Investigating the clinical, pathological and molecular profile of oncocytic adrenocortical neoplasms

Background: Malignant oncocytic adrenocortical neoplasms (OANs) are rare tumours with a distinctive biological behavior compared to conventional adrenocortical carcinoma (ACC). The current prognostic systems overestimate the malignant potential of these tumours and guidance for surveillance and treatment strategies are lacking. Aim: To evaluate the utility of clinical, pathological and molecular markers in predicting the biological behavior and outcomes of malignant OANs. Methods: A retrospective clinicopathological review of ten histologically confirmed OANs was carried out. Whole exome sequencing (WES) of germline and paired tumour samples was performed for four of the ten OAN cases and compared to WES data from five cases of conventional ACC and data from The Cancer Genome Atlas (TCGA). We reviewed all cases of malignant OAN reported in the literature and compared to our case series. Results: Eight (80%) tumours were classified as malignant, one borderline and one benign (Lin-Weiss-Bisceglia criteria: LWB). The malignant OAN were larger tumours and had higher MIB index and Helsinki scores. Molecular profiling identified a pathogenic germline variant in MSH6 in an individual in the OAN group. The OAN samples had a lower mutation burden compared to the ACC samples. Somatic driver variants were identified in OAN and ACC samples including a pathogenic missense variant in CTNNB1. Conclusion: In this study, the LWB classification demonstrated sensitivity for the differentiation of benign from malignant OAN. Molecular profiling identified dysregulation in DNA repair and Wnt signaling pathways in both OAN and ACC samples, suggesting a molecular overlap between OAN and conventional ACC.

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Use of Molecular Profiling to Guide Treatment Decisions in Patients with Neuroendocrine Tumors: Preliminary Results

The American Surgeon ◽

10.1177/000313481608200424 ◽

2016 ◽

Vol 82 (4) ◽

pp. 369-375 ◽

Cited By ~ 1

Author(s):

Holt S. Cutler ◽

Paul Ogando ◽

Joshua H. Uhr ◽

Dani O. Gonzalez ◽

Richard R.P. Warner ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Clinical Symptoms ◽

Case Series ◽

Molecular Profiling ◽

Serum Markers ◽

Carcinoid Tumors ◽

Molecular Profile ◽

Chemotherapy Response ◽

Choice Of Treatment ◽

Selection Of

This case series demonstrates the potential of molecular profiling to improve selection of anti-tumor therapies in the treatment of patients with neuroendocrine and carcinoid tumors. Carcinoid tumors resected at one institution over a 3-year period were sent for molecular profiling to guide choice of treatment. Potentially beneficial therapies were identified based on the measured expression of 20 proteins and oncogenes and a comprehensive review of the chemotherapy response literature. The clinical charts of 41 patients were reviewed retrospectively, and 12 were selected as representatives of the range of effects molecular profiling has on carcinoid treatment. Their presentation, molecular profile results, treatment, and disease progression is reviewed in the following case series. A total of nine patients were treated with drugs identified as potentially beneficial by molecular profile reports. These include capecitabine, 5-fluorouracil, temozolomide, oxaliplatin, and gemcitabine. Based on clinical symptoms, serum markers of disease, and radio-graphic evidence five of nine patients responded to treatment, two had mixed responses, and two did not respond to treatment. At this early juncture, our critique of molecular profiling for neuroendocrine tumors is favorable, as a significant number of our patients responded to drugs identified by molecular profiling as potentially beneficial.

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A Timely Update of Immunohistochemistry and Molecular Classification in the Diagnosis and Risk Assessment of Endometrial Carcinomas

Archives of Pathology & Laboratory Medicine ◽

10.5858/arpa.2021-0098-ra ◽

2021 ◽

Vol 145 (11) ◽

pp. 1367-1378

Author(s):

Minhua Wang ◽

Pei Hui

Keyword(s):

