[Show abstract][Hide abstract] ABSTRACT: Piwi-interacting RNAs (piRNAs) are a newly discovered class of small non-coding RNAs involved in silencing of transposable elements and in sequence-specific chromatin modifications. PIWI proteins (PIWIL), which belong to the family of Argonaute genes/proteins, bind to piRNAs and function mainly in germ line cells, but more recently were described to be functional also in stem cells and cancer cells. To date, there have been four PIWI proteins discovered in humans: PIWIL1, PIWIL2, PIWIL3, and PIWIL4. Recent studies suggested that deregulated expression of PIWI proteins and selected piRNAs is common to many types of cancers. We found significantly lower expression of PIWIL1 (P<0.0001) and piR-823 (P=0.0001) in tumor tissue in comparison to paired renal parenchyma. Further, we observed a progressive decrease in PIWIL1 (P=0.0228), PIWIL2 (P=0.0015), and PIWIL4 (P=0.0028) expression levels together with increasing clinical stage. PIWIL2 (P=0.0073) and PIWIL4 (P=0.0001) expression also progressively decreased with increasing Fuhrman grade. Most importantly, low-expression levels of PIWIL1 (P=0.009), PIWIL2 (P<0.0001), and PIWIL4 (P=0.0065) were significantly associated with worse overall survival in renal cell carcinoma (RCC) patients. Our results suggest the involvement of PIWIL genes and piR-823 in RCC pathogenesis, and indicate PIWIL1, PIWIL2, and PIWIL4 as potential prognostic biomarkers in patients with RCC.
Full-text · Article · Jan 2016 · OncoTargets and Therapy
[Show abstract][Hide abstract] ABSTRACT: Background:
In the Czech Republic, around 6,500 women get breast cancer each year; out of this number, nearly 1,000 women are triple negative subtype. Triple negative breast cancer is characterized by lack of expression of α-estrogen, progesterone, and HER2 receptors. Vast majority of these cases are low-differentiated carcinomas, majority belonging to the basal-like subgroup defined originally by DNA chips. Clinically, they are characterized by greater aggressiveness, fre-q-uent rate of local recurrence and organ metastases. They are more common in younger women and are associated with the occurrence of hereditary forms of breast cancer caused by pathogenic mutations in the BRCA1 gene and in rare cases also BRCA2.
The objective of this review is to provide comprehensive information about current knowledge of triple negative breast cancer. This paper summarizes information about epidemiology and etiopathogenesis of this disease, describes risk factors for both sporadic and hereditary forms of triple negative breast cancer, addresses histopathologic and molecular classification of triple negative breast cancer, and these characteristics associates with treatment and prediction of disease development. The article also addresses new anticancer drugs tested for triple negative breast cancer.
Triple negative breast cancer is a heterogeneous group of diseases with limited therapeutic options. The key to further shift in therapy is detailed knowledge of its clinical and molecular diversity and identification of predictive biomarkers. Further improvement of therapy results of triple negative breast cancer cannot be expected before targeted therapy of this disease is found.Key words: breast cancer - triple negative breast cancer - BRCA mutation - chemotherapy - basal-likeThis work was supported by grant MH CZ - RVO (MMCI, 00209805) and No. NT/14599-32013.The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 26. 11. 2015Accepted: 3. 12. 2015.
No preview · Article · Dec 2015 · Klinická onkologie: casopis Ceské a Slovenské onkologické spolecnosti
[Show abstract][Hide abstract] ABSTRACT: Ewings sarcoma is usually dia-gnosed in adolescents and young adults, peak of incidence is around 15 years of age. Primary localization is mostly in the skeleton of long bones and chest wall. Primary extraosseous involvement rarely occurs, incidence increases with age.
We present a case report of a 57year old patient with locally advanced tumors of the cervix, clinical stage IIB. Due to histological and molecular genetic examination revealing EWS ERG fusion gene, Ewings sarcoma was dia-gnosed. CT revealed pathological pelvic lymphadenopathy and multiple pulmonary bilateral methastases, scintigraphy did not prove any affection of skeleton. The patient underwent a twostage intensive chemotherapy regimens VIDE (vincristine, ifosfamide, doxorubicin, etoposide) and VAI (vincristine, actinomycin D, ifosfamide). During the second phase, concomitant radiotherapy of pelvis was aplied. According to PET/ CT, complete remission was achieved. Whole lung irradiation was applied in consolidation of the result.
