Human pathology最新文献

{"title":"Introduction to special issue on lymphoma.","authors":"L Jeffrey Medeiros","doi":"10.1016/j.humpath.2025.105721","DOIUrl":"10.1016/j.humpath.2025.105721","url":null,"abstract":"","PeriodicalId":13062,"journal":{"name":"Human pathology","volume":" ","pages":"105721"},"PeriodicalIF":2.7,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Contemporary approach to the diagnosis and classification of intestinal T-cell lymphomas.","authors":"Sanam Loghavi, L Jeffrey Medeiros","doi":"10.1016/j.humpath.2025.105720","DOIUrl":"10.1016/j.humpath.2025.105720","url":null,"abstract":"<p><p>We provide an overview of recent advances in the diagnosis and classification of intestinal T- and NK-cell lymphomas and lymphoproliferative disorders that primarily involve the gastrointestinal (GI) tract. It should be mentioned that systemic T- and NK-cell lymphomas can present initially in the GI tract but are not the focus of this review. Here, we focus on the clinical and pathologic findings of enteropathy-associated T-cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma, intestinal T-cell lymphoma, not otherwise specified, indolent T-cell lymphoma of the GI tract and indolent NK-cell lymphoproliferative disorder of the GI tract (previously known as NK-cell enteropathy). These diseases are uncommon, and their clinical manifestations and pathologic features can show overlap, but are associated with different outcomes making accurate diagnosis essential. In most cases, the diagnosis of intestinal T- and NK-cell lymphomas and lymphoproliferative disorders requires integrating the clinical context with the morphologic, immunophenotypic, and molecular alterations. In this review, we also emphasize the current understanding of the genetic drivers of these diseases.</p>","PeriodicalId":13062,"journal":{"name":"Human pathology","volume":" ","pages":"105720"},"PeriodicalIF":2.7,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143038174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Indolent clonal lymphoid disorders.","authors":"Jan Delabie, Ali Sakhdari","doi":"10.1016/j.humpath.2025.105715","DOIUrl":"10.1016/j.humpath.2025.105715","url":null,"abstract":"<p><p>Indolent clonal lymphoid disorders are not recognized as lymphomas as they generally need no systemic treatment, and depending on the lesion, need only limited clinical follow-up. These lesions are usually incidentally diagnosed during the work up for other disease. The recognition of indolent clonal lymphoid disorders is important to avoid misdiagnosis as lymphoma and unnecessary treatment. Notwithstanding, some indolent disorders, especially B-cell disorders, may give important morbidity that is not related to disease burden but related to auto-immune disease which may need treatment. Further, some of these lesions may, at various rates, ultimately progress to lymphoma. As such, the indolent clonal lymphoid disorders also give an insight into the earliest stages of clonal lymphoid disease that may increase our understanding of lymphoma, although much needs yet to be elucidated. In this article both B- and T-cell indolent clonal lymphoid disorders are reviewed. Not included in this review are lymphoid lesions that may be mistaken for lymphoma, but are not clonal, such as indolent T-lymphoblastic proliferation or marginal zone hyperplasia with immunoglobulin light chain restriction. Further, an emphasis has been given to clonal lymphoid lesions and therefore indolent plasma cell lesions have not been included. Also excluded is indolent lymphoma that may not need treatment but nonetheless requires more regular follow up. One may rightfully argue that there may be a gray zone between what constitutes an indolent clonal lymphoid disorder and an indolent lymphoma. This discussion is reflected in the different terminology used for some entities between editions of the WHO classification and between the Fifth Edition of the WHO Classification and the International Consensus Classification (ICC). The former has been used as a selection basis for this review, but cross-reference has been made to the ICC nomenclature when that differs as well as to the earlier Revised Fourth Edition of the WHO Classification (WHO-r4). For this reason, indolent T-cell lymphoma of the gastrointestinal tract (ICC: indolent clonal T-cell lymphoproliferative disorder of the gastrointestinal tract) is not included in this review.