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1.
J Prosthodont ; 32(3): e52-e63, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35771977

RESUMO

PURPOSE: Various surface roughness parameters are utilized to describe the surface in the tooth to ceramics abrasion and to assess the resulting wear. The use of three-dimensional parameters may offer a better estimation for wear and an improved deduced clinical surface treatment. The aim of this study was to determine the influence of various surface roughness parameters of zirconia and lithium disilicate ceramics on the wear of steatite antagonists. MATERIAL AND METHODS: Forty zirconia specimens with a diameter of 7 mm and a thickness of 3 mm and 40 lithium disilicate specimens with the dimensions 10×10×4 mm were each divided into five subgroups. Two subgroups were treated with different clinically established diamond burs; a third subgroup was treated with a silicone polishing set. Two additional subgroups were produced by glazing the surfaces after treatment. Surface roughness parameters were determined by laser scanning microscopy. All specimens underwent 1.2 million loading cycles using steatite antagonists. After regular intervals of cycles, precision impressions were made to assess the wear. The correlation between wear and different roughness parameters was evaluated using the Spearman correlation test. RESULTS: For the glazed zirconia, unglazed zirconia, and glazed lithium disilicate specimens no significant correlations (p > 0.05) between the investigated roughness parameters and antagonist wear could be found. In the unglazed lithium disilicate groups, significant (p ≤ 0.05) correlations with steatite substance loss could be found for several roughness parameters after 1.2 million cycles. CONCLUSIONS: For lithium disilicate, it seems not sufficient to use only one roughness parameter to indicate the wear behavior of the surface. There was no correlation between wear and the tested roughness parameters of zirconia surfaces.


Assuntos
Cerâmica , Porcelana Dentária , Propriedades de Superfície , Teste de Materiais , Zircônio
2.
Gastroenterology ; 159(3): 1019-1035.e22, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32446697

RESUMO

BACKGROUND & AIMS: Pancreatic tumor cells release small extracellular vesicles (sEVs, exosomes) that contain lipids and proteins, RNA, and DNA molecules that might promote formation of metastases. It is not clear what cargo these vesicles contain and how they are released. Protein kinase D1 (PRKD1) inhibits cell motility and is believed to be dysregulated in pancreatic ductal adenocarcinomas. We investigated whether it regulates production of sEVs in pancreatic cancer cells and their ability to form premetastatic niches for pancreatic cancer cells in mice. METHODS: We analyzed data from UALCAN and human pancreatic tissue microarrays to compare levels of PRKD1 between tumor and nontumor tissues. We studied mice with pancreas-specific disruption of Prkd1 (PRKD1KO mice), mice that express oncogenic KRAS (KC mice), and KC mice with disruption of Prkd1 (PRKD1KO-KC mice). Subcutaneous xenograft tumors were grown in NSG mice from Panc1 cells; some mice were then given injections of sEVs. Pancreata and lung tissues from mice were analyzed by histology, immunohistochemistry, and/or quantitative polymerase chain reaction; we performed nanoparticle tracking analysis of plasma sEVs. The Prkd1 gene was disrupted in Panc1 cells using CRISPR-Cas9 or knocked down with small hairpin RNAs, or PRKD1 activity was inhibited with the selective inhibitor CRT0066101. Pancreatic cancer cell lines were analyzed by gene-expression microarray, quantitative polymerase chain reaction, immunoblot, and immunofluorescence analyses. sEVs secreted by Panc1 cell lines were analyzed by flow cytometry, transmission electron microscopy, and mass spectrometry. RESULTS: Levels of PRKD1 were reduced in human pancreatic ductal adenocarcinoma tissues compared with nontumor tissues. PRKD1KO-KC mice developed more pancreatic intraepithelial neoplasia, at a faster rate, than KC mice, and had more lung metastases and significantly shorter average survival time. Serum from PRKD1KO-KC mice had increased levels of sEVs compared with KC mice. Pancreatic cancer cells with loss or inhibition of PRKD1 increased secretion of sEVs; loss of PRKD1 reduced phosphorylation of its substrate, cortactin, resulting in increased F-actin levels at the plasma membrane. sEVs from cells with loss or reduced expression of PRKD1 had altered content, and injection of these sEVs into mice increased metastasis of xenograft tumors to lung, compared with sEVs from pancreatic cells that expressed PRKD1. PRKD1-deficient pancreatic cancer cells showed increased loading of integrin α6ß4 into sEVs-a process that required CD82. CONCLUSIONS: Human pancreatic ductal adenocarcinoma has reduced levels of PRKD1 compared with nontumor pancreatic tissues. Loss of PRKD1 results in reduced phosphorylation of cortactin in pancreatic cancer cell lines, resulting in increased in F-actin at the plasma membrane and increased release of sEVs, with altered content. These sEVs promote metastasis of xenograft and pancreatic tumors to lung in mice.


