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Papers by Elwira Bakula-zalewska

European Journal of Human Genetics, 2013

Atlas of Fine Needle Aspiration Cytology

JCI insight, Jan 2, 2017

Endometrial stromal tumors include translocation-associated low- and high-grade endometrial strom... more Endometrial stromal tumors include translocation-associated low- and high-grade endometrial stromal sarcomas (ESS) and highly malignant undifferentiated uterine sarcomas (UUS). UUS is considered a poorly defined group of aggressive tumors and is often seen as a diagnosis of exclusion after ESS and leiomyosarcoma (LMS) have been ruled out. We performed a comprehensive analysis of gene expression, copy number variation, point mutations, and immune cell infiltrates in the largest series to date of all major types of uterine sarcomas to shed light on the biology of UUS and to identify potential novel therapeutic targets. We show that UUS tumors have a distinct molecular profile from LMS and ESS. Gene expression and immunohistochemical analyses revealed the presence of high numbers of tumor-associated macrophages (TAMs) in UUS, which makes UUS patients suitable candidates for therapies targeting TAMs. Our results show a high genomic instability of UUS and downregulation of several TP53-m...

European Journal of Surgical Oncology (EJSO), 2016

PLOS ONE, 2016

Retinoic acid is a promising tool in adjuvant cancer therapies, including refractory thyroid canc... more Retinoic acid is a promising tool in adjuvant cancer therapies, including refractory thyroid cancer, and its biological role is mediated by the retinoic acid receptor beta (RARβ). However, expression of RARβ is lowered in papillary thyroid carcinoma (PTC), contributing to promotion of tumor growth and inefficiency of retinoic acid and radioactive iodine treatment. The causes of aberrant RARB expression are largely unknown. We hypothesized that the culpable mechanisms include the action of microRNAs from the miR-146 family, previously identified as significantly upregulated in PTC tumors. To test this hypothesis, we assessed the expression of RARB as well as miR-146a-5p and miR-146b-5p in 48 PTC tumor/normal tissue pairs by Taqman assay to reveal that the expression of RARB was 3.28-fold decreased, and miR-146b-5p was 28.9-fold increased in PTC tumors. Direct interaction between miRs and RARB was determined in the luciferase assay and further confirmed in cell lines, where overexpression of miR-146a-5p and miR-146b-5p caused a 31% and 33% decrease in endogenous RARB mRNA levels. Inhibition of miR-146a and miR-146b resulted in 62.5% and 45.4% increase of RARB, respectively, and a concomitant decrease in proliferation rates of thyroid cancer cell lines, analyzed in xCELLigence system.We showed that two microRNAs of the miR-146 family directly regulate RARB. Inhibition of miRs resulted in restoration of RARB expression and decreased rates of proliferation of thyroid cancer cells. By restoring RARB levels, microRNA inhibitors may become part of an adjuvant therapy in thyroid cancer patients.

Journal of Ultrasonography, 2015

Shear wave elastography (SWE) is a modern method for the assessment of tissue stiffness. There ha... more Shear wave elastography (SWE) is a modern method for the assessment of tissue stiffness. There has been a growing interest in the use of this technique for characterizing thyroid focal lesions, including preoperative diagnostics. Aim: The aim of the study was to assess the clinical usefulness of SWE in medullary thyroid carcinoma (MTC) diagnostics. Materials and methods: A total of 169 focal lesions were identifi ed in the study group (139 patients), including 6 MTCs in 4 patients (mean age: 45 years). B-mode ultrasound and SWE were performed using Aixplorer (SuperSonic, Aix-en-Provence), with a 4-15 MHz linear probe. The ultrasound was performed to assess the echogenicity and echostructure of the lesions, their margin, the halo sign, the height/width ratio (H/W ratio), the presence of calcifi cations and the vascularization pattern. This was followed by an analysis of maximum and mean Young's (E) modulus values for MTC (E maxLR , E meanLR) and the surrounding thyroid tissues (E maxSR , E meanSR), as well as mean E-values (E meanLRz) for 2 mm region of interest in the stiffest zone of the lesion. The lesions were subject to pathological and/or cytological evaluation. Results: The B-mode assessment showed that all MTCs were hypoechogenic, with no halo sign, and they contained micro-and/ or macrocalcifi cations. Ill-defi ned lesion margin were found in 4 out of 6 cancers; 4 out of 6 cancers had a H/W ratio > 1. Heterogeneous echostructure and type III vascularity were found in 5 out of 6 lesions. In the SWE, the mean value of E maxLR for all of the MTCs was 89.5 kPa and (the mean value of E maxSR for all surrounding tissues was) 39.7 kPa Mean