Copy Number ◽

Treatment Strategies ◽

The United States ◽

Cancer Genome ◽

The Cancer Genome Atlas ◽

Molecular Profile ◽

Cancer Genome Atlas ◽

Endometrial Carcinomas ◽

Genome Atlas

Context.— Endometrial carcinoma is the most common gynecologic malignancy in the United States and has been traditionally classified based on histology. However, the distinction of certain histologic subtypes based on morphology is not uncommonly problematic, and as such, immunohistochemical study is often needed. Advances in comprehensive tumor sequencing have provided novel molecular profiles of endometrial carcinomas. Four distinct molecular subtypes with different prognostic values have been proposed by The Cancer Genome Atlas program: polymerase epsilon ultramutated, microsatellite instability hypermutated, copy number low (microsatellite stable or no specific molecular profile), and copy number high (serouslike, p53 mutant). Objective.— To discuss the utilities of commonly used immunohistochemical markers for the classification of endometrial carcinomas and to review the recent advancements of The Cancer Genome Atlas molecular reclassification and their potential impact on treatment strategies. Data Sources.— Literature review and authors' personal practice experience. Conclusions.— The current practice of classifying endometrial cancers is predominantly based on morphology. The use of ancillary testing, including immunohistochemistry, is helpful in the identification, differential diagnosis, and classification of these cancers. New developments such as molecular subtyping have provided insightful prognostic values for endometrial carcinomas. The proposed The Cancer Genome Atlas classification is poised to gain further prominence in guiding the prognostic evaluation for tailored treatment strategies in the near future.

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Molecular Evaluation of Endometrial Dedifferentiated Carcinoma, Endometrioid Carcinoma, Carcinosarcoma, and Serous Carcinoma Using a Custom-Made Small Cancer Panel

Pathology & Oncology Research ◽

10.3389/pore.2021.1610013 ◽

2021 ◽

Vol 27 ◽

Author(s):

Yusuke Kobayashi ◽

Ikumi Kitazono ◽

Toshiaki Akahane ◽

Shintaro Yanazume ◽

Masaki Kamio ◽

...

Keyword(s):

Molecular Classification ◽

P53 Mutation ◽

Cancer Genome ◽

The Cancer Genome Atlas ◽

Serous Carcinoma ◽

Molecular Profile ◽

Endometrioid Carcinoma ◽

Mutation Burden ◽

Custom Made ◽

Endometrial Cancers

It is often difficult to histologically differentiate among endometrial dedifferentiated carcinoma (DC), endometrioid carcinoma (EC), serous carcinoma (SC), and carcinosarcoma (CS) due to the presence of solid components. In this study, we aimed to categorize these carcinomas according to The Cancer Genome Atlas (TCGA) classification using a small custom-made cancer genome panel (56 genes and 17 microsatellite regions) for integrated molecular diagnosis. A total of 36 endometrial cancer cases with solid components were assessed using IHC, next-generation sequencing (NGS), and the custom-made panel. Among 19 EC cases, six were categorized as MMR-deficient (MMR-d) and eight were classified as having a nonspecific molecular profile. Three EC cases were classified as POLE mutation (POLEmut)-type, which had a very high tumor mutation burden (TMB) and low microsatellite instability (MSI). Increased TMB and MSI were observed in all three DC cases, classified as MMR-d with mutations in MLH1 and POLD1. Except for one case classified as MMR-d, all SC cases exhibited TP53 mutations and were classified as p53 mutation-type. SC cases also exhibited amplification of CCND1, CCNE1, and MYC. CS cases were classified as three TCGA types other than the POLEmut-type. The IHC results for p53 and ARID1A were almost consistent with their mutation status. NGS analysis using a small panel enables categorization of endometrial cancers with solid proliferation according to TCGA classification. As TCGA molecular classification does not consider histological findings, an integrated analytical procedure including IHC and NGS may be a practical diagnostic tool for endometrial cancers.

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Comprehensive assessment of PD-L1 and PD-L2 dysregulation in gastrointestinal cancers

Epigenomics ◽

10.2217/epi-2020-0093 ◽

2020 ◽

Author(s):

Qijie Zhao ◽

Jinan Guo ◽

Yueshui Zhao ◽

Jing Shen ◽

Parham Jabbarzadeh Kaboli ◽

...

