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1.
Magy Onkol ; 65(1): 71-77, 2021 Mar 17.
Artículo en Húngaro | MEDLINE | ID: mdl-33730119

RESUMEN

Our aim was to detect the effect of modulated electro-hyperthermia (mEHT) on cell viability and to examine if hyperthermia can augment the cell killing effect of various chemotherapeutic agents. B16F10 melanoma cells were treated for 30, 60, 90 and 120 minutes with mEHT using LabEHY100 (OncothermTM). Cell viability was measured using MTT assay and apoptosis by annexin V/7-AAD staining using flow cytometry 24 hours post-treatment. For analyzing gene expression with qPCR cells were harvested after 60 minutes treatment. In combined protocols, cells were treated with paclitaxel (40 nM), dacarbazine (40 µM) or nutlin-3a (10 µM) after mEHT. mEHT induced nuclear translocation of p53 which in turn regulates pro- and anti-apoptotic gene expression accounting for decreased cell viability. In combination with chemotherapy, mEHT augmented the cell killing effect of dacarbazine or nutlin-3a but not that of paclitaxel determined 48 hours post-treatment. The sensitizing effect on chemotherapeutics demonstrate the efficiency of mEHT as an adjuvant modality in cancer treatment.


Asunto(s)
Hipertermia Inducida , Melanoma , Apoptosis , Línea Celular Tumoral , Humanos , Hipertermia , Melanoma/tratamiento farmacológico
2.
Pathol Oncol Res ; 26(4): 2773-2781, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32754865

RESUMEN

Urachal carcinoma (UrC) is a rare tumor with remarkable histological and molecular similarities to colorectal cancer (CRC). Adenomatous polyposis coli (APC) is the most frequently affected gene in CRC, but the prevalence and significance of its alterations in UrC is poorly understood. In addition, loss of phosphatase and tensin homologue (PTEN) was shown to be associated with therapy resistance in CRC. Our primary aim was to assess specific genetic alterations including APC and PTEN in a large series of UrC samples in order to identify clinically significant genomic alterations. We analyzed a total of 40 UrC cases. Targeted 5-gene (APC, PTEN, DICER1, PRKAR1A, TSHR, WRN) panel sequencing was performed on the Illumina MiSeq platform (n = 34). In addition, ß-catenin (n = 38) and PTEN (n = 30) expressions were assessed by immunohistochemistry. APC and PTEN genes were affected in 15% (5/34) and 6% (2/34) of cases. Two of five APC alterations (p.Y1075*, p.K1199*) were truncating pathogenic mutations. One of the two PTEN variants was a pathogenic frameshift insertion (p.C211fs). In 29% (11/38) of samples, at least some weak nuclear ß-catenin immunostaining was detected and PTEN loss was observed in 20% (6/30) of samples. The low prevalence of APC mutations in UrC represents a characteristic difference to CRC. Based on APC and ß-catenin results, the Wnt pathway seems to be rarely affected in UrC. Considering the formerly described involvement of PTEN protein loss in anti-EGFR therapy-resistance its immunohistochemical testing may have therapeutic relevance.


Asunto(s)
Adenocarcinoma/patología , Proteína de la Poliposis Adenomatosa del Colon/genética , Cistectomía/mortalidad , Mutación , Fosfohidrolasa PTEN/genética , Neoplasias de la Vejiga Urinaria/patología , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/cirugía , Adulto , Anciano , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/cirugía , Vía de Señalización Wnt , Adulto Joven , beta Catenina/genética , beta Catenina/metabolismo
3.
Proteomics ; 20(9): e1900325, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-31926115