A case of an 83-year-old female patient, who was admitted to the Centre of Oncology in Warsaw bec... more A case of an 83-year-old female patient, who was admitted to the Centre of Oncology in Warsaw because of the right breast tumor, is presented. There was no exposure to prior irradiation. In two biopsies of the lesion, its malignant nature was not confirmed. Breast tumor removal with wide surgical margins was performed. As a result of the examination, angiosarcoma was confirmed histologically. Given the result, a simple right breast amputation was performed. External beam radiotherapy and chemotherapy, due to the rapid local recurrence and distant metastases, were also performed. The patient died after 20 months of the initial diagnosis because of the disease progression.

Cancer Research, 2014

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Introduction Endometrial st... more Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Introduction Endometrial stromal tumors (EST) are the second most prevalent uterine sarcomas. EST are divided into three histosubtypes: benign endometrial stromal nodules (ESN), low-grade endometrial stromal sarcomas (ESS) and the most malignant undifferentiated stromal sarcomas (UES). Moreover, due to clinicopathological features intermediate between classical low-grade ESS and UES, some tumors have been described in the literature as “high-grade ESS”. The histological distinction between these three subtypes has important prognostic implications. The molecular biology of these tumors remains poorly understood because of their low incidence. Patients and Methods In the present study, we performed gene expression profiling of 22 EST using microarray, RNA-Seq and qRT-PCR techniques. Our cohort included 10 classical low-grade ESS (8 with ESS-associated gene fusions), 8 UES and 4 tumors which were classified as high-grade ESS based on the presence of YWHAE-FAM22A/B fusion and histological features. Results Using gene expression microrarrays, we have identified 81 entities differentially expressed in analyzed samples (fold change > 2, p < 0.005). Hierarchical clustering analysis revealed that high-grade ESS formed a separate sub-cluster with a distinct molecular profile as compared with the low-grade ESS and UES cases. Low-grade ESS cases formed 2 distinct sub-clusters, each containing 5 cases, one of which presented gene expression profile partially corresponding to high-grade ESS cases. GO analysis of genes strongly up-regulated in UES specimens showed over-representation of immune response (GO:0006955) and immune system process (GO:0002376) pathways (MARCO, MYO1F, FCN1, GPR183, HLA-DPB1, FCGR2B, NCF1, CCL18, CD28, PTAFR, CCL13, STK4, CD14, NCF4 and CTLA4 genes) (p < 0.05). UES cases were also characterized by significant down-regulation of WT1 tumor suppressor gene as compared to the low- and high-grade ESS. Moreover, both high-grade ESS and UES cases were characterized by significantly lower expression level of PEG3 gene, which has been reported as a tumor suppressor gene. All low-grade ESS cases presented significant over-expression of estrogen receptor ESR1 gene. Microarray results were validated by RNA-Seq and qRT-PCR experiments. Conclusions This study provides gene expression profiles that distinguish between EST subtypes and sheds light on the biology of these tumors. Our results point to immune system involvement in the pathogenesis of UES and support the notion that the current EST classification should discriminate high-grade ESS as a distinct subtype. Citation Format: Joanna Przybyl, Magdalena Kowalewska, Anna Quattrone, Barbara Dewaele, Vanessa Vanspauwen, Julio Finalet-Ferreiro, Michal Swierniak, Elwira Bakula-Zalewska, Janusz A. Siedlecki, Mariusz Bidzinski, Jan Cools, Maria Debiec-Rychter. Gene expression profiling distinguishes between endometrial stromal tumors subtypes. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4698. doi:10.1158/1538-7445.AM2014-4698

Polish journal of pathology : official journal of the Polish Society of Pathologists, 2012

Myofibroblastoma (MFB) is a benign neoplasm arising most frequently in the adult breast, but it m... more Myofibroblastoma (MFB) is a benign neoplasm arising most frequently in the adult breast, but it may occur in any other tissue with the exception of the central nervous system. Adequate treatment of this neoplasm consists of local excision. MFB shows characteristic histological features and a clear immunohistochemical profile and usually does not cause any diagnostic difficulties [1-4]. A rare variant of MFB such as the epithelioid subtype with sclerotic stroma, however, can resemble lobular carcinoma in routinely stained histological sections.