Assuntos
Carcinoma Ductal Pancreático/secundário , Vesículas Extracelulares/metabolismo , Neoplasias Pulmonares/secundário , Neoplasias Pancreáticas/patologia , Proteína Quinase C/deficiência , Animais , Carcinogênese/patologia , Carcinoma Ductal Pancreático/sangue , Linhagem Celular Tumoral , Movimento Celular , Conjuntos de Dados como Assunto , Regulação para Baixo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Pulmão/patologia , Neoplasias Pulmonares/sangue , Camundongos , Camundongos Knockout , Invasividade Neoplásica/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Pâncreas/patologia , Neoplasias Pancreáticas/sangue , Fosforilação , Cultura Primária de Células , Proteína Quinase C/genética , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Br J Cancer ; 123(9): 1370-1376, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32830200

RESUMO

BACKGROUND: Gram-negative bacteria mediated gemcitabine resistance in pre-clinical models. We determined if intratumoural lipopolysaccharide (LPS) detection by immunohistochemistry is associated with outcome in advanced pancreatic ductal adenocarcinoma (PDAC) treated with gemcitabine and non-gemcitabine containing 1st-line chemotherapy. METHODS: We examined LPS on tumour tissue from 130 patients treated within the randomised AIO-PK0104 trial and a validation cohort (n = 113) and analysed the association of LPS detection to patient outcome according to treatment subgroups. RESULTS: In 24% of samples from the AIO-PK0104 study LPS was detected; in LPS-positive patients median OS was 4.4 months, compared to 7.3 months with LPS negative tumours (HR 1.732, p = 0.010). A difference in OS was detected in 1st-line gemcitabine-treated patients (n = 71; HR 2.377, p = 0.002), but not in the non-gemcitabine treatment subgroup (n = 59; HR 1.275, p = 0.478). Within the validation cohort, the LPS positivity rate was 23%, and LPS detection was correlated with impaired OS in the gemcitabine subgroup (n = 94; HR 1.993, p = 0.008) whereas no difference in OS was observed in the non-gemcitabine subgroup (n = 19; HR 2.596, p = 0.219). CONCLUSIONS: The detection of intratumoural LPS as surrogate marker for gram-negative bacterial colonisation may serve as a negative predictor for gemcitabine efficacy in advanced PDAC. CLINICAL TRIAL REGISTRY: The Clinical trial registry identifier is NCT00440167.


Assuntos
Adenocarcinoma/tratamento farmacológico , Biomarcadores Tumorais/metabolismo , Desoxicitidina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos , Lipopolissacarídeos/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/diagnóstico , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Idoso , Ensaios Clínicos Fase III como Assunto , Estudos de Coortes , Desoxicitidina/uso terapêutico , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Análise de Sobrevida , Pesquisa Translacional Biomédica , Resultado do Tratamento , Gencitabina
4.
Gastroenterology ; 155(5): 1625-1639.e2, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30092175

RESUMO

BACKGROUND & AIMS: Changes to the microenvironment of pancreatic ductal adenocarcinomas (PDACs) have been associated with poor outcomes of patients. We studied the associations between composition of the pancreatic stroma (fibrogenic, inert, dormant, or fibrolytic stroma) and infiltration by inflammatory cells and times of progression-free survival (PFS) of patients with PDACs after resection. METHODS: We obtained 1824 tissue microarray specimens from 385 patients included in the European Study Group for Pancreatic Cancer trial 1 and 3 and performed immunohistochemistry to detect alpha smooth muscle actin, type 1 collagen, CD3, CD4, CD8, CD68, CD206, and neutrophils. Tumors that expressed high and low levels of these markers were compared with patient outcomes using Kaplan-Meier curves and multivariable recursive partitioning for discrete-time survival tree analysis. Prognostic index was delineated by a multivariable Cox proportional hazards model of immune cell and stromal markers and PFS. Findings were validated using 279 tissue microarray specimens from 93 patients in a separate cohort. RESULTS: Levels of CD3, CD4, CD8, CD68, and CD206 were independently associated with tumor recurrence. Recursive partitioning for discrete-time survival tree analysis identified a high level of CD3 as the strongest independent predictor for longer PFS. Tumors with levels of CD3 and high levels of CD206 associated with a median PFS time of 16.6 months and a median prognostic index of -0.32 (95% confidence interval [CI] -0.35 to -0.31), whereas tumors with low level of CD3 cell and low level of CD8 and high level of CD68 associated with a median PFS time of 7.9 months and a prognostic index of 0.32 (95% CI 0.050-0.32); we called these patterns histologic signatures. Stroma composition, when unassociated with inflammatory cell markers, did not associate significantly with PFS. In the validation cohort, the histologic signature resulted in an error matrix accuracy of predicted response of 0.75 (95% CI 0.64-0.83; accuracy P < .001). CONCLUSIONS: In an analysis of PDAC tissue microarray specimens, we identified and validated a histologic signature, based on leukocyte and stromal factors, that associates with PFS times of patients with resected PDACs. Immune cells might affect the composition of the pancreatic stroma to affect progression of PDAC. These findings provide new insights into the immune response to PDAC.


Assuntos
Adenocarcinoma/imunologia , Carcinoma Ductal Pancreático/imunologia , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Pancreáticas/imunologia , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/análise , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/cirurgia , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia
5.
Br J Cancer ; 116(11): 1462-1469, 2017 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-28449008

RESUMO

BACKGROUND: Mutations in the KRAS gene can be detected in about 70-90% of pancreatic cancer (PC) cases. Whether these mutations have a prognostic or predictive value remains elusive. Furthermore, the clinical relevance of the extended RAS (KRAS+NRAS) mutational status is unclear in PC. METHODS: We prospectively defined a PC patient population who received erlotinib-free chemotherapy regimens. A statistically significant difference between KRAS wild-type and KRAS mutated tumours in at least 160 patients in this population would support the assumption of a rather prognostic role of KRAS. RESULTS: One hundred and seventy-eight tumour samples were collected from prospective clinical studies and successfully analysed for the extended RAS status: 37 tumours were KRAS wild-type (21%), whereas 141 (79%) carried a KRAS mutation; 132 of these mutations were found in KRAS exon 2 (74%), whereas only 9 mutations (5%) were detected in KRAS exon 3. Within KRAS exon 4 and NRAS exons 2-4, no mutations were apparent. There was no significant difference in overall survival for KRAS wild-type vs mutant patients (9.9 vs 8.3 months, P=0.70). CONCLUSIONS: Together with the results of the AIO-PK-0104-trial, the present analysis supports the notion that KRAS mutation status is rather predictive than prognostic in advanced PC.


Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , GTP Fosfo-Hidrolases/genética , Proteínas de Membrana/genética , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Adenocarcinoma/secundário , Antígeno CA-19-9/sangue , Capecitabina/administração & dosagem , Cisplatino/administração & dosagem , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Análise Mutacional de DNA , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Receptores ErbB/antagonistas & inibidores , Cloridrato de Erlotinib/uso terapêutico , Éxons , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Neoplasias Pancreáticas/patologia , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Taxa de Sobrevida , Gencitabina
6.
BMC Cancer ; 17(1): 374, 2017 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-28549417

RESUMO

BACKGROUND: Despite the introduction of novel effective treatment regimens like gemcitabine plus nab-paclitaxel and FOLFIRINOX, pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive epithelial tumors. Among the genetic alterations frequently found in PDAC, mutations in the KRAS gene might play a prognostic role regarding overall survival and may also have the potential to predict the efficacy of anti-EGFR treatment. CASE PRESENTATION: We report the clinical case of a 69 year old Caucasian female that was diagnosed with histologically confirmed locally advanced PDAC with lymph node involvement in August 2010. At the time of first diagnosis, tumor tissue obtained from an open regional lymph node biopsy showed a poorly differentiated adenocarcinoma with a wild type sequence within exon 2 (codon 12/13) of the KRAS gene. The patient initially received single-agent gemcitabine and a subsequent 5-FU-based chemoradiotherapy with a sequential maintenance chemotherapy with oral capecitabine resulting in a long term disease control. Local disease progression occurred in May 2014 and the patient underwent pancreaticoduodenectomy in September 2014. A novel KRAS gene mutation (c.35G > T, p.G12 V) in exon 2 (codon 12) was detected within the surgical specimen. As of January 2016 the patient is still alive and without evidence of the underlying disease. CONCLUSIONS: Specifically in the context of clinical trials and translational research in PDAC a re-assessment of molecular biomarkers, i. e. KRAS, at defined time points (e. g. relapse, disease progression, unusual clinical course) may be indicated in order to detect a potential switch in biomarker status during the course of disease.


Assuntos
Carcinoma Ductal Pancreático/genética , Recidiva Local de Neoplasia/genética , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Idoso , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/terapia , Quimiorradioterapia/métodos , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Feminino , Fluoruracila/uso terapêutico , Humanos , Mutação , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/terapia , Pancreaticoduodenectomia , Pesquisa Translacional Biomédica , Gencitabina , Neoplasias Pancreáticas
7.
Anticancer Drugs ; 28(7): 717-722, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28582279

RESUMO

Our aim was to explore the impact of the HER2/neu, HER3 receptor as well as their ligands' neuregulin (NRG1) expression on the outcome of patients with metastatic colorectal cancer (mCRC). NRG1, HER2/neu and HER3 expression was evaluated in 208 patients with mCRC receiving 5-FU/LV plus irinotecan or irinotecan plus oxaliplatin as the first-line treatment. Biomarker expression was correlated with the outcome of patients. NRG1 (low: 192 vs. high: 16), HER2/neu (low: 201 vs. high: 7) and HER3 (low: 69 vs. high: 139) expressions were assessed in 208 patients. High versus low NRG1 expression significantly affected progression-free survival (PFS) [4.7 vs. 8.2 months, hazard ratio (HR): 2.45; 95% confidence interval (CI): 1.45-4.13; P=0.001], but not overall survival (OS) (15.5 vs. 20.7 months, HR: 1.33; 95% CI: 0.76-2.35; P=0.32). High versus low HER3 expression (PFS: 7.1 vs. 8.8 months, HR: 1.11; 95% CI: 0.82-1.50; P=0.50; OS: 19.8 vs. 21.1 months, HR: 0.95; 95% CI: 0.70-1.30; P=0.75) and high compared with low HER2/neu expression (PFS: 7.7 vs. 8.0 months, HR: 1.07; 95% CI: 0.71-1.60; P=0.75; OS: 16.6 vs. 21.1 months, HR: 1.13; 95% CI: 0.75-1.71; P=0.57) did not influence outcome. High NRG1 expression was associated with inferior PFS in the FIRE-1 trial. We did not detect a prognostic impact of HER2/neu and HER3 overexpression in mCRC. The frequency of overexpression was comparable with other studies.


