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Night fall
When a body is found having been bound, gagged, thrown off a bridge, and with the letter 'A' carved into his forehead, Detective Inspector Neil Paget has nothing to go on until another body appears in a similar condition.
Book
Diagnosis and treatment of Paget’s disease of bone: position paper from the Italian Society of Osteoporosis, Mineral Metabolism and Skeletal Diseases (SIOMMMS)
Introduction
Paget’s disease of bone is a focal skeletal disorder causing bone deformities and impairing bone quality. Despite the prevalence of asymptomatic cases is increasing, the progression of the disease can lead to invalidating complications that compromise the quality of life. Doubts on clinical and therapeutic management aspects exist, although beneficial effects of antiresorptive drugs, particularly bisphosphonates are known. However, limited information is available from randomized controlled trials on the prevention of disease complications so that somewhat contrasting positions about treatment indications between expert panels from the main scientific societies of metabolic bone diseases exist. This task force, composed by expert representatives appointed by the Italian Society of Osteoporosis, Mineral Metabolism and Skeletal Diseases and members of the Italian Association of Paget’s disease of bone, felt the necessity for more specific and up to date indications for an early diagnosis and clinical management.
Methods
Through selected key questions, we propose evidence-based recommendations for the diagnosis and treatment of the disease. In the lack of good evidence to support clear recommendations, available information from the literature together with expert opinion of the panel was used to provide suggestions for the clinical practice.
Results and conclusion
Description of the evidence quality and support of the strength of the statements was provided on each of the selected key questions. The diagnosis of PDB should be mainly based on symptoms and the typical biochemical and radiological features. While treatment is mandatory to all the symptomatic cases at diagnosis, less evidence is available on treatment indications in asymptomatic as well as in previously treated patients in the presence of biochemical recurrence. However, given the safety and long-term efficacy of potent intravenous bisphosphonates such as zoledronate, a suggestion to treat most if not all cases at the time of diagnosis was released.
Journal Article
An Evaluation of HER2 Expression Heterogeneity in Primary Tumors and Metastatic Lymph Nodes of Patients With Advanced Extramammary Paget's Disease: Prognostic and Therapeutic Implications
Background HER2 expression in primary versus metastatic tumors in advanced Extramammary Paget's Disease (EMPD) remains inadequately characterized. This investigation aimed to assess HER2 expression heterogeneity between primary tumors and metastatic lymph nodes (LNs) in patients with advanced EMPD and to assess the prognostic value of HER2 expression and other pathological factors in determining the therapeutic value of HER2 targeting. Methods We included 170 patients diagnosed with primary EMPD. Survival outcomes were analyzed using multivariate Cox regression and log‐rank analysis, while inconsistencies in HER2 expression between primary and metastatic LNs were assessed using the kappa coefficient. Results HER2 high‐expression was observed in 71.6% of primary tumors and 68.8% of metastatic LNs, with high HER2 expression correlating with poorer overall survival. Multivariate Cox analysis identified advanced N stage and HER2 high‐expression in primary tumors as independent poor prognostic factors. In 31 paired samples, the discordance rate of HER2 status between primary tumors and corresponding LNs was 35.48% (n = 11) (Kappa 0.11, 95% CI −0.26 to 0.47; p = 0.540), with 19.4% of cases showing a shift from high HER2 expression in primary tumors to low expression in metastatic LNs. Patients treated with disitamab vedotin had an 80% objective response rate (ORR) and a 100% disease control rate (DCR), with no adverse events above grade 3–4. Conclusion HER2 was frequently expressed in both primary tumors and metastatic LNs in EMPD patients, though heterogeneity was observed. HER2 status should be assessed in both primary and metastatic sites. Disitamab vedotin shows promise for treating HER2‐positive advanced EMPD, warranting further study.
