cancer remains unclear. In this study, we found that KrasG12D mutation status as determined by ddPCR correlated with high levels of Treg infiltration in resectable pancreatic cancer tissues. Compared to wild-type tumour cells, tumours cells with the KrasG12D mutation were associated with higher levels of Tregs, and knockout of the KrasG12D mutation reversed this effect. In addition, overexpression of the KrasG12D mutation in wild-type Kras tumour cells resulted in conversion of CD4+CD25- T cells into Tregs. We also found that in tumour cells, the KrasG12D mutation activated the MEK/ERK pathway, thereby up-regulating the levels of interleukin-10 (IL-10) and transforming growth factor-ß (TGF-ß), which induced Treg conversion. In summary, KrasG12D mutation plays a critical role in Treg conversion and contributes to an immunosuppressive tumour microenvironment in pancreatic cancer. These results provide new insights into the relationship between gene mutation and immune escape.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular , Linfócitos do Interstício Tumoral/enzimologia , MAP Quinase Quinase Quinases/metabolismo , Mutação , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Linfócitos T Reguladores/enzimologia , Evasão Tumoral , Comunicação Celular , Linhagem Celular Tumoral , Técnicas de Cocultura , Humanos , Interleucina-10/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Pancreáticas/enzimologia , Neoplasias Pancreáticas/imunologia , Fenótipo , Transdução de Sinais , Linfócitos T Reguladores/imunologia , Fator de Crescimento Transformador beta/metabolismo , Microambiente Tumoral
11.
Cancer Immunol Immunother ; 67(12): 1815-1823, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30167864

RESUMO

INTRODUCTION: Natural killer cells (NK) are often believed to play a positive role in the antitumor immune response. However, this is not the case for patients with advanced pancreatic cancer. This study was performed to determine the unique subtype of "educated" NK cells and their prognostic value in patients with advanced pancreatic cancer. METHODS: We divided 378 eligible patients into a derivation cohort (September 2010 to December 2014, n = 239) and a validation cohort (January 2015 to April 2016, n = 139). Flow cytometry was performed to analyze NK cells. Enzyme-linked immunosorbent assay was used to detect interleukin-2 (IL-2), interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) production. The Kaplan-Meier method and the Cox proportional hazards model were used. RESULTS: Survival analysis showed that a high density of NK cells accompanied by a high neutrophil-to-lymphocyte ratio was associated with reduced overall survival in both the derivation and validation cohorts. Multivariable analysis also showed that high NK infiltration (HR 1.45, 95% CI 1.17 to 1.79, p = 0.001) was an independent prognostic factor. In these patients, high NK infiltration was associated with reduced levels of IL-2, IFN-γ and TNF-α, although only IFN-γ reached statistical significance, which accounted for this unique phenomenon. DISCUSSION: Natural killer cells in patients with advanced pancreatic cancer are a unique subtype with anergic features. A high density of NKs predicts poor survival in these patients, possibly because an active inflammatory response and reduced secretion of IL-2, IFN-γ and TNF-α inhibit NK activation.


Assuntos
Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/mortalidade , Comunicação Celular/imunologia , Anergia Clonal/imunologia , Células Matadoras Naturais/imunologia , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/mortalidade , Adulto , Idoso , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Citocinas/metabolismo , Feminino , Humanos , Estimativa de Kaplan-Meier , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/patologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Prognóstico , Modelos de Riscos Proporcionais , Carga Tumoral
12.
Pancreatology ; 18(8): 971-976, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30131287

RESUMO

BACKGROUND: Carbohydrate antigen 19-9 (CA19-9) is the best-validated biomarker for pancreatic cancer. The National Comprehensive Cancer Network (NCCN) guideline asserts that "CA19-9 will be undetectable in Lewis antigen-negative individuals". However, reports of CA19-9 secretion and its significance in Lewis (-) patients with pancreatic cancer have been inconsistent. This study was to examine serum CA19-9 levels in patients with pancreatic cancer according to Lewis status. METHODS: Patients with pancreatic cancer (1482 cases) were retrieved from a prospectively maintained database. Patients with benign pancreatic disease (210 cases) and normal subjects (315 cases) were used as controls. Lewis genotypes were examined by fucosyltransferase 3 (FUT3) sequencing. RESULTS: In patients with pancreatic cancer, 8.4% of subjects were Lewis (-), but only 41.9% of Lewis (-) subjects had CA19-9 values ≤ 2 U/mL. CA19-9 was even elevated (>37 U/mL) in 27.4% of Lewis (-) patients. The area under the receiver operating characteristic (ROC) curve for CA19-9 as a diagnostic biomarker was 0.842 in Lewis (-) patients with pancreatic cancer, which is closing to that of CA19-9 applied in all of patients with pancreatic cancer (0.898). Lewis (-) status was an independent prognostic factor for shorter survival in a multivariable analysis (hazard ratio (HR), 1.30, 95% confidence interval (CI), 1.03-1.64; P = 0.028). CONCLUSIONS: Not all Lewis (-) patients with pancreatic cancer are non-secretors of CA19-9. Contrary to general understanding, CA19-9 can retain its utility as a biomarker in these patients in spite of Lewis (-) genotype.