Assuntos
Biomarcadores Tumorais/biossíntese , Neoplasias Colorretais/metabolismo , Neuregulina-1/biossíntese , Receptor ErbB-2/biossíntese , Receptor ErbB-3/biossíntese , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Fluoruracila/administração & dosagem , Humanos , Irinotecano , Leucovorina/administração & dosagem , Metástase Neoplásica , Neuregulina-1/genética , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Prognóstico , Receptor ErbB-2/genética , Receptor ErbB-3/genética , Estudos Retrospectivos
8.
Int J Mol Sci ; 18(5)2017 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-28534865

RESUMO

The role of the tumor suppressor mothers against decapentaplegic homolog 4 (SMAD4) has not yet been defined in patients (pts) with advanced pancreatic cancer (aPC). This translational research study was designed to evaluate the impact of tumoral SMAD4 loss on clinicopathological parameters and outcome in PC patients receiving palliative chemotherapy. Using immunohistochemistry, we examined SMAD4 expression in tumor tissue of 143 aPC pts treated within completed prospective clinical and biomarker trials. In uni- and multivariate analyses, SMAD4 expression status was correlated to clinicopathological patient characteristics and outcome. At chemotherapy initiation, 128 pts had metastatic PC; most pts (n = 99) received a gemcitabine-based regimen. SMAD4 loss was detected in 92 pts (64%); patient characteristics such as gender, age, tumor grading, disease stage or number of metastatic sites had no significant impact on tumoral SMAD4 status. In univariate analyses, SMAD4 loss had no impact on overall survival (hazard ratio (HR) 1.008, p = 0.656); however, we observed a prolonged progression-free survival (HR 1.565, p = 0.038) in pts with tumoral SMAD4 loss. This finding was confirmed in multivariate analyses (HR 1.790, p = 0.040), but only for gemcitabine-treated pts. In contrast to previous studies in resectable PC, loss of SMAD4 expression was not associated with a negative outcome in patients with advanced PC receiving systemic chemotherapy.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Desoxicitidina/análogos & derivados , Pâncreas/efeitos dos fármacos , Neoplasias Pancreáticas/tratamento farmacológico , Proteína Smad4/análise , Biomarcadores Tumorais/análise , Desoxicitidina/uso terapêutico , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Pâncreas/patologia , Neoplasias Pancreáticas/patologia , Modelos de Riscos Proporcionais , Estudos Prospectivos , Resultado do Tratamento , Gencitabina
10.
Br J Cancer ; 115(12): 1520-1529, 2016 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-27802454

RESUMO

BACKGROUND: Conflicting results on the role of secreted protein acidic and rich in cysteins (SPARC) expression have been reported in resected pancreatic ductal adenocarcinoma (PDAC), and its prognostic and/or predictive role in advanced PDAC (aPDAC) has not been extensively investigated yet. This study was designed to evaluate SPARC expression as a biomarker in aPDAC patients (pts) not receiving nab-paclitaxel. METHODS: Using immunohistochemistry, we examined the stromal as well as the tumoral (i.e., cytoplasmic) SPARC expression in tumour tissue (primary tumours and metastases) of 134 aPDAC pts participating in completed prospective clinical and biomarker trials. The SPARC expression levels were correlated to the pts' clinicopathological parameters and survival times. RESULTS: Sixty-seven per cent of the analysed tumours showed high stromal SPARC expression, which was not associated with overall survival (OS, median 9.1 vs 7.6 months, P=0.316). A positive cytoplasmic SPARC expression was detected in 55% of the tumours and correlated significantly with inferior progression-free survival (PFS, 6.2 vs 8.6 months, P=0.004) and OS (7.8 vs 8.4 months, P=0.032). This association was strongest for pts, where primary tumour tissue was examined (PFS: 6.7 vs 10.8 months, P=0.004; OS: 7.9 vs 11.9 months, P=0.030), whereas no significant correlation was detected for pts, where only metastatic tissue was available (PFS: 5.8 vs 6.6 months, P=0.502; OS: 7.0 vs 7.8 months, P=0.452). In pts receiving gemcitabine-based chemotherapy cytoplasmic SPARC expression was significantly associated with an inferior PFS and OS (PFS: 6.2 vs 9.2 months, P=0.002; OS 7.3 vs 9.9 months, P=0.012), whereas no such association was detected for stromal SPARC expression or for pts receiving fluoropyrimidine-based chemotherapy. CONCLUSION: We identified cytoplasmic SPARC expression in the primary tumour as a biomarker associated with inferior PFS and OS in aPDAC. Cytoplasmic SPARC expression may furthermore act as a negative predictive biomarker in pts treated with gemcitabine-based chemotherapy.


Assuntos
Osteonectina/metabolismo , Paclitaxel/uso terapêutico , Neoplasias Pancreáticas/metabolismo , Algoritmos , Antineoplásicos Fitogênicos/uso terapêutico , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/tratamento farmacológico
11.
Pancreatology ; 16(4): 593-8, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27067420

RESUMO

PURPOSE: Liver metastasis represents the first site of dissemination in >80% of metastatic pancreatic cancer (PC) patients. Pulmonary metastasis as first site of dissemination in PC is a rare event and might define a biologically distinct subgroup in metastatic PC. METHODS: Consecutive PC patients who were diagnosed or treated with isolated pulmonary metastases at our high-volume comprehensive cancer center were included in a prospectively maintained database between 2002 and 2015. Medical records and correlating computed tomography findings (CT) were retrospectively analyzed. RESULTS: A total of 40 PC patients with isolated pulmonary metastases were identified. Pulmonary metastases represented disease recurrence after initial resection of PC in 22 patients and disease progression of locally advanced pancreatic cancer in 5 patients. 14 out of 27 PC patients (56%) had received chemoradiotherapy for localized disease prior to pulmonary metastasis. Data on 1st-line treatment for pulmonary metastases was available for 38 patients: most patients (71%) received a gemcitabine-based chemotherapy regimen, 5 patients (13%) received best supportive care. After a median follow-up of 37.3 months, median survival after diagnosis of pulmonary metastasis was estimated with 25.5 months (95% CI 19.1-31.8); a significantly improved survival after diagnosis of pulmonary metastasis was observed for patients with less than 10 lung metastases (31.3 vs 18.7 months, p = 0.003) and for an unilateral localization of lung involvement (31.3 vs 21.8 months, p = 0.03). CONCLUSIONS: Our results suggest a favorable outcome of PC patients with isolated pulmonary metastases. Further research is warranted to elucidate the specific molecular characteristics of this rare subgroup.


