Pub Date : 2025-11-25DOI: 10.1016/j.pathol.2025.09.009
Jared Lane, Royston Ponraj, Jad Othman, Erika Ong, Benjamin Schreiber, Umma Habiba, Arda Leyton, Jodie Giles, Toby N Trahair, Rosemary Sutton, Matthew Greenwood, Linda Lee, Michelle J Henderson, William Stevenson
Measurable residual disease (MRD) testing in acute lymphoblastic leukaemia (ALL) is considered standard of care as it is the strongest prognostic factor predicting disease outcome and is critical in therapeutic decision-making and assessing response to therapy. Across many centres, allele-specific oligonucleotide real-time quantitative polymerase chain reaction (ASO-RQPCR) has been the gold standard for assessing MRD in ALL patients for over 20 years. More recently, next-generation sequencing (NGS) technology has rapidly developed, with several platforms currently available for ALL MRD assessment. Comparative analysis between NGS and ASO-RQPCR is vital to ensure quality performance and to guide future use. Using longitudinal samples from 10 patients in a real-world clinical setting, we correlated the results of the Invivoscribe LymphoTrack system for NGS and ASO-RQPCR. Across the 10 patients, 63 timepoints were analysed showing nine discordant samples, six NGS+/PCR- and three PCR+/NGS-. Our findings are consistent with previous literature that the two methodologies are highly concordant in ALL MRD assessment (r=0.89). We also demonstrate that NGS has a greater quantitative range allowing for earlier detection of relapse in some cases. Furthermore, in our study, NGS was able to identify an MRD marker in more patients than ASO-RQPCR. Therefore, NGS MRD has potential advantages; however, clinical trials are required to evaluate clinical impact.
{"title":"Measurable Residual Disease detection in Acute Lymphoblastic Leukaemia - comparison between targeted NGS and ASO-RQPCR.","authors":"Jared Lane, Royston Ponraj, Jad Othman, Erika Ong, Benjamin Schreiber, Umma Habiba, Arda Leyton, Jodie Giles, Toby N Trahair, Rosemary Sutton, Matthew Greenwood, Linda Lee, Michelle J Henderson, William Stevenson","doi":"10.1016/j.pathol.2025.09.009","DOIUrl":"https://doi.org/10.1016/j.pathol.2025.09.009","url":null,"abstract":"<p><p>Measurable residual disease (MRD) testing in acute lymphoblastic leukaemia (ALL) is considered standard of care as it is the strongest prognostic factor predicting disease outcome and is critical in therapeutic decision-making and assessing response to therapy. Across many centres, allele-specific oligonucleotide real-time quantitative polymerase chain reaction (ASO-RQPCR) has been the gold standard for assessing MRD in ALL patients for over 20 years. More recently, next-generation sequencing (NGS) technology has rapidly developed, with several platforms currently available for ALL MRD assessment. Comparative analysis between NGS and ASO-RQPCR is vital to ensure quality performance and to guide future use. Using longitudinal samples from 10 patients in a real-world clinical setting, we correlated the results of the Invivoscribe LymphoTrack system for NGS and ASO-RQPCR. Across the 10 patients, 63 timepoints were analysed showing nine discordant samples, six NGS<sup>+</sup>/PCR<sup>-</sup> and three PCR<sup>+</sup>/NGS<sup>-</sup>. Our findings are consistent with previous literature that the two methodologies are highly concordant in ALL MRD assessment (r=0.89). We also demonstrate that NGS has a greater quantitative range allowing for earlier detection of relapse in some cases. Furthermore, in our study, NGS was able to identify an MRD marker in more patients than ASO-RQPCR. Therefore, NGS MRD has potential advantages; however, clinical trials are required to evaluate clinical impact.</p>","PeriodicalId":19915,"journal":{"name":"Pathology","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146044190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-25DOI: 10.1016/j.pathol.2025.09.010
Julia M Potter, Jackie Pratt, Melanie D'Souza, Jovanco Naumovski, Jason Yosar, Peter E Hickman, Marie M Salib
{"title":"Apparent gluco-concentration with citrate tubes is not a result of water uptake by erythrocytes.","authors":"Julia M Potter, Jackie Pratt, Melanie D'Souza, Jovanco Naumovski, Jason Yosar, Peter E Hickman, Marie M Salib","doi":"10.1016/j.pathol.2025.09.010","DOIUrl":"https://doi.org/10.1016/j.pathol.2025.09.010","url":null,"abstract":"","PeriodicalId":19915,"journal":{"name":"Pathology","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146044141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-20DOI: 10.1016/j.pathol.2025.10.005
