Enrico Berrino, Laura Annaratone, Paolo Detillo, Dora Grassini, Alberto Bragoni, Anna Sapino, Benedetta Bussolati, Giovanni Bussolati, Caterina Marchiò
Introduction: Optimization of pre-analytic procedures and tissue processing is a basic requirement for reliable and reproducible data to be obtained. Tissue fixation in formalin represents the extensively favored method for surgical tissue specimen processing in diagnostic pathology; however, formalin fixation exerts a blasting effect on DNA and RNA.
Methods: A formic acid-deprived formaldehyde solution was prepared by removing acids with an ion-exchange basic resin and the concentrated, acid-deprived formaldehyde (ADF) solution was employed to prepare a 4% ADF solution in 0.1 M phosphate buffer, pH 7.2-7.4. Human (n = 27) and mouse (n = 20) tissues were fixed in parallel and similar conditions in either ADF or neutral buffered formalin (NBF). DNAs and RNAs were extracted, and fragmentation analyses were performed.
Results: Besides no significant differences in terms of extraction yield and absorbance ratio, ADF fixation reduced DNA fragmentation, i.e., the largest fragments (>5,000 bp) were significantly more prevalent in the DNAs purified from ADF-fixed tissues (p < 0.001 in both cohorts). Moreover, we observed that DNA preservation is more stable in ADF-fixed tissue compared to NBF-fixed tissues.
Conclusion: Although DNA fragmentation in FFPE tissues is a multifactor process, we showed that the removal of formic acid is responsible for a significant improvement in DNA preservation.
{"title":"Tissue Fixation with a Formic Acid-Deprived Formalin Better Preserves DNA Integrity over Time.","authors":"Enrico Berrino, Laura Annaratone, Paolo Detillo, Dora Grassini, Alberto Bragoni, Anna Sapino, Benedetta Bussolati, Giovanni Bussolati, Caterina Marchiò","doi":"10.1159/000525523","DOIUrl":"https://doi.org/10.1159/000525523","url":null,"abstract":"<p><strong>Introduction: </strong>Optimization of pre-analytic procedures and tissue processing is a basic requirement for reliable and reproducible data to be obtained. Tissue fixation in formalin represents the extensively favored method for surgical tissue specimen processing in diagnostic pathology; however, formalin fixation exerts a blasting effect on DNA and RNA.</p><p><strong>Methods: </strong>A formic acid-deprived formaldehyde solution was prepared by removing acids with an ion-exchange basic resin and the concentrated, acid-deprived formaldehyde (ADF) solution was employed to prepare a 4% ADF solution in 0.1 M phosphate buffer, pH 7.2-7.4. Human (n = 27) and mouse (n = 20) tissues were fixed in parallel and similar conditions in either ADF or neutral buffered formalin (NBF). DNAs and RNAs were extracted, and fragmentation analyses were performed.</p><p><strong>Results: </strong>Besides no significant differences in terms of extraction yield and absorbance ratio, ADF fixation reduced DNA fragmentation, i.e., the largest fragments (>5,000 bp) were significantly more prevalent in the DNAs purified from ADF-fixed tissues (p < 0.001 in both cohorts). Moreover, we observed that DNA preservation is more stable in ADF-fixed tissue compared to NBF-fixed tissues.</p><p><strong>Conclusion: </strong>Although DNA fragmentation in FFPE tissues is a multifactor process, we showed that the removal of formic acid is responsible for a significant improvement in DNA preservation.</p>","PeriodicalId":19805,"journal":{"name":"Pathobiology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9578500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-01Epub Date: 2023-07-25DOI: 10.1159/000532053
Darius Juskevicius, Pontus Lundberg, Alexandar Tzankov, Stefan Dirnhofer, Frank Stenner
Introduction: Primary mediastinal large B-cell lymphoma (PMBL) is a rarely occurring lymphoid malignancy which typically affects young adults and presents itself as an anterior mediastinal mass. Gene expression profiling as well as somatic genetic analysis revealed that it is closely related to classical Hodgkin lymphoma, whereas morphologically, it tends to resemble diffuse large B-cell lymphoma. Familial clustering of PMBL is rare - only two reports have been published to date. While it is generally accepted that positive family history is associated with increased risk of developing a lymphoma, genetic risk factors which might predispose to PMBL are largely unknown.
