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Journal of Pathology. Clinical Research

Max Robinson, Jacqueline James, Gareth Thomas, Nicholas West, Louise Jones, Jessica Lee, Karin Oien, Alex Freeman, Clare Craig, Philip Sloan, Philip Elliot, Maggie Cheang, Manuel Rodriguez-Justo, Clare Verrill
While pathologists have always played a pivotal role in clinical trials ensuring accurate diagnosis and staging, pathology data from prognostic and predictive tests are increasingly being used to enrol, stratify and randomise patients to experimental treatments. The use of pathological parameters as primary and secondary outcome measures, either as standalone classifiers or in combination with clinical data, is also becoming more common. Moreover, reporting of estimates of residual disease, termed 'pathological complete response', have been incorporated into neoadjuvant clinical trials...
November 8, 2018: Journal of Pathology. Clinical Research
Aoife J McCarthy, Jose-Mario Capo-Chichi, Tara Spence, Sylvie Grenier, Tracy Stockley, Suzanne Kamel-Reid, Stefano Serra, Peter Sabatini, Runjan Chetty
Immunohistochemistry (IHC) for mismatch repair (MMR) proteins is used to identify MMR status; being diffusely positive (intact/retained nuclear staining) or showing loss of nuclear tumour staining (MMR protein deficient). Four colonic adenocarcinomas and a gastric adenocarcinoma with associated dysplasia that displayed heterogenous IHC staining patterns in at least 1 of the 4 MMR proteins were characterised by next generation sequencing (NGS). In order to examine a potential molecular mechanism for these staining patterns, the respective areas were macrodissected, analysed for microsatellite instability (MSI), and investigated by NGS and multiplex ligation-dependent probe amplification (MLPA) analysis of MLH1, MSH2, MSH6 and PMS2 genes, including MLH1 methylation analysis...
November 1, 2018: Journal of Pathology. Clinical Research
Khadija Slik, Sami Blom, Riku Turkki, Katja Välimäki, Samu Kurki, Harri Mustonen, Caj Haglund, Olli Carpén, Olli Kallioniemi, Eija Korkeila, Jari Sundström, Teijo Pellinen
Tumour budding predicts survival of stage II colorectal cancer (CRC) and has been suggested to be associated with epithelial-to-mesenchymal transition (EMT). However, the underlying molecular changes of tumour budding remain poorly understood. Here, we performed multiplex immunohistochemistry (mIHC) to phenotypically profile tumours using known EMT-associated markers: E-cadherin (adherence junctions), integrin β4 (ITGB4; basement membrane), ZO-1 (tight junctions), and pan-cytokeratin. A subpopulation of patients showed high ITGB4 expression in tumour buds, and this coincided with a switch of ITGB4 localisation from basal membrane of intact epithelium to the cytoplasm of budding cells...
October 25, 2018: Journal of Pathology. Clinical Research
Jamie R Kutasovic, Amy E McCart Reed, Renique Males, Sarah Sim, Jodi M Saunus, Andrew Dalley, Christopher McEvoy, Liana Dedina, Gregory Miller, Stephen Peyton, Lynne Reid, Samir Lal, Colleen Niland, Kaltin Ferguson, Andrew Fellowes, Fares Al-Ejeh, Sunil R Lakhani, Margaret C Cummings, Peter T Simpson
Breast cancer metastasis to gynaecological organs is an understudied pattern of tumour spread. We explored clinico-pathologic and molecular features of these metastases to better understand whether this pattern of dissemination is organotropic or a consequence of wider metastatic dissemination. Primary and metastatic tumours from 54 breast cancer patients with gynaecological metastases were analysed using immunohistochemistry, DNA copy number profiling and targeted sequencing of 386 cancer-related genes. The median age of primary tumour diagnosis amongst patients with gynaecological metastases was significantly younger compared to a general breast cancer population (46...
September 24, 2018: Journal of Pathology. Clinical Research
Cornelia Schuster, Lars A Akslen, Tomasz Stokowy, Oddbjørn Straume
The incidence of malignant melanoma is rising worldwide and survival for metastatic disease is still poor. Recently, new treatment options have become available. Still, predictive biomarkers are needed to optimise treatment for this patient group. In this study, we investigated the predictive value of 60 angiogenic factors in patients with metastatic melanoma treated with the anti VEGF-A antibody bevacizumab. Thirty-five patients were included in a clinical phase II trial and baseline serum samples were analysed by multiplex protein array...