RESUMEN

Identifying the target proteins of bioactive small molecules is a key step in understanding mode-of-action of the drug and addressing the underlying mechanisms responsible for a particular phenotype. Proteomics has been successfully used to elucidate the target protein profiles of unmodified and ligand-modified bioactive small molecules. In the latter approach, compounds can be modified via click chemistry and combined with activity-based protein profiling. Target proteins are then enriched by performing a pull-down with the modified ligand. Methods that utilize unmodified bioactive small molecules include the cellular thermal shift assay, thermal proteome profiling, stability of proteins from rates of oxidation, and the drug affinity responsive target stability (DARTS) determination (or read-out). This review highlights recent proteomic approaches utilizing data-dependent analysis and data-independent analysis to identify target proteins by DARTS. When combined with liquid chromatography/tandem mass spectrometry, DARTS enables the identification of proteins that bind to drug molecules that leads to a conformational change in the target protein(s). In addition, an effective strategy is proposed for selecting the target protein(s) from within the pool of analyzed candidates. With additional complementary methods, the biologically relevant target proteins that bind to the small bio-active molecules can be further validated.


Asunto(s)
Cromatografía Liquida/métodos , Proteómica/métodos , Bibliotecas de Moléculas Pequeñas/farmacología , Espectrometría de Masas en Tándem/métodos , Simulación del Acoplamiento Molecular , Preparaciones Farmacéuticas , Unión Proteica , Proteínas/química , Proteínas/genética , Proteínas/metabolismo , Interferencia de ARN , Reproducibilidad de los Resultados
4.
Magy Onkol ; 63(4): 354-358, 2019 Dec 09.
Artículo en Húngaro | MEDLINE | ID: mdl-31821390

RESUMEN

Our objective was to develop an electromagnetic tumor therapy device in a consortial cooperation between Semmelweis University and Oncotherm Ltd., to provide data and contribute to the development of the next generation of devices through preclinical, clinical and developmental modules via in vivo, in vitro studies, and patient treatments. Our numerous preclinical studies support the efficacy of mEHT. Clinical treatments were performed in 181 patients with inoperable and/or oligometastatic solid tumors. The protocols were developed, an international guideline was completed, and the planned steps of device development were realized. By optimizing previous selective RF techniques based on recent research findings, we can provide the most modern evidence-based treatment in the future.


Asunto(s)
Neoplasias , Fenómenos Electromagnéticos , Humanos
5.
Scand J Immunol ; 90(6): e12821, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31589347

RESUMEN

As a result of the cancer immunotherapy revolution, more than 2000 immuno-oncology agents are currently being tested or are in use to improve responses. Not unexpectedly, the 2018 Nobel Prize in Physiology or Medicine was awarded to James P. Allison and Tasuku Honjo for their development of cancer therapy by the blockade of co-inhibitory signals. Unfortunately, manipulation of the co-inhibitory receptors has also resulted in a safety issue: widespread iatrogenic immune-related adverse events (irAEs). Autoimmunity is emerging as the nemesis of immunotherapy. Originally, it was assumed that CTLA-4 blockade selectively targets T cells relevant to the antitumour immune response. However, an uncontrolled pan T cell activation was induced compromising tolerance to healthy self-tissues. The irAEs are very similar to that of a chronic graft-versus-host-disease (GVHD) reaction following allogeneic bone marrow transplantation (BMT). We hypothesized that ipilimumab induced a graft-versus-malignancy (GVM) effect, which eradicated metastatic melanoma in a minority of patients, but also involved an auto-GVHD reaction that resulted in widespread autoimmunity in the majority. Therefore, we argued for a profound theoretical point against the consensus of experts. The task is not to desperately put the genie back in the bottle by immune-suppressive treatments, but instead to harness the autoimmune forces. In this way, the same goal could be achieved by an antibody as by the adoptive transfer of alloreactive donor lymphocytes, but without severe GVHD. The proof-of-principle of a low-dose-combination immune checkpoint therapy, consisting only of approved drugs and treatments, was demonstrated in 111 stage IV cancer patients.


Asunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Autoinmunidad/efectos de los fármacos , Biomarcadores de Tumor/antagonistas & inhibidores , Terapia Molecular Dirigida , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Antígeno CTLA-4/antagonistas & inhibidores , Antígeno CTLA-4/genética , Antígeno CTLA-4/metabolismo , Humanos , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Metástasis de la Neoplasia , Estadificación de Neoplasias , Neoplasias/genética , Neoplasias/patología , Uso Fuera de lo Indicado , Prueba de Estudio Conceptual , Transducción de Señal/efectos de los fármacos , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/metabolismo , Resultado del Tratamiento
6.
Virchows Arch ; 470(3): 275-283, 2017 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-28101678

RESUMEN

The aim of our retrospective study was to analyze patterns of subtype specific metastatic spread and to identify the time course of distant metastases. A consecutive series of 490 patients with breast cancer who underwent surgery and postoperative treatment at Semmelweis University, Hungary, and diagnosed between the years 2000 and 2007 was identified from the archives of the 2nd Department of Pathology, Hungary. Molecular subtypes were defined based on the 2011 St. Gallen recommendations. Statistical analysis was performed with SPSS Statistics for Windows, Version 22.0. Distant metastasis free survival (DMFS) was defined as the time elapsed between the first pathological diagnosis of the tumor and the first distant metastasis detection. Distant metastases were detected in 124 patients. Mean time to develop metastasis was 29 months (range 0-127 months). The longest DMFS was observed in the Luminal A (LUMA) subtype (mean 39 months) whereas the shortest was seen in the HER2-positive (HER2+) subtype (mean 21 months; p = 0.012). We confirmed that HER2+ tumors carry a higher risk for distant metastases (42.1%). LUMA-associated metastases were found to be solitary in 59% of cases, whereas HER2+ tumors showed multiple metastases in 79.2% of cases. LUMA tumors showed a preference for bone-only metastasis as compared with HER2+ and triple negative breast cancer (TNBC) cases, which exhibited a higher rate of brain metastasis. The most frequent second metastatic sites of hormone receptor (HR) positive tumors were the lung and liver, whereas the brain was the most affected organ in HR-negative (HR-) cases. Tumor subtypes differ in DMFS and in pattern of distant metastases. HER2+ tumors featured the most aggressive clinical course. Further identification of subtype-specific factors influencing prognosis might have an impact on clinical care and decision-making.


Asunto(s)
Biomarcadores de Tumor/análisis , Neoplasias de la Mama/patología , Adulto , Anciano , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Estimación de Kaplan-Meier , Persona de Mediana Edad , Metástasis de la Neoplasia , Pronóstico , Modelos de Riesgos Proporcionales , Receptor ErbB-2/análisis , Receptor ErbB-2/biosíntesis , Receptores de Estrógenos/análisis , Receptores de Estrógenos/biosíntesis , Receptores de Progesterona/análisis , Receptores de Progesterona/biosíntesis , Estudios Retrospectivos
7.
Oncotarget ; 7(26): 39293-39301, 2016 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-27283768

RESUMEN

PURPOSE: Targeted therapy represents an attractive alternative for rare tumors such as urachal carcinoma (UrC). The aim of this study was to assess the mutations of the most commonly affected 5 genes in the targetable EGFR-pathway in UrC and comapre their frequencies to those of found in urothelial and colorectal cancer. MATERIALS AND METHODS: Mutational hot-spots of selected genes were tested in 22 UrC samples by pyrosequencing. Mutational patterns were compared to those published for colorectal and urothelial cancers. Furthermore, we sought correlations between mutations and clinicopathological and follow-up data. RESULTS: We found 11 mutations in 10 of 22 (45%) patients. The most frequently mutated gene was KRAS (27%) followed by BRAF (18%) and NRAS (5%), while no mutations were detected in the EGFR and PIK3CA genes. No correlation was found between the mutation status and clinicopathological parameters (Sheldon/Mayo stage, tumor grade, metastases). Furthermore, none of the mutations correlated with progression-free or overall survival. CONCLUSIONS: The mutation pattern of UrC is more similar to colorectal than to urothelial cancer. However, the mutation characteristics of UrC seems to be unique suggesting that clinical decision-making for UrC cannot be simply adopted from urothelial or colorectal carcinoma. The high occurence of EGFR-pathway mutations warrants the testing for KRAS and BRAF mutations when considering anti-EGFR therapy in UrC.