Assuntos
Biomarcadores Tumorais/sangue , Antígeno CA-19-9/sangue , Neoplasias Pancreáticas/sangue , Idoso , Biomarcadores Tumorais/genética , Antígeno CA-19-9/genética , Feminino , Fucosiltransferases/análise , Fucosiltransferases/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Pancreatopatias/diagnóstico , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Análise de Sobrevida
13.
Pancreas ; 47(6): 742-747, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29851752

RESUMO

OBJECTIVES: Notable modifications have been made in the American Joint Committee on Cancer (AJCC) Staging eighth edition staging for pancreatic cancer for the consideration of the irreproducible and inapplicable of the AJCC seventh edition staging. However, the new staging classification has not been systemically verified. METHODS: A comparison was performed to evaluate the application of the AJCC seventh and eighth staging classifications using the Surveillance, Epidemiology, and End Results registry (18,450 patients) and an institutional series (2040 patients). RESULTS: For the eighth staging classification, patients with tumor diameter of greater than 4 cm (T3N0M0, IIA) had similar prognosis to patients with 1 to 3 positive nodes (T1-3N1M0, IIB). For patients who underwent tumor resection and without lymph node involvement, survival curves of T1 (≤2 cm), T2 (2-4 cm), and T3 (>4 cm) were well separated. Statistical difference in survival analyses was demonstrated in N0 (0 positive node), N1 (1-3 positive nodes), and N2 (≥4 positive nodes) patients underwent tumor resection. The AJCC eighth edition had better stage distribution than the AJCC seventh edition for pancreatic cancer. CONCLUSIONS: The eighth edition of AJCC staging is more applicable and accurate than the seventh edition for pancreatic adenocarcinoma.


Assuntos
Adenocarcinoma/patologia , Estadiamento de Neoplasias/métodos , Neoplasias Pancreáticas/patologia , Idoso , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias/classificação , Reprodutibilidade dos Testes , Programa de SEER/classificação , Programa de SEER/estatística & dados numéricos , Estados Unidos
14.
J Hematol Oncol ; 11(1): 14, 2018 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-29386069

RESUMO

A poor prognosis of pancreatic ductal adenocarcinoma (PDAC) associated with chemoresistance has not changed for the past three decades. A multidisciplinary diagnosis followed by surgery and chemo(radiation)therapy is the main treatment approach. However, gemcitabine- and 5-fluorouracil-based therapies did not present satisfying outcomes. Novel regimens targeting pancreatic cancer cells, the tumor microenvironment, and immunosuppression are emerging. Biomarkers concerning the treatment outcome and patient selection are being discovered in preclinical or clinical studies. Combination therapies of classic chemotherapeutic drugs and novel agents or novel therapeutic combinations might bring hope to the dismal prognosis for PDAC patients.


Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Descoberta de Drogas , Humanos , Terapia de Alvo Molecular , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos
15.
Cancer Lett ; 418: 167-175, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29337110

RESUMO

Pancreatic cancer is the most lethal tumor. CA125 (gene symbol MUC16) is an important serum marker for pancreatic cancer diagnosis and treatment. High serum CA125 is related to metabolic tumor burden and poor prognosis. The circulating Treg subset is another independent prognostic factor for pancreatic cancer. Our unpublished data indicated that the circulating Treg proportion might be related to the serum CA125 level. However, the potential relationship and underlying mechanism of MUC16 and Treg in pancreatic cancer tissues remain unclear. In this study, we found that pancreatic cancer tissues were positive for both MUC16 C terminal (MUC16c) and Foxp3 expression and that their expression was correlated. MUC16c released into the cytoplasm via EGF induction significantly increased IL-6 expression and secretion. The PI3K/AKT pathway may participate in the regulation of IL-6 expression and secretion. By treating CD4+ T cells with IL-6 or co-culturing the cells with pancreatic cancer cells, tumor-derived IL-6 was identified to promote Foxp3 expression and Treg differentiation, which was significantly inhibited by the JAK2 inhibitor AG-490. In sum, our study demonstrated that the relationship between the MUC16c level and Foxp3 expression in the local tumor environment was consistent with that of the serum CA125 level and circulating Treg proportion in the systemic environment. MUC16c promoted Foxp3 expression and tumor-associated Treg enrichment in tumor tissues through tumor-secreted IL-6 activation of the JAK2/STAT3 pathway. These findings may provide deeper insight into potential pancreatic cancer therapy approaches.