Keyword(s):

Transcription Factor ◽

Signaling Pathways ◽

Underlying Mechanism ◽

Comprehensive Analysis ◽

The Cancer Genome Atlas ◽

Gastrointestinal Cancers ◽

Tumor Mutation Burden ◽

Mutation Burden ◽

Cancer Genome Atlas ◽

Genome Atlas

Background: PD-L1 and PD-L2 are ligands of PD-1. Their overexpression has been reported in different cancers. However, the underlying mechanism of PD-L1 and PD-L2 dysregulation and their related signaling pathways are still unclear in gastrointestinal cancers. Materials & methods: The expression of PD-L1 and PD-L2 were studied in The Cancer Genome Atlas and Genotype-Tissue Expression databases. The gene and protein alteration of PD-L1 and PD-L2 were analyzed in cBioportal. The direct transcription factor regulating PD-L1/ PD-L2 was determined with ChIP-seq data. The association of PD-L1/PD-L2 expression with clinicopathological parameters, survival, immune infiltration and tumor mutation burden were investigated with data from The Cancer Genome Atlas. Potential targets and pathways of PD-L1 and PD-L2 were determined by protein enrichment, WebGestalt and gene ontology. Results: Comprehensive analysis revealed that PD-L1 and PD-L2 were significantly upregulated in most types of gastrointestinal cancers and their expressions were positively correlated. SP1 was a key transcription factor regulating the expression of PD-L1. Conclusion: Higher PD-L1 or PD-L2 expression was significantly associated with poor overall survival, higher tumor mutation burden and more immune and stromal cell populations. Finally, HIF-1, ERBB and mTOR signaling pathways were most significantly affected by PD-L1 and PD-L2 dysregulation. Altogether, this study provided comprehensive analysis of the dysregulation of PD-L1 and PD-L2, its underlying mechanism and downstream pathways, which add to the knowledge of manipulating PD-L1/PD-L2 for cancer immunotherapy.

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Metabolic Interplay between the Immune System and Melanoma Cells: Therapeutic Implications

Biomedicines ◽

10.3390/biomedicines9060607 ◽

2021 ◽

Vol 9 (6) ◽

pp. 607

Author(s):

Alice Indini ◽

Francesco Grossi ◽

Mario Mandalà ◽

Daniela Taverna ◽

Valentina Audrito

Keyword(s):

Metabolic Pathways ◽

Cancer Metabolism ◽

Acquired Resistance ◽

Treatment Strategies ◽

Predictive Biomarkers ◽

Treatment Resistance ◽

Metastatic Potential ◽

Biological Behavior ◽

Therapeutic Implications ◽

Systemic Treatments

Malignant melanoma represents the most fatal skin cancer due to its aggressive biological behavior and high metastatic potential. Treatment strategies for advanced disease have dramatically changed over the last years due to the introduction of BRAF/MEK inhibitors and immunotherapy. However, many patients either display primary (i.e., innate) or eventually develop secondary (i.e., acquired) resistance to systemic treatments. Treatment resistance depends on multiple mechanisms driven by a set of rewiring processes, which involve cancer metabolism, epigenetic, gene expression, and interactions within the tumor microenvironment. Prognostic and predictive biomarkers are needed to guide patients’ selection and treatment decisions. Indeed, there are no recognized clinical or biological characteristics that identify which patients will benefit more from available treatments, but several biomarkers have been studied with promising preliminary results. In this review, we will summarize novel tumor metabolic pathways and tumor-host metabolic crosstalk mechanisms leading to melanoma progression and drug resistance, with an overview on their translational potential as novel therapeutic targets.

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Gliosarcoma vs. glioblastoma: a retrospective case series using molecular profiling

BMC Neurology ◽

10.1186/s12883-021-02233-5 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Christopher Dardis ◽

David Donner ◽

Nader Sanai ◽

Joanne Xiu ◽

Sandeep Mittal ◽

...

Keyword(s):