Karen Van , Jasna Aleksova , Phillip Wong , John Kanellis , Peter R. Ebeling , Frances Milat
Anaemia and bone disease commonly co-exist, particularly in chronic conditions such as haemoglobinopathies and chronic kidney disease. The effects on bone are mediated by multiple factors, including marrow expansion, iron overload, endocrine dysfunction, and disruptions in mineral metabolism. These changes compromise bone strength, increasing the risk of osteoporosis and fractures. Although therapeutic advances such as iron infusion and chelation therapy have significantly improved the management of anaemia and patient outcomes, their effects on bone health are often under-recognised with osteoporosis detection occurring after a fracture. Furthermore, with denosumab being a popular anti-resorptive choice amongst clinicians, an emerging and under-appreciated complication is the increasing number of case reports describing hypophosphataemia associated with concurrent anti-resorptive and parenteral iron. This review discusses the bi-directional relationship between anaemia and bone metabolism. By focusing on the central role of fibroblast growth factor-23 (FGF-23), as a link between anaemia, phosphate regulation, and bone metabolism, this review draws attention to under-recognised skeletal risks. Importantly, it offers practical recommendations for monitoring, bridging mechanistic insights with clinical practice where current guidelines remain limited.
{"title":"Anaemia and bone disease","authors":"Karen Van , Jasna Aleksova , Phillip Wong , John Kanellis , Peter R. Ebeling , Frances Milat","doi":"10.1016/j.pathol.2025.10.005","DOIUrl":"10.1016/j.pathol.2025.10.005","url":null,"abstract":"<div><div>Anaemia and bone disease commonly co-exist, particularly in chronic conditions such as haemoglobinopathies and chronic kidney disease. The effects on bone are mediated by multiple factors, including marrow expansion, iron overload, endocrine dysfunction, and disruptions in mineral metabolism. These changes compromise bone strength, increasing the risk of osteoporosis and fractures. Although therapeutic advances such as iron infusion and chelation therapy have significantly improved the management of anaemia and patient outcomes, their effects on bone health are often under-recognised with osteoporosis detection occurring after a fracture. Furthermore, with denosumab being a popular anti-resorptive choice amongst clinicians, an emerging and under-appreciated complication is the increasing number of case reports describing hypophosphataemia associated with concurrent anti-resorptive and parenteral iron. This review discusses the bi-directional relationship between anaemia and bone metabolism. By focusing on the central role of fibroblast growth factor-23 (FGF-23), as a link between anaemia, phosphate regulation, and bone metabolism, this review draws attention to under-recognised skeletal risks. Importantly, it offers practical recommendations for monitoring, bridging mechanistic insights with clinical practice where current guidelines remain limited.</div></div>","PeriodicalId":19915,"journal":{"name":"Pathology","volume":"58 2","pages":"Pages 220-229"},"PeriodicalIF":3.0,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145959918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-17DOI: 10.1016/j.pathol.2025.09.005
Jennifer Vu , Claudia Petrucco , Cristina Vargas , Susie Bae , Richard Carey Smith , Jayesh Desai , Andrew Johnston , Marianne Phillips , Stephen Thompson , Smaro Lazarakis , Jasmine Mar , Angela M. Hong , Fiona Maclean
Accurate subtype diagnosis of sarcoma is crucial for optimal patient management, requiring integration of clinical, radiological, morphological, immunohistochemical, and molecular findings. This systematic review examines the value of expert second opinions in the histopathological diagnosis of bone and soft tissue sarcomas. The review was conducted using the population, intervention, comparison, and outcome model over a 32-year timeframe. Notably, five studies reported major discrepancy rates exceeding 20%, impacting patient management or prognosis. Given these findings, we recommend referring all suspected sarcoma cases to specialised sarcoma centres for expert second opinions to ensure accurate diagnosis and optimal care. While all studies broadly addressed diagnostic discrepancy during second opinion review, there were difficulties in comparing the data from various studies. These difficulties related to the lack of standardised definitions of what constitutes (1) a second opinion, (2) a specialist pathologist in sarcoma, and (3) a discordant diagnosis.