Annals of Diagnostic Pathology, 2014

Endocrine Abstracts, 2014

Oncology Letters, 2012

O6-methylguanine-DNA methyltransferase (MGMT) gene promoter hypermethylation is observed in a num... more O6-methylguanine-DNA methyltransferase (MGMT) gene promoter hypermethylation is observed in a number of solid tumors and is correlated with the silencing of MGMT expression. In glioblastoma patients treated with the alkylating agent temozolomide, MGMT gene methylation status was shown to have predictive value in terms of prolonged overall survival. Recently, temozolomide has demonstrated promising activity in the treatment of soft tissue sarcomas, including those of the uterus. The tissue specimens involving tumor samples and normal uterine fragments were obtained from nine patients with smooth muscle uterine sarcoma, 11 with stromal uterine sarcoma and 17 with mixed uterine tumors. MGMT gene promoter methylation was analyzed by combined bisulfite restriction analysis (COBRA) while its expression levels were assessed using the real-time reverse transcription polymerase chain reaction (qRT-PCR). MGMT promoter methylation was observed in 27% of all tumor samples analyzed. When stratified by the disease type, 55.5% (5/9) of smooth muscle sarcomas, 23.5% (4/17) of mixed uterine tumor tissues and 9% (1/11) of stromal sarcomas showed MGMT methylation. The MGMT promoter methylation was associated with lower levels of gene expression in tumors when compared with those with an unmethylated promoter (P=0.0232) or normal tissues (P=0.0141). To conclude, MGMT promoter methylation and downregulation of gene expression is observed in a fraction of carcinosarcomas and non-epithelial malignant tumors of corpus uteri. The assessment of MGMT promoter methyla-tion status may potentially identify patients who would benefit from temozolomide treatment.

Endocrine Abstracts, 2014

Endocrine Abstracts, 2014

European Journal of Human Genetics, 2013

Atlas of Fine Needle Aspiration Cytology

JCI insight, Jan 2, 2017

Endometrial stromal tumors include translocation-associated low- and high-grade endometrial strom... more Endometrial stromal tumors include translocation-associated low- and high-grade endometrial stromal sarcomas (ESS) and highly malignant undifferentiated uterine sarcomas (UUS). UUS is considered a poorly defined group of aggressive tumors and is often seen as a diagnosis of exclusion after ESS and leiomyosarcoma (LMS) have been ruled out. We performed a comprehensive analysis of gene expression, copy number variation, point mutations, and immune cell infiltrates in the largest series to date of all major types of uterine sarcomas to shed light on the biology of UUS and to identify potential novel therapeutic targets. We show that UUS tumors have a distinct molecular profile from LMS and ESS. Gene expression and immunohistochemical analyses revealed the presence of high numbers of tumor-associated macrophages (TAMs) in UUS, which makes UUS patients suitable candidates for therapies targeting TAMs. Our results show a high genomic instability of UUS and downregulation of several TP53-m...

European Journal of Surgical Oncology (EJSO), 2016

PLOS ONE, 2016

Retinoic acid is a promising tool in adjuvant cancer therapies, including refractory thyroid canc... more Retinoic acid is a promising tool in adjuvant cancer therapies, including refractory thyroid cancer, and its biological role is mediated by the retinoic acid receptor beta (RARβ). However, expression of RARβ is lowered in papillary thyroid carcinoma (PTC), contributing to promotion of tumor growth and inefficiency of retinoic acid and radioactive iodine treatment. The causes of aberrant RARB expression are largely unknown. We hypothesized that the culpable mechanisms include the action of microRNAs from the miR-146 family, previously identified as significantly upregulated in PTC tumors. To test this hypothesis, we assessed the expression of RARB as well as miR-146a-5p and miR-146b-5p in 48 PTC tumor/normal tissue pairs by Taqman assay to reveal that the expression of RARB was 3.28-fold decreased, and miR-146b-5p was 28.9-fold increased in PTC tumors. Direct interaction between miRs and RARB was determined in the luciferase assay and further confirmed in cell lines, where overexpression of miR-146a-5p and miR-146b-5p caused a 31% and 33% decrease in endogenous RARB mRNA levels. Inhibition of miR-146a and miR-146b resulted in 62.5% and 45.4% increase of RARB, respectively, and a concomitant decrease in proliferation rates of thyroid cancer cell lines, analyzed in xCELLigence system.We showed that two microRNAs of the miR-146 family directly regulate RARB. Inhibition of miRs resulted in restoration of RARB expression and decreased rates of proliferation of thyroid cancer cells. By restoring RARB levels, microRNA inhibitors may become part of an adjuvant therapy in thyroid cancer patients.

