Special Issue "Bio-Pathological Markers in the Diagnosis and Therapy of Cancer"

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Causes, Screening and Diagnosis".

Deadline for manuscript submissions: closed (30 June 2021).

Special Issue Editors

Dr. Giuseppe Broggi
E-Mail Website
Guest Editor
Department of Medical and Surgical Sciences and Advanced Technologies, G.F. Ingrassia, Azienda Ospedaliero-Universitaria "Policlinico Vittorio Emanuele", Anatomic Pathology, School of Medicine, University of Catania, Santa Sofia 87 street, 95123 Catania, Italy
Interests: neuropathology; surgical pathology; uveal melanoma; immunohistochemistry; dermatopathology; oncology
Special Issues, Collections and Topics in MDPI journals
Dr. Lucia Salvatorelli
E-Mail Website
Guest Editor
Department of Medical and Surgical Sciences and Advanced Technologies, G.F. Ingrassia, Anatomic Patology, University of Catania, Policlinico Universitario, G. Rodolico, Catania, Italy
Interests: neuropathology; surgical pathology; uveal melanoma; immunohistochemistry; dermatopathology; oncology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The search for biological factors that may have a prognostic value or act as predictors of therapeutic response still represents one of the hottest fields in human cancer research. Nevertheless, new immunohistochemical or molecular markers that can improve diagnostic accuracy in clinical practice and make it more reproducible are constantly being studied.

This Special Issue is devoted to the study of new diagnostic tools and prognostic/predictive factors in human neoplasms. Manuscripts in which this topic is approached by immunohistochemistry (IHC) as a first step are particularly welcome, but, being aware of the strengths and limits of IHC, the use of other methods (Western blot, FISH, next-generation sequencing) is also encouraged.

Authors should demonstrate the impact of their findings in their works in combination with the morphological evaluation of histologic samples.

Clinicopathological studies, in vitro and in vivo studies with cell culture and animals, and manuscripts in which immunohistochemical findings are supported by molecular ones are particularly welcome. A limited number of relevant case reports will also be considered for publication.

Dr. Giuseppe Broggi
Dr. Lucia Salvatorelli
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2200 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • prognostic and predictive factors
  • cancer
  • immunohistochemistry
  • molecular biology
  • cellular markers
  • diagnosis
  • immunomarkers

Published Papers (22 papers)

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Editorial

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Editorial
Bio-Pathological Markers in the Diagnosis and Therapy of Cancer
Cancers 2020, 12(11), 3113; https://doi.org/10.3390/cancers12113113 - 25 Oct 2020
Cited by 4 | Viewed by 530
Abstract
The two medical sciences that mostly deal with the diagnostic approach to human neoplasms in clinical practice are undoubtedly radiology and pathology [...] Full article
(This article belongs to the Special Issue Bio-Pathological Markers in the Diagnosis and Therapy of Cancer)

