Pub Date : 2023-12-22DOI: 10.3389/pore.2023.1611518
Aypara Hasanova, Chingiz Asadov, N. Karimova, Aytan Shirinova, G. Aliyeva, Z. Alimirzoyeva
Objective: BCR-ABL1 kinase domain (KD) mutations can lead to resistance to first- and second-generation tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML). Here, we present the first report of the spectrum of mutations in the BCR-ABL1 KD of CML patients from Azerbaijan.Materials and methods: Samples for mutation screening were obtained from patients experiencing resistance to first line TKIs or from patients in acceleration phase (AP) or blast crisis (BC) at the time of diagnosis. The cDNA region corresponding to BCR-ABL1 KD was sequenced by pyrosequencing method. The χ2 test was used to assess the association of categorical variables between mutation-positive and -negative groups. In addition, the Kaplan-Meier method was applied to generate survival curves.Results: Eight different point mutations were identified in 22 (13.4%) out of 163 CML patients experiencing resistance to TKIs. The types of mutations detected were as follows: Contact binding site mutations 50% (11), SH2 domain mutations 27.4% (six), P-loop mutations 18.1% (four), and SH3 domain mutations accounting for 4.5% (one). The most common mutation was T315I, accounting for 5% (n = 8) of all patients. Significant association was identified between BCR-ABL1 mutations and additional chromosomal aberrations as well as between the mutations and disease phases (p < 0.05). Twelve out of 22 patients with BCR-ABL1 mutations and seven out of eight with T315I were in BC. Overall survival (OS) of the patients with BCR-ABL1 mutations was significantly lower comparing to the patients with no mutation (p < 0.05) and 8 patients with T315I mutation presented OS of 0%.Conclusion: T315I was the most commonly identified BCR-ABL1 mutation in TKI-resistant CML patients of Azerbaijani origin, being associated with disease progression and poor OS.
{"title":"Spectrum of BCR-ABL mutations in Azerbaijanian imatinib-resistant patients with chronic myeloid leukemia","authors":"Aypara Hasanova, Chingiz Asadov, N. Karimova, Aytan Shirinova, G. Aliyeva, Z. Alimirzoyeva","doi":"10.3389/pore.2023.1611518","DOIUrl":"https://doi.org/10.3389/pore.2023.1611518","url":null,"abstract":"Objective: BCR-ABL1 kinase domain (KD) mutations can lead to resistance to first- and second-generation tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML). Here, we present the first report of the spectrum of mutations in the BCR-ABL1 KD of CML patients from Azerbaijan.Materials and methods: Samples for mutation screening were obtained from patients experiencing resistance to first line TKIs or from patients in acceleration phase (AP) or blast crisis (BC) at the time of diagnosis. The cDNA region corresponding to BCR-ABL1 KD was sequenced by pyrosequencing method. The χ2 test was used to assess the association of categorical variables between mutation-positive and -negative groups. In addition, the Kaplan-Meier method was applied to generate survival curves.Results: Eight different point mutations were identified in 22 (13.4%) out of 163 CML patients experiencing resistance to TKIs. The types of mutations detected were as follows: Contact binding site mutations 50% (11), SH2 domain mutations 27.4% (six), P-loop mutations 18.1% (four), and SH3 domain mutations accounting for 4.5% (one). The most common mutation was T315I, accounting for 5% (n = 8) of all patients. Significant association was identified between BCR-ABL1 mutations and additional chromosomal aberrations as well as between the mutations and disease phases (p < 0.05). Twelve out of 22 patients with BCR-ABL1 mutations and seven out of eight with T315I were in BC. Overall survival (OS) of the patients with BCR-ABL1 mutations was significantly lower comparing to the patients with no mutation (p < 0.05) and 8 patients with T315I mutation presented OS of 0%.Conclusion: T315I was the most commonly identified BCR-ABL1 mutation in TKI-resistant CML patients of Azerbaijani origin, being associated with disease progression and poor OS.","PeriodicalId":20037,"journal":{"name":"Pathology and Oncology Research","volume":"75 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139164223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-21DOI: 10.3389/pore.2023.1611456
K. Kisiván, A. Farkas, Peter Kovacs, C. Glavák, G. Lukacs, K. Máhr, Z. Szabó, M. Csima, A. Gulyban, Zoltan Toth, Z. Káposztás, F. Lakosi
