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2.
Patient Saf Surg ; 15(1): 31, 2021 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-34537080

RESUMO

BACKGROUND: Colectomy with transanal ileal pouch-anal anastomosis (taIPAA) is a surgical technique that can be used to treat benign colorectal disease. Ulcerative colitis is the most frequent inflammatory bowel disease (IBD) and although pharmacological therapy has improved, colectomy rates reach up to 15%. The objective of this study was to determine anastomotic leakage rates and treatment after taIPAA as well as short- and long-term pouch function. METHODS: We conducted a retrospective analysis of a prospective database of all patients undergoing taIPAA at an academic tertiary referral center in Germany, between 01/03/2015 and 31/08/2019. Patients with indications other than ulcerative colitis or with adjuvant chemotherapy following colectomy for colorectal carcinoma were excluded for short- and long-term follow up due to diverging postoperative care yet considered for evaluation of anastomotic leakage. RESULTS: A total of 22 patients undergoing taIPAA during the study time-window were included in analysis. Median age at the time of surgery was 32 ± 12.5 (14-54) years. Two patients developed an anastomotic leakage at 11 days (early anastomotic leakage) and 9 months (late anastomotic leakage) after surgery, respectively. In both patients, pouches could be preserved with a multimodal approach. Twenty patients out of 22 met the inclusion criteria for short and long term follow-up. Data on short-term pouch function could be obtained in 14 patients and showed satisfactory pouch function with only four patients reporting intermittent incontinence at a median stool frequency of 9-10 times per day. In the long-term we observed an inflammation or "pouchitis" in 11 patients and a pouch failure in one patient. CONCLUSION: Postoperative complication rates in patients with benign colorectal disease remain an area of concern for surgical patient safety. In this pilot study on 22 selected patients, taIPAA was associated with two patients developing anastomotic leakage. Future large-scale validation studies are required to determine the safety and feasibility of taIPAA in patients with ulcerative colitis.

3.
J Biomech ; 128: 110714, 2021 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-34534790

RESUMO

Radical resection remains the only curative treatment option in pancreatic cancer. Postoperative pancreatic fistulas (POPF) occur in up to 30% of patients leading to prolonged hospital-stay, increased cost of care and morbidity and mortality. Mechanical properties of the pancreas are associated with POPF. The aim of this study is to analyze the role of extracellular matrix (ECM) and tissue mechanics in the risk of POPF. Biopsies of 41 patients receiving a partial pancreas-resection are analyzed. Clinical data, ECM components and mechanical properties are correlated with POPF. Preoperative cholestasis is correlated with reduced risk of POPF, which comes along with a dilatation of the pancreatic duct and significantly higher content of collagen I. Patients developing POPF exhibited a degenerated tissue integrity, with significantly lower content of fibronectin and a trend for lower collagen I, III, IV and hyaluronic acid. This correlated with a soft tactile sensation of the surgeon during the intervention. However, this was not reflected with tissue mechanics evaluated by ex vivo uniaxial compression testing, where a significantly higher elastic modulus and no effect on the stress relaxation time were found. In conclusion, patients with cholestasis seem to have a lower risk for POPF, and an increase in collagen I. A degenerated matrix with lower content of structural ECM components correlates with increased risk of POPF. However, ex vivo uniaxial compression testing failed to clearly explain the link of ECM properties and POPF.


Assuntos
Fístula Pancreática , Pancreaticoduodenectomia , Matriz Extracelular , Humanos , Pâncreas , Fístula Pancreática/etiologia , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Fatores de Risco
4.
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
5.
J Clin Med ; 10(5)2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33668295

RESUMO

BACKGROUND: Cardiac function can be influenced by liver cirrhosis and should be thoroughly evaluated before liver transplantation. We investigated left ventricular (LV) and, for the first time, left atrial (LA) strain and strain rate in end-stage liver cirrhosis patients of different etiologies. METHODS: This retrospective, cross-sectional study evaluated left heart function in 80 cirrhosis patients and 30 controls using standardized echocardiographic techniques and speckle tracking technology (STE) analysis. Serum markers of liver function were used for correlation analysis. RESULTS: While conventional parameters demonstrated no alteration in systolic function, speckle tracking analysis showed a significant increase in LV longitudinal strain throughout all cardiac layers, with significant correlation to model of end-stage liver disease (MELD) score. LA reservoir and conduit strain as well as LA strain rate in all phases were significantly reduced in end-stage liver disease (ESLD) patients compared to control. STE for the evaluation of LA phasic function seemed to be more sensitive than volumetric methods. Kaplan-Meier curves showed a trend towards reduced post-transplant survival in patients with a reduced LA reservoir and conduit strain. CONCLUSION: STE analysis detected increased LV and decreased LA deformation in cirrhosis patients, thus proving to be highly sensitive to cardiac changes and useful for more precise cardiac evaluation.