Journal of Ultrasonography, 2015

Shear wave elastography (SWE) is a modern method for the assessment of tissue stiffness. There ha... more Shear wave elastography (SWE) is a modern method for the assessment of tissue stiffness. There has been a growing interest in the use of this technique for characterizing thyroid focal lesions, including preoperative diagnostics. Aim: The aim of the study was to assess the clinical usefulness of SWE in medullary thyroid carcinoma (MTC) diagnostics. Materials and methods: A total of 169 focal lesions were identifi ed in the study group (139 patients), including 6 MTCs in 4 patients (mean age: 45 years). B-mode ultrasound and SWE were performed using Aixplorer (SuperSonic, Aix-en-Provence), with a 4-15 MHz linear probe. The ultrasound was performed to assess the echogenicity and echostructure of the lesions, their margin, the halo sign, the height/width ratio (H/W ratio), the presence of calcifi cations and the vascularization pattern. This was followed by an analysis of maximum and mean Young's (E) modulus values for MTC (E maxLR , E meanLR) and the surrounding thyroid tissues (E maxSR , E meanSR), as well as mean E-values (E meanLRz) for 2 mm region of interest in the stiffest zone of the lesion. The lesions were subject to pathological and/or cytological evaluation. Results: The B-mode assessment showed that all MTCs were hypoechogenic, with no halo sign, and they contained micro-and/ or macrocalcifi cations. Ill-defi ned lesion margin were found in 4 out of 6 cancers; 4 out of 6 cancers had a H/W ratio > 1. Heterogeneous echostructure and type III vascularity were found in 5 out of 6 lesions. In the SWE, the mean value of E maxLR for all of the MTCs was 89.5 kPa and (the mean value of E maxSR for all surrounding tissues was) 39.7 kPa Mean

A case of an 83-year-old female patient, who was admitted to the Centre of Oncology in Warsaw bec... more A case of an 83-year-old female patient, who was admitted to the Centre of Oncology in Warsaw because of the right breast tumor, is presented. There was no exposure to prior irradiation. In two biopsies of the lesion, its malignant nature was not confirmed. Breast tumor removal with wide surgical margins was performed. As a result of the examination, angiosarcoma was confirmed histologically. Given the result, a simple right breast amputation was performed. External beam radiotherapy and chemotherapy, due to the rapid local recurrence and distant metastases, were also performed. The patient died after 20 months of the initial diagnosis because of the disease progression.