Primary Ewings sarcoma of the cervix is an extremely rare disease. To our knowledge, only 12 cases was presented until this time. The average age at time of dia-gnosis was 35 years. Unlike the previous reports, we initially dia-gnosed distant metastases. The treatment was led according to the protocol Ewing 2008 designed for primary skeletal Ewings sarcoma. Currently, 18 months after the therapy, the patient is without signs of disease. However, longterm follow-up is necessary.Key words: Ewings sarcoma - uterine cervix - cytogenetics - EWS-ERG - chemotherapy - radiotherapyThe authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.The Editorial Board declares that the manuscript met the ICMJE "uniform requirements" for biomedical papers.Submitted: 3. 6. 2015Accepted: 25. 7. 2015.
No preview · Article · Aug 2015 · Klinická onkologie: casopis Ceské a Slovenské onkologické spolecnosti
[Show abstract][Hide abstract] ABSTRACT: Anterior gradient protein (AGR) 3 is a highly related homologue of pro-oncogenic AGR2 and belongs to the family of protein disulfide isomerases. Although AGR3 was found in breast, ovary, prostate, and liver cancer, it remains of yet poorly defined function in tumorigenesis. This study aimed to determine AGR3 expression in a cohort of 129 primary breast carcinomas and evaluate the clinical and prognostic significance of AGR3 in these tumors. The immunohistochemical analysis revealed the presence of AGR3 staining to varying degrees in 80% of analyzed specimens. The percentage of AGR3-positive cells significantly correlated with estrogen receptor, progesterone receptor (both P<0.0001) as well as low histological grade (P=0.003), and inversely correlated with the level of Ki-67 expression (P<0.0001). In the whole cohort, AGR3 expression was associated with longer progression-free survival (PFS), whereas AGR3-positive subgroup of low-histological grade tumors showed both significantly longer PFS and overall survival. In conclusion, AGR3 is associated with the level of differentiation, slowly proliferating tumors, and more favorable prognosis of breast cancer patients.
Full-text · Article · Jun 2015 · OncoTargets and Therapy
[Show abstract][Hide abstract] ABSTRACT: Objectives
. The aim of the study was to develop a clinical prediction model for assessing the probability of having invasive cancer in the definitive surgical resection specimen in patients with biopsy diagnosis of ductal carcinoma in situ (DCIS) of the breast, to facilitate decision making regarding axillary surgery.
. In 349 women with DCIS, predictors of invasion in the definitive resection specimen were identified. A model to predict the probability of invasion was developed and subsequently simplified to divide patients into two risk categories. The model’s performance was validated on another patient population.
. Multivariate logistic regression revealed four independent predictors of invasion: (i) suspicious (micro)invasion in the biopsy specimen; (ii) visibility of the lesion on ultrasonography; (iii) size of the lesion on mammography >30 mm; (iv) clinical palpability of the lesion. The actual frequency of invasion in the high-risk patient group in the test and validation population was 52.6% and 48.3%, respectively; in the low-risk group it was 16.8% and 7.1%, respectively.
. The model proved to have good performance. In patients with a low probability of invasion, an axillary procedure can be omitted without a substantial risk of additional surgery.