6.
EMBO Mol Med ; 13(4): e13191, 2021 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-33544398

RESUMO

SARS-CoV-2, the agent that causes COVID-19, invades epithelial cells, including those of the respiratory and gastrointestinal mucosa, using angiotensin-converting enzyme-2 (ACE2) as a receptor. Subsequent inflammation can promote rapid virus clearance, but severe cases of COVID-19 are characterized by an inefficient immune response that fails to clear the infection. Using primary epithelial organoids from human colon, we explored how the central antiviral mediator IFN-γ, which is elevated in COVID-19, affects epithelial cell differentiation, ACE2 expression, and susceptibility to infection with SARS-CoV-2. In mouse and human colon, ACE2 is mainly expressed by surface enterocytes. Inducing enterocyte differentiation in organoid culture resulted in increased ACE2 production. IFN-γ treatment promoted differentiation into mature KRT20+ enterocytes expressing high levels of ACE2, increased susceptibility to SARS-CoV-2 infection, and resulted in enhanced virus production in infected cells. Similarly, infection-induced epithelial interferon signaling promoted enterocyte maturation and enhanced ACE2 expression. We here reveal a mechanism by which IFN-γ-driven inflammatory responses induce a vulnerable epithelial state with robust replication of SARS-CoV-2, which may have an impact on disease outcome and virus transmission.


Assuntos
COVID-19/etiologia , Interferon gama/imunologia , Modelos Imunológicos , SARS-CoV-2 , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , COVID-19/imunologia , COVID-19/patologia , Diferenciação Celular/imunologia , Colo/imunologia , Colo/patologia , Colo/virologia , Suscetibilidade a Doenças , Enterócitos/metabolismo , Enterócitos/patologia , Enterócitos/virologia , Expressão Gênica , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Interferon gama/administração & dosagem , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Mucosa Intestinal/virologia , Camundongos , Organoides/imunologia , Organoides/patologia , Organoides/virologia , SARS-CoV-2/genética , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade , Replicação Viral/imunologia
7.
Medicina (Kaunas) ; 57(2)2021 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-33498866

RESUMO

Background and objectives: The Notch signaling pathway plays an important role both in the development of the ductal systems of the pancreas and the bile ducts as well as in cancer development and progression. The aim of this study was to examine the expression of central proteins of the Notch signaling pathway in pancreatobiliary tumors and its influence on patient survival. Materials and Methods: We compared the receptors (Notch1, Notch4), activating splicing factors (ADAM17), and target genes (HES1) of the Notch pathway and progenitor cell markers with relevance for the Notch signaling pathway (CD44, MSI1) between pancreatic adenocarcinomas (PDAC, n = 14), intrahepatic cholangiocarcinoma (iCC, n = 24), and extrahepatic cholangiocarcinoma (eCC, n = 22) cholangiocarcinomas via immunohistochemistry and ImageJ software-assisted analysis. An Immunohistochemistry (IHC)-score was determined by the percentage and intensity of stained (positive) cells (scale 0-7) and normal and malignant tissue was compared. In the IHC results, patients' (gender, age) and tumor (TNM Classification of Malignant Tumors, Union Internationale contre le Cancer (UICC) stages, grading, and lymphangitic carcinomatosa) characteristics were correlated to patient survival. Results: For eCC, the expression of CD44 (p = 0.043, IHC-score 3.94 vs. 3.54) and for iCC, the expression of CD44 (p = 0.026, IHC-score 4.04 vs. 3.48) and Notch1 (p < 0.001, IHC-score 2.87 vs. 1.78) was significantly higher in the tumor compared to non-malignant tissue. For PDAC, the expression of ADAM17 (p = 0.008, IHC-score 3.43 vs. 1.73), CD44 (p = 0.012, IHC-score 3.64 vs. 2.27), Notch1 (p = 0.012, IHC-score 2.21 vs. 0.64), and Notch4 (p = 0.008, IHC-score 2.86 vs. 0.91) was significantly higher in the tumor tissue. However, none of the analyzed Notch-signaling related components showed an association to patient survival. Conclusion: A significant overexpression of almost all studied components of the Notch signaling pathway can be found in the tumor tissue, however, without a significant influence on patient survival. Therefore, further studies are warranted to draw conclusions on Notch pathway's relevance for patient survival.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Receptor Notch1 , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/genética , Ductos Biliares Intra-Hepáticos , Colangiocarcinoma/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso , Proteínas de Ligação a RNA , Receptores Notch , Transdução de Sinais
8.
J Clin Med ; 10(1)2020 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-33379270