Asunto(s)
Adenocarcinoma/genética , Fosfatidilinositol 3-Quinasa Clase I/genética , Receptores ErbB/genética , GTP Fosfohidrolasas/genética , Proteínas de la Membrana/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Neoplasias de la Vejiga Urinaria/genética , Adulto , Anciano , Carcinoma/genética , Neoplasias Colorrectales/genética , Análisis Mutacional de ADN , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Mutación , Metástasis de la Neoplasia , Pronóstico , Recurrencia , Estudios Retrospectivos , Resultado del Tratamiento , Urotelio/patología
8.
Urol Oncol ; 34(9): 388-98, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-27267737

RESUMEN

BACKGROUND AND OBJECTIVES: Urachal carcinoma (UrC) is a rare and poorly investigated disease. Our current knowledge is mainly based on single-institutional studies. Despite growing interest in UrC, the included case numbers in recently published studies are still low. Therefore, we aimed to provide a comprehensive meta-analysis on the clinical, prognostic, and therapeutic aspects of UrC. METHODS: A systematic Medline/PubMed search was performed on UrC using the terms "urachal carcinoma," "urachal cancer," and "urachus." Original articles and reviews in English language with case numbers>10 were selected. RESULTS: The vast majority (91%, 489/532) of UrCs are diagnosed at later stages (Sheldon≥III) when the tumor invades the urinary bladder. About 21% (136/646) of UrC patients have distant metastasis at first presentation. Although for patients with non-metastatic UrC surgical treatment provides an acceptable disease control, the systemic treatment of patients with progressed/metastatic UrC-in lack of prospective clinical trials-are less well established. Comparing cisplatin-based and 5-FU-based therapies in 74 published UrC cases, we found the latter to be superior in terms of radiographic response rates (9% vs. 44%, P = 0.043), but the combination of these 2 therapies provided the lowest progression rate (14%) with a similarly high response rate (43%). CONCLUSIONS: Owing to the lack of evidence-based guidelines, the therapy of UrC remains challenging. Given the infrequency of UrC, large prospective studies comparing different systemic therapies can hardly be conducted. Our metadata indicates that 5-FU-containing chemotherapy regimens are more effective than cisplatin-based treatment modalities, whereas their combination seems to provide the strongest antitumor effect. Nevertheless, in the lack of evidences from prospective clinical trials, therapeutic decision-making necessarily remains on an individual basis. In this situation, targeted therapies may provide a reasonable alternative. Therefore, better understanding of the molecular background of UrC is needed to rationalize treatment decisions in UrC.


Asunto(s)
Uraco/patología , Neoplasias de la Vejiga Urinaria/diagnóstico , Neoplasias de la Vejiga Urinaria/terapia , Humanos , Pronóstico , Estudios Prospectivos
9.
Magy Onkol ; 59(4): 286-91, 2015 Dec.
Artículo en Húngaro | MEDLINE | ID: mdl-26665188

RESUMEN

In the second half of the 20th century research focusing to breast carcinomas at the Semmelweis University had been mostly linked to the 2nd Department of Pathology. Nowadays, following the rapidly improving treatment modalities in breast cancer there is an increasing need for defining new predictive and prognostic markers. The modern molecular pathological approach helps tremendously in mapping the biological behavior of individual cases of breast cancers and meanwhile, it is one of the prerequisites of a more efficient treatment both in neoadjuvant and adjuvant settings, as well as in metastatic disease. We provide a brief review of the relevant results we have obtained in breast cancer research between 2000 and 2015.