</p>","PeriodicalId":13062,"journal":{"name":"Human pathology","volume":" ","pages":"105715"},"PeriodicalIF":2.7,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142964616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ovarian epithelioid tumor with FUS::CREM fusion and multilineage protein expression: Report of a case in the EWSR1/FUS-CREB tumor spectrum.","authors":"J Kenneth Schoolmeester, Sounak Gupta, Jennifer M Boland, Hussam Al Kateb, Amy A Swanson","doi":"10.1016/j.humpath.2024.105712","DOIUrl":"10.1016/j.humpath.2024.105712","url":null,"abstract":"","PeriodicalId":13062,"journal":{"name":"Human pathology","volume":" ","pages":"105712"},"PeriodicalIF":2.7,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142964617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vulvar and vaginal leiomyosarcomas: Immunohistochemical, molecular genetic and MDM2 fluorescence in situ hybridization analysis of three cases.","authors":"Nooshin K Dashti, Sounak Gupta, Amy A Swanson, Gary L Keeney, Michael Michal, J Kenneth Schoolmeester","doi":"10.1016/j.humpath.2024.105713","DOIUrl":"https://doi.org/10.1016/j.humpath.2024.105713","url":null,"abstract":"","PeriodicalId":13062,"journal":{"name":"Human pathology","volume":" ","pages":"105713"},"PeriodicalIF":2.7,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142948179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hepatocyte nuclear factor 4α as a sensitive marker for uterine endocervical adenocarcinomas and their precursors","authors":"Yuri Noda ,&nbsp;Yoko Tokuyama ,&nbsp;Wataru Sumita ,&nbsp;Masato Kita ,&nbsp;Koji Tsuta","doi":"10.1016/j.humpath.2025.105714","DOIUrl":"10.1016/j.humpath.2025.105714","url":null,"abstract":"<div><h3>Context</h3><div>Hepatocyte nuclear factor (HNF)-4α is a marker of gastrointestinal tumor differentiation; however, its expression in endocervical tumors remains unclear.</div></div><div><h3>Objective</h3><div>We aimed to assess the utility of HNF4α expression as a marker for endocervical adenocarcinomas (ECAs) and adenocarcinoma in situs (AISs), and to establish a minimal panel for distinguishing them from nonneoplastic endocervical glandular lesions and metastases.</div></div><div><h3>Design</h3><div>HNF4α expression was analyzed immunohistochemically (positive, H-score ≥10) in 323 tissue samples: 57 endocervical neoplasms including 35 glandular neoplasms and 22 squamous neoplasms, 144 nonneoplastic endocervical lesions, and 122 tumors from other organs. The panel for distinguishing endocervical glandular neoplasms from nonneoplastic glands and from metastases comprised HNF4α, p16, CDX2, and SATB2; staining was assessed.</div></div><div><h3>Results</h3><div>HNF4α was expressed significantly in ECAs and AISs, both HPV-independent and -associated types, but not in nonneoplastic glandular and squamous lesions (<em>p</em> &lt; 0.05). The immunohistochemical detection sensitivity and specificity for endocervical ECA and AIS were 77% and 95%, respectively. For AIS alone, these were 79% and 94%, and for ECA alone, 75% and 94%, respectively. Either HNF4α(+) or p16(+) or double positive identified endocervical gland and squamous neoplasms (sensitivity, 96%; specificity, 76%). HNF4α(+) and SATB2(−) and CDX2(−) profiles suggested ECAs (sensitivity, 69%; specificity, 88%). HNF4α(+) and SATB2(+) or CDX2(+) profiles suggested adenocarcinomas of the gastrointestinal or genital tract (sensitivity, 81%; specificity, 88%).