{"title":"The value of a second expert opinion in histopathological diagnosis of bone and soft tissue sarcoma: a systematic review","authors":"Jennifer Vu , Claudia Petrucco , Cristina Vargas , Susie Bae , Richard Carey Smith , Jayesh Desai , Andrew Johnston , Marianne Phillips , Stephen Thompson , Smaro Lazarakis , Jasmine Mar , Angela M. Hong , Fiona Maclean","doi":"10.1016/j.pathol.2025.09.005","DOIUrl":"10.1016/j.pathol.2025.09.005","url":null,"abstract":"<div><div>Accurate subtype diagnosis of sarcoma is crucial for optimal patient management, requiring integration of clinical, radiological, morphological, immunohistochemical, and molecular findings. This systematic review examines the value of expert second opinions in the histopathological diagnosis of bone and soft tissue sarcomas. The review was conducted using the population, intervention, comparison, and outcome model over a 32-year timeframe. Notably, five studies reported major discrepancy rates exceeding 20%, impacting patient management or prognosis. Given these findings, we recommend referring all suspected sarcoma cases to specialised sarcoma centres for expert second opinions to ensure accurate diagnosis and optimal care. While all studies broadly addressed diagnostic discrepancy during second opinion review, there were difficulties in comparing the data from various studies. These difficulties related to the lack of standardised definitions of what constitutes (1) a second opinion, (2) a specialist pathologist in sarcoma, and (3) a discordant diagnosis.</div></div>","PeriodicalId":19915,"journal":{"name":"Pathology","volume":"58 1","pages":"Pages 1-7"},"PeriodicalIF":3.0,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145752021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-17DOI: 10.1016/j.pathol.2025.09.007
Ïa Robert-Montaner, Amy Sheen, Loretta Sioson, Mahsa S Ahadi, John Turchini, Adele Clarkson, Roderick J Clifton-Bligh, Matti L Gild, Venessa Tsang, Ahmad Aniss, Catherine Luxford, Alexander Papachristos, Stanley B Sidhu, Mark Sywak, Michael Elliott, Ruta Gupta, Dennis Kee, Anthony J Gill, Angela Chou
Patients with secondary or tertiary hyperparathyroidism due to chronic renal failure who fail medical treatment require sub-total or total parathyroidectomy. The histological characteristics of parathyroid glands resected in this setting are not well studied; however, there is awareness that the findings may mimic malignancy. We conducted a detailed clinicopathological study of parathyroid resection specimens from an unselected Royal North Shore Hospital (RNSH) cohort (n=110) and an external consultation cohort (n=44). The most common atypical features observed in the RNSH cohort were fibrous bands (43%) and fibrous capsule (29%), while sheet-like/trabecular architecture (12%), invasive/pseudoinvasive growth pattern (4%) and mitotic activity (9%) were less prevalent. Clinical follow-up data were available for these cases, and none showed recurrence or metastasis. In the external consultation cohort, fibrous bands (84%) and fibrous capsule (66%) were also the most frequently observed features; however, invasive/pseudoinvasive growth pattern (34%) and sheet-like/trabecular architecture (34%) were more commonly seen in this group. One case in this cohort demonstrated unequivocal vascular invasion, fulfilling the diagnostic criteria for parathyroid carcinoma. However, at 5-year follow-up, there was no evidence of recurrence or metastasis. In summary, atypical histological features are common in parathyroid glands resected for secondary or tertiary hyperparathyroidism and should not be misinterpreted as atypical parathyroid tumour or carcinoma. Parathyroid carcinoma is exceedingly rare in this context, and even when strict diagnostic histological criteria are met, the long-term prognosis may be favourable.