Case presentation: We performed germline and tumor genetic analyses by whole-exome sequencing and array-CGH of a family, in which the father and the son both developed a PMBL. Germline investigations of both affected patients and of their two unaffected family members have not been able to provide a single risk factor associated with lymphoma predisposition. In addition, genes that were previously implicated in increased risk for PMBL, namely MLL (KMT2A) and TIRAP, were found to be intact in all investigated family members. Somatic genetic investigations identified known as well as novel genetic aberrations in tumors of the affected subjects.
Conclusion: We conclude that predisposition to a PMBL might be inherited through a combination of low- or moderate-risk factors and provide a shortlist of the most likely selected candidates, which can be used in future studies.
{"title":"Genetic Factors in Familial Manifestation of Primary Mediastinal Large B-Cell Lymphoma over Two Generations.","authors":"Darius Juskevicius, Pontus Lundberg, Alexandar Tzankov, Stefan Dirnhofer, Frank Stenner","doi":"10.1159/000532053","DOIUrl":"10.1159/000532053","url":null,"abstract":"<p><strong>Introduction: </strong>Primary mediastinal large B-cell lymphoma (PMBL) is a rarely occurring lymphoid malignancy which typically affects young adults and presents itself as an anterior mediastinal mass. Gene expression profiling as well as somatic genetic analysis revealed that it is closely related to classical Hodgkin lymphoma, whereas morphologically, it tends to resemble diffuse large B-cell lymphoma. Familial clustering of PMBL is rare - only two reports have been published to date. While it is generally accepted that positive family history is associated with increased risk of developing a lymphoma, genetic risk factors which might predispose to PMBL are largely unknown.</p><p><strong>Case presentation: </strong>We performed germline and tumor genetic analyses by whole-exome sequencing and array-CGH of a family, in which the father and the son both developed a PMBL. Germline investigations of both affected patients and of their two unaffected family members have not been able to provide a single risk factor associated with lymphoma predisposition. In addition, genes that were previously implicated in increased risk for PMBL, namely MLL (KMT2A) and TIRAP, were found to be intact in all investigated family members. Somatic genetic investigations identified known as well as novel genetic aberrations in tumors of the affected subjects.</p><p><strong>Conclusion: </strong>We conclude that predisposition to a PMBL might be inherited through a combination of low- or moderate-risk factors and provide a shortlist of the most likely selected candidates, which can be used in future studies.</p>","PeriodicalId":19805,"journal":{"name":"Pathobiology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10733924/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9867626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Josep Gumà, Karla Beatríz Peña, Francesc Riu, Clara Lucia-Gozálvez, Ana Vidaller, Vanesa Maldonado, David Parada
Introduction: Liquid biopsy is an innovative and efficient method for studying circulating tumor DNA. In conjunction with innovative techniques such as next-generation sequencing, it can provide real-time information on prognostic and predictive factors.
Case presentation: We report a case of advanced, unresectable medullary thyroid carcinoma with various rearranged during transfection (RET) and Kirsten rat sarcoma viral (KRAS) mutations in both blood liquid and tissue biopsies. After the initial failure of treatment with a tyrosine kinase inhibitor (TKI), a liquid biopsy analyzed by next-generation sequencing showed the presence of six different RET mutations and KRAS. Tissue biopsy also revealed two RET mutations. Due to these biopsy findings, the treatment was changed to another TKI, and the patient is now clinically stable.
Discussion/conclusion: Liquid biopsy makes it possible to analyze different genetic alterations that may have implications as predictive factors. It also reveals tumor heterogeneity and its implications for prognostic factors.
{"title":"Blood Liquid Biopsy in an Advanced Medullary Thyroid Carcinoma: A Case Study with Rearranged during Transfection Heterogeneity.","authors":"Josep Gumà, Karla Beatríz Peña, Francesc Riu, Clara Lucia-Gozálvez, Ana Vidaller, Vanesa Maldonado, David Parada","doi":"10.1159/000527184","DOIUrl":"https://doi.org/10.1159/000527184","url":null,"abstract":"<p><strong>Introduction: </strong>Liquid biopsy is an innovative and efficient method for studying circulating tumor DNA. In conjunction with innovative techniques such as next-generation sequencing, it can provide real-time information on prognostic and predictive factors.</p><p><strong>Case presentation: </strong>We report a case of advanced, unresectable medullary thyroid carcinoma with various rearranged during transfection (RET) and Kirsten rat sarcoma viral (KRAS) mutations in both blood liquid and tissue biopsies. After the initial failure of treatment with a tyrosine kinase inhibitor (TKI), a liquid biopsy analyzed by next-generation sequencing showed the presence of six different RET mutations and KRAS. Tissue biopsy also revealed two RET mutations. Due to these biopsy findings, the treatment was changed to another TKI, and the patient is now clinically stable.</p><p><strong>Discussion/conclusion: </strong>Liquid biopsy makes it possible to analyze different genetic alterations that may have implications as predictive factors. It also reveals tumor heterogeneity and its implications for prognostic factors.</p>","PeriodicalId":19805,"journal":{"name":"Pathobiology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9968930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-01Epub Date: 2023-06-08DOI: 10.1159/000531456
João Lobo, João Gama, Rita Luis, Dina Tiniakos, Maria Augusta Cipriano
Introduction: Recent studies have highlighted the presence of hepatic progenitor cells (HPCs) in metastatic liver carcinomas. We provide further evidence of this phenomenon, presenting a case of a gastrointestinal stromal tumour (GIST) liver metastasis with evidence of intra- and peritumoral HPC.
