Research

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14 pages, 5451 KiB

Open AccessArticle

p53 Protein Isoform Profiles in AML: Correlation with Distinct Differentiation Stages and Response to Epigenetic Differentiation Therapy

by Ingvild Haaland, Sigrun M. Hjelle, Håkon Reikvam, André Sulen, Anita Ryningen, Emmet McCormack, Øystein Bruserud and Bjørn Tore Gjertsen

Cells 2021, 10(4), 833; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10040833 - 07 Apr 2021

Cited by 3 | Viewed by 2218

Abstract

p53 protein isoform expression has been found to correlate with prognosis and chemotherapy response in acute myeloid leukemia (AML). We aimed to investigate how p53 protein isoforms are modulated during epigenetic differentiation therapy in AML, and if p53 isoform expression could be a [...] Read more.

p53 protein isoform expression has been found to correlate with prognosis and chemotherapy response in acute myeloid leukemia (AML). We aimed to investigate how p53 protein isoforms are modulated during epigenetic differentiation therapy in AML, and if p53 isoform expression could be a potential biomarker for predicting a response to this treatment. p53 full-length (FL), p53β and p53γ protein isoforms were analyzed by 1D and 2D gel immunoblots in AML cell lines, primary AML cells from untreated patients and AML cells from patients before and after treatment with valproic acid (VPA), all-trans retinoic acid (ATRA) and theophylline. Furthermore, global gene expression profiling analysis was performed on samples from the clinical protocol. Correlation analyses were performed between p53 protein isoform expression and in vitro VPA sensitivity and FAB (French–American–British) class in primary AML cells. The results show downregulation of p53β/γ and upregulation of p53FL in AML cell lines treated with VPA, and in some of the patients treated with differentiation therapy. p53FL positively correlated with in vitro VPA sensitivity and the FAB class of AML, while p53β/γ isoforms negatively correlated with the same. Our results indicate that p53 protein isoforms are modulated by and may predict sensitivity to differentiation therapy in AML. Full article

(This article belongs to the Special Issue Identification of Prognostic Markers in Cancer Biology)

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19 pages, 3804 KiB

Open AccessArticle

Digital Immunophenotyping Predicts Disease Free and Overall Survival in Early Stage Melanoma Patients

by Francesco De Logu, Francesca Galli, Romina Nassini, Filippo Ugolini, Sara Simi, Mara Cossa, Clelia Miracco, Andrea Gianatti, Vincenzo De Giorgi, Eliana Rulli, Antonio Cossu, Daniela Massi and Mario Mandalà

Cells 2021, 10(2), 422; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10020422 - 17 Feb 2021

Cited by 6 | Viewed by 2430

Abstract

Background: the prognostic significance of tumor infiltrating lymphocytes (TILs) in intermediate/thick primary cutaneous melanoma (PCM) remains controversial, partially because conventional evaluation is not reliable, due to inter-observer variability and diverse scoring methods. We aimed to assess the prognostic impact of the density and [...] Read more.