Assuntos
Neoplasias Pulmonares/secundário , Neoplasias Pancreáticas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/uso terapêutico , Quimiorradioterapia , Terapia Combinada , Bases de Dados Factuais , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Progressão da Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/terapia , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Tomografia Computadorizada por Raios X , Gencitabina
12.
Tumour Biol ; 36(4): 2631-40, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25472579

RESUMO

The present prospective single-center study investigated the prognostic role of novel serum biomarkers in advanced pancreatic cancer (PC). Patients (pts) with locally advanced or metastatic PC treated with first-line palliative chemotherapy were included. Among others, the serum markers CYFRA 21-1, haptoglobin, serum-amyloid A (SAA), and 25-OH vitamin D3 were determined at baseline and categorized by pre-defined cut-offs [median values (MV), upper limits of normal (ULN), lower limits of normal (LLN), or the natural logarithm (ln)] and correlated with overall survival (OS). Among the 59 pts included, pre-treatment CYFRA 21-1 levels showed a strong correlation with OS independent of the applied cut-off (MV 4.9 ng/ml-14.2 vs. 4.2 months, HR 0.18, p = 0.001; ULN 3.3 ng/ml-14.2 vs. 4.4 months, HR 0.28, p = 0.003; [ln] CYFRA 21-1-HR 0.77, p = 0.013). Lower values of haptoglobin were additionally associated with an improvement in OS (categorized by LLN of 2.05 g/l-10.4 vs. 5.5 months, HR 0.46, p = 0.023; [ln] haptoglobin-HR 0.51, p = 0.036). Pts with baseline SAA values below the MV of 22 mg/l also had a prolonged OS (10.4 vs. 5.0 months, HR 0.47, p = 0.036). For 25-OH vitamin D3 levels, no significant correlation with OS was found. In multivariate analyses, pre-treatment CYFRA 21-1 levels (categorized by MV-HR 0.15, p = 0.032) as well as [ln] haptoglobin (HR 0.30, p = 0.006) retained their independent prognostic significance for OS. CYFRA 21-1, haptoglobin, and SAA might provide useful prognostic information in advanced PC. An external multicenter validation of these results is necessary.


Assuntos
Antígenos de Neoplasias/sangue , Colecalciferol/sangue , Haptoglobinas , Queratina-19/sangue , Neoplasias Pancreáticas/sangue , Proteína Amiloide A Sérica , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Biomarcadores Tumorais/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Cuidados Paliativos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Prognóstico , Análise de Sobrevida
13.
Acta Oncol ; 54(7): 993-1000, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25924969

RESUMO

BACKGROUND: Drug-induced skin toxicity may correlate with treatment efficacy in cancer patients receiving chemotherapy or biological agents. The correlation of the capecitabine-associated hand-foot skin reaction (HFS) on outcome parameters in pancreatic cancer (PC) has not yet been investigated. METHODS: Within the multicentre phase III AIO-PK0104 trial, patients with confirmed advanced PC were randomly assigned to first-line treatment with either capecitabine plus erlotinib (150 mg/day, arm A) or gemcitabine plus erlotinib (150 mg/day, arm B). A cross-over to either gemcitabine (arm A) or capecitabine (arm B) was performed after failure of the first-line regimen. Data on skin toxicity were correlated with efficacy study endpoints using uni- and multivariate analyses. To control for guarantee-time bias (GTB), we focused on subgroup analyses of patients who had completed two and three or more treatment cycles. RESULTS: Of 281 randomised patients, skin toxicity data were available for 255 patients. Median time to capecitabine-attributed HFS was two cycles, 36 of 47 (77%) HFS events had been observed by the end of treatment cycle three. Considering HFS during first-line treatment in 101 patients treated with capecitabine for at least two cycles within the capecitabine plus erlotinib arm, time to treatment failure after first- and second-line therapy (TTF2) and overall survival (OS) both were significantly prolonged for the 44 patients (44%) with HFS compared to 57 patients without HFS (56%) (TTF2: 7.8 vs. 3.8 months, HR 0.50, p = 0.001; OS: 10.4 vs. 5.9 months, HR 0.55, p = 0.005). A subgroup analysis of 70 patients on treatment with capecitabine for at least three cycles showed similar results (TTF2: 8.3 vs. 4.4 months, HR 0.53, p = 0.010; OS: 10.4 vs. 6.7 months, HR 0.62, p = 0.056). CONCLUSION: The present subgroup analysis from AIO-PK0104 suggests that HFS may serve as an independent clinical predictor for treatment outcome in capecitabine-treated patients with advanced PC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Síndrome Mão-Pé/epidemiologia , Neoplasias Pancreáticas/tratamento farmacológico , Adulto , Idoso , Capecitabina/administração & dosagem , Capecitabina/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Cloridrato de Erlotinib/administração & dosagem , Cloridrato de Erlotinib/efeitos adversos , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/mortalidade , Resultado do Tratamento , Gencitabina
14.
BMC Cancer ; 14: 624, 2014 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-25164437