10.
Breast Cancer ; 22(3): 245-52, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25874688

RESUMEN

Genomic assays measuring the expression of multiple genes have made their way into clinical practice and their utilization is now recommended by major international guidelines. A basic property of these tests is their capability to sub-divide patients into high- and low-risk cohorts thereby providing prognostic, and in certain settings, predictive decision support. Here, we summarize commercially available assays for breast cancer including RT-PCR and gene chip-based tests. Given the relative uncertainty in cancer treatment, multigene tests have the potential for a significant cost reduction as they can pinpoint those patients for whom chemotherapy proves to be unnecessary. However, concordance of risk assessment for an individual patient is still far from optimal. Additionally, emerging multigene approaches focus on predicting therapy response, which is a black spot of current tests. Promising techniques include the homologous recombination deficiency score, utilization of massive parallel sequencing to identify driver genes, employment of internet-based meta-analysis tools and investigation of miRNA expression signatures. Combination of multiple simultaneous analyses at diagnosis, including classical histopathological diagnostics, monogenic markers, genomic signatures and clinical parameters will most likely bring maximal benefit for patients. As the main driving force behind such genomic tests is the power to achieve cost reduction due to avoiding unnecessary systemic treatment, the future is most likely to hold a further proliferation of such assays.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Perfilación de la Expresión Génica , Análisis de Secuencia por Matrices de Oligonucleótidos , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/tratamiento farmacológico , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Estadificación de Neoplasias , Pronóstico , Medición de Riesgo
11.
Magy Onkol ; 58(3): 204-10, 2014 Sep.
Artículo en Húngaro | MEDLINE | ID: mdl-25260085

RESUMEN

The optimal oncological result of radical prostatectomy (RP) is complete removal of the prostate gland and seminal vesicles with negative surgical margins. Preoperative diagnostic biopsies are examined and reported by the pathologist according to standardized rules. Staging of the disease is based on modern preoperative image analysis, most commonly multiparametric MRI. Pathological assessment and reporting of RP specimens is based on the International Society of Uropathology guidelines issued by the 2009 Consensus Conference. Positive surgical margin (PSM) is reported by the pathologist in approximately 1/3rd of RP cases. PSM increases the risk of biochemical, local and systemic progression. Pseudo-whole mount assessment of these specimens is the basis for radio-pathological correlation, thus providing quality control for preoperative MRI as well as assisting preoperative image analysis, sampling and diagnostic workup.


Asunto(s)
Prostatectomía , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/cirugía , Biomarcadores de Tumor/sangre , Humanos , Imagen por Resonancia Magnética , Masculino , Recurrencia Local de Neoplasia/prevención & control , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Pronóstico , Antígeno Prostático Específico/sangre , Prostatectomía/normas , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/diagnóstico por imagen , Radiografía
12.
Breast Cancer Res Treat ; 140(2): 219-32, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23836010

RESUMEN

To date, three molecular markers (ER, PR, and CYP2D6) have been used in clinical setting to predict the benefit of the anti-estrogen tamoxifen therapy. Our aim was to validate new biomarker candidates predicting response to tamoxifen treatment in breast cancer by evaluating these in a meta-analysis of available transcriptomic datasets with known treatment and follow-up. Biomarker candidates were identified in Pubmed and in the 2007-2012 ASCO and 2011-2012 SABCS abstracts. Breast cancer microarray datasets of endocrine therapy-treated patients were downloaded from GEO and EGA and RNAseq datasets from TCGA. Of the biomarker candidates, only those identified or already validated in a clinical cohort were included. Relapse-free survival (RFS) up to 5 years was used as endpoint in a ROC analysis in the GEO and RNAseq datasets. In the EGA dataset, Kaplan-Meier analysis was performed for overall survival. Statistical significance was set at p < 0.005. The transcriptomic datasets included 665 GEO-based and 1,208 EGA-based patient samples. All together 68 biomarker candidates were identified. Of these, the best performing genes were PGR (AUC = 0.64, p = 2.3E-07), MAPT (AUC = 0.62, p = 7.8E-05), and SLC7A5 (AUC = 0.62, p = 9.2E-05). Further genes significantly correlated to RFS include FOS, TP53, BTG2, HOXB7, DRG1, CXCL10, and TPM4. In the RNAseq dataset, only ERBB2, EDF1, and MAPK1 reached statistical significance. We evaluated tamoxifen-resistance genes in three independent platforms and identified PGR, MAPT, and SLC7A5 as the most promising prognostic biomarkers in tamoxifen treated patients.