Preview · Article · Jul 2014 · BioMed Research International
[Show abstract][Hide abstract] ABSTRACT: Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer next to hepatocellular carcinoma (HCC). Despite the significant difference of the therapeutic strategy for both diseases, their histological appearance may be very similar. Thus the correct diagnosis is crucial for treatment choice but is often difficult to achieve. The aim of our study was to evaluate anterior gradient 3 (AGR3) as a new diagnostic marker helping to distinguish between ICC and HCC. AGR3 is a putative transmembrane protein implicated in breast, prostate and ovary tumorigenesis and belongs to the family of protein disulphide isomerases. Since there is little information on how AGR3 is expressed in normal and diseased tissues and what its exact function is, we analyzed its expression pattern in normal liver and tumor tissue of ICC and HCC. The immunohistochemical analysis in normal tissue revealed specific AGR3 expression in intrahepatic bile duct cholangiocytes which was not present in liver hepatocytes. Consequently we analyzed AGR3 expression in 74 representative samples of puncture biopsies, tissue excisions and resection specimens from which 48 samples were diagnosed as HCC and 26 as ICC. Our results showed AGR3 expression negative and weakly positive respectively in hepatocellular carcinomas compared to stronger AGR3 positivity in cholangiocellular carcinomas. AGR3 expression statistically significantly correlated to acid mucopolysaccharide expression and negatively correlated to glypican-3 expression. We conclude that according to receiver operating characteristics (ROC) analysis AGR3 expression is relatively specific for ICC and is potentially linked to mucosecretion, which may indicate potential implication in treatment resistance.
No preview · Article · Apr 2014 · Experimental and Molecular Pathology
[Show abstract][Hide abstract] ABSTRACT: Biobanking is a well-organized, sophisticated system that consists in programmed storage of biological material and corresponding data that is accessible for scientific investigation. In this article, we briefly describe the principles of a tumour biobank; namely sample collection, storage and distribution. The key role of pathologists in the process of biobank sample selection is highlighted; it is an integral part of gross specimen handling as a diagnostic procedure. The harmonization of standard operating procedures is an important issue; the biological material stored in a biobank must be processed in a manner that allows compatibility with other biobanks. Material withdrawal must be accompanied by a Material Transfer Agreement to cover all technical and ethical/legal issues concerning the scientific utilization of the released material. Key words: biobanks - standards - translational research.
No preview · Article · Apr 2014 · Rozhledy v chirurgii: měsíčník Československé chirurgické společnosti
[Show abstract][Hide abstract] ABSTRACT: Inoperable c kit negative gastrointestinal stromal tumor (GIST) is commonly considered to be highly resistant to systemic therapy. We present a case of a woman with an abdominal sarcomalike tumor dia-gnosed at the age of 26. The patient underwent several surgical procedures and courses of cytostatic therapy without any substantial effect. Later, the tumor was reclassified as c kit negative GIST harbouring the mutation in exon 12 of PDGFRA gene. Hence, the therapy with imatinib mesylate was initiated, resulting in partial remission of metastatic lesions and further stabilization of the disease for five yeas to date. We therefore consider imatinib mesylate an appropriate therapy for c kit negative GIST bearing PDGFRA mutations. Key words: gastrointestinal stromal tumors - c kit receptor - PDGF alpha receptor - imatinib mesylate.
Preview · Article · Feb 2014 · Klinická onkologie: casopis Ceské a Slovenské onkologické spolecnosti
[Show abstract][Hide abstract] ABSTRACT: Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer next to hepatocellular carcinoma (HCC). Despite the significant difference of the therapeutic strategy for both diseases, their histological appearance may be very similar. Thus the correct diagnosis is crucial for treatment choice but is often difficult to achieve. The aim of our study was to evaluate anterior gradient 3 (AGR3) as a new diagnostic marker helping to distinguish between ICC and HCC. AGR3 is a putative transmembrane protein implicated in breast, prostate and ovary tumorigenesis and belongs to the family of protein disulphide isomerases.
Since there is little information on how AGR3 is expressed in normal and diseased tissues and what its exact function is, we analyzed its expression pattern in normal liver and tumor tissue of ICC and HCC. The immunohistochemical analysis in normal tissue revealed specific AGR3 expression in intrahepatic bile duct cholangiocytes which was not present in liver hepatocytes. Consequently we analyzed AGR3 expression in 74 representative samples of puncture biopsies, tissue excisions and resection specimens from which 48 samples were diagnosed as HCC and 26 as ICC. Our results showed AGR3 expression negative and weakly positive respectively in hepatocellular carcinomas compared to stronger AGR3 positivity in cholangiocellular carcinomas. AGR3 expression statistically significantly correlated to acid mucopolysaccharide expression and negatively correlated to glypican-3 expression. We conclude that according to receiver operating characteristics (ROC) analysis AGR3 expression is relatively specific for ICC and is potentially linked to mucosecretion, which may indicate potential implication in treatment resistance.