RESUMO

BACKGROUND: The role of pERK, pAKT and p53 as biomarkers in patients with advanced pancreatic cancer has not yet been defined. METHODS: Within the phase III study AIO-PK0104 281 patients with advanced pancreatic cancer received an erlotinib-based 1st-line regimen. Archival tissue from 153 patients was available for central immunohistochemistry staining for pERK, pAKT and p53. Within a subgroup analysis, biomarker data were correlated with efficacy endpoints and skin rash using a Cox regression model. RESULTS: Fifty-five out of 153 patients were classified as pERKlow and 98 patients as pERKhigh; median overall survival (OS) was 6.2 months and 5.7 months, respectively (HR 1.29, p = 0.16). When analysing pERK as continuous variable, the pERK score was significantly associated with OS (HR 1.06, 95% CI 1.0-1.12, p = 0.05). Twenty-one of 35 patients were pAKTlow and 14/35 pAKThigh with a corresponding median OS of 6.4 months and 6.8 months, respectively (HR 1.03, p = 0.93). Four out of 50 patients had a complete loss of p53 expression, 20 patients a regular expression and 26 patients had tumors with p53 overexpression. The p53 status had no impact on OS (p = 0.91); however, a significant improvement in progression-free survival (PFS) (6.0 vs 1.8 months, HR 0.24, p = 0.02) and a higher rate of skin rash (84% vs 25%, p = 0.02) was observed for patients with a regular p53 expression compared to patients with a complete loss of p53. CONCLUSION: pERK expression may have an impact on OS in erlotinib-treated patients with advanced pancreatic cancer; p53 should be further investigated for its potential role as a predictive marker for PFS and skin rash. TRIAL REGISTRATION: NCT00440167 (registration date: February 22, 2007).


Assuntos
Biomarcadores Tumorais/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quinazolinas/uso terapêutico , Proteína Supressora de Tumor p53/metabolismo , eIF-2 Quinase/metabolismo , Adulto , Cloridrato de Erlotinib , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Fosforilação , Quinazolinas/efeitos adversos , Análise de Sobrevida , Proteína Supressora de Tumor p53/genética , Adulto Jovem
15.
Anticancer Drugs ; 25(7): 854-6, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24637577

RESUMO

Diffuse malignant peritoneal mesothelioma (DMPM) is a rare disease. Although most patients eligible for surgery undergo cytoreductive surgery in combination with hyperthermic intraperitoneal chemotherapy, the role of perioperative systemic chemotherapy still remains undefined. Here we report the case of a 52-year-old female patient with advanced sarcomatoid DMPM. After five cycles of systemic pemetrexed and cisplatin, along with two cycles of regional hyperthermia, tumor resection with histomorphological examination showed a complete pathological response. We therefore conclude that there is a subgroup of DMPM patients that might benefit from systemic neoadjuvant chemotherapy with pemetrexed and cisplatin.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Hipertermia Induzida , Mesotelioma/terapia , Terapia Neoadjuvante , Neoplasias Peritoneais/terapia , Sarcoma/terapia , Cisplatino/administração & dosagem , Feminino , Glutamatos/administração & dosagem , Guanina/administração & dosagem , Guanina/análogos & derivados , Humanos , Mesotelioma/patologia , Pessoa de Meia-Idade , Pemetrexede , Neoplasias Peritoneais/patologia , Sarcoma/patologia
16.
Sci Total Environ ; 943: 173807, 2024 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-38852873

RESUMO

There is growing concern about the rising levels of dissolved organic matter (DOM) in surface waters across the Northern hemisphere. However, only limited research has been conducted to unveil its precise origin. Compositional changes along terrestrial-aquatic pathways can help determine the terrestrial sources of DOM in streams. Stream water, soil water and soil horizons were sampled at four sites representing typical settings within a forested catchment in the Ore Mountains (Erzgebirge, Germany) from winter 2020 to spring 2022. The samples were analyzed using pyrolysis-gas chromatography/mass spectrometry (Py-GC/MS). The resulting data were successfully subjected to semi-automatic processing of the molecular composition of DOM, reaching a percentage of identified peaks up to 98 %. Principal component analysis (PCA) and cluster analyses were carried out to identify distinct differences between DOM from the potential sources and in the streams. According to the PCA, organic soil horizons, soil water, and stream water samples could be clearly distinguished. Cluster analysis revealed that soil water DOM at all depths of Peats and deeper horizons of the Peaty Gleysols contributed the most to DOM in the stream section dominated by organic soils. In areas dominated by mineral soils, stream DOM resembled the DOM from the deeper mineral horizons of Cambisols and Podzols. Overall, our results suggested that most of the DOM exported from the catchment was derived from deeper mineral soil horizons, with little contribution of DOM derived from organic soils. Therefore, DOM fingerprint analysis of in-situ soil water proved to be a promising approach for tracing back the main sources of stream water DOM.