Research

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Article
Predictors of Invasive Adenocarcinomas among Pure Ground-Glass Nodules Less Than 2 cm in Diameter
Cancers 2021, 13(16), 3945; https://doi.org/10.3390/cancers13163945 - 05 Aug 2021
Viewed by 852
Abstract
Benign lesions, atypical adenomatous hyperplasia (AAH), and malignancies such as adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (IA) may feature a pure ground-glass nodule (pGGN) on a thin-slide computed tomography (CT) image. According to the World Health Organization (WHO) [...] Read more.
Benign lesions, atypical adenomatous hyperplasia (AAH), and malignancies such as adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (IA) may feature a pure ground-glass nodule (pGGN) on a thin-slide computed tomography (CT) image. According to the World Health Organization (WHO) classification for lung cancer, the prognosis of patients with IA is worse than those with AIS and MIA. It is relatively risky to perform a core needle biopsy of a pGGN less than 2 cm to obtain a reliable pathological diagnosis. The early and adequate management of patients with IA may provide a favorable prognosis. This study aimed to disclose suggestive signs of CT to accurately predict IA among the pGGNs. A total of 181 pGGNs of less than 2 cm, in 171 patients who had preoperative CT-guided localization for surgical excision of a lung nodule between December 2013 and August 2019, were enrolled. All had CT images of 0.625 mm slice thickness during CT-guided intervention to confirm that the nodules were purely ground glass. The clinical data, CT images, and pathological reports of those 171 patients were reviewed. The CT findings of pGGNs including the location, the maximal diameter in the long axis (size-L), the maximal short axis diameter perpendicular to the size-L (size-S), and the mean value of long and short axis diameters (size-M), internal content, shape, interface, margin, lobulation, spiculation, air cavity, vessel relationship, and pleural retraction were recorded and analyzed. The final pathological diagnoses of the 181 pGGNs comprised 29 benign nodules, 14 AAHs, 25 AISs, 55 MIAs, and 58 IAs. Statistical analysis showed that there were significant differences among the aforementioned five groups with respect to size-L, size-S, and size-M (p = 0.029, 0.043, 0.025, respectively). In the univariate analysis, there were significant differences between the invasive adenocarcinomas and the non-invasive adenocarcinomas with respect to the size-L, size-S, size-M, lobulation, and air cavity (p = 0.009, 0.016, 0.008, 0.031, 0.004, respectively) between the invasive adenocarcinomas and the non-invasive adenocarcinomas. The receiver operating characteristic (ROC) curve of size for discriminating invasive adenocarcinoma also revealed similar area under curve (AUC) values among size-L (0.620), size-S (0.614), and size-M (0.623). The cut-off value of 7 mm in size-M had a sensitivity of 50.0% and a specificity of 76.4% for detecting IAs. In the multivariate analysis, the presence of air cavity was a significant predictor of IA (p = 0.042). In conclusion, the possibility of IA is higher in a pGGN when it is associated with a larger size, lobulation, and air cavity. The air cavity is the significant predictor of IA. Full article
(This article belongs to the Special Issue Bio-Pathological Markers in the Diagnosis and Therapy of Cancer)
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Article
Diffuse PRAME Expression Is Highly Specific for Thin Melanomas in the Distinction from Severely Dysplastic Nevi but Does Not Distinguish Metastasizing from Non-Metastasizing Thin Melanomas
Cancers 2021, 13(15), 3864; https://doi.org/10.3390/cancers13153864 - 31 Jul 2021
Cited by 2 | Viewed by 627
Abstract
Background: PReferentially expressed Antigen in MElanoma (PRAME) immunohistochemistry is increasingly used as diagnostic adjunct in the evaluation of melanocytic tumors. The expression and prognostic significance of PRAME in melanomas ≤1.0 mm and its diagnostic utility in the distinction from severely dysplastic compound nevi [...] Read more.