No preview · Article · Jan 2014 · Experimental and Molecular Pathology
[Show abstract][Hide abstract] ABSTRACT: Endocrine resistance is a significant problem in breast cancer treatment. Thus identification and validation of novel resistance determinants is important to improve treatment efficacy and patient outcome. In our work, AGR2 expression was determined by qRT-PCR in Tru-Cut needle biopsies from tamoxifen-treated postmenopausal breast cancer patients. Our results showed inversed association of AGR2 mRNA levels with primary treatment response (P = 0.0011) and progression-free survival (P = 0.0366) in 61 ER-positive breast carcinomas. As shown by our experimental and clinical evaluations, elevated AGR2 expression predicts decreased efficacy of tamoxifen treatment. From this perspective, AGR2 is a potential predictive biomarker enabling selection of an optimal algorithm for adjuvant hormonal therapy in postmenopausal ER-positive breast cancer patients.
[Show abstract][Hide abstract] ABSTRACT: Standardized gynecological oncological therapeutical guidelines are based on ordinary predictive factors, such as depth of stromal invasion, histopathological type of tumor, lymphovascular space invasion, lymph node metastases. Unfortunately, the power of these prognostic factors is not able to determine the safety of this procedure in the relation to disease recurrence in a group of patients who are indicated for conservative operations. This is the appropriate area for new, especially biomolecular prognostic factors (proteins: p63, TAp63, p16, p21, p27, COX-2, genes: hTERC, MYCC). Moreover, comprehensive evaluation of cervical cancer prognostic factors and assessment of new biomarkers of cancer can ease prediction of risk of spread outside primary localization and determine probability of disease recurrence. This information can help to individualize surgical, radiotherapeutic and chemotherapeutic treatment. Key words: carcinoma of the cervix - prognostic factors - lymphovascular space invasion - lymph node metastases - tumor size - protein - expression.
Preview · Article · Apr 2013 · Klinická onkologie: casopis Ceské a Slovenské onkologické spolecnosti
[Show abstract][Hide abstract] ABSTRACT: Background:
The incidence of renal cell carcinoma in the Czech Republic is one of the highest in the world. Curative treatment is still possible only surgically, while in the palliative treatment, partial success was reached using targeted therapies. While prognostic factors and models are commonly used in clinical practice, unfortunately, predictive biomarkers have not been found. The aim of our study was to verify the validity of selected prognostic factors on a consecutive patient cohort from the Czech population.
Patients and methods:
The patient cohort consisted of 544 patients with RCC diagnosed and/or treated at our institute from 2003 to 2010. Individual clinical and histological prognostic factors and Heng prognostic model were validated.
Median time of follow-up for our cohort was 42 months (range 0.3-326 months), median age at diagnosis was 62 years, and almost 64% of patients were men. Distribution of clinical stages was as follows: 46.5% of I, II. 10.7%, III. 13.1%, IV. 20%. 26.4% of patients in stage I-III relapsed. We diagnosed mainly clear cell (84.6%) and papillary carcinoma (9.2%). Initially, 95.8% of patients underwent surgical treatment, systemic adjuvant and palliative treatment was applied in 3.7 and 37.7% of patients, respectively. Palliative targeted therapy was received by a total of 163 patients (30%). In first-line targeted therapy, the following median TTP was reached (in months): 10.8 for sunitinib, 6.3 for sorafenib and 5.2 months for immunotherapy. The most significant prognostic factors (p < 0.00001) were: stage of disease (HR = 9.61), size of the primary tumor (HR = 5.83), lymph nodes (HR = 8.26), presence of sarcomatoid tumor sections in the tumor (HR = 7.29), and tumor grade (HR = 4.0). Besides these, we also confirmed the prognostic importance of presence of eosinophilic granulations in the tumor (HR = 1.91, p = 0.02). When applying the Heng prognostic model, we achieved similar results for patients treated with targeted therapies.
The obtained epidemiological and clinico-pathological data are consistent with previously published data. These prognostic factors can be used for a differentiated approach to patients with RCC, both for establishing follow-up plan for patients after surgery as well as indication for targeted therapies.