Background: the prognostic significance of tumor infiltrating lymphocytes (TILs) in intermediate/thick primary cutaneous melanoma (PCM) remains controversial, partially because conventional evaluation is not reliable, due to inter-observer variability and diverse scoring methods. We aimed to assess the prognostic impact of the density and spatial distribution of immune cells in early stage intermediate/thick PCM. Materials and Methods: digital image acquisition and quantitative analysis of tissue immune biomarkers (CD3, CD4, CD8, CD68, PD-L1, CD163, FOX-P3, and PD-1) was carried out in a training cohort, which included patients with primary PCM ≥ 2 mm diagnosed, treated, and followed-up prospectively in three Italian centers. Results were validated in an independent Italian cohort. Results: in the training cohort, 100 Stage II–III melanoma patients were valuable. At multivariable analysis, a longer disease free survival (DFS) was statistically associated with higher levels of CD4⁺ intratumoral T-cells (aHR [100 cell/mm² increase] 0.98, 95%CI 0.95–1.00, p = 0.041) and CD163⁺ inner peritumoral (aHR [high vs. low] 0.56, 95%CI 0.32–0.99, p = 0.047). A statistically significant longer DFS (aHR [high-high vs. low-low] 0.52, 95%CI 0.28–0.99, p = 0.047) and overall survival (OS) (aHR [high-high vs. low-low] 0.39, 95%CI 0.18–0.85, p = 0.018) was found in patients with a high density of both intratumoral CD8⁺ T-cells and CD68⁺ macrophages as compared to those with low density of both intratumoral CD8⁺ T-cells and CD68⁺ macrophages. Consistently, in the validation cohort, patients with high density of both intratumoral CD8⁺ and CD3⁺ T-cells were associated to a statistically better DFS (aHR[high-high vs. low-low] 0.24, 95%CI 0.10–0.56, p < 0.001) and those with high density of both intratumoral CD8⁺ and CD68⁺ were associated to a statistically longer OS (aHR[high-high vs. low-low] 0.28, 95%CI 0.09–0.86, p = 0.025). Conclusion: our findings suggest that a specific preexisting profile of T cells and macrophages distribution in melanomas may predict the risk of recurrence and death with potential implications for the stratification of stage II–III melanoma patients. Full article

(This article belongs to the Special Issue Identification of Prognostic Markers in Cancer Biology)

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12 pages, 1654 KiB

Open AccessArticle

Prognostic Significance of Lymph Node Examination by the OSNA Method in Lung Cancer Patients—Comparison with the Standard Histopathological Procedure

by Josef Vodicka, Martin Pesta, Vlastimil Kulda, Katerina Houfkova, Bohuslava Vankova, Jakub Sebek, Martin Skala, Jakub Fichtl, Kristyna Prochazkova and Ondrej Topolcan

Cells 2020, 9(12), 2611; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9122611 - 04 Dec 2020

Cited by 3 | Viewed by 1847

Abstract

The aim of the study was to compare the prognostic significance of lymph node status of patients with lung cancer analyzed by three different methods: hematoxylin and eosin (H&E), immunohistochemistry of cytokeratin 19 (IHC CK19), and One-Step Nucleic Acid Amplification (OSNA). The clinical [...] Read more.

The aim of the study was to compare the prognostic significance of lymph node status of patients with lung cancer analyzed by three different methods: hematoxylin and eosin (H&E), immunohistochemistry of cytokeratin 19 (IHC CK19), and One-Step Nucleic Acid Amplification (OSNA). The clinical relevance of the results was evaluated based on relation to prognosis; the disease-free interval (DFI) and overall survival (OS) were analyzed. During radical surgical treatment, a total of 1426 lymph nodes were obtained from 100 patients, creating 472 groups of nodes (4–5 groups per patient) and examined by H&E, IHC CK19 and OSNA. The median follow-up was 44 months. Concordant results on the lymph node status of the H&E, IHC CK19 and OSNA examinations were reported in 78% of patients. We recorded shorter OS in patients with positive results provided by both OSNA and H&E. The study demonstrated a higher percentage of detected micrometastases in lymph nodes by the OSNA method. However, the higher sensitivity of the OSNA, with the cut-off value 250 copies of mRNA of CK19/µL, resulted in a lower association of OSNA positivity with progress of the disease compared to H&E. Increasing the cut-off to 615 copies resulted in an increase in concordance between the OSNA and H&E, which means that the higher cut-off is more relevant in the case of lung tumors. Full article

(This article belongs to the Special Issue Identification of Prognostic Markers in Cancer Biology)

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Review

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11 pages, 1066 KiB

Open AccessReview

Breast Cancer with Bone Metastasis: Molecular Insights and Clinical Management

by Konstantinos Venetis, Roberto Piciotti, Elham Sajjadi, Marco Invernizzi, Stefania Morganti, Carmen Criscitiello and Nicola Fusco

Cells 2021, 10(6), 1377; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10061377 - 02 Jun 2021

Cited by 36 | Viewed by 9152

Abstract

Despite the remarkable advances in the diagnosis and treatment of breast cancer patients, the presence or development of metastasis remains an incurable condition. Bone is one of the most frequent sites of distant dissemination and negatively impacts on patient’s survival and overall frailty. [...] Read more.