RESUMO

INTRODUCTION: The laparoscopic approach for TME is proven to be non-inferior in oncological outcome compared to open surgery. Anatomical limitations in the male and obese pelvis with resulting pathological shortcomings and high conversion rates were stimuli for alternative approaches. The transanal approach for TME (TaTME) was introduced to overcome these limitations. The aim of this study was to evaluate the outcomes of TaTME for mid and low rectal cancer at our center. METHODS: TaTME is a hybrid procedure of simultaneously laparoscopic and transanal mesorectal excision. A retrospective analysis of all consecutive TaTME procedures performed at our center for mid and low rectal cancer between December 2014 and January 2020 was conducted. RESULTS: A total of 157 patients underwent TaTME, with 72.6% receiving neoadjuvant chemoradiation. Mean tumor height was 6.1 ± 2.3 cm from the anal verge, 72.6% of patients had undergone neoadjuvant chemoradiotherapy, and 34.2% of patients presented with a threatened CRM upon pretherapeutic MRI. Abdominal conversion rate was 5.7% with no conversion for the transanal dissection. Early anastomotic leakage occurred in 7.0% of the patients. Mesorectum specimen was complete in 87.3%, R1 resection rate was 4.5% (involved distal resection margin) and in 7.6%, the CRM was positive. The three-year local recurrence rate of 58 patients with a follow-up ≥ 36 months was 3.4%. Overall survival was 92.0% after 12 months, and 82.2% after 36 months. CONCLUSION: TaTME can be performed safely with acceptable long-term oncological outcome. Low rectal cancer can be well addressed by TaTME, which is an appropriate alternative with low conversion, local recurrence, adequate mesorectal quality and CRM positivity rates.

9.
Exp Clin Transplant ; 18(5): 591-597, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32799788

RESUMO

OBJECTIVES: Biliary complications such as an ischemic-type biliary lesion can increase morbidity and mortality after liver transplant. Former studies have investigated several risk factors, but the underlying pathomechanism remains unclear. The focus of this study was to investigate factors causing early-onset (< 12 mo after liver transplant) versus late-onset ischemic-type biliary lesions (> 12 mo after liver transplant). MATERIALS AND METHODS: This retrospective study included 641 patients. Patients were grouped to those who developed ischemic-type biliary lesion and those who did not. Patients developing ischemic-type biliary lesions were further subgrouped into those diagnosed early (< 12 mo) and late (> 12 mo) after liver transplant. We analyzed demographic data, characteristics, and comorbidities of the recipients and donors, operative variables, and postoperative course, as well as laboratory values. RESULTS: The incidence of ischemic-type biliary lesions was 4.9%. Retransplant was performed more frequently in patients developing ischemic-type biliary lesions. The number of transfusions of blood products was higher in ischemic-type biliary lesion patients, especially in the early-onset ischemic-type biliary lesion group. Bilirubin levels were higher in patients with ischemic-type biliary lesions starting from day 7 after the operation, particularly in the early-onset group. Survival tended to be best in the late-onset ischemic-type biliary lesion group; however, this difference was not significant. CONCLUSIONS: This study serves as a supplement to current data and the understanding of ischemic-type biliary lesions with emphasis on the relevance of disease onset and causes. We could in fact determine transfusion of blood products as a determinant of an early onset of ischemic-type biliary lesion. Bilirubin could be a surrogate marker for ischemic-type biliary lesions, especially in its early-onset form.


Assuntos
Doenças Biliares/etiologia , Isquemia/etiologia , Transplante de Fígado/efeitos adversos , Adolescente , Adulto , Idoso , Doenças Biliares/diagnóstico , Doenças Biliares/mortalidade , Doenças Biliares/cirurgia , Feminino , Humanos , Isquemia/diagnóstico , Isquemia/mortalidade , Isquemia/cirurgia , Transplante de Fígado/mortalidade , Masculino , Pessoa de Meia-Idade , Reoperação , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
10.
Invest Radiol ; 55(12): 769-774, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32796197

