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1.
Cell Mol Life Sci ; 75(2): 323-334, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28849249

RESUMO

Colorectal cancer (CRC) is one of the most frequent malignancies in the Western world. Early tumor detection and intervention are important determinants on CRC patient survival. During early tumor proliferation, dissemination and angiogenesis, platelets store and segregate proteins actively and selectively. Hence, the platelet proteome is a potential source of biomarkers denoting early malignancy. By comparing protein profiles of platelets between healthy volunteers (n = 12) and patients with early- (n = 7) and late-stage (n = 5) CRCs using multiplex fluorescence two-dimensional gel electrophoresis (2D-DIGE), we aimed at identifying differentially regulated proteins within platelets. By inter-group comparisons, 94 differentially expressed protein spots were detected (p < 0.05) between healthy controls and patients with early- and late-stage CRCs and revealed distinct separations between all three groups in principal component analyses. 54 proteins of interest were identified by mass spectrometry and resulted in high-ranked Ingenuity Pathway Analysis networks associated with Cellular function and maintenance, Cellular assembly and organization, Developmental disorder and Organismal injury and abnormalities (p < 0.0001 to p = 0.0495). Target proteins were validated by multiplex fluorescence-based Western blot analyses using an additional, independent cohort of platelet protein samples [healthy controls (n = 15), early-stage CRCs (n = 15), late-stage CRCs (n = 15)]. Two proteins-clusterin and glutathione synthetase (GSH-S)-featured high impact and were subsequently validated in this independent clinical cohort distinguishing healthy controls from patients with early- and late-stage CRCs. Thus, the potential of clusterin and GSH-S as platelet biomarkers for early detection of CRC could improve existing screening modalities in clinical application and should be confirmed in a prospective multicenter trial.


Assuntos
Plaquetas/metabolismo , Clusterina/metabolismo , Neoplasias Colorretais/metabolismo , Glutationa Sintase/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/diagnóstico , Detecção Precoce de Câncer , Eletroforese em Gel Bidimensional , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mapas de Interação de Proteínas , Proteoma/metabolismo
2.
Int J Colorectal Dis ; 28(6): 767-75, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23296402

RESUMO

PURPOSE: Presently, no markers exist to predict metachronous metastasis at the time a primary colorectal cancer is diagnosed. While aneuploidy indicates poor survival prognosis and elevated carcinoembryonic antigen (CEA) levels the presence of recurrent disease, the predictive value of both markers regarding imminent metachronous metastases is unclear. METHODS: Sixty patients with distant recurrence throughout a 5-year follow-up (TM+) were randomly chosen and 60 patients without metastasis matched to this cohort (TM-). In addition, an enlarged collective (n = 217; n TM+ = 85, n TM- = 132) with median follow-up of 79.2 months was assessed by logistic regression regarding metachronous metastases. Univariate and stepwise regression analyses included clinicopathological characteristics, preoperative CEA levels and aneuploidy assessed by DNA image cytometry. RESULTS: The matched-pair collective showed aneuploidy in 71.1 % (TM-) and 85.0 % (TM+; p = 0.076), and elevated CEA in 24.5 % (TM-) and 52.2 % [TM+; odds ratio (OR), 3.414; p = 0.007]. The enlarged collective presented aneuploidy in 71.2 % (TM-) and 83.5 % (TM+; OR 2.050, p = 0.038), and elevated CEA in 28.6 % (TM-) and 48.9 % (TM+; OR 2.391, p = 0.020). Elevated CEA and aneuploidy did not show any association (p = 0.919). In contrast, logistic regression analyses demonstrated that besides increased T category (OR 1.745, p = 0.019), both elevated CEA level (OR 2.633, p = 0.015) and aneuploidy (OR 1.929, p = 0.058) were independent predictive markers for metachronous metastasis. CONCLUSIONS: Our data show that aneuploidy and elevated CEA levels besides increased T category could serve for individual risk assessment to predict metachronous metastases. The fact that still aneuploidy missed the significance level by a small margin emphasizes the need for larger validation studies.


Assuntos
Aneuploidia , Antígeno Carcinoembrionário/sangue , Neoplasias Colorretais/sangue , Neoplasias Colorretais/genética , Segunda Neoplasia Primária/sangue , Segunda Neoplasia Primária/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/patologia , Demografia , Feminino , Citometria de Fluxo , Humanos , Modelos Logísticos , Masculino , Análise por Pareamento , Pessoa de Meia-Idade , Fatores de Risco , Análise de Sobrevida , Adulto Jovem
3.
Cell Mol Life Sci ; 69(2): 325-33, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21739232