September 18, 2018: Journal of Pathology. Clinical Research
Yihong Wang, Shaolei Lu, Jinjun Xiong, Kamaljeet Singh, Yiang Hui, Chaohui Zhao, Alexander S Brodsky, Dongfang Yang, Grant Jolly, Madhu Ouseph, Christoph Schorl, Ronald A DeLellis, Murray B Resnick
The tumor microenvironment regulates tissue development and homeostasis, and its dysregulation contributes to neoplastic progression. Increased expression of type X collagen α-1 (ColXα1) in tumor-associated stroma correlates with poor pathologic response to neoadjuvant chemotherapy in estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2)-positive breast cancers. Evaluation of ColXα1 expression patterns suggests a potential connection with elastin fibers. To investigate the possible interaction between ColXα1 and elastin, we evaluated the expression of ColXα1 in relation to elastin fibers in normal breast tissue, ductal carcinoma in situ, and invasive breast carcinomas at cellular and subcellular levels...
September 12, 2018: Journal of Pathology. Clinical Research
Marieke E Ijsselsteijn, Thomas P Brouwer, Ziena Abdulrahman, Eileen Reidy, Ana Ramalheiro, A Marijne Heeren, Alexander Vahrmeijer, Ekaterina S Jordanova, Noel F C C de Miranda
Checkpoint blockade immunotherapies have revolutionised cancer treatment in the last decade. Nevertheless, these are only beneficial for a small proportion of cancer patients. Important prognosticators for response to immunotherapy are the mutation burden of tumours as well as the quality and quantity of tumour-infiltrating immune cells. High-throughput multiplex immunophenotyping technologies have a central role in deciphering the complexity of anti-tumour immune responses. Current techniques for the immunophenotyping of solid tumours are held back by the lack of spatial context, limitations in the number of targets that can be visualised simultaneously, and/or cumbersome protocols...
September 7, 2018: Journal of Pathology. Clinical Research
Shuchun Zhao, Arturo Molina, Abigail Yu, Jeff Hanson, Harry Cheung, Xiaofan Li, Yasodha Natkunam
CD74 is a type II transmembrane glycoprotein that functions as an MHC class II chaperone and displays diverse roles in immune responses. Recently, anti-CD74 immunotherapy has shown promise as an effective treatment strategy for lymphoid neoplasms in preclinical models. Using a humanized anti-CD74 antibody (SP7219), we defined the expression of CD74 protein in both normal and over 790 neoplastic hematolymphoid tissue samples. We found that CD74 is expressed broadly in normal B-cell compartments including primary and secondary lymphoid follicles and in the thymic medulla...
September 7, 2018: Journal of Pathology. Clinical Research
Andrew Dodson, Suzanne Parry, Merdol Ibrahim, John Ms Bartlett, Sarah Pinder, Mitch Dowsett, Keith Miller
We describe a collated data set of results from clinical testing of breast cancers carried out between 2009 and 2016 in the United Kingdom and Republic of Ireland. More than 199 000 patient biomarker data sets, together with clinicopathological parameters were collected. Our analyses focused on human epidermal growth factor receptor-2 (HER2), oestrogen receptor (ER) and progesterone receptor (PR), with the aim of the study being to provide robust confirmatory evidence on known associations in these biomarkers and to uncover new data on previously undescribed or unconfirmed associations, thus strengthening the evidence-base in clinical breast cancer testing...
October 2018: Journal of Pathology. Clinical Research
Peter F Rambau, Robert A Vierkant, Maria P Intermaggio, Linda E Kelemen, Marc T Goodman, Esther Herpel, Paul D Pharoah, Stefan Kommoss, Mercedes Jimenez-Linan, Beth Y Karlan, Aleksandra Gentry-Maharaj, Usha Menon, Susanna Hernando Polo, Francisco J Candido Dos Reis, Jennifer Anne Doherty, Simon A Gayther, Raghwa Sharma, Melissa C Larson, Paul R Harnett, Emma Hatfield, Jurandyr M de Andrade, Gregg S Nelson, Helen Steed, Joellen M Schildkraut, Micheal E Carney, Estrid Høgdall, Alice S Whittemore, Martin Widschwendter, Catherine J Kennedy, Frances Wang, Qin Wang, Chen Wang, Sebastian M Armasu, Frances Daley, Penny Coulson, Micheal E Jones, Micheal S Anglesio, Christine Chow, Anna de Fazio, Montserrat García-Closas, Sara Y Brucker, Cezary Cybulski, Holly R Harris, Andreas D Hartkopf, Tomasz Huzarski, Allan Jensen, Jan Lubiński, Oleg Oszurek, Javier Benitez, Fady Mina, Annette Staebler, Florin Andrei Taran, Jana Pasternak, Aline Talhouk, Mary Anne Rossing, Joy Hendley, Robert P Edwards, Sian Fereday, Francesmary Modugno, Roberta B Ness, Weiva Sieh, Mona A El-Bahrawy, Stacey J Winham, Jenny Lester, Susanne K Kjaer, Jacek Gronwald, Peter Sinn, Peter A Fasching, Jenny Chang-Claude, Kirsten B Moysich, David D Bowtell, Brenda Y Hernandez, Hugh Luk, Sabine Behrens, Mitul Shah, Audrey Jung, Prafull Ghatage, Jennifer Alsop, Kathryn Alsop, Jesús García-Donas, Pamela J Thompson, Anthony J Swerdlow, Chloe Karpinskyj, Alicia Cazorla-Jiménez, María J García, Susha Deen, Lynne R Wilkens, José Palacios, Andrew Berchuck, Jennifer M Koziak, James D Brenton, Linda S Cook, Ellen L Goode, David G Huntsman, Susan J Ramus, Martin Köbel
We aimed to validate the prognostic association of p16 expression in ovarian high-grade serous carcinomas (HGSC) and to explore it in other ovarian carcinoma histotypes. p16 protein expression was assessed by clinical-grade immunohistochemistry in 6525 ovarian carcinomas including 4334 HGSC using tissue microarrays from 24 studies participating in the Ovarian Tumor Tissue Analysis consortium. p16 expression patterns were interpreted as abnormal (either overexpression referred to as block expression or absence) or normal (heterogeneous)...