Case description: A 64-year-old man presented with a gastric mass diagnosed as a high-risk KIT-mutated GIST. The patient was treated with imatinib, recurring 5 years later with a liver mass. Liver biopsy disclosed a GIST metastasis, hallmarked by a proliferation of ductular structures without cytological atypia intermingled with the tumour cells, with a CK7/CK19/CD56-positive immunophenotype and rare CD44 positivity. The patient underwent liver resection, and the same ductular structures were present in the tumour interior and at its periphery.
Conclusion: We document for the time the presence of HPC in the form of ductular structures in a GIST liver metastasis, further supporting their role in the liver metastatic niche.
{"title":"Hepatic Progenitor Cells in the Form of Ductular Structures within a GIST Liver Metastasis: Supporting a Putative Role in the Hepatic Metastatic Niche.","authors":"João Lobo, João Gama, Rita Luis, Dina Tiniakos, Maria Augusta Cipriano","doi":"10.1159/000531456","DOIUrl":"10.1159/000531456","url":null,"abstract":"<p><strong>Introduction: </strong>Recent studies have highlighted the presence of hepatic progenitor cells (HPCs) in metastatic liver carcinomas. We provide further evidence of this phenomenon, presenting a case of a gastrointestinal stromal tumour (GIST) liver metastasis with evidence of intra- and peritumoral HPC.</p><p><strong>Case description: </strong>A 64-year-old man presented with a gastric mass diagnosed as a high-risk KIT-mutated GIST. The patient was treated with imatinib, recurring 5 years later with a liver mass. Liver biopsy disclosed a GIST metastasis, hallmarked by a proliferation of ductular structures without cytological atypia intermingled with the tumour cells, with a CK7/CK19/CD56-positive immunophenotype and rare CD44 positivity. The patient underwent liver resection, and the same ductular structures were present in the tumour interior and at its periphery.</p><p><strong>Conclusion: </strong>We document for the time the presence of HPC in the form of ductular structures in a GIST liver metastasis, further supporting their role in the liver metastatic niche.</p>","PeriodicalId":19805,"journal":{"name":"Pathobiology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9598919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Noemi Eiro, Eva Barreiro-Alonso, Maria Fraile, Luis O González, Antonio Altadill, Francisco J Vizoso
Introduction: Experimental and clinical data involve matrix metalloproteases (MMPs) and their tissue inhibitors (TIMPs) in the pathogenesis of inflammatory bowel diseases. However, the impact of MMPs/TIMPs expression by inflamed mucosa on medical response therapy has scarcely been investigated.
Methods: The expression of MMP-2, MMP-7, MMP-9, and TIMP-1 was determined by immunohistochemical analysis in inflamed mucosa samples at diagnosis in 82 patients with ulcerative colitis (UC; 22 never-treated with corticosteroids, 28 nonresponders, and 32 responders to corticosteroid therapy) and 15 patients with acute diverticulitis (AD). The global expression (score value) of each factor was analyzed by computer-generated image analysis.
Results: UC samples showed higher MMP-2 and MMP-9 expression but lower TIMP-1 expression than the AD samples (p < 0.0001, for all). High MMP-9 and TIMP-1 scores were significantly associated with no need for corticosteroid treatment (p < 0.001 and p = 0.017, respectively); whereas higher score in the MMP-7 expression was significantly associated with nonresponse to corticosteroid therapy (p = 0.037). In addition, in this latter UC subgroup, MMP-7 correlated positively with the younger age of the patients and with the extension of the disease (p = 0.030 and p = 0.010, respectively).