RESUMO

DNA aneuploidy has been identified as a prognostic factor in the majority of epithelial malignancies. We aimed at identifying ploidy-associated protein expression in endometrial cancer of different prognostic subgroups. Comparison of gel electrophoresis-based protein expression patterns between normal endometrium (n = 5), diploid (n = 7), and aneuploid (n = 7) endometrial carcinoma detected 121 ploidy-associated protein forms, 42 differentially expressed between normal endometrium and diploid endometrioid carcinomas, 37 between diploid and aneuploid endometrioid carcinomas, and 41 between diploid endometrioid and aneuploid uterine papillary serous cancer. Proteins were identified by mass spectrometry and evaluated by Ingenuity Pathway Analysis. Targets were confirmed by liquid chromatography/mass spectrometry. Mass spectrometry identified 41 distinct polypeptides and pathway analysis resulted in high-ranked networks with vimentin and Nf-κB as central nodes. These results identify ploidy-associated protein expression differences that overrule histopathology-associated expression differences and emphasize particular protein networks in genomic stability of endometrial cancer.


Assuntos
Carcinoma Endometrioide/genética , Cistadenocarcinoma Seroso/genética , Neoplasias do Endométrio/genética , Instabilidade Genômica , Idoso , Idoso de 80 Anos ou mais , Aneuploidia , Carcinoma Endometrioide/metabolismo , Carcinoma Endometrioide/patologia , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patologia , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Endométrio/metabolismo , Endométrio/patologia , Feminino , Humanos , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Análise Serial de Proteínas , Proteômica , Vimentina/metabolismo
4.
Langenbecks Arch Surg ; 398(2): 251-8, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23292500

RESUMO

PURPOSE: Research projects and clinical trials strongly rely on high-quality biospecimens which are provided by biobanks. Since differences in sample processing and storage can strongly affect the outcome of such studies, standardization between biobanks is necessary to guarantee reliable results of large, multicenter studies. The German Cancer Aid Foundation (Deutsche Krebshilfe e.V.) has therefore initiated the priority program "tumor tissue banks" in 2010 by funding four biobank networks focusing on central nervous system tumors, melanomas, breast carcinomas, and colorectal carcinomas. The latter one, the North German Tumor Bank of Colorectal Cancer (ColoNet) is managed by surgeons, pathologists, gastroenterologists, oncologists, scientists, and medical computer scientists. METHODS AND RESULTS: The ColoNet consortium has developed and harmonized standard operating procedures concerning all biobanking aspects. Crucial steps for quality assurance have been implemented and resulted in certification according to DIN EN ISO 9001. A further achievement is the construction of a web-based database for exploring available samples. In addition, common scientific projects have been initiated. Thus, ColoNet's repository will be used for research projects in order to improve early diagnosis, therapy, follow-up, and prognosis of colorectal cancer patients. Apart from the routine sample storage at -170 °C, the tumor banks' unique characteristic is the participation of outpatient clinics and private practices to further expand the sample and clinical data collection. CONCLUSION: The first 2 years of funding by the German Cancer Aid Foundation have already led to a closer scientific connection between the participating institutions and to a substantial collection of biospecimens obtained under highly standardized conditions.


Assuntos
Neoplasias Colorretais/patologia , Bancos de Tecidos/organização & administração , Pesquisa Biomédica , Neoplasias Colorretais/epidemiologia , Alemanha/epidemiologia , Humanos
5.
BMC Cancer ; 12: 393, 2012 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-22954206

RESUMO

BACKGROUND: More than 1.2 million new cases of colorectal cancer are reported each year worldwide. Despite actual screening programs, about 50% of the patients are diagnosed at advanced tumor stages presenting poor prognosis. Innovative screening tools could aid the detection at early stages and allow curative treatment interventions. METHODS: A nine target multiplex serum protein biochip was generated and evaluated using a training- and validation-set of 317 highly standardized, liquid nitrogen preserved serum samples comprising controls, adenomas, and colon cancers. RESULTS: Serum levels of CEA, IL-8, VEGF, S100A11, MCSF, C3adesArg, CD26, and CRP showed significant differences between cases and controls. The largest areas under the receiver operating characteristics curve were observed for CEA, IL-8, and CRP. At threshold levels yielding 90% specificity, sensitivities for CEA, IL-8 and CRP were 26%, 22%, and 17%, respectively. The most promising marker combinations were CEA + IL-8 reaching 37% sensitivity at 83% specificity and CEA + CRP with 35% sensitivity at 81% specificity. In an independent validation set CEA + IL-8 reached 47% sensitivity at 86% specificity while CEA + CRP obtained 39% sensitivity at 86% specificity. Early carcinomas were detected with 33% sensitivity for CEA + IL-8 and 28% for CEA + CRP. CONCLUSIONS: Apart from CEA, IL-8, and CRP, the screening value of additional blood markers and the potential advantage of combining serum biochip testing with fecal occult blood testing needs to be studied. Multiplex biochip array technology utilizing serum samples offers an innovative approach to colorectal cancer screening.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias do Colo/sangue , Técnicas de Diagnóstico Molecular/métodos , Adenoma/sangue , Adenoma/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Proteína C-Reativa/metabolismo , Antígeno Carcinoembrionário/sangue , Estudos de Casos e Controles , Neoplasias do Colo/diagnóstico , Biologia Computacional , Feminino , Ensaios de Triagem em Larga Escala , Humanos , Interleucina-8/sangue , Masculino , Pessoa de Meia-Idade , Análise Serial de Proteínas/métodos , Curva ROC
6.
BMC Gastroenterol ; 12: 24, 2012 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-22443372