{"title":"Atypical morphological features in secondary and tertiary hyperparathyroidism mimic malignancy: a detailed clinicopathological study.","authors":"Ïa Robert-Montaner, Amy Sheen, Loretta Sioson, Mahsa S Ahadi, John Turchini, Adele Clarkson, Roderick J Clifton-Bligh, Matti L Gild, Venessa Tsang, Ahmad Aniss, Catherine Luxford, Alexander Papachristos, Stanley B Sidhu, Mark Sywak, Michael Elliott, Ruta Gupta, Dennis Kee, Anthony J Gill, Angela Chou","doi":"10.1016/j.pathol.2025.09.007","DOIUrl":"https://doi.org/10.1016/j.pathol.2025.09.007","url":null,"abstract":"<p><p>Patients with secondary or tertiary hyperparathyroidism due to chronic renal failure who fail medical treatment require sub-total or total parathyroidectomy. The histological characteristics of parathyroid glands resected in this setting are not well studied; however, there is awareness that the findings may mimic malignancy. We conducted a detailed clinicopathological study of parathyroid resection specimens from an unselected Royal North Shore Hospital (RNSH) cohort (n=110) and an external consultation cohort (n=44). The most common atypical features observed in the RNSH cohort were fibrous bands (43%) and fibrous capsule (29%), while sheet-like/trabecular architecture (12%), invasive/pseudoinvasive growth pattern (4%) and mitotic activity (9%) were less prevalent. Clinical follow-up data were available for these cases, and none showed recurrence or metastasis. In the external consultation cohort, fibrous bands (84%) and fibrous capsule (66%) were also the most frequently observed features; however, invasive/pseudoinvasive growth pattern (34%) and sheet-like/trabecular architecture (34%) were more commonly seen in this group. One case in this cohort demonstrated unequivocal vascular invasion, fulfilling the diagnostic criteria for parathyroid carcinoma. However, at 5-year follow-up, there was no evidence of recurrence or metastasis. In summary, atypical histological features are common in parathyroid glands resected for secondary or tertiary hyperparathyroidism and should not be misinterpreted as atypical parathyroid tumour or carcinoma. Parathyroid carcinoma is exceedingly rare in this context, and even when strict diagnostic histological criteria are met, the long-term prognosis may be favourable.</p>","PeriodicalId":19915,"journal":{"name":"Pathology","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146086695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-15DOI: 10.1016/j.pathol.2025.10.004
Carmela Caputo , Yi Yuen Wang , Penelope A. McKelvie
Over the last decade, IgG4-related hypophysitis (IgG4-RH) has been increasingly recognised as a manifestation of IgG4-related disease (IgG4-RD). Concurrently, several cases of ‘isolated IgG4-RH’ have been reported, without any features of typical manifestations of IgG4-RD. Furthermore, IgG4 histological inflammatory infiltrates are being reported in other pituitary pathologies leading to some diagnostic confusion as to the possibility of it being a manifestation of IgG4-RD. This paper examines recent published cases of IgG4-RH to provide an updated understanding of the clinical landscape of IgG4 inflammatory changes in the pituitary gland, with a particular focus on isolated IgG4-RH. Literature review of all detailed case reports or case series of IgG4-RH reported between 2014 and 2025 was conducted. IgG4 inflammatory infiltrates are defined as the presence >10 IgG4-positive cells per high-power field and/or >40% IgG4 plasma cells with storiform fibrosis. Cases were divided into three groups: isolated IgG4-RH, IgG4-RH-associated IgG4-RD and IgG4 inflammatory infiltrates with cystic and other pituitary pathologies. Nineteen cases of isolated IgG4-RH and 12 cases of IgG4-RH-associated IgG4-RD have been reported since 2014. The group with isolated IgG4-RH was significantly different from that with IgG4-RH-associated IgG4-RD, with a female preponderance of 3.8:1 and younger age (mean 39 years versus 60 years). Fourteen cases of typical IgG4 inflammatory infiltrates were also documented in other pituitary lesions; most notably these were Rathke’s cleft cysts. The findings of IgG4 inflammatory infiltrates in the pituitary gland can be found in numerous pituitary pathologies. Isolated IgG4-RH disproportionately affects younger females and generally necessitates medical therapies: it may be a form of lymphocytic hypophysitis rather than a forme fruste of IgG4-RH associated with IgG4-RD. Histopathology of IgG4 inflammatory infiltrates in the pituitary gland is non-diagnostic: it requires histopathologists, endocrinologists and neurosurgeons to consider the clinical status and radiological findings in each case to clarify the diagnosis.