</div></div><div><h3>Conclusions</h3><div>HNF4α is a promising marker for detecting both HPV-independent and -associated ECAs and AIS with high accuracy. Its combination with p16, CDX2, and SATB2 has potential use in diagnostic panels.</div></div>","PeriodicalId":13062,"journal":{"name":"Human pathology","volume":"155 ","pages":"Article 105714"},"PeriodicalIF":2.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-myxoid solid variant of extraskeletal myxoid chondrosarcoma: An underrecognized subtype","authors":"Sandra Gjorgova Gjeorgjievski,&nbsp;Jatin S. Gandhi,&nbsp;Armita Bahrami","doi":"10.1016/j.humpath.2025.105719","DOIUrl":"10.1016/j.humpath.2025.105719","url":null,"abstract":"<div><h3>Introduction</h3><div>Extraskeletal myxoid chondrosarcoma (EMC) is a rare sarcoma defined by <em>NR4A3</em> gene rearrangements, typically featuring uniform cells with eosinophilic cytoplasm and mild atypia, arranged in cords or clusters within a chondromyxoid stroma. A cellular variant, characterized by increased cellular density and a solid growth pattern, has been recognized.</div></div><div><h3>Methods</h3><div>We encountered three cases of round cell sarcomas, diagnosed as EMC based on <em>NR4A3</em> or <em>NR4A2</em> rearrangements. To identify additional pure solid EMC cases, we performed a retrospective review of our institutional files spanning 22 years, focusing on cases labeled as \"myxoid chondrosarcoma\" with \"cellular\" features. Histologic slides and clinical data were reviewed.</div></div><div><h3>Results</h3><div>In addition to the three study cases, 43 cases of EMC with cellular features were identified, none of which exhibited the exclusive round-to-spindle cell morphology seen in the study cases. The three unique cases involved two females and one male (ages 42–62) with tumors in the proximal extremities and trunk. The tumors (3.5–10 cm) were well-circumscribed and densely cellular. One tumor exhibited a biphasic pattern with distinct round and spindle cell areas, whereas the other two were composed purely of round/epithelioid cells. High-grade nuclear atypia and brisk mitotic activity (9–13 per 10 HPFs) were observed, with necrosis identified in one case. Next-generation sequencing revealed <em>TCF12::NR4A3</em>, <em>EWSR1::NR4A3</em>, and <em>EWSR1::NR4A2</em> fusions. Two patients developed metastases (lymph nodes and lungs), whereas one remained disease-free at last follow-up.</div></div><div><h3>Conclusion</h3><div>We describe a round cell subtype of EMC, distinct from the traditional cellular variant, characterized by a sheet-like proliferation of large, uniform round-to-epithelioid cells and the absence of chondromyxoid stroma. This potentially underrecognized subtype requires molecular testing for accurate diagnosis. Moreover, the presence of <em>NR4A2</em> fusions, although rare, suggests that the absence of <em>NR4A3</em> rearrangements does not entirely exclude EMC.</div></div>","PeriodicalId":13062,"journal":{"name":"Human pathology","volume":"155 ","pages":"Article 105719"},"PeriodicalIF":2.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expression evaluated by digital image analysis techniques of PRAME more than MCM6 is associated with poor prognosis in neuroblastoma: A pilot study with 84 cases","authors":"Samuel Touioui ,&nbsp;Emmanuel Desandes ,&nbsp;Leo Jannot ,&nbsp;Ludovic Mansuy ,&nbsp;Delphine Clabaut ,&nbsp;Michel Peuchmaur ,&nbsp;Nathalie Rioux-leclercq ,&nbsp;Pierre Khneisser ,&nbsp;Pierre-Alain Thiebaut ,&nbsp;Mathieu Gallo ,&nbsp;Christophe Nemos ,&nbsp;Gudrun Schleiermacher ,&nbsp;Pascal Chastagner ,&nbsp;Herve Sartelet","doi":"10.1016/j.humpath.2025.105718","DOIUrl":"10.1016/j.humpath.2025.105718","url":null,"abstract":"<div><div>Neuroblastoma