Conclusion: Our results suggest the relevance of MMPs and TIMPs for predicting treatment response to both 5-aminosalicylates and corticosteroids in UC.
{"title":"Expression of MMP-2, MMP-7, MMP-9, and TIMP-1 by Inflamed Mucosa in the Initial Diagnosis of Ulcerative Colitis as a Response Marker for Conventional Medical Treatment.","authors":"Noemi Eiro, Eva Barreiro-Alonso, Maria Fraile, Luis O González, Antonio Altadill, Francisco J Vizoso","doi":"10.1159/000524978","DOIUrl":"https://doi.org/10.1159/000524978","url":null,"abstract":"<p><strong>Introduction: </strong>Experimental and clinical data involve matrix metalloproteases (MMPs) and their tissue inhibitors (TIMPs) in the pathogenesis of inflammatory bowel diseases. However, the impact of MMPs/TIMPs expression by inflamed mucosa on medical response therapy has scarcely been investigated.</p><p><strong>Methods: </strong>The expression of MMP-2, MMP-7, MMP-9, and TIMP-1 was determined by immunohistochemical analysis in inflamed mucosa samples at diagnosis in 82 patients with ulcerative colitis (UC; 22 never-treated with corticosteroids, 28 nonresponders, and 32 responders to corticosteroid therapy) and 15 patients with acute diverticulitis (AD). The global expression (score value) of each factor was analyzed by computer-generated image analysis.</p><p><strong>Results: </strong>UC samples showed higher MMP-2 and MMP-9 expression but lower TIMP-1 expression than the AD samples (p < 0.0001, for all). High MMP-9 and TIMP-1 scores were significantly associated with no need for corticosteroid treatment (p < 0.001 and p = 0.017, respectively); whereas higher score in the MMP-7 expression was significantly associated with nonresponse to corticosteroid therapy (p = 0.037). In addition, in this latter UC subgroup, MMP-7 correlated positively with the younger age of the patients and with the extension of the disease (p = 0.030 and p = 0.010, respectively).</p><p><strong>Conclusion: </strong>Our results suggest the relevance of MMPs and TIMPs for predicting treatment response to both 5-aminosalicylates and corticosteroids in UC.</p>","PeriodicalId":19805,"journal":{"name":"Pathobiology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9312345","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Introduction: Esophageal cancer is the sixth leading cause of cancer-related death worldwide. However, molecular targeted therapy and novel therapeutic targets are needed for esophageal squamous cell cancer (ESCC). In a previous study, we reported that protocadherin (PCDH) B9 plays an important role in several cancers. Therefore, in this study, we examined the clinical significance of PCDHB9 expression in ESCC.
Methods: PCDHB9 expression was examined using immunohistochemistry in 128 cases and using quantitative reverse transcription-polymerase chain reaction in 16 cases of ESCC. PCDHB9 function in ESCC cells was examined using RNA interference.
Results: High PCDHB9 expression was identified in 5 of 16 (31.3%). In total, 51 (40%) ESCC cases showed strong PCDHB9 expression, whereas nonneoplastic mucosa rarely showed its expression. High PCDHB9 expression was significantly associated with T classification, N grade, and stage in ESCC. In ESCC cell lines, PCDHB9 knockdown affected cell growth, migration, and adhesion. Further, the expression of integrin (ITG) A3, ITGA4, ITGA5, ITGB1, ITGB6, vimentin, snail family transcriptional repressor 1, and cadherin 2 (NCAD) was significantly reduced and cadherin 1 was significantly increased in PCDHB9 knockdown ESCC cells.
Conclusion: These results suggest that PCDHB9 plays a tumor-promoting role and is a potential biomarker and therapeutic target in ESCC.