{"title":"Pituitary IgG4 inflammatory infiltrates: a shared finding in different pituitary conditions","authors":"Carmela Caputo , Yi Yuen Wang , Penelope A. McKelvie","doi":"10.1016/j.pathol.2025.10.004","DOIUrl":"10.1016/j.pathol.2025.10.004","url":null,"abstract":"<div><div>Over the last decade, IgG4-related hypophysitis (IgG4-RH) has been increasingly recognised as a manifestation of IgG4-related disease (IgG4-RD). Concurrently, several cases of ‘isolated IgG4-RH’ have been reported, without any features of typical manifestations of IgG4-RD. Furthermore, IgG4 histological inflammatory infiltrates are being reported in other pituitary pathologies leading to some diagnostic confusion as to the possibility of it being a manifestation of IgG4-RD. This paper examines recent published cases of IgG4-RH to provide an updated understanding of the clinical landscape of IgG4 inflammatory changes in the pituitary gland, with a particular focus on isolated IgG4-RH. Literature review of all detailed case reports or case series of IgG4-RH reported between 2014 and 2025 was conducted. IgG4 inflammatory infiltrates are defined as the presence >10 IgG4-positive cells per high-power field and/or >40% IgG4 plasma cells with storiform fibrosis. Cases were divided into three groups: isolated IgG4-RH, IgG4-RH-associated IgG4-RD and IgG4 inflammatory infiltrates with cystic and other pituitary pathologies. Nineteen cases of isolated IgG4-RH and 12 cases of IgG4-RH-associated IgG4-RD have been reported since 2014. The group with isolated IgG4-RH was significantly different from that with IgG4-RH-associated IgG4-RD, with a female preponderance of 3.8:1 and younger age (mean 39 years versus 60 years). Fourteen cases of typical IgG4 inflammatory infiltrates were also documented in other pituitary lesions; most notably these were Rathke’s cleft cysts. The findings of IgG4 inflammatory infiltrates in the pituitary gland can be found in numerous pituitary pathologies. Isolated IgG4-RH disproportionately affects younger females and generally necessitates medical therapies: it may be a form of lymphocytic hypophysitis rather than a <em>forme fruste</em> of IgG4-RH associated with IgG4-RD. Histopathology of IgG4 inflammatory infiltrates in the pituitary gland is non-diagnostic: it requires histopathologists, endocrinologists and neurosurgeons to consider the clinical status and radiological findings in each case to clarify the diagnosis.</div></div>","PeriodicalId":19915,"journal":{"name":"Pathology","volume":"58 1","pages":"Pages 8-18"},"PeriodicalIF":3.0,"publicationDate":"2025-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145763521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-13DOI: 10.1016/j.pathol.2025.09.006
Jocelyn Hume , Nilanthy Vigneswaran , Kym Lowry , Emma L. Sweeney , David M. Whiley , Bradley J. Gardiner
{"title":"Optimising diagnosis of resistant cytomegalovirus using next-generation sequencing","authors":"Jocelyn Hume , Nilanthy Vigneswaran , Kym Lowry , Emma L. Sweeney , David M. Whiley , Bradley J. Gardiner","doi":"10.1016/j.pathol.2025.09.006","DOIUrl":"10.1016/j.pathol.2025.09.006","url":null,"abstract":"","PeriodicalId":19915,"journal":{"name":"Pathology","volume":"58 1","pages":"Pages 105-107"},"PeriodicalIF":3.0,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145743676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-13DOI: 10.1016/j.pathol.2025.10.003
Dimitri Sokolowskei , Achira Shah , Alexander J. Trostle , Conan Juan , Mimi C. Sammarco , Robert J. Tower
Spatial transcriptomics (ST) is a powerful technology that facilitates the measurement of gene expression levels within the native tissue architecture. Spatial-omics applications in musculoskeletal research have proven crucial in elucidating aspects of cellular heterogeneity, molecular mechanisms underlying injury, and gene expression patterning in tissue homeostasis and disease. However, the necessity for bone tissue decalcification and processing presents unique tissue-based challenges for the application of ST. Furthermore, ST intrinsic platform limitations, workflow bottlenecks, and analysis complications impose significant challenges to widespread utilisation. Here, we review current ST platforms and outline their respective advantages and limitations, discuss the current state of bone sample processing for use in omics-based approaches, and summarise basic bioinformatics considerations for downstream analysis. We describe how ST has been applied across different musculoskeletal tissues and animal models in the field so far and, finally, provide some potential future directions for the field in how ST approaches could be used to address lingering and future biological questions.