Copy Number ◽

Epithelial To Mesenchymal Transition ◽

Clinical Care ◽

Case Series ◽

Molecular Profiling ◽

Retrospective Case ◽

Who Grade ◽

Exact Test ◽

Mesenchymal Transition ◽

Dna And Rna

Abstract Background Gliosarcoma (GS) refers to the presence of mesenchymal differentiation (as seen using light microscopy) in the setting of glioblastoma (GB, an astrocytoma, WHO Grade 4). Although the same approach to treatment is typically adopted for GS and GB, there remains some debate as to whether GS should be considered a discrete pathological entity. Differences between these tumors have not been clearly established at the molecular level. Methods Patients with GS (n=48) or GB (n=1229) underwent molecular profiling (MP) with a pan-cancer panel of tests as part of their clinical care. The methods employed included next-generation sequencing (NGS) of DNA and RNA, copy number variation (CNV) of DNA and immunohistochemistry (IHC). The MP comprised 1153 tests in total, although results for each test were not available for every tumor profiled. We analyzed this data retrospectively in order to determine if our results were in keeping with what is known about the pathogenesis of GS by contrast with GB. We also sought novel associations between the MP and GS vs. GB which might improve our understanding of pathogenesis of GS. Results Potentially meaningful associations (p<0.1, Fisher’s exact test (FET)) were found for 14 of these tests in GS vs. GB. A novel finding was higher levels of proteins mediating immuno-evasion (PD-1, PD-L1) in GS. All of the differences we observed have been associated with epithelial-to-mesenchymal transition (EMT) in other tumor types. Many of the changes we saw in GS are novel in the setting of glial tumors, including copy number amplification in LYL1 and mutations in PTPN11. Conclusions GS shows certain characteristics of EMT, by contrast with GB. Treatments targeting immuno-evasion may be of greater therapeutic value in GS relative to GB.

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Increased VEGF-A in solid type of lung adenocarcinoma reduces the patients’ survival

Scientific Reports ◽

10.1038/s41598-020-79907-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Woon Yong Jung ◽

Kyueng-Whan Min ◽

Young Ha Oh

Keyword(s):

Immune Response ◽

Survival Analysis ◽

Lung Adenocarcinoma ◽

Survival Rates ◽

Treatment Strategies ◽

Enrichment Analysis ◽

Genetic Alterations ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Solid Type

AbstractThe histological classification of lung adenocarcinoma includes 5 types: lepidic, acinar, papillary, micropapillary and solid. The complex gene interactions and anticancer immune response of these types are not well known. The aim of this study was to reveal the survival rates, genetic alterations and immune activities of the five histological types and provide treatment strategies. This study reviewed the histological findings of 517 patients with lung adenocarcinoma from The Cancer Genome Atlas (TCGA) database and classified them into five types. We performed gene set enrichment analysis (GSEA) and survival analysis according to the different types. We found six oncogenic gene sets that were higher in lung adenocarcinoma than in normal tissues. In the survival analysis of each type, the acinar type had a favorable prognosis, and the solid subtype had an unfavorable prognosis; however, the survival differences between the other types were not significant. Our study focused on the solid type, which had the poorest prognosis. The solid type was related to adaptive immune resistance associated with elevated CD8 T cells and high CD274 (encoding PD-L1) expression. In the pathway analyses, the solid type was significantly related to high vascular endothelial growth factor (VEGF)-A expression, reflecting tumor angiogenesis. Non-necrosis/low immune response affected by high VEGF-A was associated with worse prognosis. The solid type associated with high VEGF-A expression may contribute to the development of therapeutic strategies for lung adenocarcinoma.

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Explore the Rare—Molecular Identification and Wine Evaluation of Two Autochthonous Greek Varieties: “Karnachalades” and “Bogialamades”

Plants ◽

10.3390/plants10081556 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1556

Author(s):

Dimitrios Evangelos Miliordos ◽

Georgios Merkouropoulos ◽

Charikleia Kogkou ◽

Spyridon Arseniou ◽

Anastasios Alatzas ◽

...

Keyword(s):

Molecular Data ◽

Molecular Profiling ◽

Scientific Data ◽

Financial Impact ◽

Molecular Profile ◽

Red Wines ◽

Grape Berries ◽

Quality Aspects ◽

Commercial Vineyard ◽

Of Greece

Wines produced from autochthonous Vitis vinifera varieties have an essential financial impact on the national economy of Greece. However, scientific data regarding characteristics and quality aspects of these wines is extremely limited. The aim of the current study is to define the molecular profile and to describe chemical and sensory characteristics of the wines produced by two autochthonous red grapevine varieties—“Karnachalades” and “Bogialamades”—grown in the wider area of Soufli (Thrace, Greece). We used seven microsatellites to define the molecular profile of the two varieties, and then we compared their profile to similar molecular data from other autochthonous as well as international varieties. Grape berries were harvested at optimum technological maturity from a commercial vineyard for two consecutive vintages (2017–2018) and vilification was performed using a common vinification protocol: the 2017 vintage provided wines, from both varieties, with greater rates of phenolics and anthocyanins than 2018, whereas regarding the sensory analysis, “Bogialamades” wine provided a richer profile than “Karnachalades”. To our knowledge, this is the first study that couples both molecular profiling and exploration of the enological potential of the rare Greek varieties “Karnachalades” and “Bogialamades”; they represent two promising varieties for the production of red wines in the historic region of Thrace.