Despite the remarkable advances in the diagnosis and treatment of breast cancer patients, the presence or development of metastasis remains an incurable condition. Bone is one of the most frequent sites of distant dissemination and negatively impacts on patient’s survival and overall frailty. The interplay between tumor cells and the bone microenvironment induces bone destruction and tumor progression. To date, the clinical management of bone metastatic breast cancer encompasses anti-tumor systemic therapies along with bone-targeting agents, aimed at slowing bone resorption to reduce the risk of skeletal-related events. However, their effect on patients’ survival remains controversial. Unraveling the biology that governs the interplay between breast neoplastic cells and bone tissue would provide means for the development of new therapeutic agents. This article outlines the state-of-the art in the characterization and targeting the bone metastasis in breast cancer, focusing on the major clinical and translational studies on this clinically relevant topic. Full article

(This article belongs to the Special Issue Identification of Prognostic Markers in Cancer Biology)

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12 pages, 614 KiB

Open AccessReview

Artificial Intelligence & Tissue Biomarkers: Advantages, Risks and Perspectives for Pathology

by Cesare Lancellotti, Pierandrea Cancian, Victor Savevski, Soumya Rupa Reddy Kotha, Filippo Fraggetta, Paolo Graziano and Luca Di Tommaso

Cells 2021, 10(4), 787; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10040787 - 02 Apr 2021

Cited by 24 | Viewed by 4932

Abstract

Tissue Biomarkers are information written in the tissue and used in Pathology to recognize specific subsets of patients with diagnostic, prognostic or predictive purposes, thus representing the key elements of Personalized Medicine. The advent of Artificial Intelligence (AI) promises to further reinforce the [...] Read more.

Tissue Biomarkers are information written in the tissue and used in Pathology to recognize specific subsets of patients with diagnostic, prognostic or predictive purposes, thus representing the key elements of Personalized Medicine. The advent of Artificial Intelligence (AI) promises to further reinforce the role of Pathology in the scenario of Personalized Medicine: AI-based devices are expected to standardize the evaluation of tissue biomarkers and also to discover novel information, which would otherwise be ignored by human review, and use them to make specific predictions. In this review we will present how AI has been used to support Tissue Biomarkers evaluation in the specific field of Pathology, give an insight to the intriguing field of AI-based biomarkers and discuss possible advantages, risk and perspectives for Pathology. Full article

(This article belongs to the Special Issue Identification of Prognostic Markers in Cancer Biology)

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15 pages, 3942 KiB

Open AccessReview

Predictive and Prognostic Molecular Factors in Diffuse Large B-Cell Lymphomas

by Stefano A. Pileri, Claudio Tripodo, Federica Melle, Giovanna Motta, Valentina Tabanelli, Stefano Fiori, Maria Carmela Vegliante, Saveria Mazzara, Sabino Ciavarella and Enrico Derenzini

Cells 2021, 10(3), 675; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10030675 - 18 Mar 2021

Cited by 9 | Viewed by 3119

Abstract

Diffuse large B-cell lymphoma (DLBCL) is the commonest form of lymphoid malignancy, with a prevalence of about 40% worldwide. Its classification encompasses a common form, also termed as “not otherwise specified” (NOS), and a series of variants, which are rare and at least [...] Read more.