Background: We aim to present our linear accelerator-based workflow for pancreatic stereotactic ablative radiotherapy (SABR) in order to address the following issues: intrafractional organ motion management, Cone Beam CT (CBCT) image quality, residual errors with dosimetric consequences, treatment time, and clinical results.Methods: Between 2016 and 2021, 14 patients with locally advanced pancreatic cancer were treated with induction chemotherapy and SABR using volumetric modulated arc therapy (VMAT). Internal target volume (ITV) concept (5), phase-gated (4), or breath hold (5) techniques were used. Treatment was verified by CBCT before and after irradiation, while tumor motion was monitored and controlled by kV triggered imaging and beam hold using peritumoral surgical clips. Beam interruptions and treatment time were recorded. The CBCT image quality was scored and supplemented by an agreement analysis (Krippendorff’s-α) of breath-hold CBCT images to determine the position of OARs relative to the planning risk volumes (PRV). Residual errors and their dosimetry impact were also calculated. Progression free (PFS) and overall survival (OS) were assessed by the Kaplan-Meier analysis with acute and late toxicity reporting (CTCAEv4).Results: On average, beams were interrupted once (range: 0–3) per treatment session on triggered imaging. The total median treatment time was 16.7 ± 10.8 min, significantly less for breath-hold vs. phase-gated sessions (18.8 ± 6.2 vs. 26.5 ± 13.4, p < 0.001). The best image quality was achieved by breath hold CBCT. The Krippendorff’s-α test showed a strong agreement among five radiation therapists (mean K-α value: 0.8 (97.5%). The mean residual errors were <0.2 cm in each direction resulting in an average difference of <2% in dosimetry for OAR and target volume. Two patients received offline adaptation. The median OS/PFS after induction chemotherapy and SABR was 20/12 months and 15/8 months. No Gr. ≥2 acute/late RT-related toxicity was noted.Conclusion: Linear accelerator based pancreatic SABR with the combination of CBCT and triggered imaging + beam hold is feasible. Peritumoral fiducials improve utility while breath-hold CBCT provides the best image quality at a reasonable treatment time with offline adaptation possibilities. In well-selected cases, it can be an effective alternative in clinics where CBCT/MRI-guided online adaptive workflow is not available.
{"title":"Pancreatic SABR using peritumoral fiducials, triggered imaging and breath-hold","authors":"K. Kisiván, A. Farkas, Peter Kovacs, C. Glavák, G. Lukacs, K. Máhr, Z. Szabó, M. Csima, A. Gulyban, Zoltan Toth, Z. Káposztás, F. Lakosi","doi":"10.3389/pore.2023.1611456","DOIUrl":"https://doi.org/10.3389/pore.2023.1611456","url":null,"abstract":"Background: We aim to present our linear accelerator-based workflow for pancreatic stereotactic ablative radiotherapy (SABR) in order to address the following issues: intrafractional organ motion management, Cone Beam CT (CBCT) image quality, residual errors with dosimetric consequences, treatment time, and clinical results.Methods: Between 2016 and 2021, 14 patients with locally advanced pancreatic cancer were treated with induction chemotherapy and SABR using volumetric modulated arc therapy (VMAT). Internal target volume (ITV) concept (5), phase-gated (4), or breath hold (5) techniques were used. Treatment was verified by CBCT before and after irradiation, while tumor motion was monitored and controlled by kV triggered imaging and beam hold using peritumoral surgical clips. Beam interruptions and treatment time were recorded. The CBCT image quality was scored and supplemented by an agreement analysis (Krippendorff’s-α) of breath-hold CBCT images to determine the position of OARs relative to the planning risk volumes (PRV). Residual errors and their dosimetry impact were also calculated. Progression free (PFS) and overall survival (OS) were assessed by the Kaplan-Meier analysis with acute and late toxicity reporting (CTCAEv4).Results: On average, beams were interrupted once (range: 0–3) per treatment session on triggered imaging. The total median treatment time was 16.7 ± 10.8 min, significantly less for breath-hold vs. phase-gated sessions (18.8 ± 6.2 vs. 26.5 ± 13.4, p < 0.001). The best image quality was achieved by breath hold CBCT. The Krippendorff’s-α test showed a strong agreement among five radiation therapists (mean K-α value: 0.8 (97.5%). The mean residual errors were <0.2 cm in each direction resulting in an average difference of <2% in dosimetry for OAR and target volume. Two patients received offline adaptation. The median OS/PFS after induction chemotherapy and SABR was 20/12 months and 15/8 months. No Gr. ≥2 acute/late RT-related toxicity was noted.Conclusion: Linear accelerator based pancreatic SABR with the combination of CBCT and triggered imaging + beam hold is feasible. Peritumoral fiducials improve utility while breath-hold CBCT provides the best image quality at a reasonable treatment time with offline adaptation possibilities. In well-selected cases, it can be an effective alternative in clinics where CBCT/MRI-guided online adaptive workflow is not available.","PeriodicalId":20037,"journal":{"name":"Pathology and Oncology Research","volume":"35 7","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138948742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-11DOI: 10.3389/pore.2023.1611547