{"title":"Protocadherin B9 Is Associated with Human Esophageal Squamous Cell Carcinoma Progression.","authors":"Yuto Fujiki, Akira Ishikawa, Shintaro Akabane, Shoichiro Mukai, Ryota Maruyama, Yuji Yamamoto, Aya Kido, Narutaka Katsuya, Daiki Taniyama, Kazuhiro Sentani, Naohide Oue, Wataru Yasui","doi":"10.1159/000523817","DOIUrl":"https://doi.org/10.1159/000523817","url":null,"abstract":"<p><strong>Introduction: </strong>Esophageal cancer is the sixth leading cause of cancer-related death worldwide. However, molecular targeted therapy and novel therapeutic targets are needed for esophageal squamous cell cancer (ESCC). In a previous study, we reported that protocadherin (PCDH) B9 plays an important role in several cancers. Therefore, in this study, we examined the clinical significance of PCDHB9 expression in ESCC.</p><p><strong>Methods: </strong>PCDHB9 expression was examined using immunohistochemistry in 128 cases and using quantitative reverse transcription-polymerase chain reaction in 16 cases of ESCC. PCDHB9 function in ESCC cells was examined using RNA interference.</p><p><strong>Results: </strong>High PCDHB9 expression was identified in 5 of 16 (31.3%). In total, 51 (40%) ESCC cases showed strong PCDHB9 expression, whereas nonneoplastic mucosa rarely showed its expression. High PCDHB9 expression was significantly associated with T classification, N grade, and stage in ESCC. In ESCC cell lines, PCDHB9 knockdown affected cell growth, migration, and adhesion. Further, the expression of integrin (ITG) A3, ITGA4, ITGA5, ITGB1, ITGB6, vimentin, snail family transcriptional repressor 1, and cadherin 2 (NCAD) was significantly reduced and cadherin 1 was significantly increased in PCDHB9 knockdown ESCC cells.</p><p><strong>Conclusion: </strong>These results suggest that PCDHB9 plays a tumor-promoting role and is a potential biomarker and therapeutic target in ESCC.</p>","PeriodicalId":19805,"journal":{"name":"Pathobiology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10612690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-01Epub Date: 2023-01-26DOI: 10.1159/000529320
Dimitri Vanhauwaert, Harry Pinson, Katrijn Vanschoenbeek, Franceska Dedeurwaerdere, Cindy De Gendt, Tom Boterberg, Steven De Vleeschouwer
Introduction: The objective of this study was to cross-check and, if necessary, adjust registered ICD-O-3 topography and morphology codes with the findings in pathology reports available at the Belgian Cancer Registry (BCR) for glioma patients. Additionally, integration of molecular markers in the pathological diagnosis and concordance with WHO 2016 classification is investigated.
Methods: Since information regarding molecular tests and corresponding conclusions are not available as structured data at population level, a manual screening of all pseudonymized pathology reports available at the BCR for registered glioma patients (2017-2019) was conducted. ICD-O-3 morphology and topography codes from the BCR database (based on information as provided by hospital oncological care programmes and pathology laboratories), were, at tumour level, cross-checked with the data from the pathology reports and, if needed, specified or corrected. Relevant molecular markers (IDH1/2, 1p19q codeletion, promoter region of the MGMT gene [MGMTp]) were manually extracted from the pathology reports.
Results: In 95.3% of gliomas, the ICD-O-3 morphology code was correct. Non-specific topography codes were specified in 9.3%, while 3.3% of specific codes were corrected. The IDH status was known in 75.2% of astrocytic tumours. The rate of correct integrated diagnoses varied from 47.6% to 56.4% among different gliomas. MGMTp methylation status was available in 32.2% of glioblastomas.
Conclusion: Both the integration of molecular markers in the conclusion of the pathology reports and the delivery of those reports to the BCR can be improved. The availability of distinct ICD-O-3 codes for each molecularly defined tumour entity within the WHO classification would increase the consistency of cancer registration, facilitate population level research and international benchmarking.