October 2018: Journal of Pathology. Clinical Research
Kelly Y Kim, James S Lewis, Zhong Chen
While a variety of human papillomavirus (HPV) tests and surrogate markers are available, currently there is no consensus on the best detection method(s) that should be used to identify HPV-related oropharyngeal squamous cell carcinomas and serve as a standard test (or tests) for routine diagnostic use. As we begin to consider using the results of HPV testing for clinical purposes beyond simple prognostication, such as making decisions on treatment dose or duration or for targeted therapies that may be highly dependent on viral-mediated pathways, we need to be more rigorous in assessing and ensuring the performance of the test (or tests) used...
October 2018: Journal of Pathology. Clinical Research
Suzanne M Garland, Wayne Dimech, Peter Collignon, Louise Cooley, Graeme R Nimmo, David W Smith, Rob Baird, William Rawlinson, Anna-Maria Costa, Geoff Higgins
Along with the reduction in human papillomavirus (HPV) infection and cervical abnormalities as a result of the successful HPV vaccination program, Australia is adopting a new screening strategy. This involves a new paradigm moving from cervical cytological screening to molecular nucleic acid technology (NAT), using HPV DNA assays as primary screening methodology for cervical cancer prevention. These assays must strike a balance between sufficient clinical sensitivity to detect or predict high-grade cervical intraepithelial lesions, the precursor to cervical cancer, without being too sensitive and detecting transient infection not destined for disease...
October 2018: Journal of Pathology. Clinical Research
Camilla Coulson-Gilmer, Matthew P Humphries, Sreekumar Sundara Rajan, Alastair Droop, Sharon Jackson, Alexandra Condon, Gabor Cserni, Lee B Jordan, Louise J Jones, Rani Kanthan, Anna Di Benedetto, Marcella Mottolese, Elena Provenzano, Janina Kulka, Abeer M Shaaban, Andrew M Hanby, Valerie Speirs
Breast cancer can occur in either gender; however, it is rare in men, accounting for <1% of diagnosed cases. In a previous transcriptomic screen of male breast cancer (MBC) and female breast cancer (FBC) occurrences, we observed that Stanniocalcin 2 (STC2) was overexpressed in the former. The aim of this study was to confirm the expression of STC2 in MBC and to investigate whether this had an impact on patient prognosis. Following an earlier transcriptomic screen, STC2 gene expression was confirmed by RT-qPCR in matched MBC and FBC samples as well as in tumour-associated fibroblasts derived from each gender...
October 2018: Journal of Pathology. Clinical Research
Raymond Barnhill, Peter Vermeulen, Sofie Daelemans, Pieter-Jan van Dam, Sergio Roman-Roman, Vincent Servois, Ilse Hurbain, Sophie Gardrat, Graça Raposa, André Nicolas, Rémi Dendale, Gaëlle Pierron, Laurence Desjardins, Nathalie Cassoux, Sophie Piperno-Neumann, Pascale Mariani, Claire Lugassy
Up to 50% of uveal melanomas (UM) metastasise to the liver within 10 years of diagnosis, and these almost always prove rapidly fatal. As histopathological growth patterns (HGPs) of liver metastases of the replacement and desmoplastic type, particularly from colon and breast carcinoma, may import valuable biological and prognostic information, we have studied HGP in a series of 41 UM liver metastases originating from 41 patients from the period 2006-2017. Twenty patients underwent enucleation while 21 had radiation therapy...
