Department of Pathology and Laboratory Medicine Works
Permanent URI for this collection
Browse
Recent Submissions
Item Incidence and spectrum of sporadic Creutzfeldt–Jakob disease variants with mixed phenotype and co-occurrence of PrPSc types: an updated classification(Springer, 2009-11-01) Parchi, Piero; Strammiello, Rosaria; Notari, Silvio; Giese, Armin; Langeveld, Jan P. M.; Ladogana, Anna; Zerr, Inga; Roncaroli, Federico; Cras, Patrich; Ghetti, Bernardino; Pocchiari, Maurizio; Kretzschmar, Hans; Capellari, Sabina; Pathology and Laboratory Medicine, IU School of MedicineSix subtypes of sporadic Creutzfeldt–Jakob disease with distinctive clinico-pathological features have been identified largely based on two types of the abnormal prion protein, PrPSc, and the methionine (M)/valine (V) polymorphic codon 129 of the prion protein. The existence of affected subjects showing mixed phenotypic features and concurrent PrPSc types has been reported but with inconsistencies among studies in both results and their interpretation. The issue currently complicates diagnosis and classification of cases and also has implications for disease pathogenesis. To explore the issue in depth, we carried out a systematic regional study in a large series of 225 cases. PrPSc types 1 and 2 concurrence was detected in 35% of cases and was higher in MM than in MV or VV subjects. The deposition of either type 1 or 2, when concurrent, was not random and always characterized by the coexistence of phenotypic features previously described in the pure subtypes. PrPSc type 1 accumulation and related pathology predominated in MM and MV cases, while the type 2 phenotype prevailed in VVs. Neuropathological examination best identified the mixed types 1 and 2 features in MMs and most MVs, and also uniquely revealed the co-occurrence of pathological variants sharing PrPSc type 2. In contrast, molecular typing best detected the concurrent PrPSc types in VV subjects and MV cases with kuru plaques. The present data provide an updated disease classification and are of importance for future epidemiologic and transmission studies aimed to identify etiology and extent of strain variation in sporadic Creutzfeldt–Jakob disease.Item Towards a new WHO classification of renal cell tumor: what the clinician needs to know—a narrative review(AME Publishing, 2021-03) Cimadamore, Alessia; Cheng, Liang; Scarpelli, Marina; Massari, Francesco; Mollica, Veronica; Santoni, Matteo; Lopez-Beltran, Antonio; Montironi, Rodolfo; Moch, Holger; Pathology and Laboratory Medicine, School of MedicineIn 1952, renal cell carcinomas had been divided into 2 categories—clear cell or granular cell—depending upon their cytoplasmic staining characteristics. In the following years, the inventory of renal epithelial tumors has expanded by the addition of tumors named by their architectural pattern (i.e., papillary RCC, tubulocystic RCC), anatomic location (i.e., collecting duct carcinoma, renal medullary carcinoma), associated diseases (i.e., acquired cystic disease-associated RCCs). With the extensive application of molecular diagnostic techniques, it becomes possible to detect genetic distinctions between various types of renal neoplasm and discover new entities, otherwise misdiagnosed or diagnosed as unclassified RCC. Some tumors such as ALK rearrangement-associated RCC, MiT family translocation renal carcinomas, SDH-deficient renal cancer or FH-deficient RCC, are defined by their molecular characteristics. The most recent World Health Organization (WHO) classification of renal neoplasms account for more than 50 entities and provisional entities. New entities might be included in the upcoming WHO classification. The aim of this review is to summarise and discuss the newly acquired data and evidence on the clinical, pathological, molecular features and on the prognosis of new RCC entities, which will hopefully increase the awareness and the acceptance of these entities among clinicians and improve prognostication for individual patients.Item Narrative review: update on immunotherapy and pathological features in patients with bladder cancer(AME Publishing, 2021-03) Aurilio, Gaetano; Cimadamore, Alessia; Lopez-Beltran, Antonio; Scarpelli, Marina; Massari, Francesco; Verri, Elena; Cheng, Liang; Santoni, Matteo; Montironi, Rodolfo; Pathology and Laboratory Medicine, School of MedicineOver the last few years efficacy of