RESUMO

OBJECTIVES: Estimations of tumor volume and boundary in pancreatic ductal adenocarcinoma (PDAC) are crucial for surgery planning. The aim of the study is to evaluate tomoelastography for detection of PDAC and quantification of PDAC volume based on tissue stiffness. MATERIALS AND METHODS: From March 2018 to December 2019, a total of 102 participants (30 healthy participants and 72 patients with histologically proven PDAC) were prospectively enrolled in a multicenter study. Multifrequency magnetic resonance elastography was combined with tomoelastography postprocessing to generate maps of shear wave speed (SWS) depicting highly resolved anatomical details of tissue stiffness. Subregional analysis of pancreatic head, body, and tail and reproducibility tests were performed in healthy participants, whereas tumorous (PDAC-T) and nontumorous (PDAC-NT) pancreatic tissue analysis was conducted in patients. In all patients, tumor volumes measured by computed tomography (CT) were compared with SWS-derived volumes. In addition, in 32 patients, tumor sizes were evaluated by macroscopy after resection. RESULTS: Tumor volumes were quantified in 99% and 87% of all cases with tomoelastography and CT, respectively. Pancreatic SWS was highly reproducible (repeatability coefficient = 0.12) and did not vary regionally or with patient age, sex, or body mass index (all P > 0.08). Shear wave speed was higher in PDAC-T (2.08 ± 0.38 m/s) than in healthy (1.25 ± 0.09 m/s; P < 0.001) and PDAC-NT (1.28 ± 0.14 m/s; P < 0.001) participants. A threshold of 1.47 m/s separated PDAC-T from healthy volunteers (area under the curve = 1.0, sensitivity = 100%, specificity = 100%), while 1.49 m/s separated PDAC-T from PDAC-NT with high accuracy (area under the curve = 0.99, sensitivity = 90%, specificity = 100%). Tomoelastography-derived tumor volume correlated with CT volume (r = 0.91, P < 0.001) and ex vivo tumor volume (r = 0.66, P < 0.001). CONCLUSIONS: Tomoelastography provides a quantitative imaging marker for tissue stiffness depicting PDAC boundaries and separates PDAC from unaffected pancreatic tissue.


Assuntos
Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/patologia , Técnicas de Imagem por Elasticidade , Fenômenos Mecânicos , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/patologia , Carga Tumoral , Adulto , Fenômenos Biomecânicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes
11.
Clin Cancer Res ; 26(14): 3732-3739, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32234756

RESUMO

PURPOSE: We performed next-generation sequencing (NGS) in the CONKO-001 phase III trial to identify clinically relevant prognostic and predictive mutations and conducted a functional validation in The Cancer Genome Atlas (TCGA) sequencing data. EXPERIMENTAL DESIGN: Patients of the CONKO-001 trial received curatively intended surgery for pancreatic adenocarcinoma (PDAC) followed by adjuvant chemotherapy with gemcitabine (Gem) or observation only (Obs). Tissue samples of 101 patients were evaluated by NGS of 37 genes. Cox proportional hazard models were applied for survival analysis. In addition, functional genomic analyses were performed in an NGS and RNA-sequencing dataset of 146 pancreatic tumors from TCGA. RESULTS: The most common mutations in the CONKO cohort were KRAS (75%), TP53 (60%), SMAD4 (10%), CDKNA2 (9%), as well as SWI/SNF (12%) complex alterations. In untreated patients, TP53 mutations were a negative prognostic factor for disease-free survival (DFS; HR mut vs. WT 2.434, P = 0.005). With respect to gemcitabine treatment, TP53 mutations were a positive predictive factor for gemcitabine efficacy [TP53mut: HR for DFS Gem vs. Obs, 0.235 (0.130 - 0.423; P < 0.001); TP53wt: HR for DFS Gem vs. Obs, 0.794 (0.417 - 1.513; P = 0.483)] with a significant test for interaction (P = 0.003). In the TCGA dataset, TP53 mutations were associated with shortened DFS. CONCLUSIONS: In CONKO-001, the benefit from adjuvant gemcitabine was confined to the TP53mut patient group. This potentially clinical relevant observation needs to be confirmed in independent prospective studies. The sensitivity of TP53mut PDAC to gemcitabine in CONKO-001 provides a lead for further mechanistic investigations.