E. Makk, Noémi Bohonyi, A. Oszter, Klára Éles, Tamás Tornóczky, Arnold Tóth, Endre Kálmán, Krisztina Kovács
Introduction: The role of p16 and p53 immunohistochemistry in the diagnosis of rare and aggressive uterine carcinosarcoma (UCS) has been well established. However, enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and a member of the polycomb group family is a relatively new biomarker, with limited published data on its significance in this tumor type. The goal of this study was to examine EZH2 expression in UCS and its components, in correlation with morphological features, and p16 and p53 staining patterns.Methods: Twenty-eight UCSs were included in the study. EZH2, p16 and p53 immunoreactivity were assessed independently by two pathologists in both tumor components (epithelial and mesenchymal). EZH2 and p16 immunostains were scored semiquantitatively: based on the percentage and intensity of tumor cell staining a binary staining index (“high- or low-expressing”) was calculated. The p53 staining pattern was evaluated as wild-type or aberrant (diffuse nuclear, null, or cytoplasmic expression). Statistical tests were used to evaluate the correlation between staining patterns for all three markers and the different tumor components and histotypes.Results: High EZH2 and p16 expression and aberrant p53 patterns were present in 89.3% 78.6% and 85.7% of the epithelial component and in 78.6%, 62.5% and 82.1% of the mesenchymal component, respectively. Differences among these expression rates were not found to be significant (p > 0.05). Regarding the epithelial component, aberrant p53 pattern was found to be significantly (p = 0.0474) more frequent in the serous (100%) than in endometrioid (66.6%) histotypes. Within the mesenchymal component, p53 null expression pattern occurred significantly (p = 0.0257) more frequently in heterologous sarcoma components (71.4%) compared to the homologous histotype (18.8%).Conclusion: In conclusion, EZH2, p16 and p53 seem to play a universal role in the pathogenesis of UCS; however, a distinctive pattern of p53 expression appears to exist between the serous and endometrioid carcinoma components and also between the homologous and heterologous sarcoma components.
{"title":"Comparative analysis of EZH2, p16 and p53 expression in uterine carcinosarcomas","authors":"E. Makk, Noémi Bohonyi, A. Oszter, Klára Éles, Tamás Tornóczky, Arnold Tóth, Endre Kálmán, Krisztina Kovács","doi":"10.3389/pore.2023.1611547","DOIUrl":"https://doi.org/10.3389/pore.2023.1611547","url":null,"abstract":"Introduction: The role of p16 and p53 immunohistochemistry in the diagnosis of rare and aggressive uterine carcinosarcoma (UCS) has been well established. However, enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and a member of the polycomb group family is a relatively new biomarker, with limited published data on its significance in this tumor type. The goal of this study was to examine EZH2 expression in UCS and its components, in correlation with morphological features, and p16 and p53 staining patterns.Methods: Twenty-eight UCSs were included in the study. EZH2, p16 and p53 immunoreactivity were assessed independently by two pathologists in both tumor components (epithelial and mesenchymal). EZH2 and p16 immunostains were scored semiquantitatively: based on the percentage and intensity of tumor cell staining a binary staining index (“high- or low-expressing”) was calculated. The p53 staining pattern was evaluated as wild-type or aberrant (diffuse nuclear, null, or cytoplasmic expression). Statistical tests were used to evaluate the correlation between staining patterns for all three markers and the different tumor components and histotypes.Results: High EZH2 and p16 expression and aberrant p53 patterns were present in 89.3% 78.6% and 85.7% of the epithelial component and in 78.6%, 62.5% and 82.1% of the mesenchymal component, respectively. Differences among these expression rates were not found to be significant (p > 0.05). Regarding the epithelial component, aberrant p53 pattern was found to be significantly (p = 0.0474) more frequent in the serous (100%) than in endometrioid (66.6%) histotypes. Within the mesenchymal component, p53 null expression pattern occurred significantly (p = 0.0257) more frequently in heterologous sarcoma components (71.4%) compared to the homologous histotype (18.8%).Conclusion: In conclusion, EZH2, p16 and p53 seem to play a universal role in the pathogenesis of