immunotherapy using immune checkpoint inhibitors (ICI) has been investigated in patients with bladder cancer (BC) at all stages. The present article aims to assess new therapeutic options with emerging agents in BC patients, shedding light on ICI-based treatments encompassing all disease stages, from non-muscle invasive (NMIBC) to muscle-invasive (MIBC) BC, concluding with metastatic MIBC. In bacillus Calmette-Guerin (BCG) unresponsive patients with carcinoma in situ, pembrolizumab has been recently approved. In the neoadjuvant setting, results from two clinical trials seem to identify pathological and genomic features of highly responsive tumors. Squamous cells and lymphoepithelioma/like histotypes, programmed cell-death ligand 1 (PD-L1) expression and high levels of activate T cells have been associated with higher response rate. In the metastatic setting, only 30% of patient may respond to ICI. A panel of biomarkers for patient selection is an actual need since the correlation between response and PD-L1 expression seem inconsistent across clinical trials, with some exceptions. Molecular characterization of BC, tumor mutation burden and immune-gene expression profiling might introduce new molecular biomarkers, hopefully transferable into the clinical-pathological practice.Item Narrative review: predicting future molecular and clinical profiles of prostate cancer in the United States(AME Publishing, 2021-03) Santoni, Matteo; Cimadamore, Alessia; Massari, Francesco; Sorgentoni, Giulia; Cheng, Liang; Lopez-Beltran, Antonio; Battelli, Nicola; Montironi, Rodolfo; Pathology and Laboratory Medicine, School of MedicineProstate cancer represents the most frequent tumor in men, accounting for the 21% of all diagnosed tumors, with 191,930 new cases and 33,330 deaths estimated in 2020. Advanced prostate cancer represents a heterogeneous disease, ranging from hormone naive or hormone sensitive to castration resistant. The therapeutic armamentarium for this disease has been implemented in the last years by novel hormonal therapies and chemotherapies. However, the percentage of patients who achieve complete responses still results negligible. On this scenario, the design of clinical trials investigating new therapeutic approaches represent a dramatic medical need. Predicting cancer incidence may be fundamental to design specific clinical trials, to optimize the allocation of economic resources, and to plan future cancer control programs. ERG, SPOP and DDR genes alterations can act as therapeutic targets in prostate cancer patients and can be tested to identify a gene-selected patient population to enrol in specific trials. According to our predictions, ERG gene fusions will be the most predominant molecular subtype, accounting for 69,050 new cases in 2030. Mutation in SPOP gene will be diagnosed in 16,512 tumors, corresponding to the number of cases associated with alterations in DDR genes (including 7,956 BRCA2 mutated tumors). In this article, we analyzed and discussed the future molecular and clinical profiles of prostate cancer in the United States, aimed to describe a series of distinct subpopulations and to quantify potential clinical trial candidates in the next years.Item Digital diagnostics and artificial intelligence in prostate cancer treatment in 5 years from now(AME, 2021-03) Cimadamore, Alessia; Cheng, Liang; Scarpelli, Marina; Lopez-Beltran, Antonio; Montironi, Rodolfo; Pathology and Laboratory Medicine, School of MedicineItem Narrative review of prostate cancer grading systems: will the Gleason scores be replaced by the Grade Groups?(AME Publishing, 2021-03) Montironi, Rodolfo; Cheng, Liang; Cimadamore, Alessia; Mazzucchelli, Roberta; Scarpelli, Marina; Santoni, Matteo; Massari, Francesco; Lopez-Beltran, Antonio; Pathology and Laboratory Medicine, School of MedicineThe Gleason grading system, proposed by Dr. Donald F. Gleason in 1966, is one of the most important prognostic factors in men with prostate cancer (PCa). At consensus conferences held in 2005 and 2014, organized by the International Society of Urological Pathology (ISUP), the system was modified to reflect the current diagnostic and therapeutic approaches. In particular, in the 2014 Conference, it was recognized that there were weaknesses with the original and the 2005 ISUP modified Gleason systems. Based on the results of a research conducted by Prof. JI Epstein and his group, a