Assuntos
Carcinoma Ductal Pancreático/terapia , Desoxicitidina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos/genética , Recidiva Local de Neoplasia/epidemiologia , Neoplasias Pancreáticas/terapia , Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Quimioterapia Adjuvante/métodos , Ensaios Clínicos Fase III como Assunto , Análise Mutacional de DNA , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Intervalo Livre de Doença , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia/genética , Pancreatectomia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Gencitabina
12.
Anticancer Res ; 40(3): 1267-1275, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32132023

RESUMO

BACKGROUND/AIM: Pancreatic ductal adenocarcinoma (PDAC) and extrahepatic cholangio-carcinoma (eCC) represent two cancer entities with devastating prognoses. Despite recent progress in research and treatment, therapy remains challenging. Cancer stem cells (CSCs) have been shown to play an important role in metastasis and chemoresistance. Therefore, CSCs may play a promising role as a potential therapeutic target. MATERIALS AND METHODS: A total of 31 patients (23 PDAC, 8 eCC) were included in the study. CSCs were analyzed in a single-cell suspension of tumor samples via fluorescence-activated cell scanning (FACS) with a functional Hoechst 33342 staining as well as a cell surface marker staining of the CSC-panel (CD24, CD44 and EpCAM) and markers to identify fibroblasts, leukocytes and components of the notch signaling pathway. Furthermore, the potential presence of CSCs among primary cancer-associated fibroblasts (CAFs) was assessed using the same FACS-panel. RESULTS: We showed that CSCs are present in patient-derived dissociated tumor tissue. The functional and surface marker profile of CSC-detection did in fact correlate. The amount of CSCs was significantly correlated with tumor characteristics such as a higher UICC stadium and nodal invasion. CSCs were not restricted to the epithelial cell fraction in tumor tissues, which has been verified in independent analysis of primary cell cultures of CAFs. CONCLUSION: Our study confirms the in vivo presence of CSCs in PDAC and eCC, stating a clinical significance thereof and thus their plausibility as therapeutic targets. In addition, stem-like cells also seem to constitute a part of the CAFs.


Assuntos
Carcinoma Ductal Pancreático/patologia , Células-Tronco Neoplásicas/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , Prognóstico
13.
Langenbecks Arch Surg ; 405(1): 71-80, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32002628

RESUMO

INTRODUCTION: Colorectal carcinomas represent the third most common cause of cancer-related deaths in Germany. Although the incidence is significantly higher in men compared with women and gender is a well-established crucial factor for outcome in other diseases, detailed gender comparisons for colon cancer are lacking. METHODS: This retrospective population-based cohort study included all patients diagnosed with colon cancer in Germany between 2000 and 2016 who were included in the common dataset of colorectal cancer patients from the quality conference of the German Cancer Society. We compared clinical, histopathological, and therapeutic characteristics as well as overall and recurrence-free survival. RESULTS: A total of 185,967 patients were included in the study, of which 85,685 were female (46.1%) and 100,282 were male (53.9%). The proportion of women diagnosed with colon cancer decreased from 2000 to 2016 (f: 26.6 to 40.1%; m: 24.9 to 41.9%; p < 0.001), and the proportion of very old patients was especially high in women (f: 27.3%; m: 15.6%; p < 0.001). The localization in women was more right-sided (f: 45.0%, m: 36.7%; p < 0.001), and women had a higher tumor grading and a higher UICC stage (especially stage III nodal-positive) at diagnosis of primary colon cancer (UICC III: f: 22.7%, m: 21.0%; p < 0.001). We could detect a significantly better overall (hazard ratio: 0.853, lower 95%: 0.841, upper 95%: 0.864; p < 0.001) and recurrence-free survival (hazard ratio: 0.857, lower 95%: 0.845, upper 95%: 0.868; p < 0.001) in women compared with men, even though women received chemotherapy less frequently compared with men (f: 26.1%, m: 28.1%; p < 0.001). CONCLUSION: We could detect several variables that differed significantly between men and women regarding clinical, histopathological, therapeutic, and outcome factors. We believe that it is crucial to consider gender as a key factor in the diagnosis and treatment of colon cancer. Sex-specific diagnostic tools could lead to an earlier diagnosis of colon cancer in women, and ways to increase the rate of chemotherapy in women should be evaluated. Furthermore, we recommend stratifying randomized trials by gender.


Assuntos
Neoplasias do Colo/epidemiologia , Neoplasias do Colo/diagnóstico , Neoplasias do Colo/patologia , Neoplasias do Colo/terapia , Feminino , Alemanha/epidemiologia , Humanos , Masculino , Avaliação de Resultados em Cuidados de Saúde , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais
14.
Invest Radiol ; 55(5): 270-276, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31985600