Assuntos
Antígeno Ca-125/imunologia , Interleucina-6/imunologia , Proteínas de Membrana/imunologia , Neoplasias Pancreáticas/imunologia , Linfócitos T Reguladores/imunologia , Antígeno Ca-125/genética , Antígeno Ca-125/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Diferenciação Celular/imunologia , Linhagem Celular Tumoral , Técnicas de Cocultura , Fatores de Transcrição Forkhead/imunologia , Fatores de Transcrição Forkhead/metabolismo , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Estimativa de Kaplan-Meier , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Transdução de Sinais/imunologia , Linfócitos T Reguladores/metabolismo
16.
Cancer Lett ; 412: 188-193, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29107104

RESUMO

Radical surgical resection represents the only hope of cure for pancreatic neuroendocrine tumor (PanNET). Adjuvant therapy is rarely used because there is no evidence to distinguish patients with high recurrence risk. Here we investigated the recurrence feature of resected PanNET and established a novel risk stratification to predict its recurrence. We analyzed 505 PanNET patients who underwent R0 resection at our institute from January 2004 through May 2015. The median follow-up was 71months (range: 12months-143months), 129 patients (25.5%) experienced recurrence with median disease-free survival (mDFS) of 19months. Restricted cubic spline (RCS) functions revealed a positive, linear relationship between Ki-67 index and recurrence. Multivariate analysis showed T stage, N stage, insulinoma and Ki-67 index were independent predictors of recurrence (P < 0.05). Based on scores of these independent factors, we generated a recurrent-risk stage system with HCI of 0.806, superior to TNM stage (HCI 0.704) and grading system (HCI 0.706). Resected PanNET were classified into low risk (65.3%, mDFS not reached), intermediate risk (16.6%, mDFS 48months, 95%CI 26.5-73.4), high risk (13.3%, mDFS 24months, 95%CI 19.4-50.5) and very high risk (4.8%, mDFS 10months, 95%CI 6.9-13.0) (Hazard ratio: 2.650, 95%CI: 2.233-3.145, P < 0.001). This novel risk stratification thus identified PanNET patients of different recurrent-risk. Patients with very high recurrence risk may be suitable for post-operative clinical trials investigating adjuvant treatment.


Assuntos
Recidiva Local de Neoplasia/etiologia , Tumores Neuroendócrinos/cirurgia , Neoplasias Pancreáticas/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Antígeno Ki-67/análise , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/patologia , Modelos de Riscos Proporcionais , Fatores de Risco , Adulto Jovem
17.
Oncol Lett ; 14(6): 6795-6800, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29163700

RESUMO

Carbohydrate antigen 19-9 (CA19-9) is not generally considered to be a biomarker in pancreatic neuroendocrine tumors (pNETs), as the majority of pNETs present with a normal range of CA19-9. The present study aimed to evaluate the role of serum CA19-9 levels as a prognostic factor in a relatively large number of patients with pNETs. Consecutive patients were retrospectively collected from a single institution between June 2006 and February 2015. The receiver operating characteristic (ROC) curve and the area under the ROC curve were used to select the cut-off values for the baseline CA19-9 levels. The primary end point was set as overall survival. Potential factors associated with the abnormal elevation of CA19-9 expression levels in pNETs were also investigated. The cut-off value for CA19-9 was 16 U/ml as determined by the ROC curve, and for the area under the ROC curve it was 0.68. In total, 32.7% of patients (51/156) had CA19-9 expression levels higher than the cut-off value. Univariate analysis demonstrated that CA19-9 >16 U/ml was an adverse prognostic factor for patients' overall survival. The CA19-9 >16 U/ml group had a statistically higher proportion of tumor node metastasis (TNM) stage III or IV, as compared with the CA19-9 ≤16 U/ml group. To the best of our knowledge, the present study is the first to demonstrate that CA19-9 is a prognostic biomarker of pNETs, one that may reflect its aggressiveness and severity.

18.
FEBS Open Bio ; 7(11): 1660-1671, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-29123975

RESUMO

The Lewis (FUT3) and Secretor (FUT2) genes, corresponding to secretion of Lewis ABO (H) histo-blood group antigen CA19-9, are highly polymorphic with differences between populations. In this study, the FUT3 and FUT2 genes in 316 Chinese participants were sequenced to detect polymorphisms, and the associated CA19-9 antigen secretion was also measured. In total, 14 genotypes of FUT3 and 10 genotypes of FUT2 were verified. Le/Le, Le/le59,508 and Le/le59 were the main genotypes of FUT3 with frequencies of 53.2%, 10.7% and 3.5%, respectively. Se/Se, Se/se385 and se385/se385 were the main genotypes of FUT2, with frequencies of 21.4%, 18.6% and 16.2%, respectively. The alleles le1067 and le508 were found extensively in the Chinese population, and the frequency of allele se385 was shown to be higher than previously reported. Phenotype analysis revealed that 9.8% of individuals were the Lewis-negative type and 22.5% were the secretor-negative type. Combined phenotypes showed that 3.2% of participants were of 'double-negative' phenotype (le, se) and 19.3% were of single dominant non-secretor phenotype (Le, se). Serum Lewis antigen CA19-9 levels were significantly different between subgroups and consistent with the defined phenotype. Our study revealed the unique distribution of Lewis and Secretor polymorphisms in a large Chinese population, and decoded the combined genotypes of the two CA19-9-related genes.