{"title":"Spatial transcriptomics in bone research: navigating hype and hurdles","authors":"Dimitri Sokolowskei , Achira Shah , Alexander J. Trostle , Conan Juan , Mimi C. Sammarco , Robert J. Tower","doi":"10.1016/j.pathol.2025.10.003","DOIUrl":"10.1016/j.pathol.2025.10.003","url":null,"abstract":"<div><div>Spatial transcriptomics (ST) is a powerful technology that facilitates the measurement of gene expression levels within the native tissue architecture. Spatial-omics applications in musculoskeletal research have proven crucial in elucidating aspects of cellular heterogeneity, molecular mechanisms underlying injury, and gene expression patterning in tissue homeostasis and disease. However, the necessity for bone tissue decalcification and processing presents unique tissue-based challenges for the application of ST. Furthermore, ST intrinsic platform limitations, workflow bottlenecks, and analysis complications impose significant challenges to widespread utilisation. Here, we review current ST platforms and outline their respective advantages and limitations, discuss the current state of bone sample processing for use in omics-based approaches, and summarise basic bioinformatics considerations for downstream analysis. We describe how ST has been applied across different musculoskeletal tissues and animal models in the field so far and, finally, provide some potential future directions for the field in how ST approaches could be used to address lingering and future biological questions.</div></div>","PeriodicalId":19915,"journal":{"name":"Pathology","volume":"58 2","pages":"Pages 243-249"},"PeriodicalIF":3.0,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145878790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-13DOI: 10.1016/j.pathol.2025.09.003
Eric Wenlong Li , Ing-Soo Tiong , Clare Gould , Alberto Catalano , Hnin Aung , Louise Seymour , Deborah White , Ella Thompson , Piers Blombery , Harry Iland , Dale Wright
Targeted RNA-based next-generation sequencing (targeted RNA-Seq) is increasingly incorporated into oncogenic gene fusion diagnostics. The absence of external quality assurance programs presents a challenge to the quality management of this novel diagnostic methodology. Four Australian molecular diagnostics laboratories employing Archer FusionPlex or Qiagen Fusion XP platforms compared results from six diagnostic samples with a reference method. Three of four laboratories identified all five gene fusions (BCR::ABL1, ETV6::RUNX1, ETV6::SRR, NUP98::HOXD13, KMT2A::USP2), and one laboratory missed the novel ETV6::SRR fusion. All laboratories missed the IGH::EPOR fusion identified by whole-transcriptome sequencing at a research laboratory; however, they were able to detect EPOR overexpression driven by the gene fusion. Diagnostic report comparison highlighted variations in the use of variant description nomenclature (Human Genome Variation Society vs International System for Human Cytogenomic Nomenclature), reference transcript, inclusion of genomic coordinates, and pathogenicity classification. This study demonstrates high concordance between laboratories in gene fusion identification using targeted RNA-Seq. Detecting non-chimeric gene producing rearrangements involving regulatory elements is a technical limitation of the current platforms. The incorporation of gene expression analysis, with confirmation using orthogonal methods, may help improve diagnostic yield. Developing practice guidelines will help harmonise reporting content and minimise interlaboratory variations.