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Mismatch Repair Deficiency as a Predictive and Prognostic Biomarker in Molecularly Classified Endometrial Carcinoma

Cancers ◽

10.3390/cancers13133124 ◽

2021 ◽

Vol 13 (13) ◽

pp. 3124

Author(s):

Mikko Loukovaara ◽

Annukka Pasanen ◽

Ralf Bützow

Keyword(s):

Risk Factors ◽

Mismatch Repair ◽

Molecular Classification ◽

The Cancer Genome Atlas ◽

Molecular Profile ◽

New Therapeutic Approaches ◽

Increased Risk ◽

Mmr Deficiency ◽

Endometrial Carcinomas ◽

Risk Of Cancer

The aggressiveness of mismatch repair (MMR) deficient endometrial carcinomas was examined in a single institution retrospective study. Outcomes were similar for MMR proficient (n = 508) and deficient (n = 287) carcinomas, identified by immunohistochemistry. In accordance with molecular classification based on The Cancer Genome Atlas (TCGA), tumors with abnormal p53 staining or polymerase-ϵ exonuclease domain mutation were excluded from the MMR proficient subgroup, termed as “no specific molecular profile” (NSMP). Compared with NSMP (n = 218), MMR deficiency (n = 191) was associated with poor disease-specific survival (p = 0.001). MMR deficiency was associated with an increased risk of cancer-related death when controlling for confounders (hazard ratio 2.0). In the absence of established clinicopathologic risk factors, MMR deficiency was invariably associated with an increased risk of cancer-related death in univariable analyses (hazard ratios ≥ 2.0). In contrast, outcomes for MMR deficient and NSMP subgroups did not differ when risk factors were present. Lymphatic dissemination was more common (p = 0.008) and the proportion of pelvic relapses was higher (p = 0.029) in the MMR deficient subgroup. Our findings emphasize the need for improved triage to adjuvant therapy and new therapeutic approaches in MMR deficient endometrial carcinomas.

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Treatment of digital ulcers in systemic sclerosis: Case series study of thirteen patients and discussion on outcome

Revista da Associação Médica Brasileira ◽

10.1590/1806-9282.63.05.422 ◽

2017 ◽

Vol 63 (5) ◽

pp. 422-426 ◽

Cited By ~ 3

Author(s):

Yahia Abuowda ◽

Raquel Sousa Almeida ◽

Ana Alves Oliveira ◽

Petra Pego ◽

Cristina Santos ◽

...

Keyword(s):

Systemic Sclerosis ◽

Treatment Protocol ◽

Treatment Strategies ◽

Case Series ◽

Tissue Loss ◽

Repeated Treatment ◽

Digital Ulcers ◽

Case Series Study ◽

Clinical Description ◽

Soft Tissue Loss

Summary Introduction: In systemic sclerosis (SSc), digital ulcers (DU) are debilitating and recurrent. They are markers of prognosis and are associated with disability and mortality. Treatment strategies have been developed to block the proposed mechanisms of this complication. Objective: Clinical description of a population of SSc patients with DU, treatment, complications and outcome. Method: Analysis of 48 SSc patients meeting 2013 ACR-EULAR criteria, followed between 1999-2015; 13 patients had DU. Treatment protocol applied included cycles of 21 days of alprostadil, which can be repeated in the absence of DU healing. After DU healing, bosentan was initiated. Results: DU healing was achieved with intravenous prostanoid in 12 patients; seven patients required repeated treatment for DU healing. Twelve patients were later treated with bosentan; three of them experienced recurrence of DU, while one was anti-B2-GPI positive. Four patients had soft tissue loss and three other suffered digital amputation, these being late diagnosis. Conclusion: Younger patients and early referrals had better outcomes. Endothelin receptor antagonist toxicity should be monitored, particularly in patients previously exposed to hepatotoxic drugs.

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