Journal Article
Comparison of the biomarkers for targeted therapies in primary extra‐mammary and mammary Paget's disease
Background Primary Extra‐mammary Paget's disease (EMPD) is a very rare cutaneous adenocarcinoma affecting anogenital or axillary regions. It is characterized by a prolonged course with recurrences and eventually distant metastatic spread for which no specific therapy is known. Methods Eighteen EMPD (13 vulvar and five scrotal) and ten mammary Paget's disease (MPD) cases were comprehensively profiled for gene mutations, fusions and copy number alterations, and for therapy‐relevant protein biomarkers). Results Mutations in TP53 and PIK3CA were the most frequent in both cohorts: 7/15 and 5/15 in EMPD; 1/6 and 4/7 in MPD HER2 gene amplification was detected in 4/18 EMPD (3 vulvar and 1 scrotal case) in contrast to MPD where it was detected in the majority (7/8) of cases. TOP2A gene amplification was seen in 2/12 EMPD and 1/6 MPD, respectively. Similarly, no difference in estrogen receptor expression was seen between the EMPD (4/15) and MPD (3/10). Androgen receptor was also expressed in the majority of both cohorts (12/16 EMPD) and (7/8 MPD).Here ARv7 splice variant was detected in 1/7 EMPD and 1/4 MPD cases, respectively. PD‐L1 expression on immune cells was exclusively observed in three vulvar EMPD. In contrast to MPD, six EMPDs harbored a “high” tumor mutation burden (≥10 mutations/Mb). All tested cases from both cohorts were MSI stable. Conclusions EMPD shares some targetable biomarkers with its mammary counterpart (steroid receptors, PIK3CA signaling pathways, TOP2A amplification). HER2 positivity is notably lower in EMPD while biomarkers to immune checkpoint inhibitors (high TMB and PD‐L1) were observed in some EMPD. Given that no consistent molecular alteration characterizes EMPD, comprehensive theranostic profiling is required to identify individual patients with targetable molecular alterations. Comprehensive molecular profiling of primary Extra‐mammary Paget's Disease (EMPD) indicates that individually profiled cases harbor potentially targetable molecular alterations. EMPD shares some but not all molecular features with its mammary counterpart. Potential therapeutic targets in EMPD include steroid receptors (ER and AR), HER2, and PIK3CA signaling pathways, TOP2A amplification, and immune checkpoints (PD‐L1).
Journal Article
Programmed Death-Ligand 1 and Programmed Death-Ligand 2 Expression Can Affect Prognosis in Extramammary Paget’s Disease
Extramammary Paget's disease (EMPD) is a type of carcinoma that usually progresses slowly but may cause metastasis and subsequent death of patients. We investigated the relationship between the expression of programmed death-ligand 1 (PD-L1)/programmed death-ligand 2 (PD-L2) and stromal CD8
tumor-infiltrating lymphocytes (TILs) in EMPD and clinicopathological findings, including prognosis.
We examined 47 cases of EMPD and performed immunohistochemical staining of formalin-fixed paraffin-embedded full-face sections.
PD-L1 expression in tumor cells was observed in 13 cases (27.7%) while PD-L2 expression was observed in 21 cases (44.7%). The cumulative postoperative recurrence-free rate in the group with positivity for PD-L1 and/or PD-L2 with a low CD8
TIL count was significantly lower than that of the corresponding group with a high CD8
TIL count and of the PD-L1- and PD-L2-negative group (p=0.026).
The expression of PD-L1/PD-L2 in tumor cells was shown to be a factor for poor prognosis.
Journal Article
Paget’s disease of the nipple
Paget’s disease of the breast is a disorder of the nipple–areola complex that, while rare, is often associated with an underlying carcinoma. It is characterized by eczematoid changes of the nipple. Two theories have been proposed to explain the pathogenesis of Paget’s disease. The Epidermotropic, which is the most accepted theory, suggests that Paget’s cells originate from ductal cancer cells that had migrated from the underlying breast parenchyma. It is supported by the predominance of breast cancer markers found in Paget’s disease. This article provides an overview of Paget’s disease of the breast with special attention to immunohistochemistry and raises the question of new therapeutic approaches.