Asunto(s)
Biomarcadores de Tumor/biosíntesis , Neoplasias de la Mama/tratamiento farmacológico , Regulación Neoplásica de la Expresión Génica , Tamoxifeno/administración & dosificación , Antineoplásicos Hormonales/administración & dosificación , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Transportador de Aminoácidos Neutros Grandes 1/metabolismo , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Pronóstico , Piridinas/metabolismo , Resultado del Tratamiento , Proteínas tau/metabolismo
13.
BMC Cancer ; 13: 50, 2013 Feb 02.
Artículo en Inglés | MEDLINE | ID: mdl-23374644

RESUMEN

BACKGROUND: Several classification systems are available to assess pathological response to neoadjuvant chemotherapy in breast cancer, but reliable biomarkers to predict the efficiency of primary systemic therapy (PST) are still missing. Deregulation of gap junction channel forming connexins (Cx) has been implicated in carcinogenesis and tumour progression through loss of cell cycle control. In this study we correlated Cx expression and cell proliferation with disease survival and pathological response to neoadjuvant chemotherapy in breast cancers using existing classification systems. METHODS: The expression of Cx26, Cx32, Cx43, Cx46 and Ki67 was evaluated in 96 breast cancer patients prior to and after neoadjuvant chemotherapy using duplicate cores in tissue microarrays (TMA). Cx plaques of <1µm were detected with multilayer, multichannel fluorescence digital microscopy. Current classifications to assess residual tumour burden after primary systemic therapy included the EWGBSP, CPS-EG, Miller-Payne, Sataloff and NSABP systems. RESULTS: In our cohort dominated by hormone receptor (ER/PR) positive and HER2 negative cases, only the CPS-EG classification showed prognostic relevance: cases with scores 1-2 had significantly better overall survival (p=0.015) than cases with scores 3-5. Pre-chemotherapy Cx43 expression correlated positively with hormone receptor status both before and after chemotherapy and had a negative correlation with HER2 expression pre-chemotherapy. There was a positive correlation between Cx32 and HER2 expression pre-chemotherapy and between Cx32 and Ki67 expression post-chemotherapy. A negative correlation was found between post-chemotherapy Cx46 and Ki67 expression. Decreased post-chemotherapy Cx26 expression (<5%) statistically correlated with better overall survival (p=0.011). Moderate or higher Cx46 expression (>20%) pre- and post-chemotherapy correlated with significantly better survival in the intermediate prognostic subgroups of EWGBSP TR2b (p(pre-chemo)=0.006; Sataloff TB (p(pre-chemo)=0.005; p(post-chemo)=0.029) and in Miller-Payne G3 (p(pre-chemo)=0.002; p(post-chemo)=0.012) classifications. Pre-chemotherapy, Cx46 expression was the only marker that correlated with overall survival within these subgroups. CONCLUSION: Our results suggest that Cx46 and Cx26 expression in breast cancer may improve the assessment of pathological response and refine intermediate prognostic subgroups of residual tumour classifications used after neoadjuvant chemotherapy.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Carcinoma/tratamiento farmacológico , Carcinoma/metabolismo , Conexinas/metabolismo , Terapia Neoadyuvante , Adulto , Anciano , Neoplasias de la Mama/clasificación , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Carcinoma/clasificación , Carcinoma/mortalidad , Carcinoma/patología , Quimioterapia Adyuvante , Distribución de Chi-Cuadrado , Conexina 26 , Conexina 43/metabolismo , Femenino , Humanos , Estimación de Kaplan-Meier , Antígeno Ki-67/metabolismo , Persona de Mediana Edad , Neoplasia Residual , Modelos de Riesgos Proporcionales , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Análisis de Matrices Tisulares , Resultado del Tratamiento , Proteína beta1 de Unión Comunicante
14.
Magy Onkol ; 56(3): 209-12, 2012 Sep.
Artículo en Húngaro | MEDLINE | ID: mdl-23139925