Background: PReferentially expressed Antigen in MElanoma (PRAME) immunohistochemistry is increasingly used as diagnostic adjunct in the evaluation of melanocytic tumors. The expression and prognostic significance of PRAME in melanomas ≤1.0 mm and its diagnostic utility in the distinction from severely dysplastic compound nevi (SDN) have not been studied. Methods: We investigated and compared the immunohistochemical PRAME expression in 70 matched thin metastasizing and non-metastasizing melanomas and 45 nevi from patients with long-term follow-up (35 SDN and 10 unequivocally benign compound nevi). Results: Diffuse PRAME staining in >75% of lesional epidermal and dermal melanocytes identified 58.6% of thin melanomas but did not distinguish metastasizing from non-metastasizing melanomas (p = 0.81). A superficial atypical melanocytic proliferation of uncertain significance, in which the final diagnostic interpretation favored a SDN was the only nevus with diffuse PRAME expression (1/45). Melanomas and SDN with PRAME immunoreactivity exhibited different staining patterns. Most melanomas (67.6%) showed uniform PRAME expression in the in situ and invasive component, whereas most SDN (81.0%) showed a decreasing gradient with depth. Conclusion: Diffuse intraepidermal and dermal PRAME staining is highly specific for melanomas in the distinction from SDN. PRAME expression is not a prognostic biomarker in melanomas ≤1.0 mm. Full article
(This article belongs to the Special Issue Bio-Pathological Markers in the Diagnosis and Therapy of Cancer)
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Article
Pursuit of Gene Fusions in Daily Practice: Evidence from Real-World Data in Wild-Type and Microsatellite Instable Patients
Cancers 2021, 13(13), 3376; https://doi.org/10.3390/cancers13133376 - 05 Jul 2021
Viewed by 815
Abstract
Agnostic biomarkers such as gene fusions allow to address cancer patients to targeted therapies; however, the low prevalence of these alterations across common malignancies poses challenges and needs a feasible and sensitive diagnostic process. RNA-based targeted next generation sequencing was performed on 125 [...] Read more.
Agnostic biomarkers such as gene fusions allow to address cancer patients to targeted therapies; however, the low prevalence of these alterations across common malignancies poses challenges and needs a feasible and sensitive diagnostic process. RNA-based targeted next generation sequencing was performed on 125 samples of patients affected either by colorectal carcinoma, melanoma, or lung adenocarcinoma lacking genetic alterations in canonical driver genes, or by a colorectal carcinoma with microsatellite instability. Gene fusion rates were compared with in silico data from MSKCC datasets. For NTRK gene fusion detection we also employed a multitarget qRT-PCR and pan-TRK immunohistochemistry. Gene fusions were detected in 7/55 microsatellite instable colorectal carcinomas (12.73%), and in 4/70 of the “gene driver free” population (5.71%: 3/28 melanomas, 10.7%, and 1/12 lung adenocarcinomas, 8.3%). Fusion rates were significantly higher compared with the microsatellite stable and “gene driver positive” MSKCC cohorts. Pan-TRK immunohistochemistry showed 100% sensitivity, 91.7% specificity, and the occurrence of heterogeneous and/or subtle staining patterns. The enrichment of gene fusions in this “real-world” cohort highlights the feasibility of a workflow applicable in clinical practice. The heterogeneous expression in NTRK fusion positive tumours unveils challenging patterns to recognize and raises questions on the effective translation of the chimeric protein. Full article
(This article belongs to the Special Issue Bio-Pathological Markers in the Diagnosis and Therapy of Cancer)
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Article
Evaluation of Integrated HPV DNA as Individualized Biomarkers for the Detection of Recurrent CIN2/3 during Post-Treatment Surveillance
Cancers 2021, 13(13), 3309; https://doi.org/10.3390/cancers13133309 - 01 Jul 2021
Viewed by 506
Abstract
Purpose: Post-treatment follow-up in women with cervical pre-cancers (CIN3) is mandatory due to relapse in up to 10% of patients. Standard follow-up based on hrHPV-DNA/cytology co-testing has high sensitivity but limited specificity. The aim of our prospective, multicenter, observational study was to test [...] Read more.