Diffuse large B-cell lymphoma (DLBCL) is the commonest form of lymphoid malignancy, with a prevalence of about 40% worldwide. Its classification encompasses a common form, also termed as “not otherwise specified” (NOS), and a series of variants, which are rare and at least in part related to viral agents. Over the last two decades, DLBCL-NOS, which accounts for more than 80% of the neoplasms included in the DLBCL chapter, has been the object of an increasing number of molecular studies which have led to the identification of prognostic/predictive factors that are increasingly entering daily practice. In this review, the main achievements obtained by gene expression profiling (with respect to both neoplastic cells and the microenvironment) and next-generation sequencing will be discussed and compared. Only the amalgamation of molecular attributes will lead to the achievement of the long-term goal of using tailored therapies and possibly chemotherapy-free protocols capable of curing most (if not all) patients with minimal or no toxic effects. Full article

(This article belongs to the Special Issue Identification of Prognostic Markers in Cancer Biology)

27 pages, 764 KiB

Open AccessReview

Immune Infiltrates in Breast Cancer: Recent Updates and Clinical Implications

by Maria Vittoria Dieci, Federica Miglietta and Valentina Guarneri

Cells 2021, 10(2), 223; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10020223 - 23 Jan 2021

Cited by 111 | Viewed by 6495

Abstract

In recent decades, the increasing interest in the field of immunotherapy has fostered an intense investigation of the breast cancer (BC) immune microenvironment. In this context, tumor-infiltrating lymphocytes (TILs) have emerged as a clinically relevant and highly reproducible biomarker capable of affecting BC [...] Read more.

In recent decades, the increasing interest in the field of immunotherapy has fostered an intense investigation of the breast cancer (BC) immune microenvironment. In this context, tumor-infiltrating lymphocytes (TILs) have emerged as a clinically relevant and highly reproducible biomarker capable of affecting BC prognosis and response to treatment. Indeed, the evaluation of TILs on primary tumors proved to be strongly prognostic in triple-negative (TN) BC patients treated with either adjuvant or neoadjuvant chemotherapy, as well as in early TNBC patients not receiving any systemic treatment, thus gaining level-1b evidence in this setting. In addition, a strong relationship between TILs and pathologic complete response after neoadjuvant chemotherapy has been reported in all BC subtypes and the prognostic role of higher TILs in early HER2-positive breast cancer patients has also been demonstrated. The interest in BC immune infiltrates has been further fueled by the introduction of the first immune checkpoint inhibitors in the treatment armamentarium of advanced TNBC in patients with PD-L1-positive status by FDA-approved assays. However, despite these advances, a biomarker capable of reliably and exhaustively predicting immunotherapy benefit in BC is still lacking, highlighting the imperative need to further deepen this issue. Finally, more comprehensive evaluation of immune infiltrates integrating both the quantity and quality of tumor-infiltrating immune cells and incorporation of TILs in composite scores encompassing other clinically or biologically relevant biomarkers, as well as the adoption of software-based and/or machine learning platforms for a more comprehensive characterization of BC immune infiltrates, are emerging as promising strategies potentially capable of optimizing patient selection and stratification in the research field. In the present review, we summarize available evidence and recent updates on immune infiltrates in BC, focusing on current clinical applications, potential clinical implications and major unresolved issues. Full article

(This article belongs to the Special Issue Identification of Prognostic Markers in Cancer Biology)

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13 pages, 1023 KiB

Open AccessReview

New Prognostic Biomarkers in Metastatic Castration-Resistant Prostate Cancer

by Vincenza Conteduca, Alessandra Mosca, Nicole Brighi, Ugo de Giorgi and Pasquale Rescigno

Cells 2021, 10(1), 193; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10010193 - 19 Jan 2021

Cited by 27 | Viewed by 7170

Abstract

Prostate cancer is one of the most frequent cancers in men and is a common cause of cancer-related death. Despite significant progress in the diagnosis and treatment of this tumor, patients who relapse after radical treatments inevitably develop metastatic disease. Patient stratification is [...] Read more.