19.
BMC Cancer ; 17(1): 521, 2017 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-28778195

RESUMO

BACKGROUND: The clinicopathological characteristics of small intestinal neuroendocrine neoplasms (SI-NENs) and the prognostic validity of WHO grading classification for SI-NENs are still unknown in Asian patients. METHODS: 277 patients and 8315 patients with SI-NENs were retrieved respectively from eleven Chinese hospitals and Surveillance, Epidemiology, and End Results (SEER) cancer registry. Overall survival was used as the major study outcome. Survival analysis using Kaplan-Meier analysis with log-rank test and cox regression analysis were applied. RESULTS: Clinicopathological characteristics of SI-NENs were quite different among different races. Duodenum was the predominant tumor site in Chinese patients and Asian/Pacific Islander patients but not in white patients from SEER database. Patients with duodenal NENs tended to have more localized disease than patients with jejunal/ileal NENs which were confirmed by patients from SEER database. Grade 3 or poorly differentiated/undifferentiated tumor were more common and tumor size was significantly larger in ampullary NENs compared with that in non-ampullary duodenal NENs. As for the prognostic validity of WHO grading classification, survival between patients with grade 1 and grade 2 disease was not significantly different. Ki-67 index of 5% might be a better threshold between grade 1 and grade 2 than Ki-67 index of 2% in SI-NENs. CONCLUSIONS: Our study revealed that the clinicopathological characteristics of SI-NENs among different races were quite different. This might because duodenal NENs was much more common in Chinese patients and Asian/Pacific Islander patients. Duodenal NENs and jejunal/ileal NENs, ampullary and non-ampullary duodenal NENs shared different characteristics. Ki-67 index of 5% might be a better threshold between grade 1 and grade 2 in SI-NENs.


Assuntos
Neoplasias Intestinais/mortalidade , Neoplasias Intestinais/patologia , Intestino Delgado/patologia , Tumores Neuroendócrinos/mortalidade , Tumores Neuroendócrinos/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Neoplasias Intestinais/epidemiologia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Tumores Neuroendócrinos/epidemiologia , Prognóstico , Modelos de Riscos Proporcionais , Adulto Jovem
20.
Cancer Chemother Pharmacol ; 80(3): 507-516, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28707013

RESUMO

PURPOSE: To determine the efficacy and safety of sunitinib in Chinese patients with unresectable or metastatic pancreatic neuroendocrine tumors (pNETs) and the clinical significance of steady-state sunitinib serum concentrations. METHODS: We conducted a multicenter retrospective study including six centers from across China. A total of 60 patients with unresectable or metastatic pNETs who were treated with sunitinib were evaluated retrospectively. RESULTS: The median overall survival (OS) was 47.5 months and the median time to progression (TTP) was 15.3 months. The objective response rate was 5.0%, and the stable disease (SD) rate was 81.7%. About 35.2% of patients required a dosage decrease from 37.5 to 25 mg/day due to adverse events, which in most cases were alleviated or disappeared with the dosage reduction. In 14 patients who experienced sunitinib-related hypertension, 2 achieved a partial response (PR) and 11 had SD. The median OS and TTP of these 14 patients experienced hypertension were both not reached. The median Css of sunitinib was similar between patients treated with sunitinib 37.5 and 25 mg/day (P = 0.955), but higher in patients who had PR than in those who achieved SD or progressive disease, although no statistically significant difference was found (P = 0.173). CONCLUSIONS: Sunitinib had similar treatment efficacy to western patients with pNET in China. A 25 mg/day dosage was better tolerated than 37.5 mg/day in Chinese patients, and there were no significant differences in sunitinib Css between the two dosage groups. Patients with higher sunitinib Css seem to have better efficacy. Sunitinib-related hypertension may be a predictor of a better treatment effect.


Assuntos
Indóis/uso terapêutico , Tumores Neuroendócrinos/tratamento farmacológico , Pirróis/uso terapêutico , Adulto , Idoso , China , Feminino , Humanos , Indóis/administração & dosagem , Indóis/farmacologia , Masculino , Pessoa de Meia-Idade , Pirróis/administração & dosagem , Pirróis/farmacologia , Estudos Retrospectivos , Sunitinibe , Adulto Jovem
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