RESUMO

BACKGROUND: Lymphadenectomy is performed to assess patient prognosis and to prevent metastasizing. Recently, it was questioned whether lymph node metastases were capable of metastasizing and therefore, if lymphadenectomy was still adequate. We evaluated whether the nodal status impacts on the occurrence of distant metastases by analyzing a highly selected cohort of colon cancer patients. METHODS: 1,395 patients underwent surgery exclusively for colon cancer at the University of Lübeck between 01/1993 and 12/2008. The following exclusion criteria were applied: synchronous metastasis, R1-resection, prior/synchronous second carcinoma, age < 50 years, positive family history, inflammatory bowel disease, FAP, HNPCC, and follow-up < 5 years. The remaining 421 patients were divided into groups with (TM+, n = 75) or without (TM-, n = 346) the occurrence of metastasis throughout a 5-year follow-up. RESULTS: Five-year survival rates for TM + and TM- were 21% and 73%, respectively (p < 0.0001). Survival rates differed significantly for N0 vs. N2, grading 2 vs. 3, UICC-I vs. -II and UICC-I vs. -III (p < 0.05). Regression analysis revealed higher age upon diagnosis, increasing N- and increasing T-category to significantly impact on recurrence free survival while increasing N-and T-category were significant parameters for the risk to develop metastases within 5-years after surgery (HR 1.97 and 1.78; p < 0.0001). CONCLUSIONS: Besides a higher T-category, a positive N-stage independently implies a higher probability to develop distant metastases and correlates with poor survival. Our data thus show a prognostic relevance of lymphadenectomy which should therefore be retained until conclusive studies suggest the unimportance of lmyphadenectomy.


Assuntos
Carcinoma/mortalidade , Carcinoma/secundário , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Excisão de Linfonodo , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Carcinoma/cirurgia , Neoplasias do Colo/cirurgia , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Taxa de Sobrevida , Fatores de Tempo
7.
Int J Colorectal Dis ; 27(6): 789-95, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22249437

RESUMO

PURPOSE: For treatment of rectal prolapse, abdominal approaches are generally offered to younger patients, whereas perineal, less invasive procedures are considered more beneficial in the elderly. The aim of this study was to analyze whether laparoscopic resection rectopexy (LRR) is suitable for older patients. PATIENTS/METHODS: Patients who received LRR for rectal prolapse were selected from a prospective laparoscopic colorectal surgery database. Perioperative and long-term outcome were compared between patients <75 years old (group A) and ≥75 years old (group B). RESULTS: Of 154 patients, 111 were in group A and 43 in group B. There was one conversion that occurred in group B. Overall mortality rate was 1.3% (n = 2). Both patients were in group B (group B, 4.7%; p = 0.079). Differences in major and minor complications between the groups were not significant. Rates of improvement for incontinence were 62.7% (group A) and 66.7% (group B; p = 0.716); for constipation, the rates were 78.9% (group A) and 73.3% (group B; p = 0.832). All recurrences occurred in group A (n = 10; overall, 10.3%; group A, 13%). After exclusion of patients who had previously received perineal prolapse surgery, recurrence rate was 3.3% overall (group A, 4.3%). CONCLUSIONS: This study supports the benefits of LRR for rectal prolapse in elderly patients. Age per se is not a contraindication for LRR. Elderly patients encounter complications slightly more frequently (although not statistically significant) than younger patients. Therefore, a very careful patient selection in the elderly is of paramount importance. However, the long-term outcome does not seem to differ between younger and elderly patients.


Assuntos
Procedimentos Cirúrgicos do Sistema Digestório/métodos , Laparoscopia , Prolapso Retal/cirurgia , Reto/cirurgia , Idoso , Constipação Intestinal/etiologia , Demografia , Incontinência Fecal/etiologia , Seguimentos , Alemanha/epidemiologia , Hospitalização , Humanos , Tempo de Internação , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Prolapso Retal/mortalidade , Resultado do Tratamento
8.
Cell Mol Life Sci ; 68(19): 3261-74, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21290163