Purpose: Post-treatment follow-up in women with cervical pre-cancers (CIN3) is mandatory due to relapse in up to 10% of patients. Standard follow-up based on hrHPV-DNA/cytology co-testing has high sensitivity but limited specificity. The aim of our prospective, multicenter, observational study was to test the hypothesis that an individualized viral-cellular-junction test (vcj-PCR) combined with cytology has a lower false positive rate for the prediction of recurrence compared to standard co-testing. Methods: Pre-surgical cervical swabs served for the identification of HPV16/18 DNA integration sites by next-generation-sequencing (NGS). Samples taken at 6, 12 and 24 months post-surgery were evaluated by cytology, hrHPV-DNA and the patients’ individual HPV-integration sites (vcj-PCR on the basis of NGS). Results: Integration sites were detected in 48 of 445 patients (10.8%), 39 of them had valid follow-up data. The false positive rate was 18.2% (95% CI 8.6–34.4%) for standard hrHPV/cytology at six months compared to 12.1% (95% CI 4.8–27.3%) for vcj-PCR/cytology, respectively (McNemar p = 0.50). Six patients developed recurrences (1 CIN2, 5 CIN3) during follow-up. Standard co-testing detected all, whereas vcj-PCR/cytology detected only five patients with recurrences. Data of 269 patients without evidence of HPV16/18 integration were subject to post-hoc analyses. Standard co-testing revealed a false positive rate of 15.7% (95% CI 11.7–20.7%) and predicted ten of fourteen recurrences at six months. Conclusions: Although highly specific on its own vcj-PCR could not detect all recurrent CIN2/3. Possible reasons for this unexpected result may be multifocal lesions, intratumoral heterogeneity with respect to HPV integration and/or incident CIN. Full article
(This article belongs to the Special Issue Bio-Pathological Markers in the Diagnosis and Therapy of Cancer)
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Article
Nectin-1 Expression Correlates with the Susceptibility of Malignant Melanoma to Oncolytic Herpes Simplex Virus In Vitro and In Vivo
Cancers 2021, 13(12), 3058; https://doi.org/10.3390/cancers13123058 - 19 Jun 2021
Viewed by 673
Abstract
Talimogene laherparepvec (T-VEC), an oncolytic herpes simplex virus, is approved for intralesional injection of unresectable stage IIIB/IVM1a melanoma. However, it is still unclear which parameter(s) predict treatment response or failure. Our study aimed at characterizing surface receptors Nectin-1 and the herpes virus entry [...] Read more.
Talimogene laherparepvec (T-VEC), an oncolytic herpes simplex virus, is approved for intralesional injection of unresectable stage IIIB/IVM1a melanoma. However, it is still unclear which parameter(s) predict treatment response or failure. Our study aimed at characterizing surface receptors Nectin-1 and the herpes virus entry mediator (HVEM) in addition to intracellular molecules cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) as potential bio-markers for oncolytic virus treatment. In 20 melanoma cell lines, oncolytic activity of T-VEC was correlated with the expression of Nectin-1 but not HVEM, as evaluated via flow cytometry and immunohistochemistry. Knockout using CRISPR/Cas9 technology confirmed the superior role of Nectin-1 over HVEM for entry and oncolytic activity of T-VEC. Neither cGAS nor STING as evaluated by Western Blot and immunohistochemistry correlated with T-VEC induced oncolysis. The role of these biomarkers was retrospectively analyzed for the response of 35 cutaneous melanoma metastases of 21 patients to intralesional T-VEC injection, with 21 (60.0%) of these lesions responding with complete (n = 16) or partial regression (n = 5). Nectin-1 expression in pretreatment biopsies significantly predicted treatment outcome, while the expression of HVEM, cGAS, and STING was not prognostic. Altogether, Nectin-1 served as biomarker for T-VEC-induced melanoma regression in vitro and in vivo. Full article
(This article belongs to the Special Issue Bio-Pathological Markers in the Diagnosis and Therapy of Cancer)
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Article
Local Immune Changes in Early Stages of Inflammation and Carcinogenesis Correlate with the Collagen Scaffold Changes of the Colon Mucosa
Cancers 2021, 13(10), 2463; https://doi.org/10.3390/cancers13102463 - 18 May 2021
Viewed by 678
Abstract
Continuous activation of the immune system inside a tissue can lead to remodelling of the tissue structure and creation of a specific microenvironment, such as during the tumour development. Chronic inflammation is a central player in stimulating changes that alter the tissue stroma [...] Read more.