new grading system was proposed by the ISUP in order to address some of such deficiencies: i.e., the five distinct Grade Groups (GGs). Since 2014, results of studies have been published by different groups and societies, including the Genitourinary Pathology Society (GUPS), giving additional support to the prognostic role of the architectural Gleason patterns and, in particular, of the GGs. A revised GG system, taking into account the percentage of Gleason pattern (GP) 4, cribriform and intraductal carcinoma, tertiary GP 5, and reactive stroma grade, has shown to have some advantages, however not ready for adoption in the current practice. The aim of this contribution was to review the major updates and recommendations regarding the GPs and GSs, as well as the GGs, trying to give an answer to the following questions: “How has the grade group system been used in the routine?” and “will the Gleason scoring system be replace by the grade groups?” We also discussed the potential implementation in the future of molecular pathology and artificial intelligence in grading to further define risk groups in patients with PCa.Item EZH2-mediated Downregulation of the Tumor Suppressor DAB2IP Maintains Ovarian Cancer Stem Cells(American Association for Cancer Research, 2020-10-15) Zong, Xingyue; Wang, Weini; Ozes, Ali; Fang, Fang; Sandusky, George E.; Nephew, Kenneth P.; Pathology and Laboratory Medicine, School of MedicineThe majority of women diagnosed with epithelial ovarian cancer (OC) eventually develop recurrence which rapidly evolves into chemoresistant disease. Persistence of ovarian cancer stem cells (OCSC) at the end of therapy may be responsible for emergence of resistant tumors. In this study, we demonstrate that in OCSC, the tumor suppressor Disabled Homolog 2-Interacting Protein (DAB2IP) is silenced by EZH2-mediated H3K27 trimethylation of the DAB2IP promoter. CRISPR/Cas9-mediated deletion of DAB2IP in epithelial OC cell lines upregulated expression of stemness-related genes and induced conversion of non-CSC to CSC, while enforced expression of DAB2IP suppressed CSC properties. Transcriptomic analysis showed that overexpression of DAB2IP in OC significantly altered stemness-associated genes and bioinformatic analysis revealed WNT signaling as a dominant pathway mediating the CSC inhibitory effect of DAB2IP. Specifically, DAB2IP inhibited WNT signaling via downregulation of WNT5B, an important stemness inducer. Reverse Phase Protein Array further demonstrated activation of non-canonical WNT signaling via C-JUN as a downstream target of WNT5B, which was blocked by inhibiting RAC1, a prominent regulator of C-JUN activation. Co-administration of EZH2 inhibitor GSK126 and RAC1 inhibitor NSC23766 suppressed OCSC survival in vitro and inhibited tumor growth and increased platinum sensitivity in vivo. Overall, these data establish that DAB2IP suppresses the cancer stem cell phenotype via inhibition of WNT5B-induced activation of C-JUN and can be epigenetically silenced by EZH2 in OCSC. Targeting the EZH2/DAB2IP/C-JUN axis therefore presents a promising strategy to prevent OC recurrence and has potential for clinical translation.Item Adjuvant therapy in renal cell carcinoma: is it the right strategy to inhibit VEGF?(AME Publishing, 2021-03) Mollica, Veronica; Rizzo, Alessandro; Di Nunno, Vincenzo; Santoni, Matteo; Cheng, Liang; Lopez-Beltran, Antonio; Scarpelli, Marina; Cimadamore, Alessia; Montironi, Rodolfo; Massari, Francesco; Pathology and Laboratory Medicine, School of MedicineDespite several clinical trials have assessed different agents in the adjuvant setting, renal cell carcinoma (RCC) still remains a disease orphan of an effective adjuvant treatment. In fact, systemic therapies targeting angiogenesis that have been observed to be effective in metastatic setting failed to show an improvement in terms of clinical outcomes when used ad adjuvant treatments. In this study, we performed a meta-analysis of 5 randomized clinical trials to assess the impact of tyrosine kinase inhibitors (TKIs) targeting angiogenesis after surgery: ASSURE, S-TRAC, PROTECT, ATLAS, SORCE. Among the 6,531 patients assessed, we confirmed the lack of efficacy of adjuvant treatments in terms of disease-free survival (DFS) (pooled-HR 0.93, 95% CI, 0.84–1.02, P=0.16) and overall survival (OS) (pooled-HR 0.98, 95% CI, 0.88–1.09, P=0.54). To the best of our knowledge, we still