17.
Plant Cell ; 22(8): 2594-617, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20798327

RESUMO

Restriction of phosphoenolpyruvate (PEP) supply to plastids causes lethality of female and male gametophytes in Arabidopsis thaliana defective in both a phosphoenolpyruvate/phosphate translocator (PPT) of the inner envelope membrane and the plastid-localized enolase (ENO1) involved in glycolytic PEP provision. Homozygous double mutants of cue1 (defective in PPT1) and eno1 could not be obtained, and homozygous cue1 heterozygous eno1 mutants [cue1/eno1(+/-)] exhibited retarded vegetative growth, disturbed flower development, and up to 80% seed abortion. The phenotypes of diminished oil in seeds, reduced flavonoids and aromatic amino acids in flowers, compromised lignin biosynthesis in stems, and aberrant exine formation in pollen indicate that cue1/eno1(+/-) disrupts multiple pathways. While diminished fatty acid biosynthesis from PEP via plastidial pyruvate kinase appears to affect seed abortion, a restriction in the shikimate pathway affects formation of sporopollonin in the tapetum and lignin in the stem. Vegetative parts of cue1/eno1(+/-) contained increased free amino acids and jasmonic acid but had normal wax biosynthesis. ENO1 overexpression in cue1 rescued the leaf and root phenotypes, restored photosynthetic capacity, and improved seed yield and oil contents. In chloroplasts, ENO1 might be the only enzyme missing for a complete plastidic glycolysis.


Assuntos
Arabidopsis/metabolismo , Células Germinativas Vegetais/crescimento & desenvolvimento , Fosfoenolpiruvato/metabolismo , Plastídeos/metabolismo , Arabidopsis/genética , Arabidopsis/crescimento & desenvolvimento , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Cruzamentos Genéticos , Regulação da Expressão Gênica de Plantas , Técnicas de Inativação de Genes , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Microscopia Confocal , Microscopia Eletrônica de Varredura , Mutação , Fenótipo , Fosfopiruvato Hidratase/genética , Fosfopiruvato Hidratase/metabolismo , Plastídeos/genética , Pólen/ultraestrutura
18.
Complement Med Res ; 30(4): 289-298, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36843013

RESUMO

INTRODUCTION: Studies on mind-body approaches in patients with advanced pancreatic ductal adenocarcinoma (PDAC) are rare. We performed a pilot study with follow-up until 1 year to explore changes in pain, quality of life (QoL), stress, and negative emotions in patients with advanced PDAC, who regularly practiced a standardized form of spiritual meditation in addition to standard medical care. METHODS: At baseline and every 2 months for a maximum of 1 year, global pain, QoL (global, SEIQoL, FACT-G), spiritual well-being (FACIT-Sp), perceived stress (PSQ-20), anxiety and depression (HADS), and diurnal cortisol secretion (cortisol slope) were assessed. Changes from baseline were explored by pairwise comparisons of available cases. RESULTS: Twenty participants (11 women, 62 ± 9.9 SD years) participated in the study, of whom 9 patients survived the study year. Pairwise comparisons revealed transient improvements of pain after 4 and 6 months (both p values < 0.05), of global QoL after 4, 6, 8, 10 months (all p values < 0.05), of SeiQoL scores after 4 months (p < 0.05), of FACT-G scores after 6 months (p < 0.05), and of FACIT-Sp scores after 2 and 6 months (both p values < 0.05). Furthermore, overall stress levels (PSQ-20) decreased from baseline to 2, 6, and 8 months (all p values < 0.05), and anxiety declined from baseline to 6 months (p < 0.05). Depression scores and the cortisol slope did not change. CONCLUSION: This pilot study demonstrated the acceptability and feasibility of studies on spiritual meditation in patients with advanced PDAC. Randomized controlled trials are warranted to study the effects of spiritual meditation and other mind-body interventions on pain, QoL, and emotional well-being in this patient population.EinleitungBislang gibt es kaum Studien zu Mind-Body-Ansätzen bei Patienten mit fortgeschrittenem duktalem Adenokarzinom der Bauchspeicheldrüse (PDAC). Wir führten eine explorative Pilotstudie mit einer einjährigen Nachbe- obachtungszeit durch, um Veränderungen von Schmerzen, Lebensqualität, Stress und negativen Emotionen bei Patienten mit fortgeschrittenem PDAC zu untersuchen, die zusätzlich zur medizinischen Standardversorgung regelmäßig eine standardisierte Form der spirituellen Meditation praktizierten.MethodenZu Beginn der Studie und alle zwei Monate wurden über einen Zeitraum von maximal einem Jahr die globalen Schmerzen, die Lebensqualität (global, SEIQoL, FACT-G), das psychologische Wohlbefinden (FACIT-Sp), Stress (PSQ-20), Angst und Depression (HADS) sowie die circadiane Cortisolausschüttung (Cortisolabfall) untersucht. Die Änderungen gegenüber dem Ausgangswert wurden mit paarweisen Vergleichen der jeweils verfügbaren Fälle auf Signifikanz getestet.Ergebnisse20 Patienten (11 Frauen, 62 ± 9.9 SD Jahre) nahmen an der Studie teil, von denen 9 das Studienjahr überlebten. Paarweise Vergleiche zeigten vorübergehende Verbesserungen der Schmerzen nach 4 und 6 Monaten (beide p-Werte < 0.05), der globalen Lebensqualität nach 4, 6, 8 und 10 Monaten (alle p-Werte < 0.05), der SeiQoL-Werte nach 4 Monaten (p < 0.05), der FACT-G-Werte nach 6 Monaten (p < 0.05) und der FACIT-Sp-Werte nach 2 und 6 Monaten (beide p-Werte < 0.05). Außerdem war der Gesamtstress (PSQ-20) nach 2, 6 und 8 Monaten (alle p-Werte < 0.05) sowie die Ängstlichkeit nach 6 Monaten (p < 0.05) signifikant gesunken. Die Depressionswerte und der circadiane Cortisolabfall änderten sich nicht.SchlussfolgerungDiese Pilotstudie weist auf die Akzeptanz und Durchführbarkeit von Studien zu spiritueller Meditation bei Patienten mit fortgeschrittenem PDAC hin. Randomisierte kontrollierte Studie sollten folgen, um die Effekte von spiritueller Meditation und anderen Mind-Body-Interventionen auf Schmerzen, Lebensqualität und emotionales Wohlbefinden in dieser Patientengruppe zu untersuchen.