Cancer Research, 2014

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Introduction Endometrial st... more Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Introduction Endometrial stromal tumors (EST) are the second most prevalent uterine sarcomas. EST are divided into three histosubtypes: benign endometrial stromal nodules (ESN), low-grade endometrial stromal sarcomas (ESS) and the most malignant undifferentiated stromal sarcomas (UES). Moreover, due to clinicopathological features intermediate between classical low-grade ESS and UES, some tumors have been described in the literature as “high-grade ESS”. The histological distinction between these three subtypes has important prognostic implications. The molecular biology of these tumors remains poorly understood because of their low incidence. Patients and Methods In the present study, we performed gene expression profiling of 22 EST using microarray, RNA-Seq and qRT-PCR techniques. Our cohort included 10 classical low-grade ESS (8 with ESS-associated gene fusions), 8 UES and 4 tumors which were classified as high-grade ESS based on the presence of YWHAE-FAM22A/B fusion and histological features. Results Using gene expression microrarrays, we have identified 81 entities differentially expressed in analyzed samples (fold change > 2, p < 0.005). Hierarchical clustering analysis revealed that high-grade ESS formed a separate sub-cluster with a distinct molecular profile as compared with the low-grade ESS and UES cases. Low-grade ESS cases formed 2 distinct sub-clusters, each containing 5 cases, one of which presented gene expression profile partially corresponding to high-grade ESS cases. GO analysis of genes strongly up-regulated in UES specimens showed over-representation of immune response (GO:0006955) and immune system process (GO:0002376) pathways (MARCO, MYO1F, FCN1, GPR183, HLA-DPB1, FCGR2B, NCF1, CCL18, CD28, PTAFR, CCL13, STK4, CD14, NCF4 and CTLA4 genes) (p < 0.05). UES cases were also characterized by significant down-regulation of WT1 tumor suppressor gene as compared to the low- and high-grade ESS. Moreover, both high-grade ESS and UES cases were characterized by significantly lower expression level of PEG3 gene, which has been reported as a tumor suppressor gene. All low-grade ESS cases presented significant over-expression of estrogen receptor ESR1 gene. Microarray results were validated by RNA-Seq and qRT-PCR experiments. Conclusions This study provides gene expression profiles that distinguish between EST subtypes and sheds light on the biology of these tumors. Our results point to immune system involvement in the pathogenesis of UES and support the notion that the current EST classification should discriminate high-grade ESS as a distinct subtype. Citation Format: Joanna Przybyl, Magdalena Kowalewska, Anna Quattrone, Barbara Dewaele, Vanessa Vanspauwen, Julio Finalet-Ferreiro, Michal Swierniak, Elwira Bakula-Zalewska, Janusz A. Siedlecki, Mariusz Bidzinski, Jan Cools, Maria Debiec-Rychter. Gene expression profiling distinguishes between endometrial stromal tumors subtypes. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4698. doi:10.1158/1538-7445.AM2014-4698

Polish journal of pathology : official journal of the Polish Society of Pathologists, 2012

Myofibroblastoma (MFB) is a benign neoplasm arising most frequently in the adult breast, but it m... more Myofibroblastoma (MFB) is a benign neoplasm arising most frequently in the adult breast, but it may occur in any other tissue with the exception of the central nervous system. Adequate treatment of this neoplasm consists of local excision. MFB shows characteristic histological features and a clear immunohistochemical profile and usually does not cause any diagnostic difficulties [1-4]. A rare variant of MFB such as the epithelioid subtype with sclerotic stroma, however, can resemble lobular carcinoma in routinely stained histological sections.

Annals of Diagnostic Pathology, 2014

Endocrine Abstracts, 2014

Oncology Letters, 2012

O6-methylguanine-DNA methyltransferase (MGMT) gene promoter hypermethylation is observed in a num... more O6-methylguanine-DNA methyltransferase (MGMT) gene promoter hypermethylation is observed in a number of solid tumors and is correlated with the silencing of MGMT expression. In glioblastoma patients treated with the alkylating agent temozolomide, MGMT gene methylation status was shown to have predictive value in terms of prolonged overall survival. Recently, temozolomide has demonstrated promising activity in the treatment of soft tissue sarcomas, including those of the uterus. The tissue specimens involving tumor samples and normal uterine fragments were obtained from nine patients with smooth muscle uterine sarcoma, 11 with stromal uterine sarcoma and 17 with mixed uterine tumors. MGMT gene promoter methylation was analyzed by combined bisulfite restriction analysis (COBRA) while its expression levels were assessed using the real-time reverse transcription polymerase chain reaction (qRT-PCR). MGMT promoter methylation was observed in 27% of all tumor samples analyzed. When stratified by the disease type, 55.5% (5/9) of smooth muscle sarcomas, 23.5% (4/17) of mixed uterine tumor tissues and 9% (1/11) of stromal sarcomas showed MGMT methylation. The MGMT promoter methylation was associated with lower levels of gene expression in tumors when compared with those with an unmethylated promoter (P=0.0232) or normal tissues (P=0.0141). To conclude, MGMT promoter methylation and downregulation of gene expression is observed in a fraction of carcinosarcomas and non-epithelial malignant tumors of corpus uteri. The assessment of MGMT promoter methyla-tion status may potentially identify patients who would benefit from temozolomide treatment.

Endocrine Abstracts, 2014

Endocrine Abstracts, 2014