RESUMO

OBJECTIVES: Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumor with a very low 5-year survival rate of 8%. The aims of this study are to determine reference values and physiologic confounders in healthy pancreas and to assess the diagnostic accuracy of ultrasound time-harmonic elastography (THE) in the detection of PDAC. MATERIALS AND METHODS: From March 2017 through May 2019, a total of 54 study participants with healthy pancreas (n = 33, CTR) or PDAC (n = 21) were prospectively enrolled. Repeatability of THE was tested in a CTR subgroup (n = 5) undergoing repeat measurement on 4 different days. Interobserver variability was analyzed in 10 healthy volunteers. Age-matched and sex-matched subgroups of CTR (n = 13) and PDAC (n = 13) were compared. In participants with histopathologically proven PDAC, measurements were performed separately in tumorous (PDAC-T) and nontumorous pancreatic tissue (PDAC-NT). Diagnostic performance of pancreatic THE was assessed by receiver operating characteristic curve analysis. RESULTS: Time-harmonic elastography was highly repeatable (intraclass correlation coefficient, 0.99), and interobserver agreement was excellent (intraclass correlation coefficient, 0.97). Shear wave speed (SWS) of PDAC-T (mean [95% confidence interval] in meters per second, 1.88 ± 0.07 [1.84-1.92]) was higher than SWS of CTR (1.63 ± 0.04 [1.60-1.66], P < 0.001) and PDAC-NT (1.59 ± 0.03 [1.57-1.61], P < 0.001). The exploratory diagnostic performance of THE in separating PDAC-T was excellent (area under the receiver operating characteristic curve, 1.0). Tumorous pancreatic ductal adenocarcinoma was distinguished from CTR and PDAC-NT with cutoff values of 1.73 m/s and 1.70 m/s, respectively. CONCLUSIONS: Pancreatic ultrasound THE has high repeatability and provides excellent imaging contrast based on SWS, allowing detection of PDAC without overlap to nontumorous pancreatic tissue.


Assuntos
Carcinoma Ductal Pancreático/diagnóstico , Técnicas de Imagem por Elasticidade/métodos , Pâncreas/diagnóstico por imagem , Neoplasias Pancreáticas/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Valores de Referência , Adulto Jovem
15.
Biomarkers ; 25(1): 62-68, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31701763

RESUMO

Context: Alcoholic liver cirrhosis is a significant risk factor for the development of hepatocellular carcinoma (HCC). The importance of tumour-associated cirrhosis in the development or progression of HCC is not understood. MiRNAs are important regulators for HCC development, but their role in HCC due to alcoholic liver cirrhosis is unclear.Objective: The aim of this study is the detection of miRNA expression in alcoholic liver cirrhosis, tumour-associated cirrhosis, and HCC.Materials and methods: We analysed the differences in the miRNA profiles of HCC, tumour-associated cirrhosis, and cirrhosis without HCC samples from 30 patients who underwent liver transplantation because of alcoholic liver disease.Results: Microarray analyses revealed 40 significantly differentially expressed miRNAs between HCC tissue and tumour-associated cirrhosis tissue. Furthermore, the microarray analysis discovered 56 differentially expressed miRNAs in tumour-associated cirrhosis and cirrhosis without HCC.Discussion: The differences of miRNA profile in alcoholic liver cirrhosis with and without HCC could improve understanding of HCC development, as well as lead to a new diagnostic tool in HCC screening.Conclusion: We were able to show for the first time, the differences of miRNA profile as promising biomarker in HCC, tumour-associated cirrhosis, and cirrhosis without HCC in context of alcoholic liver disease.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Perfilação da Expressão Gênica , Cirrose Hepática Alcoólica/genética , Neoplasias Hepáticas/genética , MicroRNAs/genética , Transcriptoma , Adulto , Carcinoma Hepatocelular/etiologia , Feminino , Alemanha , Humanos , Cirrose Hepática Alcoólica/etiologia , Neoplasias Hepáticas/etiologia , Masculino , Pessoa de Meia-Idade
16.
J Clin Med ; 8(9)2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31443575

RESUMO

BACKGROUND: Data regarding cardiac remodeling in patients with alcoholic liver cirrhosis are scarce. We sought to investigate right atrial (RA) and right ventricular (RV) structure, function, and mechanics in patients with alcoholic liver cirrhosis. METHODS: This retrospective cross-sectional investigation included 67 end-stage cirrhotic patients, who were referred for evaluation for liver transplantation and 36 healthy controls. All participants underwent echocardiographic examination including strain analysis, which was performed offline. RESULTS: RV basal diameter and RV thickness were significantly higher in patients with cirrhosis. Conventional parameters of the RV systolic function were similar between the observed groups. Global, endocardial, and epicardial RV longitudinal strains were significantly lower in patients with cirrhosis. Active RA function was significantly higher in cirrhotic patients than in controls. The RA reservoir and conduit strains were significantly lower in cirrhotic patients, while there was no difference in the RA contractile strain. Early diastolic and systolic RA strain rates were significantly lower in cirrhotic patients than in controls, whereas there was no difference in the RA late diastolic strain rate between the two groups. Transaminases and bilirubin correlated negatively with RV global longitudinal strain and RV-free wall strain in patients with end-stage liver cirrhosis. The Model for End-stage Liver Disease (MELD) score, predictor of 3-month mortality, correlated with parameters of RV structure and systolic function, and RA active function in patients with end-stage liver cirrhosis. CONCLUSIONS: RA and RV remodeling is present in patients with end-stage liver cirrhosis even though RV systolic function is preserved. Liver enzymes, bilirubin, and the MELD score correlated with RV and RA remodeling.