October 2018: Journal of Pathology. Clinical Research
Martin Köbel, Michael S Anglesio, James D Brenton
Detecting mutations in single cells from cancer specimens is now a major area of translational research. In a recent article in this journal, Khalique et al validated an immunohistochemistry assay for ARID1A that reliably identifies loss of function mutations in single cells in tissue sections. This work exemplifies best practice for developing and orthogonally validating immunohistochemical assays to provide clearly interpretable mutational results with spatial context.
July 2018: Journal of Pathology. Clinical Research
Ismaël Bah, Somayyeh Fahiminiya, Louis R Bégin, Nancy Hamel, Maria D D'Agostino, Simon Tanguay, William D Foulkes
We report an atypical tuberous sclerosis complex (TSC) phenotype presenting as familial multiple renal cell carcinomas (RCCs) with (angio)leiomyomatous stroma (RCCLS) (5/7 familial RCCs) on a background of multiple angiomyolipomas, hypopigmented skin macules, and absence of neurological anomalies. In the index case and three relatives, germline genetic testing identified a heterozygous TSC2 missense pathogenic variant [c.2714 G > A, (p.Arg905Gln)], a rare TSC-associated alteration which has previously been associated with a milder TSC phenotype...
July 2018: Journal of Pathology. Clinical Research
Saira Khalique, Kalnisha Naidoo, Ayoma D Attygalle, Divya Kriplani, Frances Daley, Anne Lowe, James Campbell, Thomas Jones, Michael Hubank, Kerry Fenwick, Nicholas Matthews, Alistair G Rust, Christopher J Lord, Susana Banerjee, Rachael Natrajan
ARID1A is a tumour suppressor gene that is frequently mutated in clear cell and endometrioid carcinomas of the ovary and endometrium and is an important clinical biomarker for novel treatment approaches for patients with ARID1A defects. However, the accuracy of ARID1A immunohistochemistry (IHC) as a surrogate for mutation status has not fully been established for patient stratification in clinical trials. Here we tested whether ARID1A IHC could reliably predict ARID1A mutations identified by next-generation sequencing...
July 2018: Journal of Pathology. Clinical Research
Anthoula Lazaris, Abdellatif Amri, Stephanie K Petrillo, Paublo Zoroquiain, Nisreen Ibrahim, Ayat Salman, Zu-Hua Gao, Peter B Vermeulen, Peter Metrakos
Current treatment for metastatic disease targets angiogenesis. With the increasing data demonstrating that cancer cells do not entirely rely on angiogenesis but hijack the existing vasculature through mechanisms such as co-option of existing blood vessels, identification of targets has become of utmost importance. Our study looks at the vasculature of chemonaïve and treated colorectal carcinoma liver metastases (CRCLMs) to obtain a basic understanding of the microvessel density, type of vasculature (mature versus immature), and correlation with histopathological growth patterns that demonstrate unique patterns of angiogenesis...
July 2018: Journal of Pathology. Clinical Research
Annette Arndt, Konrad Steinestel, Alexis Rump, Manveer Sroya, Tetiana Bogdanova, Leonila Kovgan, Matthias Port, Michael Abend, Stefan Eder
Childhood radiation exposure has been associated with increased papillary thyroid carcinoma (PTC) risk. The role of anaplastic lymphoma kinase (ALK) gene rearrangements in radiation-related PTC remains unclear, but STRN-ALK fusions have recently been detected in PTCs from radiation exposed persons after Chernobyl using targeted next-generation sequencing and RNA-seq. We investigated ALK and RET gene rearrangements as well as known driver point mutations in PTC tumours from 77 radiation-exposed patients (mean age at surgery 22...
July 2018: Journal of Pathology. Clinical Research
Hege L Pedersen, Kjersti D Horvei, Dhivya Thiyagarajan, Gudrun E Norby, Natalya Seredkina, Gabriella Moroni, Gro Ø Eilertsen, Hallvard Holdaas, Erik H Strøm, Gunnstein Bakland, Pier-Luigi Meroni, Ole P Rekvig
Renal DNase I is lost in advanced stages of lupus nephritis. Here, we determined if loss of renal DNase I reflects a concurrent loss of urinary DNase I, and whether absence of urinary DNase I predicts disease progression. Mouse and human DNase I protein and DNase I endonuclease activity levels were determined by western blot, gel, and radial activity assays at different stages of the murine and human forms of the disease. Cellular localization of DNase I was analyzed by immunohistochemistry, immunofluorescence, confocal microscopy, and immunoelectron microscopy...
July 2018: Journal of Pathology. Clinical Research
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