Full-text · Article · Apr 2013 · Klinická onkologie: casopis Ceské a Slovenské onkologické spolecnosti
[Show abstract][Hide abstract] ABSTRACT: Background:
Malignant melanoma is considered to be highly resistant to chemotherapy, radiotherapy, hormonotherapy and standard immunotherapy (interleukin 2, interferon alpha). Radical surgery in the early stages of the disease is still the most efficient method. Since the development of immunotherapy and targeted therapy, the role of palliative chemotherapy for advanced disease may be changing.
A case report regarding 44-year-old woman with extensive tumor of the pectoral wall with contralateral axillary lymphadenopathy is presented. On the basis of imaging methods, histology and immunohistochemistry, the tumor was defined as a sarcoma. Due to PAX7-FKHR fusion gene positivity, rhabdomyosarcoma was the most probable classification. The patient was treated with radical chemotherapy including iphosphamide, vincristine, actinomycin D and doxorubicin with the effect of partial regression of the tumor. This enabled radical surgery of the chest wall tumor. Pathology proved 70% necrosis of the tumor. A contralateral axillary dissection was performed with a finding of two lymph nodes infiltrated with melanoma. The immunohistochemistry markers S100, HMB-45 and Melan A were positive. This resulted in a reclassification of the chest wall tumor to malignant melanoma. The following PET/CT scan was negative. A massive progression of the disease occurred after 5 months. B-RAF mutation leads to a plan of targeted therapy with vemurafenib.
The case demonstrates the limits of the sensitivity and specificity of immunohistochemical markers of melanoma and the ability of this tumor to imitate various tumors including soft tissue sarcomas. A rare -PAX7-FKHR fusion gene positivity considered specific for rhabdomyosarcoma was found. An extraordinary response to radical chemotherapy with surgical resection led to an improvement of the quality of life and to a prolonged survival comparable with the effect of new targeted treatment for malignant melanoma.
Full-text · Article · Feb 2013 · Klinická onkologie: casopis Ceské a Slovenské onkologické spolecnosti
[Show abstract][Hide abstract] ABSTRACT: Background
Rectal cancer accounts for approximately one third of all colorectal cancers (CRC), which belong among leading causes of cancer deaths worldwide. Standard treatment for locally advanced rectal cancer (cT3/4 and/or cN+) includes neoadjuvant chemoradiotherapy with fluoropyrimidines (capecitabine or 5-fluorouracil) followed by radical surgical resection. Unfortunately, a significant proportion of tumors do not respond enough to the neoadjuvant treatment and these patients are at risk of relapse. MicroRNAs (miRNAs) are small non-coding RNAs playing significant roles in the pathogenesis of many cancers including rectal cancer. MiRNAs could present the new predictive biomarkers for rectal cancer patients.
We selected 20 patients who underwent neoadjuvant chemoradiotherapy for advanced rectal cancer and whose tumors were classified as most sensitive or resistant to the treatment. These two groups were compared using large-scale miRNA expression profiling.
Expression levels of 8 miRNAs significantly differed between two groups. MiR-215, miR-190b and miR-29b-2* have been overexpressed in non-responders, and let-7e, miR-196b, miR-450a, miR-450b-5p and miR-99a* have shown higher expression levels in responders. Using these miRNAs 9 of 10 responders and 9 of 10 non-responders (p < 0.05) have been correctly classified.
Our pilot study suggests that miRNAs are part of the mechanisms that are involved in response of rectal cancer to the chemoradiotherapy and that miRNAs may be promising predictive biomarkers for such patients. In most miRNAs we identified (miR-215, miR-99a*, miR-196b, miR-450b-5p and let-7e), the connection between their expression and radioresistance or chemoresistance to inhibitors of thymidylate synthetase was already established.