17.
J Gastrointest Surg ; 23(3): 492-502, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30187320

RESUMO

BACKGROUND: Pancreatic surgery at high-volume centers has undergone major changes over the last decades. However, the quality of surgery remains to be considered as one important factor for achieving long-term survival especially in patients at advanced stages of disease. METHODS: Between January 1990 and June 2017, 3000 consecutive patients have undergone pancreatic resections at our institution. Relevant postoperative data and histopathological findings as well as overall survival were analyzed. In addition, a SWOT (strengths, weaknesses, opportunities, threats) analysis of pancreatic surgery at high-volume centers was performed. RESULTS: A total of 2218 pancreatic head resections (74%), 494 distal pancreatectomies (16%), 200 total pancreatectomies (7%), and 88 other resections (3%) were performed within our study period. Despite additional vascular resections in 265 patients (9%) and additional liver resections in 167 patients (6%), overall perioperative mortality did not exceed 3%. Overall survival strongly depended on the underlying disease, as well as on lymph node stage (p = < 0.001) and surgical radicality (p = < 0.001). CONCLUSIONS: The decentralization of pancreatic surgery over the last decades has led to a focus on high-volume centers to perform extended procedures in complex patients. The present SWOT analysis underlines the significance of a centralization of pancreatic surgery for patient safety and to increase the chance of long-term survival.


Assuntos
Pancreatectomia/estatística & dados numéricos , Neoplasias Pancreáticas/cirurgia , Complicações Pós-Operatórias/epidemiologia , Adulto , Idoso , Feminino , Hepatectomia , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Pancreatectomia/efeitos adversos , Pancreatectomia/mortalidade , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Reoperação , Estudos Retrospectivos , Taxa de Sobrevida
18.
Surg Oncol ; 27(4): 688-694, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30449494

RESUMO

BACKGROUND: The role of hepatectomy for patients with liver metastases from ductal adenocarcinoma of the pancreas (PLM) remains controversial. Therefore, the aim of our study was to examine the postoperative morbidity, mortality, and long-term survivals after liver resection for synchronous PLM. METHODS: Clinicopathological data of patients who underwent hepatectomy for PLM between 1993 and 2015 were assessed. Major endpoint of this study was to identify predictors of overall survival (OS). RESULTS: During the study period, 76 patients underwent resection for pancreatic cancer and concomitant hepatectomy for synchronous PLM. Pancreatoduodenectomy, distal pancreatectomy, and total pancreatectomy were performed in 67%, 25%, and 8% of the patients, respectively. The median PLM size was 1 (1-13) cm and 36% of patients had multiple PLM. The majority of patients (96%) underwent a minor liver resection. After a median follow-up time of 130 months, 1-, 3-, and 5-year OS rates were 41%, 13%, and 7%, respectively. Postoperative morbidity and mortality rates were 50% and 5%, respectively. Preoperative and postoperative chemotherapy was administered to 5% and 72% of patients, respectively. In univariate analysis, type of pancreatic procedure (P = .020), resection and reconstruction of the superior mesenteric artery (P = .016), T4 stage (P = .086), R1 margin status at liver resection (P = .001), lymph node metastases (P = .016), poorly differentiated cancer (G3) (P = .037), no preoperative chemotherapy (P = .013), and no postoperative chemotherapy (P = .005) were significantly associated with worse OS. In the multivariate analysis, poorly differentiated cancer (G3) (hazard ratio [HR] = 1.87; 95% confidence interval [CI] = 1.08-3.24; P = .026), R1 margin status at liver resection (HR = 4.97; 95% CI = 1.46-16.86; P = .010), no preoperative chemotherapy (HR = 4.07; 95% CI = 1.40-11.83; P = .010), and no postoperative chemotherapy (HR = 1.88; 95% CI = 1.06-3.29; P = .030) independently predicted worse OS. CONCLUSIONS: Liver resection for PLM is feasible and safe and may be recommended within the framework of an individualized cancer therapy. Multimodal treatment strategy including perioperative chemotherapy and hepatectomy may provide prolonged survival in selected patients with metastatic pancreatic cancer.