{"title":"Cancer Registration, Molecular Marker Status, and Adherence to the WHO 2016 Classification of Pathology Reports for Glioma Diagnosed during 2017-2019 in Belgium.","authors":"Dimitri Vanhauwaert, Harry Pinson, Katrijn Vanschoenbeek, Franceska Dedeurwaerdere, Cindy De Gendt, Tom Boterberg, Steven De Vleeschouwer","doi":"10.1159/000529320","DOIUrl":"10.1159/000529320","url":null,"abstract":"<p><strong>Introduction: </strong>The objective of this study was to cross-check and, if necessary, adjust registered ICD-O-3 topography and morphology codes with the findings in pathology reports available at the Belgian Cancer Registry (BCR) for glioma patients. Additionally, integration of molecular markers in the pathological diagnosis and concordance with WHO 2016 classification is investigated.</p><p><strong>Methods: </strong>Since information regarding molecular tests and corresponding conclusions are not available as structured data at population level, a manual screening of all pseudonymized pathology reports available at the BCR for registered glioma patients (2017-2019) was conducted. ICD-O-3 morphology and topography codes from the BCR database (based on information as provided by hospital oncological care programmes and pathology laboratories), were, at tumour level, cross-checked with the data from the pathology reports and, if needed, specified or corrected. Relevant molecular markers (IDH1/2, 1p19q codeletion, promoter region of the MGMT gene [MGMTp]) were manually extracted from the pathology reports.</p><p><strong>Results: </strong>In 95.3% of gliomas, the ICD-O-3 morphology code was correct. Non-specific topography codes were specified in 9.3%, while 3.3% of specific codes were corrected. The IDH status was known in 75.2% of astrocytic tumours. The rate of correct integrated diagnoses varied from 47.6% to 56.4% among different gliomas. MGMTp methylation status was available in 32.2% of glioblastomas.</p><p><strong>Conclusion: </strong>Both the integration of molecular markers in the conclusion of the pathology reports and the delivery of those reports to the BCR can be improved. The availability of distinct ICD-O-3 codes for each molecularly defined tumour entity within the WHO classification would increase the consistency of cancer registration, facilitate population level research and international benchmarking.</p>","PeriodicalId":19805,"journal":{"name":"Pathobiology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10615750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Introduction: Malignant mesothelioma is an aggressive cancer associated with asbestos exposure. Currently, the efficacy of therapeutics is limited in malignant mesothelioma, and developing more effective therapies is the need of the hour. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), have attracted attention as therapeutic targets. To explore potential therapeutic targets, we focused on miR-142-3p expression, which was found to be significantly downregulated in mesothelioma cell lines in our previous study.
Methods: Mesothelioma cell lines and tissues were validated for expression of miR-142-3p or integrin subunit alpha-V (ITGAV). We transfected mesothelioma cell lines with miR-142-3p mimic and ITGAV siRNA and analyzed their biological functions.
Results: We found that miR-142-3p was significantly downregulated in mesothelioma tissues. Transfection with miR-142-3p mimic significantly suppressed cell proliferation, migration, and invasion. Bioinformatics analysis of potential targets of miR-142-3p identified ITGAV. Membrane ITGAV expression in mesothelioma cell lines was confirmed using immunocytochemistry. ITGAV was significantly upregulated in mesothelioma tissues. Moreover, transfection of miR-142-3p mimics into mesothelioma cell lines significantly suppressed ITGAV expression, indicating that miR-142-3p targets ITGAV. Next, ITGAV siRNA transfection into mesothelioma cell lines inhibited cell proliferation, migration, and invasion. Further investigation of cell adhesion mechanisms showed that the miR-142-3p/ITGAV axis specifically affects mesothelioma cell adhesion via vitronectin in the extracellular matrix.
Conclusion: This study proposed that the miR-142-3p/ITGAV axis is involved in tumor progression in malignant mesothelioma.