RESUMO

DNA aneuploidy has been identified as a prognostic factor for epithelial malignancies. Further understanding of the translation of DNA aneuploidy into protein expression will help to define novel biomarkers to improve therapies and prognosis. DNA ploidy was assessed by image cytometry. Comparison of gel-electrophoresis-based protein expression patterns of three diploid and four aneuploid colorectal cancer cell lines detected 64 ploidy-associated proteins. Proteins were identified by mass spectrometry and subjected to Ingenuity Pathway Analysis resulting in two overlapping high-ranked networks maintaining Cellular Assembly and Organization, Cell Cycle, and Cellular Growth and Proliferation. CAPZA1, TXNL1, and HDAC2 were significantly validated by Western blotting in cell lines and the latter two showed expression differences also in clinical samples using a tissue microarray of normal mucosa (n=19), diploid (n=31), and aneuploid (n=47) carcinomas. The results suggest that distinct protein expression patterns, affecting TXNL1 and HDAC2, distinguish aneuploid with poor prognosis from diploid colorectal cancers.


Assuntos
Aneuploidia , Carcinoma/genética , Neoplasias Colorretais/genética , Diploide , Histona Desacetilase 2/genética , Tiorredoxinas/genética , Western Blotting , Proteína de Capeamento de Actina CapZ/genética , Proteína de Capeamento de Actina CapZ/metabolismo , Proteína de Capeamento de Actina CapZ/fisiologia , Carcinoma/diagnóstico , Carcinoma/patologia , Linhagem Celular Tumoral , Estudos de Coortes , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/patologia , DNA de Neoplasias/química , Instabilidade Genômica , Histona Desacetilase 2/metabolismo , Histona Desacetilase 2/fisiologia , Humanos , Prognóstico , Tiorredoxinas/metabolismo , Tiorredoxinas/fisiologia
9.
Mol Cancer ; 10: 132, 2011 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-22040021

RESUMO

BACKGROUND: In addition to clinical characteristics, DNA aneuploidy has been identified as a prognostic factor in epithelial malignancies in general and in endometrial cancers in particular. We mapped ploidy-associated chromosomal aberrations and identified corresponding gene and protein expression changes in endometrial cancers of different prognostic subgroups. METHODS: DNA image cytometry classified 25 endometrioid cancers to be either diploid (n = 16) or aneuploid (n = 9), and all uterine papillary serous cancers (UPSC) to be aneuploid (n = 8). All samples were subjected to comparative genomic hybridization and gene expression profiling. Identified genes were subjected to Ingenuity pathway analysis (IPA) and were correlated to protein expression changes. RESULTS: Comparative genomic hybridization revealed ploidy-associated specific, recurrent genomic imbalances. Gene expression analysis identified 54 genes between diploid and aneuploid endometrioid carcinomas, 39 genes between aneuploid endometrioid cancer and UPSC, and 76 genes between diploid endometrioid and aneuploid UPSC to be differentially expressed. Protein profiling identified AKR7A2 and ANXA2 to show translational alterations consistent with the transcriptional changes. The majority of differentially expressed genes and proteins belonged to identical molecular functions, foremost Cancer, Cell Death, and Cellular Assembly and Organization. CONCLUSIONS: We conclude that the grade of genomic instability rather than the histopathological subtype correlates with specific gene and protein expression changes. The identified genes and proteins might be useful as molecular targets for improved diagnostic and therapeutic intervention and merit prospective validation.


Assuntos
Neoplasias do Endométrio/genética , Perfilação da Expressão Gênica/métodos , Proteoma/genética , Transcriptoma , Aneuploidia , Neoplasias do Endométrio/classificação , Neoplasias do Endométrio/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Instabilidade Genômica , Humanos
10.
Mod Pathol ; 24(4): 542-55, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21102417

RESUMO

Individual colorectal adenomas have different propensities to progress to invasive disease. In this study, we explored whether these differences could be explained by gene copy number alterations. We evaluated 18 adenomas of patients without synchronous or subsequent carcinoma (6.5 years follow-up), 23 adenomas of carcinoma patients, and 6 related carcinomas. All samples were measured for their DNA ploidy status. Centromere probes for chromosomes 17 and 18, as well as gene-specific probes for SMAD7, EGFR, NCOA3, TP53, MYC, and RAB20 were assessed by multicolor fluorescence in situ hybridization. An increased genomic instability index of CEP17, SMAD7, and EGFR, as well as TP53 deletions and MYC amplifications defined adenomas of patients with synchronous carcinoma (P<0.05). Diploid NCOA3 signal counts were associated with longer adenoma recurrence-free surveillance (P=0.042). In addition, NCOA3, MYC, EGFR, and RAB20 amplifications, as well as TP53 deletions correlated with increased DNA stem line values and/or aneuploidy in adenomas (P<0.05). Furthermore, aberrations of NCOA3, MYC, and RAB20 were associated with histopathologically defined high-risk adenomas (P<0.05). RAB20 amplifications were also correlated with high-grade dysplastic adenomas (P=0.002). We conclude that genomic instability in colorectal adenomas is reflected by EGFR, MYC, NCOA3, and RAB20 amplifications that do correlate with histomorphological features and are indicative for adenoma recurrence and the presence of synchronous carcinomas.