Assuntos
Adenocarcinoma/mortalidade , Hepatectomia/mortalidade , Neoplasias Hepáticas/mortalidade , Neoplasias Primárias Múltiplas/mortalidade , Neoplasias Pancreáticas/mortalidade , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/patologia , Neoplasias Primárias Múltiplas/cirurgia , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
19.
Hepatobiliary Pancreat Dis Int ; 17(5): 461-472, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30243879

RESUMO

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant solid tumor with a dismal prognosis. The stroma component makes up to 90% of the tumor mass and is thought to be one of the main reasons for the tumor's high chemoresistance. Cancer associated fibroblasts (CAFs) have previously been identified to be the key stromal players. This is the first time we provide detailed in vitro experiments investigating tumor-stromal interactions when exposed to three well-known chemotherapeutic agents. METHODS: Monocultures, indirect and direct co-cultures of two PDAC cell lines (AsPC and Panc-1) and six primary patients derived CAFs were treated with gemcitabine, nab-paclitaxel and the γ-secretase-inhibitor (GSI) DAPT. The cell viability of each component was measured with XTT. Finally, IL-6 concentrations of the supernatants were analyzed. RESULTS: On the contrary to PDAC cell lines, CAF monocultures hardly responded to any treatment which suggested that stroma (CAFs) itself is more resistant to standard chemo-treatments than the epithelial cancer cells. Moreover, only a weak chemotherapeutic response was observed in direct co-cultures of cancer cells with CAFs. A change in the morphology of direct co-cultures was accompanied with the chemoresistance. CAFs were observed to build cage-like structures around agglomerates of tumor cells. High levels of IL-6 were also associated with a reduced response to therapy. Indirect co-cultures make the tumor-stromal interaction more complex. CONCLUSIONS: CAFs are highly chemoresistant. Direct cell-cell contact and high levels of IL-6 correlate with a high chemoresistance.


Assuntos
Fibroblastos Associados a Câncer/efeitos dos fármacos , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Desoxicitidina/análogos & derivados , Paclitaxel/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Fibroblastos Associados a Câncer/patologia , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Cocultura , Desoxicitidina/farmacologia , Feminino , Humanos , Masculino , Fatores de Risco , Sensibilidade e Especificidade , Células Estromais/efeitos dos fármacos , Células Estromais/patologia , Células Tumorais Cultivadas , Gencitabina
20.
Anticancer Res ; 38(9): 5379-5386, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30194192

RESUMO

BACKGROUND: Periampullary carcinomas generally confer a poor outcome. Choosing the most effective treatment regimen for each sub-entity proves challenging and is usually based on experience from pancreatic adenocarcinoma (PDAC). PATIENTS AND METHODS: The long-term follow-up is presented of 472 patients with periampullary tumors [PDAC, distal cholangiocarcinoma (dCC) and ampullary carcinomas (AC)] who underwent radical resection considering clinical characteristics, paraclinical findings and histopathological features in order to define factors of prognostic relevance. RESULTS: Patients with PDACs presented with larger tumor sizes, more frequent R1 resection, higher rate of nodal and perineural invasion, higher tumor stage according to the classification of tumors of the Union Internationale contre le Cancer when compared to those with dCCs and ACs. In a multivariate analysis, age >65 years, postoperative complications and higher grading of the tumor proved to be independent prognostic factors for survival. CONCLUSION: Patients suffering from PDAC have the worst prognosis and greatest benefit from radical resection of all patients with periampullary tumors. More detailed studies are warranted to better distinguish between the different entities.


Assuntos
Ampola Hepatopancreática/patologia , Carcinoma Ductal Pancreático/patologia , Colangiocarcinoma/patologia , Neoplasias do Ducto Colédoco/patologia , Neoplasias Duodenais/patologia , Neoplasias Pancreáticas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Ampola Hepatopancreática/cirurgia , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/cirurgia , Distribuição de Qui-Quadrado , Colangiocarcinoma/mortalidade , Colangiocarcinoma/cirurgia , Tomada de Decisão Clínica , Neoplasias do Ducto Colédoco/mortalidade , Neoplasias do Ducto Colédoco/cirurgia , Neoplasias Duodenais/mortalidade , Neoplasias Duodenais/cirurgia , Feminino , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/cirurgia , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Carga Tumoral
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