RESUMEN

Different expression of claudins and E-cadherin has been described in the pathogenesis and progression of breast cancer. Changes in the expression of these junctional molecules have also been described as being of prominent importance in other cancers as well. Thus, we aimed at exploring the potential prognostic relevance of these cell junctional molecules in breast carcinoma cases. Expression of claudin-1, -3, -4, -5, -7, -8, -10, -15, -18 and E-cadherin at mRNA level was evaluated in correlation with survival in publicly available datasets containing expression measurements of 1809 breast cancer patients. Breast cancer tissues of 636 patients were evaluated with tissue microarray technique and immunohistochemical method for claudin-1, -2, -3, -4, -5, -7 and E-cadherin protein expression. In 96 cases lymph node metastases were also subjects of the study. Claudin expression bears prognostic information in itself. Based on bioinformatic data analysis, the meta-gene of claudin-3, -4, -7 and E-cadherin has proved the most powerful in predicting survival. An immunohistochemical protein profile consisting of claudin-2, -4 and E-cadherin was able to predict outcome in the most effective manner in the training set. Combining the overlapping members of the distinct methods resulted in the CC index (consisting of claudin-4 and E-cadherin, a.k.a. CURIO), which was able to accurately predict relapse-free survival in the validation cohort (p=0.029) in a more efficient way than its components. Cox regression analysis including clinicopathological variables and the average CC score showed that in univariate analysis most of them were prognostic but most of them lost independent prognostic value in multivariate analysis except for the CC index, the subtypes defined by immunoprofiling and vascular invasion. On the other hand, the CC index was able to further refine prognosis splitting good vs. poor prognosis patients into two clusters in these subgroups. Evaluation of lymph node metastases has shown that decreased expression of claudin-1 and elevated expression of claudin-4 can predict worse prognosis in breast cancers spreading to the regional lymph nodes. The defined claudin-cadherin index provides additional prognostic information besides the routinely utilized diagnostic approaches and factors. The level of expression of certain claudins can be of prognostic significance in regional lymph node metastases.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/metabolismo , Cadherinas/metabolismo , Claudinas/metabolismo , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Cadherinas/genética , Claudina-1/metabolismo , Claudina-3/metabolismo , Claudina-4/metabolismo , Claudina-5/metabolismo , Claudinas/genética , Regulación hacia Abajo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Metástasis Linfática/diagnóstico , Valor Predictivo de las Pruebas , Pronóstico , ARN Mensajero/metabolismo , Medición de Riesgo , Factores de Riesgo , Tasa de Supervivencia , Análisis de Matrices Tisulares , Regulación hacia Arriba
15.
Magy Onkol ; 56(2): 75-8, 2012 May.
Artículo en Húngaro | MEDLINE | ID: mdl-22629543

RESUMEN

There is a reasonable heterogeneity in the morphological appearance and the immunohistochemical properties of distinct breast tumors. Furthermore, it is also known that cancer arising in young women have different prognosis than the ones developing in the elderly. We analyzed breast tumors of 41 young (<35 years) and 33 older women (>65 years) regarding histopathological properties and immunohistochemical reactions for ER, PgR, HER2 and Ki-67, as well as HER2 FISH. The longest diameters, thus largest available surface areas of the tumors were included in the evaluation. Different regions were marked for morphology and in all immunohistochemical reactions. The regions in the distinct tumors showing different pathological and immunohistochemical appearance were identical (p<0.001). The number of morphologically different tumor regions were more frequent in tumors developing in the young (1.82 vs. 1.48 regions/tumor), and 53.6% of tumors with heterogeneous architecture were in young vs. 39.4% in the elderly. However, regarding HER2 staining, cancers in the young patients have shown greater variability among the different tumor areas (p=0.007). The origin of tumor cells predicting prognosis remains undetermined. Whether the analysis of the expression pattern of the whole tumor is conducted or the minute regions are separately examined and averaged, the same results can be achieved. With the development of molecular techniques and accurate prognostic and treatment information rendered to samples the question may be soon answered.


Asunto(s)
Biomarcadores de Tumor/análisis , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Antígeno Ki-67/análisis , Receptor ErbB-2/análisis , Receptores de Estrógenos/análisis , Receptores de Progesterona/análisis , Adulto , Factores de Edad , Anciano , Femenino , Humanos , Inmunohistoquímica , Inmunofenotipificación , Hibridación Fluorescente in Situ , Pronóstico
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