is a common childhood tumor originating from neural crest progenitors with variable clinical behavior. Despite improved overall survival, factors such as stage, histoprognosis, <em>MYCN</em> status, and age still influence outcome. MCM6 regulates DNA replication and contributes to cancer progression. PRAME, first identified in melanoma, also acts on cell replication, epithelial-mesenchymal transition, and cell migration and has been associated with poor outcomes in several cancers, including neuroblastoma, using molecular biology techniques. The study aims to investigate MCM6 and PRAME expression and prognostic roles in neuroblastoma.</div><div>A retrospective study was conducted, which included data of 84 patients with neuroblastoma diagnosed between 2000 and 2022, sourced from the pediatric tumor registry. Patient's characteristics and prognostic tumor factors were collected. Expression of MCM6 and PRAME proteins was evaluated using digital image analysis techniques. Univariate and multivariate analyses were performed using Cox regression to assess the impact of protein expression on survival and their associations with these prognostic factors.</div><div>A total of 84 children diagnosed with neuroblastoma were included. MCM6 and PRAME were associated with unfavorable histologies (p = 0.03). PRAME was associated with bone marrow metastases (p &lt; 0.01), high mitotic-karyorrhectic index (p = 0.04), and poor histoprognosis (p &lt; 0.01).</div><div>PRAME and MCM6 expression was correlated with several neuroblastoma prognostic factors. PRAME was significantly (p = 0.05) associated with poor event-free survival (EFS) and not significantly (p = 0.08) associated with overall survival (OS). Although statistical significance was not reached in multivariate analysis, the trends strongly suggested that the overexpression of MCM6 and PRAME was correlated with decreased survival.</div></div>","PeriodicalId":13062,"journal":{"name":"Human pathology","volume":"155 ","pages":"Article 105718"},"PeriodicalIF":2.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143023281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An immunohistochemical and molecular genetic study of 60 colorectal carcinoma brain metastases in pursuit of predictive biomarkers for cancer therapy","authors":"Jerzy Lasota ,&nbsp;Maciej Kaczorowski ,&nbsp;Małgorzata Chłopek ,&nbsp;Justyna Miłek-Krupa ,&nbsp;Magdalena Szczepaniak ,&nbsp;Kris Ylaya ,&nbsp;Miłosz Chodyna ,&nbsp;Ewa Iżycka-Świeszewska ,&nbsp;Anna Scherping ,&nbsp;Piotr Czapiewski ,&nbsp;Ireneusz Dziuba ,&nbsp;Yukinari Kato ,&nbsp;Agnieszka Hałoń ,&nbsp;Artur Kowalik ,&nbsp;Markku Miettinen","doi":"10.1016/j.humpath.2025.105717","DOIUrl":"10.1016/j.humpath.2025.105717","url":null,"abstract":"<div><div>Colorectal carcinoma brain metastases (n = 60) were studied using next-generation sequencing and immunohistochemistry. <em>RAS</em> and <em>BRAF</em> mutations were detected in 58.2% and 7.3% of cases, respectively. Patients with <em>RAS</em>- and <em>BRAF</em>-mutant tumors could potentially benefit from the treatment with inhibitors. <em>TP53</em> mutations were detected in 69.1% of metastases. Moreover, altered p53 expression was seen in 91.2% of cases. <em>APC</em> mutations were present in 41.8% of tumors. Diffuse nuclear accumulation of β-catenin was seen in 10.2% of metastases, although only 1 <em>CTNNB1</em> mutant was identified. Nevertheless, targeting p53 and Wnt/β-catenin pathways may have potential therapeutic implications. Casein kinase 1α1 expression indicating susceptibility to protein kinase inhibitors, was seen in 95% metastases including 10 with strong immunoreactivity. The immune checkpoint marker CD276, a promising target for immunotherapy, was present on tumor cells in 50.8% of metastases and on stromal cells in almost