Assuntos
Adenoma/genética , Carcinoma/genética , Neoplasias Colorretais/genética , Amplificação de Genes , Instabilidade Genômica , Recidiva Local de Neoplasia , Neoplasias Primárias Múltiplas , Oncogenes , Adenoma/mortalidade , Adenoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma/mortalidade , Carcinoma/patologia , Distribuição de Qui-Quadrado , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Progressão da Doença , Feminino , Alemanha , Humanos , Hibridização in Situ Fluorescente , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Ploidias , Prognóstico , Medição de Risco , Fatores de Risco , Fatores de Tempo
11.
Ann Surg ; 252(1): 74-83, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20531006

RESUMO

OBJECTIVE: Aneuploidy is an independent risk factor for forthcoming carcinogenesis in ulcerative colitis (UC). An inferior prognosis of patients with ulcerative colitis-associated colorectal cancer (UCC) compared with those with sporadic colorectal cancer (SCC) has been reported, but remains controversial. This prompted us to investigate if aneuploidy can be observed in UCCs as frequently as in their sporadic counterpart and if aneuploidy per se might be a driving feature of poor prognosis in UCC. BACKGROUND DATA: We obtained clinical follow-up for 257 SCC patients (average observation time 57 months) and 31 UCC patients (51 months). Touch preparation slides or tissue sections were prepared of all 288 carcinomas for ploidy analysis. METHODS: Ploidy status was assessed for 260 SCCs and 31 UCCs by image cytometry and correlated to clinical features. Survival data were analyzed using Kaplan-Meier estimates. RESULTS: Aneuploidy was detected in 74.6% of SCCs and in all 31 UCCs. Logistic regression analysis yielded age (odds ratio [OR], 1.05; 95% CI, 1.02-1.09; P = 0.003) and aneuploidy (OR, 4.07; 95% CI, 1.46-11.36; P = 0.007) as independent prognostic factors for R0-resected patients devoid of metastases. Diploid SCCs had a more favorable 5-year survival (88.2%) than aneuploid SCCs (69.0%) and UCCs (73.1%) (P = 0.074). CONCLUSIONS: UC-associated carcinomas presented aneuploidy at significantly higher frequency than sporadic colorectal carcinomas (P < 0.0006). UCCs and aneuploid SCCs share a similar prognosis inferior to that of diploid SCCs. Aneuploidy proved to be the strongest independent prognostic marker for R0-resected colorectal cancer patients overall.


Assuntos
Colite Ulcerativa/complicações , Neoplasias Colorretais/genética , Idoso , Aneuploidia , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/patologia , DNA de Neoplasias/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico
12.
Surg Endosc ; 24(10): 2401-6, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20177911

RESUMO

BACKGROUND: Many different techniques to treat rectal prolapse have been introduced. Laparoscopic resection rectopexy has been shown to entail benefits regarding both perioperative results and short-term outcome, whereas data for long-term outcome are scarce. METHODS: Between 1993 and 2008, all laparoscopic resection rectopexies for rectal prolapse II° or III° were selected from a prospective laparoscopic colorectal surgery database. We analyzed demographic, perioperative, and follow-up results. We defined two periods (1993-2000 and 2001-2008) for comparison of data. Long-term follow-up was obtained by sending questionnaires to all patients. Evaluation included constipation, incontinence, and recurrence of prolapse. RESULTS: Between January 1993 and November 2008, we performed 152 laparoscopic resection rectopexies for rectal prolapse. Median age was 64.1 years (± 14.6). Conversion rate was 0.7% (1), mean operation time was 204 (± 65.3) min, and was significantly shorter in the second period compared with the first (P < 0.0001). Mortality was 0.7% (n = 1). Complication rates were 4% (n = 6; major) and 19.2% (n = 29; minor), respectively. Mean length of hospital stay was 11.3 (± 6.4) days and was significantly shorter in the second period compared with the first period (P < 0.0001). Mean time of follow-up was 47.7 (± 41.6) months. Improvement or complete elimination of constipation was stated by 81.3% (65), and improvement or elimination of incontinence was stated by 67.3% (72). Overall recurrence rate was 11.1% (n = 10) with a rate of 5.6% (n = 5) for a 5-year period. Of those patients with previous perineal surgery for rectal prolapse, 53.8% (7/13) experienced recurrent prolapse after laparoscopic resection rectopexy in contrast to 3.9% (3/77) of patients without previous perineal prolapse surgery (P < 0.0001). CONCLUSIONS: Our data support the benefits of laparoscopic resection rectopexy for rectal prolapse regarding both perioperative results and long-term functional outcome. Preceding perineal or open abdominal operations have an impact on recurrence after laparoscopic resection rectopexy.