{"title":"Advancing diagnostic targeted RNA sequencing for haematological malignancies within an Australian sample exchange program","authors":"Eric Wenlong Li , Ing-Soo Tiong , Clare Gould , Alberto Catalano , Hnin Aung , Louise Seymour , Deborah White , Ella Thompson , Piers Blombery , Harry Iland , Dale Wright","doi":"10.1016/j.pathol.2025.09.003","DOIUrl":"10.1016/j.pathol.2025.09.003","url":null,"abstract":"<div><div>Targeted RNA-based next-generation sequencing (targeted RNA-Seq) is increasingly incorporated into oncogenic gene fusion diagnostics. The absence of external quality assurance programs presents a challenge to the quality management of this novel diagnostic methodology. Four Australian molecular diagnostics laboratories employing Archer FusionPlex or Qiagen Fusion XP platforms compared results from six diagnostic samples with a reference method. Three of four laboratories identified all five gene fusions (<em>BCR</em>::<em>ABL1</em>, <em>ETV6</em>::<em>RUNX1</em>, <em>ETV6</em>::<em>SRR</em>, <em>NUP98</em>::<em>HOXD13</em>, <em>KMT2A</em>::<em>USP2</em>), and one laboratory missed the novel <em>ETV6</em>::<em>SRR</em> fusion. All laboratories missed the <em>IGH</em>::<em>EPOR</em> fusion identified by whole-transcriptome sequencing at a research laboratory; however, they were able to detect <em>EPOR</em> overexpression driven by the gene fusion. Diagnostic report comparison highlighted variations in the use of variant description nomenclature (Human Genome Variation Society vs International System for Human Cytogenomic Nomenclature), reference transcript, inclusion of genomic coordinates, and pathogenicity classification. This study demonstrates high concordance between laboratories in gene fusion identification using targeted RNA-Seq. Detecting non-chimeric gene producing rearrangements involving regulatory elements is a technical limitation of the current platforms. The incorporation of gene expression analysis, with confirmation using orthogonal methods, may help improve diagnostic yield. Developing practice guidelines will help harmonise reporting content and minimise interlaboratory variations.</div></div>","PeriodicalId":19915,"journal":{"name":"Pathology","volume":"58 1","pages":"Pages 59-66"},"PeriodicalIF":3.0,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145768551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-13DOI: 10.1016/j.pathol.2025.10.002
Huihui Wang , Shuang Chen , Doudou Tang , Mingjie Chen , Hongling Peng , Guangsen Zhang , Yewei Wang
Interferon regulatory factor 4 (IRF4), also known as multiple myeloma oncogene 1 (MUM1), is a member of the IRF family of transcription factors with pivotal roles in the immune system, particularly in B-lymphocyte lineage commitment, differentiation, and immune regulation. Unlike other IRFs, IRF4 expression is tightly regulated by immune microenvironmental signals rather than classical interferon pathways. In B-lymphocytes, IRF4 orchestrates critical steps of development, including pre-B-cell differentiation, germinal centre formation, and terminal plasma cell maturation. Its dosage- and context-dependent functions regulate gene networks pivotal for both normal immunity and antibody production, with loss of function resulting in profound immunodeficiency. Recent genomic and molecular studies have revealed that IRF4 is central to the pathogenesis of multiple B-cell malignancies. Acting either as a tumour suppressor in B-cell precursor acute lymphoblastic leukaemia or as an oncogenic driver in diseases such as activated B-cell-like diffuse large B-cell lymphoma, and especially in multiple myeloma (MM), IRF4 modulates transcriptional programs responsible for proliferation, survival, and resistance to therapy. Chromosomal translocations, somatic mutations, and aberrant activation of IRF4 regulatory networks underpin disease progression and heterogeneity. Given its multifaceted roles, IRF4 is emerging as a critical biomarker, prognostic factor, and therapeutic target in B-cell disorders. This review synthesises current advances in IRF4 biology and pathology, highlighting promising therapeutic strategies that disrupt IRF4-driven molecular circuits. Continued elucidation of IRF4's diverse functions will pave the way for precision medicine initiatives in B-lymphoid malignancies.
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