ignore why some treatments active in the metastatic setting do not show similar efficacy as adjuvant treatment. Exploring possible reasons of this apparently conflicting results is important as it may offer new insights that should be evaluated in next generation adjuvant trials. Immune checkpoint inhibitors (ICIs) have reported significant results—as monotherapy or in combinations with other anticancer agents—in metastatic setting, and the results of trials evaluating these agents in the adjuvant setting are awaited.Item Developmental vascular malformations in EPAS1 gain-of-function syndrome(American Society for Clinical Investigation, 2021-03-08) Rosenblum, Jared S.; Wang, Herui; Dmitriev, Pauline M.; Cappadona, Anthony J.; Mastorakos, Panagiotis; Xu, Chen; Jha, Abhishek; Edwards, Nancy; Donahue, Danielle R.; Munasinghe, Jeeva; Nazari, Matthew A.; Knutsen, Russell H.; Rosenblum, Bruce R.; Smirniotopoulos, James G.; Pappo, Alberto; Spetzler, Robert F.; Vortmeyer, Alexander; Gilbert, Mark R.; McGavern, Dorian B.; Chew, Emily; Kozel, Beth A.; Heiss, John D.; Zhuang, Zhengping; Pacak, Karel; Pathology and Laboratory Medicine, School of MedicineMutations in EPAS1, encoding hypoxia-inducible factor-2α (HIF-2α), were previously identified in a syndrome of multiple paragangliomas, somatostatinoma, and polycythemia. HIF-2α, when dimerized with HIF-1β, acts as an angiogenic transcription factor. Patients referred to the NIH for new, recurrent, and/or metastatic paraganglioma or pheochromocytoma were confirmed for EPAS1 gain-of-function mutation; imaging was evaluated for vascular malformations. We evaluated the Epas1A529V transgenic syndrome mouse model, corresponding to the mutation initially detected in the patients (EPAS1A530V), for vascular malformations via intravital 2-photon microscopy of meningeal vessels, terminal vascular perfusion with Microfil silicate polymer and subsequent intact ex vivo 14T MRI and micro-CT, and histologic sectioning and staining of the brain and identified pathologies. Further, we evaluated retinas from corresponding developmental time points (P7, P14, and P21) and the adult dura via immunofluorescent labeling of vessels and confocal imaging. We identified a spectrum of vascular malformations in all 9 syndromic patients and in all our tested mutant mice. Patient vessels had higher variant allele frequency than adjacent normal tissue. Veins of the murine retina and intracranial dura failed to regress normally at the expected developmental time points. These findings add vascular malformation as a new clinical feature of EPAS1 gain-of-function syndrome.Item TNM staging towards a personalized approach in metastatic urothelial carcinoma: what will the future be like?—a narrative review(AME Publishing, 2021-03) Rizzo, Alessandro; Mollica, Veronica; Cimadamore, Alessia; Santoni, Matteo; Scarpelli, Marina; Schiavina, Riccardo; Cheng, Liang; Lopez-Beltran, Antonio; Brunocilla, Eugenio; Montironi, Rodolfo; Massari, Francesco; Pathology and Laboratory Medicine, School of MedicineThe American Joint Committee of Cancer (AJCC) tumor-node-metastasis (TNM) classification, with its periodical updates and modifications, has represented and still represents the basis of cancer staging. The historical, long-standing limitations of anatomic-based TNM staging have been recently “threatened” by the impressive amount of data derived from molecular analyses, which have led to an unprecedented level of understanding of cancer genomics. In fact, current era of personalized oncology has witnessed important efforts towards the integration between clinical, anatomical and molecular features; however, despite the promises, personalized oncology faces many obstacles, due to the complex relationship between tumor biomarkers, previously unknown cancer subtypes and clinical and anatomical characteristics. With regard to urothelial carcinoma (UC), the characterization of tumors in large cohorts of patients has provided important information concerning genetic alterations, revealing the presence of biologically relevant subtypes of UC. In the current review, we will provide an overview regarding this recent “translation” from the anatomic-based TNM to a novel horizon, aiming at further “tailoring” personalized oncology, especially focusing on recently published data about the molecular landscape of UC with its therapeutic and prognostic implications.