Assuntos
Laparoscopia , Prolapso Retal/cirurgia , Feminino , Humanos , Laparoscopia/efeitos adversos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Prolapso Retal/patologia , Reto/cirurgia , Reoperação , Resultado do Tratamento
13.
Int J Cancer ; 124(7): 1552-64, 2009 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-19101988

RESUMO

Recently, expression profiling of breast carcinomas has revealed gene signatures that predict clinical outcome, and discerned prognostically relevant breast cancer subtypes. Measurement of the degree of genomic instability provides a very similar stratification of prognostic groups. We therefore hypothesized that these features are linked. We used gene expression profiling of 48 breast cancer specimens that profoundly differed in their degree of genomic instability and identified a set of 12 genes that defines the 2 groups. The biological and prognostic significance of this gene set was established through survival prediction in published datasets from patients with breast cancer. Of note, the gene expression signatures that define specific prognostic subtypes in other breast cancer datasets, such as luminal A and B, basal, normal-like, and ERBB2+, and prognostic signatures including MammaPrint and Oncotype DX, predicted genomic instability in our samples. This remarkable congruence suggests a biological interdependence of poor-prognosis gene signatures, breast cancer subtypes, genomic instability, and clinical outcome.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Perfilação da Expressão Gênica , Instabilidade Genômica , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico
14.
Acta Oncol ; 47(8): 1493-501, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18759147

RESUMO

BACKGROUND: Head and neck cancer continues to be one of the most common tumor entities worldwide. Within this group of malignancies, tonsillar squamous cell carcinoma represent approximately 15-20% of all intraoral and oropharyngeal carcinomas in the United States. Accurate and early stage diagnosis still remains a major challenge, as patients are often presented at an advanced stage of disease, causing a low overall survival rate. Thus, new diagnostic markers are highly desirable and could allow for a more reliable diagnosis, with further insights into carcinogenesis and tumor biology. Furthermore, these markers could be the basis for new therapeutic targets and early disease detection. To address these issues, we decided to use a global proteomic approach to characterize tonsillar squamous cell carcinoma. MATERIALS AND METHODS: A total of 19 tonsillar carcinoma samples and 12 benign controls acquired from the corresponding normal epithelium were analyzed by 2-D gel electrophoresis. 2-DE gels were silver stained and analyzed using the PDQuest analysis software (BioRad). Tumor specific spots were detected and identified by consecutive MALDI-TOF-MS or MS/MS polypeptide identification. RESULTS: In total, 70 proteins showed significant quantitative differences in protein expression, with 50 polypeptides accessible for identification. Of those 50 polypeptides, we were able to identify a total of 27 proteins and protein isoforms, significantly up- or down-regulated in tonsillar cancer samples. In addition to previously reported polypeptides in head and neck cancers, we were able to identify several new potential marker proteins in this study. CONCLUSION: Our results show that a combination of tonsillar cancer specific proteins can be used for histopathological diagnosis and may serve as a basis for discovering further biomarkers for early detection and prediction of response to treatment in the future.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteoma/análise , Proteômica/métodos , Neoplasias Tonsilares/metabolismo , Idoso , Western Blotting , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Eletroforese em Gel Bidimensional , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tonsila Palatina/metabolismo , Prognóstico , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Neoplasias Tonsilares/patologia
15.
Langenbecks Arch Surg ; 393(1): 93-104, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17938952

RESUMO

BACKGROUND AND AIMS: Colorectal cancer is the second leading cause of cancer-related death. Current clinical practice in colorectal cancer screening (fecal occult blood test, FOBT; colonoscopy) has contributed to a reduction of mortality. However, despite these screening programs, about 70% of carcinomas are detected at advanced tumor stages (UICC III/IV) presenting poor patient prognosis. Thus, innovative tools and methodologies for early cancer detection can directly result in improving patient survival rates. PATIENTS/METHODS: Biomedical research has advanced rapidly in recent years with the availability of technologies such as global gene and protein expression profiling. Comprehensive tumor profiling has become a field of intensive research aiming at identifying biomarkers relevant for improved diagnostics and therapeutics. RESULTS: In this paper, we report a comprehensive review of genomic, transcriptomic, and proteomic approaches for biomarker identification in tissue and blood with a main emphasis on two-dimensional gel-electrophoresis (2-DE) and mass spectrometry analyses. CONCLUSION: Proteomics-based technologies enable to distinguish the healthy patient from the tumor patient with high sensitivity and specificity and could greatly improve common classification systems and diagnostics. However, this progress has not yet been transferred from bench to bedside but could open the door to a more accurate and target specific personalized medicine with improved patient survival.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Marcadores Genéticos/genética , Genoma , Proteoma , Aneuploidia , Neoplasias Colorretais/patologia , Eletroforese em Gel Bidimensional , Perfilação da Expressão Gênica , Humanos , Espectrometria de Massas , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Análise Serial de Proteínas , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
16.
J Laparoendosc Adv Surg Tech A ; 17(1): 53-7, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17362180