恶性间皮瘤是一种与石棉接触有关的侵袭性癌症。目前,治疗方法对恶性间皮瘤的疗效有限,开发更有效的治疗方法是当务之急。非编码rna (ncRNAs),包括microRNAs (miRNAs),作为治疗靶点受到了广泛关注。为了探索潜在的治疗靶点,我们重点研究了miR-142-3p的表达,在我们之前的研究中发现,miR-142-3p在间皮瘤细胞系中显著下调。方法:验证间皮瘤细胞系和组织中miR-142-3p或整合素亚单位α - v (ITGAV)的表达。我们用miR-142-3p模拟物和ITGAV siRNA转染间皮瘤细胞系,分析它们的生物学功能。结果:我们发现miR-142-3p在间皮瘤组织中显著下调。转染miR-142-3p模拟物可显著抑制细胞增殖、迁移和侵袭。miR-142-3p鉴定ITGAV潜在靶点的生物信息学分析。免疫细胞化学方法证实了ITGAV在间皮瘤细胞株中的表达。间皮瘤组织中ITGAV表达显著上调。此外,在间皮瘤细胞系中转染miR-142-3p模拟物可显著抑制ITGAV表达,表明miR-142-3p靶向ITGAV。接下来,将ITGAV siRNA转染到间皮瘤细胞系中,抑制细胞增殖、迁移和侵袭。对细胞粘附机制的进一步研究表明,miR-142-3p/ITGAV轴通过细胞外基质中的玻璃体连接蛋白特异性影响间皮瘤细胞的粘附。结论:本研究提出miR-142-3p/ITGAV轴参与恶性间皮瘤的肿瘤进展。
{"title":"miR-142-3p Suppresses Invasion and Adhesion of Mesothelioma Cells by Downregulating ITGAV.","authors":"Ihiro Endo, Vishwa Jeet Amatya, Kei Kushitani, Tetsuya Nakagiri, Kohei Aoe, Yukio Takeshima","doi":"10.1159/000528670","DOIUrl":"https://doi.org/10.1159/000528670","url":null,"abstract":"<p><strong>Introduction: </strong>Malignant mesothelioma is an aggressive cancer associated with asbestos exposure. Currently, the efficacy of therapeutics is limited in malignant mesothelioma, and developing more effective therapies is the need of the hour. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), have attracted attention as therapeutic targets. To explore potential therapeutic targets, we focused on miR-142-3p expression, which was found to be significantly downregulated in mesothelioma cell lines in our previous study.</p><p><strong>Methods: </strong>Mesothelioma cell lines and tissues were validated for expression of miR-142-3p or integrin subunit alpha-V (ITGAV). We transfected mesothelioma cell lines with miR-142-3p mimic and ITGAV siRNA and analyzed their biological functions.</p><p><strong>Results: </strong>We found that miR-142-3p was significantly downregulated in mesothelioma tissues. Transfection with miR-142-3p mimic significantly suppressed cell proliferation, migration, and invasion. Bioinformatics analysis of potential targets of miR-142-3p identified ITGAV. Membrane ITGAV expression in mesothelioma cell lines was confirmed using immunocytochemistry. ITGAV was significantly upregulated in mesothelioma tissues. Moreover, transfection of miR-142-3p mimics into mesothelioma cell lines significantly suppressed ITGAV expression, indicating that miR-142-3p targets ITGAV. Next, ITGAV siRNA transfection into mesothelioma cell lines inhibited cell proliferation, migration, and invasion. Further investigation of cell adhesion mechanisms showed that the miR-142-3p/ITGAV axis specifically affects mesothelioma cell adhesion via vitronectin in the extracellular matrix.</p><p><strong>Conclusion: </strong>This study proposed that the miR-142-3p/ITGAV axis is involved in tumor progression in malignant mesothelioma.</p>","PeriodicalId":19805,"journal":{"name":"Pathobiology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9959931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-01Epub Date: 2022-05-03DOI: 10.1159/000524452
Enrique Dorado-Fernández, José Aso-Escario, Alberto Aso-Vizán, Ildefonso Ramírez-González, Manuel F Carrillo-Rodríguez, David Cáceres-Monllor, Jorge Murillo-González
Introduction: Acute plastic deformation refers to a traumatic bending or bowing without a detectable cortical defect.
Case presentation and discussion: We describe a rare case from an individual that was exhumed from the Hispano-Mudejar necropolis in Uceda (Guadalajara, Spain) dated between the 13th and 14th centuries AD. The case corresponds to an adult woman, with a bowing involvement of the left ulna and radius. After making the differential diagnosis with various pathologies likely to present with this alteration, we reached the diagnosis of acute plastic deformation of the forearm through external and radiological examination and comparison with the healthy contralateral forearm.
Conclusions: Acute plastic deformation is a rare traumatic injury, not described until the last century and only rarely described in palaeopathological contexts. We contribute a new case, the first being sufficiently documented, contributing to the knowledge and diagnosis of this type of trauma in the ancient bone, while deepening the knowledge of the living conditions of the medieval Mudejar population of Uceda.