all cases. PRAME, another immunotherapy target, was expressed in 21.7% of tumors. HER2 membrane immunostaining detected in 13.3% of cases implicated potential treatment with HER2 inhibitors. Expression of SLFN11, a predictor of response to DNA-damaging chemotherapies, and a biomarker of sensitivity to PARP inhibitors was seen in 8.3% of tumors. In 6.7% of metastases loss or partial loss of MTAP expression suggested sensitivity to PRMT5 inhibitors. CD44v5 expressed in 35% of cases indicated potential therapeutic utility of anti-CD44v5 monoclonal antibody treatment. Identification of predictive biomarkers through genomic profiling and proteomic analyses is a crucial step toward individually tailored therapeutic regimens for patients with colorectal carcinoma brain metastases.</div></div>","PeriodicalId":13062,"journal":{"name":"Human pathology","volume":"155 ","pages":"Article 105717"},"PeriodicalIF":2.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unravelling the difference of immune microenvironment characteristics between esophageal basaloid squamous cell carcinoma and conventional esophageal squamous cell carcinoma","authors":"Dongxian Jiang ,&nbsp;Yuhao Xiao ,&nbsp;Zixiang Yu ,&nbsp;Minying Deng,&nbsp;Qi Song,&nbsp;Jie Huang,&nbsp;Jieakesu Su,&nbsp;Chen Xu,&nbsp;Yingyong Hou","doi":"10.1016/j.humpath.2025.105716","DOIUrl":"10.1016/j.humpath.2025.105716","url":null,"abstract":"<div><h3>Objectives</h3><div>Esophageal basaloid squamous cell carcinoma (basaloid ESCC) is an uncommon variant of esophageal squamous cell carcinoma (ESCC). We characterized the tumor immune microenvironment features of basaloid ESCC, and compared them with conventional ESCC.</div></div><div><h3>Methods and results</h3><div>One hundred and four basaloid ESCC patients and 55 conventional ESCC patients were included in Cohort 1. Among 104 basaloid ESCC, 81 were pure basaloid ESCC, and 23 were mixed basaloid ESCC with invasive basaloid ESCC components and ESCC components. In pure basaloid ESCC, there were more immature desmoplastic reaction (<em>P</em> &lt; 0.001), fewer peritumoral tertiary lymphoid structures (TLSs) (<em>P</em> &lt; 0.001), and lower tumor proportional score (TPS) and combined positive score (CPS) (<em>P</em> &lt; 0.001 and <em>P</em> = 0.004) than in conventional ESCC. In mixed basaloid ESCC, the number of mature or intermediate desmoplastic reaction (<em>P</em> &lt; 0.001), the tumor-infiltrating lymphocytes (TILs) score (<em>P</em> = 0.043), the proportion of stromal CD8⁺ TILs (<em>P</em> = 0.047), the number of intratumoral CD20⁺ TILs (<em>P</em> &lt; 0.001), the number of peritumoral TLSs (<em>P</em> = 0.001), the number of peritumoral matureTLSs (<em>P</em> = 0.021), and the PD-L1 (22C3) CPS (<em>P</em> = 0.016) were lower in the basaloid ESCC components than in the conventional ESCC components. In addition, the data of 141 ESCC patients with neoadjuvant chemoimmunotherapy (nICT) were collected to compare immunotherapeutic outcomes. Among 141 nICT-treated patients, 115 patients had residual tumor cells remaining, including 101 with conventional ESCC and 11 with basaloid ESCC. In basaloid ESCC, 18.2% patients had less than 10% residual viable tumor in the esophageal wall (effective response), which was lower than 58.6% in conventional ESCC (<em>P</em> = 0.025).</div></div><div><h3>Conclusions</h3><div>Our data indicated that basaloid ESCC had less benefits from immunotherapy than conventional ESCC, and manifested as immune “cold” with immature-type desmoplastic reaction, lower TILs, lower peritumoral TLSs, and lower PD-L1 expression than conventional ESCC.</div></div>","PeriodicalId":13062,"journal":{"name":"Human pathology","volume":"155 ","pages":"Article 105716"},"PeriodicalIF":2.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142964618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}