RESUMO

PURPOSE: Laparoscopic radiofrequency ablation is safe, practicable, and combines minimally invasive surgery with the advantages of laparotomy. However, application of the laparoscopic freehand puncture is restricted because of capnoperitoneum and the consequent fixation of the needle on two different points. The use of a laparoscopic ultrasound probe with a canal for puncture can solve this problem and improve precision. However, a stiff needle limits the necessary angulation that is needed to reach right-lateral and cranial liver metastases. Therefore we present a new navigation tool for laparoscopic interventions. MATERIALS AND METHODS: The US Guide 2000 (Ultra Guide, Tirat Hacarmel, Israel) is an independent navigation system compatible with all ultrasound machines and has six degrees of freedom. After proper evaluation of this system under operating room conditions during transcutaneous radiofrequency ablation, we used this technique in laparoscopic radiofrequency ablation. A special adapter was developed to attach the ultrasound-based navigation system to a laparoscopic ultrasound probe. After calibrating the system with an ultrasound phantom, laparoscopic navigation in a liver organ model was studied. RESULTS: Even in cases of angulation of the ultrasound probe no disturbances of the navigation system could be detected. Anatomic landmarks in the liver could be safely reached. No interaction between the navigation system and the laparoscopic ultrasound probe or operating instruments was observed. CONCLUSION: Our preliminary results show the feasibility of this technique in laparoscopic radiofrequency ablation. The use of an ultrasound-based laparoscopic inline navigation system offers the possibility of out-of-plane needle placement and could combine the flexibility of freehand puncture with the accuracy of a canal for puncture. This could increase the safety and accuracy of punctures.


Assuntos
Ablação por Cateter/métodos , Laparoscopia/métodos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/cirurgia , Ablação por Cateter/instrumentação , Humanos , Imagens de Fantasmas , Ultrassonografia/instrumentação , Ultrassonografia/métodos
17.
Adv Exp Med Biol ; 587: 161-77, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-17163165

RESUMO

Biomedical research has advanced rapidly in recent years with the sequencing of the human genome and the availability of technologies such as global gene and protein expression profiling using different chip platforms. However, this progress has not yet been transferred to the bedside. While detection of cancer at early stages is critical for curative treatment interventions, efficient diagnostic and therapeutic markers for the majority of malignancies still seem to be lacking. Comprehensive tumor profiling has therefore become a field of intensive research aiming at identifying biomarkers relevant for improved diagnostics and therapeutics. This chapter will demonstrate a genomic and proteomic approach while focusing on tumor profiling during colorectal cancer development.


Assuntos
Neoplasias Colorretais/genética , Perfilação da Expressão Gênica/tendências , Genômica/tendências , Proteômica/tendências , Animais , Perfilação da Expressão Gênica/métodos , Genômica/métodos , Humanos , Proteômica/métodos
18.
Cancer Res ; 64(3): 904-9, 2004 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-14871819

RESUMO

Numerous investigations have shown that in primary breast adenocarcinomas DNA aneuploidy in contrast to DNA diploidy indicates high malignancy potential. On the basis of the study of 104 breast carcinomas, we describe a subtype of aneuploidy, which demonstrates a low degree of malignancy. In image cytometric DNA histograms, this subtype possessed a low percentage (< or = 8.8%) of nonmodal DNA values as measured by the stemline scatter index (SSI), which is defined as sum of the percentage of cells in the S-phase region, the G(2) exceeding rate and the coefficient of variation of the tumor stemline. The cut point of SSI = 8.8% (P = 0.03) enabled us to also subdivide diploid and tetraploid tumors into clinically low and high malignant variants. One possible reason for aneuploidy is impaired distribution of chromosomes at mitosis caused by numerical or structural centrosome aberrations. Cyclins A and E seem to be involved in centrosome duplication. Real-time quantitative PCR measurements of cyclin A and E transcript levels and immunohistochemical determination of cyclin A protein expression showed statistically significantly increased values in the tumors with a high SSI (>8.8%), compared with those with a low SSI. A pilot study demonstrated centrosomal aberrations in an average of 9.6% of the measured cells in four aneuploid carcinomas with high SSI values and in an average of 2.5% of the cells in three aneuploid and three diploid tumors with low SSI. Our data indicate that the SSI, most likely reflecting the degree of genomic instability, allows additional classifying of the known aneuploid, diploid, and tetraploid categories of primary breast adenocarcinomas into low and high malignant subtypes.