{"title":"A Case of Acute Plastic Deformation of the Forearm in a Medieval Hispano-Mudejar Skeleton (13-14th Centuries AD).","authors":"Enrique Dorado-Fernández, José Aso-Escario, Alberto Aso-Vizán, Ildefonso Ramírez-González, Manuel F Carrillo-Rodríguez, David Cáceres-Monllor, Jorge Murillo-González","doi":"10.1159/000524452","DOIUrl":"10.1159/000524452","url":null,"abstract":"<p><strong>Introduction: </strong>Acute plastic deformation refers to a traumatic bending or bowing without a detectable cortical defect.</p><p><strong>Case presentation and discussion: </strong>We describe a rare case from an individual that was exhumed from the Hispano-Mudejar necropolis in Uceda (Guadalajara, Spain) dated between the 13th and 14th centuries AD. The case corresponds to an adult woman, with a bowing involvement of the left ulna and radius. After making the differential diagnosis with various pathologies likely to present with this alteration, we reached the diagnosis of acute plastic deformation of the forearm through external and radiological examination and comparison with the healthy contralateral forearm.</p><p><strong>Conclusions: </strong>Acute plastic deformation is a rare traumatic injury, not described until the last century and only rarely described in palaeopathological contexts. We contribute a new case, the first being sufficiently documented, contributing to the knowledge and diagnosis of this type of trauma in the ancient bone, while deepening the knowledge of the living conditions of the medieval Mudejar population of Uceda.</p>","PeriodicalId":19805,"journal":{"name":"Pathobiology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10612701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-01Epub Date: 2023-03-31DOI: 10.1159/000530430
Sebastian Schwarz, Cathleen Nientiedt, Elena-Sophie Prigge, Adam Kaczorowski, Christine Geisler, Carlota Lucena Porcel, Magnus von Knebel Doeberitz, Markus Hohenfellner, Stefan Duensing
Introduction: Local tumor invasion is a critical factor for the outcome of men with prostate cancer. In particular, seminal vesicle invasion (SVI) has been reported to be associated with a more unfavorable prognosis. A better understanding of the functional state of invading prostate cancer cells is crucial to develop novel therapeutic strategies for patients with locally advanced disease.
Methods: The prognostic impact of local tumor progression was ascertained in over 1,000 men with prostate cancer. Prostate cancer specimens were stained by double-immunohistochemistry for the proliferation marker Ki-67 and the senescence marker p16INK4A. The migratory properties of senescent prostate cancer cells were analyzed in vitro using a wound healing assay and immunofluorescence microscopy for p16INK4A.
Results: We confirm the notion that patients with SVI have a more unfavorable prognosis than patients with extraprostatic extension alone. Surprisingly, we found that the tumor invasion front frequently harbors p16INK4A-positive and Ki-67-negative, i.e., senescent, tumor cells. While the intraprostatic tumor periphery was a hotspot for both proliferation and expression of p16INK4A, the area of SVI showed less proliferative activity but was at the same time a hotspot of cells with increased nuclear p16INK4A expression. Senescence was associated with an accelerated migration of prostate cancer cells in vitro.
Conclusion: This proof-of-concept study shows that invading prostate cancer cells frequently show signs of cellular senescence. This finding may open new avenues for neoadjuvant and adjuvant treatment concepts in men with locally advanced prostate cancer.
{"title":"Senescent Tumor Cells Are Frequently Present at the Invasion Front: Implications for Improving Disease Control in Patients with Locally Advanced Prostate Cancer.","authors":"Sebastian Schwarz, Cathleen Nientiedt, Elena-Sophie Prigge, Adam Kaczorowski, Christine Geisler, Carlota Lucena Porcel, Magnus von Knebel Doeberitz, Markus Hohenfellner, Stefan Duensing","doi":"10.1159/000530430","DOIUrl":"10.1159/000530430","url":null,"abstract":"<p><strong>Introduction: </strong>Local tumor invasion is a critical factor for the outcome of men with prostate cancer. In particular, seminal vesicle invasion (SVI) has been reported to be associated with a more unfavorable prognosis. A better understanding of the functional state of invading prostate cancer cells is crucial to develop novel therapeutic strategies for patients with locally advanced disease.</p><p><strong>Methods: </strong>The prognostic impact of local tumor progression was ascertained in over 1,000 men with prostate cancer. Prostate cancer specimens were stained by double-immunohistochemistry for the proliferation marker Ki-67 and the senescence marker p16INK4A. The migratory properties of senescent prostate cancer cells were analyzed in vitro using a wound healing assay and immunofluorescence microscopy for p16INK4A.</p><p><strong>Results: </strong>We confirm the notion that patients with SVI have a more unfavorable prognosis than patients with extraprostatic extension alone. Surprisingly, we found that the tumor invasion front frequently harbors p16INK4A-positive and Ki-67-negative, i.e., senescent, tumor cells. While the intraprostatic tumor periphery was a hotspot for both proliferation and expression of p16INK4A, the area of SVI showed less proliferative activity but was at the same time a hotspot of cells with increased nuclear p16INK4A expression. Senescence was associated with an accelerated migration of prostate cancer cells in vitro.</p><p><strong>Conclusion: </strong>This proof-of-concept study shows that invading prostate cancer cells frequently show signs of cellular senescence. This finding may open new avenues for neoadjuvant and adjuvant treatment concepts in men with locally advanced prostate cancer.</p>","PeriodicalId":19805,"journal":{"name":"Pathobiology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10614482/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9227777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}