Journal Article
Immunotherapy may be more appropriate for ERBB2 low-expressing extramammary paget’s disease patients: a prognosis analysis and exploration of targeted therapy and immunotherapy of extramammary paget’s disease patients
Extramammary Paget’s disease (EMPD) is a rare cutaneous malignancy characterized by its uncertain etiology and metastatic potential. Surgery remains the first-line clinical treatment for EMPD, but the efficacy of radiotherapy and chemotherapy remains to be fully evaluated, and new therapies for EMPD are urgently needed. In this study, we initially screened 815 EMPD patients in the Surveillance, Epidemiology, and End Results (SEER) database and analyzed their clinical features and prognostic factors. Using the dataset from the Genome Sequence Archive (GSA) database, we subsequently conducted weighted gene coexpression network analysis (WGCNA), gene set enrichment analysis (GSEA), gene set variation analysis (GSVA), and immune infiltration analyses, grouping the samples based on EMPD disease status and the levels of ERBB2 expression. The prognostic analysis based on the SEER database identified increased age at diagnosis, distant metastasis, and receipt of radiotherapy as independent risk factors for EMPD. Moreover, our results indicated that patients who received chemotherapy had worse prognoses than those who did not, highlighting the urgent need for novel treatment approaches for EMPD. Functional analysis of the GSA-derived dataset revealed that EMPD tissues were significantly enriched in immune-related pathways compared with normal skin tissues. Compared with those with high ERBB2 expression, tissues with low ERBB2 expression displayed greater immunogenicity and enrichment of immune pathways, particularly those related to B cells. These findings suggest that patients with low ERBB2 expression are likely to benefit from immunotherapy, especially B-cell-related immunotherapy.
Journal Article
Utility of special AT-rich sequence-binding protein 2 (SATB2) immunohistochemistry as a marker for secondary perianal paget disease
A panel-based approach using immunohistochemistry (IHC) is currently used for subtyping perianal Paget disease (PPD) in the absence of a synchronous neoplasm. Special AT-rich Sequence Binding Protein 2 (SATB2) has been established as a sensitive and specific marker for lower gastrointestinal tract carcinomas. We evaluated its performance as a marker of secondary PPD. A panel of IHCs including CK7, CK20, GCDFP-15, CDX2, and SATB2 were performed on fifteen cases of PPD (identified between 1991–2001) and seven cases of primary vulvar Paget disease with perianal involvement. Eight cases (53%) were classified as secondary PPD based on the presence of a synchronous (n = 7) or a metachronous neoplasm (n = 1). There was no differential staining for CK7 (positive in 7/7 primary vs. 7/8 secondary PPD; P = 1.00) and CK20 (positive in 4/7 primary vs. 8/8 secondary PPD; P = .08). GCDFP-15 was positive in 5/7 cases of primary PPD while negative in all cases of secondary PPD (P = .01). CDX2 was positive in all cases of secondary PPD (P = .001) while SATB2 was positive in 7/8 cases of secondary PPD (P = .01). Both CDX2 and SATB2 were positive in 1/7 cases of primary PPD. The addition of an IHC panel in conjunction with clinical/imaging findings can help definitively classify PPD as either primary or secondary in most cases. We show that SATB2 has comparable performance to CDX2 and can be a helpful additional tool.
Journal Article
A multicenter study on TROP2 as a potential targeted therapy for extramammary Paget disease in Japan
Extramammary Paget disease (EMPD) is a rare skin cancer that typically occurs in the anogenital area of older people. Since efficacy of treatments for metastatic or unresectable EMPD remains poor, development of a novel therapeutic approach is strongly desired. However, the lack of EMPD models has hampered investigation of EMPD. Here we investigated whether trophoblast cell surface antigen 2 (TROP2) could be a promising therapeutic target for EMPD. We retrospectively collected 108 samples from 54 patients with primary and metastatic EMPD from 10 Japanese institutions, and compared TROP2 expression between primary and metastatic lesions of each paired sample. In vitro assays were performed using a newly established EMPD cell line, KS-EMPD-1. TROP2 was strongly and homogeneously expressed in patient tissues, regardless of primary or metastatic lesions. The KS-EMPD-1 cells were treated with a TROP2-targeted antibody–drug conjugate (ADC), sacituzumab govitecan, and it significantly reduced cell viability in a dose-dependent manner compared with that of the cells treated with sacituzumab alone. Knockdown of TROP2 reduced cell viability and cell migration, and caused slight upregulation of the apoptosis-related factors, together with downregulation of the epithelial-to-mesenchymal transition-related factors. These findings suggest that a TROP2-targeted ADC may be a promising treatment option for unresectable EMPD.
Journal Article