Assuntos
Adenocarcinoma , Meditação , Neoplasias Pancreáticas , Humanos , Feminino , Qualidade de Vida/psicologia , Projetos Piloto , Hidrocortisona , Emoções , Neoplasias Pancreáticas/terapia , Dor , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias Pancreáticas
19.
Oncol Res Treat ; 46(3): 106-115, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36529119

RESUMO

INTRODUCTION: To this date, surgery remains the only potentially curative approach in the treatment of pancreatic cancer. To analyse the clinical impact of a structured post-operative follow-up programme, we retrospectively analysed a cohort of resected pancreatic adenocarcinoma patients treated at LMU Munich. METHODS: Pancreatic adenocarcinoma patients who underwent resection and presented for regular follow-up visits at our centre between 2002 and 2017 were identified from two existing study cohorts. Diagnosis of recurrences was categorised by timing (within or outside a scheduled follow-up visit) and detection modality (imaging, CA 19-9 increase, or clinical deterioration) and correlated with disease-free survival and overall survival (OS). RESULTS: One hundred and twenty-five patients with resected pancreatic adenocarcinoma were included in this analysis. Median OS in the whole cohort was 21.1 months. Of these 125 patients, 103 (82.4%) patients had a documented relapse. Tumour recurrences detected within a scheduled follow-up visit (n = 86, 83.5%) compared to recurrences becoming apparent at an unplanned visit (n = 17, 16.5%) were associated with a significantly improved OS (median 25.5 vs. 20.2 months, p = 0.019). Compared to patients with recurrence detected by clinical deterioration (n = 4, 3.9%), patients with recurrences detected by imaging or laboratory abnormalities (n = 99, 96.0%) had a longer median OS (24.8 vs. 15.1 months, p = 0.007). DISCUSSION: A structured follow-up after pancreatic ductal adenocarcinoma resection may have an impact on patient outcome. Prospective trials are needed to evaluate the clinical impact of post-operative follow-up programmes.


Assuntos
Adenocarcinoma , Carcinoma Ductal Pancreático , Deterioração Clínica , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Estudos Retrospectivos , Adenocarcinoma/patologia , Estudos Prospectivos , Recidiva Local de Neoplasia , Carcinoma Ductal Pancreático/patologia , Seguimentos , Neoplasias Pancreáticas
20.
J Cancer Res Clin Oncol ; 149(6): 2463-2474, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35737090

RESUMO

PURPOSE: Novel biomarkers to better predict outcome and select the best therapeutic strategy for the individual patient are necessary for pancreatic ductal adenocarcinoma (PDAC). METHODS: Using a panel assay, multiple biomarkers (IFN-γ, IL-10, IL-6, IL-8, TNF-α, CEA, CA 19-9, CYFRA 21-1, HE4, PD-1 and PD-L1 levels) were measured in serum samples of 162 patients with resected, locally advanced and metastatic PDAC in this retrospective single-center study. Optimal cut-off values to differentiate prognostic subgroups with significantly different overall survival (OS) were determined by receiver operator characteristics and Youden Index analysis. Marker levels were assessed before the start of chemotherapy and correlated with OS by univariate and multivariate Cox analysis. RESULTS: Median OS for resected patients was 28.2 months, for locally advanced patients 17.9 months and for patients with metastatic disease 8.6 months. CYFRA 21-1 and IL-8 discriminated metastatic from locally advanced patients best (AUC 0.85 and AUC 0.81, respectively). In univariate analyses, multiple markers showed prognostic relevance in the various subgroups. However, multivariate Cox models comprised only CYFRA 21-1 in the resected group (HR 1.37, p = 0.015), IL-10 in locally advanced PDAC (HR 10.01, p = 0.014), as well as CYFRA 21-1 and CA 19-9 in metastatic PDAC (p = 0.008 and p = 0.010) as an independent prognostic marker for overall survival. CONCLUSION: IL-10 levels may have independent prognostic value in locally advanced PDAC, whereas CYFRA 21-1 levels are prognostic after PDAC surgery. CYFRA 21-1 and IL-8 have been identified to best discriminate metastatic from locally advanced patients.


Assuntos
Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Biomarcadores Tumorais , Interleucina-10 , Fator de Necrose Tumoral alfa/uso terapêutico , Receptor de Morte Celular Programada 1 , Antígeno B7-H1 , Estudos Retrospectivos , Interleucina-8 , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/patologia , Prognóstico , Adenocarcinoma/patologia , Neoplasias Pancreáticas
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