UCS; however, a distinctive pattern of p53 expression appears to exist between the serous and endometrioid carcinoma components and also between the homologous and heterologous sarcoma components.","PeriodicalId":20037,"journal":{"name":"Pathology and Oncology Research","volume":"12 13","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138980294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Human papillomavirus type 8 (HPV8) has been implicated in the progress of non-melanoma skin cancers and their precursor lesions. The HPV8 E7 oncoprotein plays a key role in the tumorigenesis of HPV-associated cutaneous tumors. However, the exact role of HPV8 E7 in human epidermal carcinogenesis has not been fully elucidated. Methods: To investigate the potential carcinogenic effects of HPV8 E7 on epithelial cells, we used RNA-sequencing technology to analyze the gene expression profile of HPV8 E7-overexpressed normal human epidermal keratinocytes (NHEKs). Results: RNA-sequencing revealed 831 differentially expressed genes (DEGs) between HPV8 E7-expressing NHEKs and control cells, among which, 631 genes were significantly upregulated, and 200 were downregulated. Gene ontology annotation enrichment analysis showed that HPV8 E7 mainly affected the expression of genes associated with protein heterodimerization activity, DNA binding, nucleosomes, and nucleosome assembly. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis revealed that overexpression of HPV8 E7 affected the expression of gene clusters associated with viral carcinogenesis and transcriptional misregulation in cancer and necroptosis signaling pathways that reportedly play crucial roles in HPV infection promotion and cancer progression. We also found the DEGs, such as HKDC1 and TNFAIP3, were associated with epigenetic modifications, immune regulation, and metabolic pathways. Conclusion: Our results demonstrate that the pro-carcinogenic effect of HPV8 expression in epithelial cells may be attributed to the regulatory effect of oncogene E7 on gene expression associated with epigenetic modifications and immune and metabolic status-associated gene expression. Although our data are based on an in vitro experiment, it provides the theoretical evidence that the development of squamous cell carcinoma can be caused by HPV.
{"title":"Gene Expression Profile Analysis of Human Epidermal Keratinocytes Expressing Human Papillomavirus Type 8 E7","authors":"Xianzhen Chen, Ma Li, Yiyun Tang, Qi-Ying Liang, Chunting Hua, Huiqin He, Yin-jing Song, Hao Cheng","doi":"10.3389/pore.2022.1610176","DOIUrl":"https://doi.org/10.3389/pore.2022.1610176","url":null,"abstract":"Background: Human papillomavirus type 8 (HPV8) has been implicated in the progress of non-melanoma skin cancers and their precursor lesions. The HPV8 E7 oncoprotein plays a key role in the tumorigenesis of HPV-associated cutaneous tumors. However, the exact role of HPV8 E7 in human epidermal carcinogenesis has not been fully elucidated. Methods: To investigate the potential carcinogenic effects of HPV8 E7 on epithelial cells, we used RNA-sequencing technology to analyze the gene expression profile of HPV8 E7-overexpressed normal human epidermal keratinocytes (NHEKs). Results: RNA-sequencing revealed 831 differentially expressed genes (DEGs) between HPV8 E7-expressing NHEKs and control cells, among which, 631 genes were significantly upregulated, and 200 were downregulated. Gene ontology annotation enrichment analysis showed that HPV8 E7 mainly affected the expression of genes associated with protein heterodimerization activity, DNA binding, nucleosomes, and nucleosome assembly. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis revealed that overexpression of HPV8 E7 affected the expression of gene clusters associated with viral carcinogenesis and transcriptional misregulation in cancer and necroptosis signaling pathways that reportedly play crucial roles in HPV infection promotion and cancer progression. We also found the DEGs, such as HKDC1 and TNFAIP3, were associated with epigenetic modifications, immune regulation, and metabolic pathways. Conclusion: Our results demonstrate that the pro-carcinogenic effect of HPV8 expression in epithelial cells may be attributed to the regulatory effect of oncogene E7 on gene expression associated with epigenetic modifications and immune and metabolic status-associated gene expression. Although our data are based on an in vitro experiment, it provides the theoretical evidence that the development of squamous cell carcinoma can be caused by HPV.","PeriodicalId":20037,"journal":{"name":"Pathology and Oncology Research","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81993107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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