Assuntos
Adenocarcinoma/genética , Adenocarcinoma/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Instabilidade Genômica/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Núcleo Celular/genética , Núcleo Celular/metabolismo , Centrossomo/fisiologia , Ciclina A/genética , Ciclina E/genética , DNA de Neoplasias/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Ploidias , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
19.
Oncotarget ; 6(18): 16517-26, 2015 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-26203049

RESUMO

Cancer proteomics provide a powerful approach to identify biomarkers for personalized medicine. Particularly, biomarkers for early detection, prognosis and therapeutic intervention of bone cancers, especially osteosarcomas, are missing. Initially, we compared two-dimensional gel electrophoresis (2-DE)-based protein expression pattern between cell lines of fetal osteoblasts, osteosarcoma and pulmonary metastasis derived from osteosarcoma. Two independent statistical analyses by means of PDQuest® and SameSpot® software revealed a common set of 34 differentially expressed protein spots (p < 0.05). 17 Proteins were identified by mass spectrometry and subjected to Ingenuity Pathway Analysis resulting in one high-ranked network associated with Gene Expression, Cell Death and Cell-To-Cell Signaling and Interaction. Ran/TC4-binding protein (RANBP1) and Cathepsin D (CTSD) were further validated by Western Blot in cell lines while the latter one showed higher expression differences also in cytospins and in clinical samples using tissue microarrays comprising osteosarcomas, metastases, other bone malignancies, and control tissues. The results show that protein expression patterns distinguish fetal osteoblasts from osteosarcomas, pulmonary metastases, and other bone diseases with relevant sensitivities between 55.56% and 100% at ≥87.50% specificity. Particularly, CTSD was validated in clinical material and could thus serve as a new biomarker for bone malignancies and potentially guide individualized treatment regimes.


Assuntos
Neoplasias Ósseas/patologia , Catepsina D/biossíntese , Neoplasias Pulmonares/secundário , Proteínas Nucleares/biossíntese , Osteossarcoma/patologia , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Catepsina D/genética , Linhagem Celular Tumoral , Eletroforese em Gel Bidimensional , Perfilação da Expressão Gênica , Humanos , Neoplasias Pulmonares/patologia , Espectrometria de Massas , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Osteoblastos/metabolismo , Proteômica , Análise Serial de Tecidos
20.
BMC Cell Biol ; 4: 8, 2003 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-12875657

RESUMO

BACKGROUND: The progression of normal cells through the cell cycle is meticulously regulated by checkpoints guaranteeing the exact replication of the genome during S-phase and its equal division at mitosis. A prerequisite for this achievement is synchronized DNA-replication and centrosome duplication. In this context the expression of cyclins A and E has been shown to play a principal role. RESULTS: Our results demonstrated a correlation between centrosome amplification, cell cycle fidelity and the level of mRNA and protein expression of cyclins A and E during the part of the cell cycle defined as G1-phase by means of DNA content based histogram analysis. It is shown that the normal diploid breast cell line HTB-125, the genomically relatively stable aneuploid breast cancer cell line MCF-7, and the genomically unstable aneuploid breast cancer cell line MDA-231 differ remarkably concerning both mRNA and protein expression of the two cyclins during G1-phase. In MDA-231 cells the expression of e.g. cyclin A mRNA was found to be ten times higher than in MCF-7 cells and about 500 times higher than in HTB-125 cells. Topoisomerase II alpha showed high mRNA expression in MDA compared to MCF-7 cells, but the difference in protein expression was small. Furthermore, we measured centrosome aberrations in 8.4% of the MDA-231 cells, and in only 1.3% of the more stable aneuploid cell line MCF-7. MDA cells showed 27% more incorporation of BrdU than reflected by S-phase determination with flow cytometric DNA content analysis, whereas these values were found to be of the same size in both HTB-125 and MCF-7 cells. CONCLUSIONS: Our data indicate that the breast cancer cell lines MCF-7 and MDA-231, although both DNA-aneuploid, differ significantly regarding the degree of cell cycle disturbance and centrosome aberrations, which partly could explain the different genomic stability of the two cell lines. The results also question the reliability of cytometric DNA content based S-phase determination in genomically unstable tumor cell populations.


Assuntos
Centrossomo/metabolismo , Ciclina A/genética , Ciclina E/genética , DNA Topoisomerases Tipo II/genética , Instabilidade Genômica/genética , Fase S/genética , Antígenos de Neoplasias , Bromodesoxiuridina/metabolismo , Ciclo Celular/genética , Linhagem Celular , Linhagem Celular Tumoral , Ciclina A/metabolismo , Ciclina E/metabolismo , DNA/genética , DNA/metabolismo , DNA Topoisomerases Tipo II/metabolismo , Proteínas de Ligação a DNA , Citometria de Fluxo/métodos , Técnica Indireta de Fluorescência para Anticorpo , Fase G1/genética , Expressão Gênica , Humanos , Microscopia de Fluorescência , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reprodutibilidade dos Testes
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