Prostate cancer is one of the most frequent cancers in men and is a common cause of cancer-related death. Despite significant progress in the diagnosis and treatment of this tumor, patients who relapse after radical treatments inevitably develop metastatic disease. Patient stratification is therefore key in this type of cancer, and there is an urgent need for prognostic biomarkers that can define patients’ risk of cancer-related death. In the last 10 years, multiple prognostic factors have been identified and studied. Here, we review the literature available and discuss the most common aberrant genomic pathways in metastatic castration-resistant prostate cancer shown to have a prognostic relevance in this setting. Full article

(This article belongs to the Special Issue Identification of Prognostic Markers in Cancer Biology)

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20 pages, 1375 KiB

Open AccessReview

BRAF: A Two-Faced Janus

by Pasquale Pisapia, Francesco Pepe, Antonino Iaccarino, Roberta Sgariglia, Mariantonia Nacchio, Gianluca Russo, Gianluca Gragnano, Umberto Malapelle and Giancarlo Troncone

Cells 2020, 9(12), 2549; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9122549 - 27 Nov 2020

Cited by 22 | Viewed by 3177

Abstract

Gain-of-function of V-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAF) is one of the most frequent oncogenic mutations in numerous cancers, including thyroid papillary carcinoma, melanoma, colon, and lung carcinomas, and to a lesser extent, ovarian and glioblastoma multiforme. This mutation [...] Read more.

Gain-of-function of V-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAF) is one of the most frequent oncogenic mutations in numerous cancers, including thyroid papillary carcinoma, melanoma, colon, and lung carcinomas, and to a lesser extent, ovarian and glioblastoma multiforme. This mutation aberrantly activates the mitogen-activated protein (MAP) kinase extracellular signal-regulated kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway, thereby eliciting metastatic processes. The relevance of BRAF mutations stems from its prognostic value and, equally important, from its relevant therapeutic utility as an actionable target for personalized treatment. Here, we discuss the double facets of BRAF. In particular, we argue the need to implement diagnostic molecular algorithms that are able to detect this biomarker in order to streamline and refine diagnostic and therapeutic decisions. Full article

(This article belongs to the Special Issue Identification of Prognostic Markers in Cancer Biology)

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22 pages, 3926 KiB

Open AccessReview

Tumour PD-L1 Expression in Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis

by Emmanuel Acheampong, Afaf Abed, Michael Morici, Samantha Bowyer, Benhur Amanuel, Weitao Lin, Michael Millward and Elin S. Gray

Cells 2020, 9(11), 2393; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9112393 - 31 Oct 2020

Cited by 34 | Viewed by 3946

Abstract

Antibodies against programmed death-1 (PD-1), and its ligand, (PD-L1) have been approved recently for the treatment of small-cell lung cancer (SCLC). Although there are previous reports that addressed PD-L1 detection on tumour cells in SCLC, there is no comprehensive meta-analysis on the prevalence [...] Read more.

Antibodies against programmed death-1 (PD-1), and its ligand, (PD-L1) have been approved recently for the treatment of small-cell lung cancer (SCLC). Although there are previous reports that addressed PD-L1 detection on tumour cells in SCLC, there is no comprehensive meta-analysis on the prevalence of PD-L1 expression in SCLC. We performed a systematic search of the PubMed, Cochrane Library and EMBASE databases to assess reports on the prevalence of PD-L1 expression and the association between PD-L1 expression and overall survival (OS). This meta-analysis included 27 studies enrolling a total of 2792 patients. The pooled estimate of PD-L1 expression was 26.0% (95% CI 17.0–37.0), (22.0% after removing outlying studies). The effect size was significantly heterogeneous (I² = 97.4, 95% CI: 95.5–98.5, p < 0.0001).Positive PD-L1 expression was a favourable prognostic factor for SCLC but not statistically significant (HR = 0.86 (95% CI (0.49–1.50), p = 0.5880; I² = 88.7%, p < 0.0001). Begg’s funnel plots and Egger’s tests indicated no publication bias across included studies (p > 0.05). Overall, there is heterogeneity in the prevalence of PD-L1 expression in SCLC tumour cells across studies. This is significantly moderated by factors such as immunohistochemistry (IHC) evaluation cut-off values, and assessment of PD-L1 staining patterns as membranous and/or cytoplasmic. There is the need for large size, prospective and multicentre studies with well-defined protocols and endpoints to advance the clinical value of PD-L1 expression in SCLC. Full article

(This article belongs to the Special Issue Identification of Prognostic Markers in Cancer Biology)

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