Full-text · Article · Nov 2012 · Radiation Oncology
[Show abstract][Hide abstract] ABSTRACT: Trastuzumab is effective in about half of HER2-positive breast cancer patients. The PI3K/Akt signalling pathway plays an important role in the process of primary and secondary resistance to anti-HER2 targeted therapy. We evaluated the relationship between expression, activation and subcellular localization of selected Akt isoforms and response to trastuzumab-based anti-HER2 targeted therapy in patients with HER2-positive metastatic breast cancer. Seventy-four women with verified HER2-positive breast cancer were treated with trastuzumab for metastatic disease. Immunohistochemistry was used to evaluate Akt1, Akt2, pAkt Thr308 and pAkt Ser473 expression. For pAkt, cytoplasmic and nuclear fractions were assessed separately. Even though Akt isoforms were expressed in the majority of tumours, activated Akt (pAkt) was present in the cytoplasm only and not in the nucleus in >20% of tumours, and there was no pAkt at all in another 7-13% of tumours. Patients whose tumours showed strong Akt2 expression and had pAkt (pAkt-Thr308 and/or pAkt-Ser473) detectable in the cytoplasm as well as nucleus (n+c), exhibited improved time to progression (TTP) and overall survival from the initiation of trastuzumab therapy (OSt). Patients with tumours with strong Akt2 and pAkt Thr308 (n+c) had superior TTP (17.0 vs. 7.6 months, P=0.024; HR 0.52) and OSt (51.8 vs. 16.8 months, P=0.0009; HR 0.34) compared to other tumours. Similar results were found for strong Akt2 and pAkt Ser473 (n+c): TTP 13.1 vs. 7.2 months (P=0.085, HR 0.62) and OSt 50.8 vs. 17.0 months (P=0.009; HR 0.45). This study is the first to prove the significance of Akt kinase isoform, activity and compartmentalization for the prediction of response to trastuzumab-based therapy in patients with HER2-positive metastatic breast cancer.
Full-text · Article · Jul 2012 · International Journal of Oncology
[Show abstract][Hide abstract] ABSTRACT: Triple-negative breast cancer (TNBC) represents a heterogeneous group of breast cancers that do not express ER-α, PgR and Her-2 receptors. Generally, these tumors are aggressive and more common in younger women, in which an association of TNBC with mutations in the BRCA1 gene was documented. The aim of our study was to create a representative group of patients with TNBC, which could be analyzed and the data gathered to build basic epidemiological, molecular and clinical characteristics of Czech patients with TNBC.
We performed basic clinical-pathologic correlations in a group of 335 patients diagnosed and/or treated for TNBC at the Masaryk Memorial Cancer Institute between 2004 and 2009. We also performed immunohistochemical examination of expression of cytokeratin 5/6, cytokeratin 14 and EGFR to identify the basal-like subset of TNBC.
The median age of patients with TNBC was 56 years, range 25-88 years. A total of 9.25% of TNBC cases were diagnosed in patients under the age of 34, and another 15.22% of cases were in the age group of 35 to 44 years. 'Basal-like' carcinomas accounted for 75% of TNBC. We confirmed the aggressive nature of this disease: in the follow-up period we observed a relapse in 25% of patients: 55% of deaths due to disease progression occured within 2 years after diagnosis of the disease. Treatment strategies include chemotherapy, in most cases (88.4%). Chemotherapy was mostly based on regimens with anthracyclines or in combination with taxanes. The most important negative prognostic factors in relation to OS (disease specific OS) were: higher clinical stage (p < 0.0001), pN - positive status (p < 0.0001), high proliferative activity (as measured by Ki-67, cut-off 50%, HR = 0.4740, p = 0.0411) and positive expression of CK5/6 (HR = 0.4274, p = 0.0338). In relation to DFS, the negative prognostic significance was found for these factors: higher clinical stage (p < 0.0001), pN positive status (p < 0.0001), high proliferative activity (Ki-67, cut-off 50%, HR = 0.04993, p = 0.0240). DFS was longer in patients with a higher number of applied cycles of anthracycline-based chemotherapy (> 4 cycles, HR = 1.7273, p = 0.0467).
TNBC is an aggressive form of breast cancer, which may occur in patients of all ages, but more frequently in younger patients. Only early detection of disease and intensive treatment gives a high chance of cure. Unfortunately, no reliable predictive factors have been identified so far. Better therapeutic results can be expected from targeted therapy.
No preview · Article · Jun 2012 · Klinická onkologie: casopis Ceské a Slovenské onkologické spolecnosti