Continuous activation of the immune system inside a tissue can lead to remodelling of the tissue structure and creation of a specific microenvironment, such as during the tumour development. Chronic inflammation is a central player in stimulating changes that alter the tissue stroma and can lead to fibrotic evolution. In the colon mucosa, regulatory mechanisms, including TGF-β1, avoid damaging inflammation in front of the continuous challenge by the intestinal microbiome. Inducing either DSS colitis or AOM colorectal carcinogenesis in AVN-Wistar rats, we evaluated at one month after the end of each treatment whether immunological changes and remodelling of the collagen scaffold were already in development. At this time point, we found in both models a general downregulation of pro-inflammatory cytokines and even of TGF-β1, but not of IL-6. Moreover, we demonstrated by multi-photon microscopy the simultaneously presence of pro-fibrotic remodelling of the collagen scaffold, with measurable changes in comparison to the control mucosa. The scaffold was significantly modified depending on the type of induced stimulation. These results suggest that at one month after the end of the DSS or AOM inductions, a smouldering inflammation is present in both induced conditions, since the pro-inflammatory cytokines still exceed, in proportion, the local homeostatic regulation of which TGF-β1 is a part (inflammatory threshold). Such an inflammation appears sufficient to sustain remodelling of the collagen scaffold that may be taken as a possible pathological marker for revealing pre-neoplastic inflammation. Full article
(This article belongs to the Special Issue Bio-Pathological Markers in the Diagnosis and Therapy of Cancer)
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Article
Diagnostic Utility of the Immunohistochemical Expression of Serine and Arginine Rich Splicing Factor 1 (SRSF1) in the Differential Diagnosis of Adult Gliomas
Cancers 2021, 13(9), 2086; https://doi.org/10.3390/cancers13092086 - 26 Apr 2021
Cited by 7 | Viewed by 670
Abstract
Background: The aim of this study was to investigate the immunohistochemical expression and distribution of serine and arginine rich splicing factor 1 (SRSF1) in a series of 102 cases of both diffuse and circumscribed adult gliomas to establish the potential diagnostic role of [...] Read more.
Background: The aim of this study was to investigate the immunohistochemical expression and distribution of serine and arginine rich splicing factor 1 (SRSF1) in a series of 102 cases of both diffuse and circumscribed adult gliomas to establish the potential diagnostic role of this protein in the differential diagnosis of brain tumors. Methods: This retrospective immunohistochemical study included 42 glioblastoma cases, 21 oligodendrogliomas, 15 ependymomas, 15 pilocytic astrocytomas, 5 sub-ependymal giant cell astrocytoma and 4 pleomorphic xanthoastrocytomas. Results: Most glioblastoma (81%), oligodendroglioma (71%), sub-ependymal giant cell astrocytoma (80%) and pleomorphic xanthoastrocytoma (75%) cases showed strong SRSF1 immunoexpression, while no detectable staining was found in the majority of ependymomas (87% of cases) and pilocytic astrocytomas (67% of cases). Conclusions: The immunohistochemical expression of SRSF1 may be a promising diagnostic marker of astrocytomas and oligodendrogliomas and its increased expression might allow for excluding entities that often enter into differential diagnosis, such as ependymomas and pilocytic astrocytomas. Full article
(This article belongs to the Special Issue Bio-Pathological Markers in the Diagnosis and Therapy of Cancer)
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Article
Evaluation of Fast Molecular Detection of Lymph Node Metastases in Prostate Cancer Patients Using One-Step Nucleic Acid Amplification (OSNA)
Cancers 2021, 13(5), 1117; https://doi.org/10.3390/cancers13051117 - 05 Mar 2021
Cited by 2 | Viewed by 1063
Abstract
Background: In clinical routine, only fractions of lymph nodes (LNs) are examined histopathologically, often resulting in missed (micro-)metastases and incorrect staging of prostate cancer (PCa). One-step nucleic acid amplification (OSNA) analyzes the entire LN by detecting cytokeratin 19 (CK19) mRNA as a [...] Read more.
Background: In clinical routine, only fractions of lymph nodes (LNs) are examined histopathologically, often resulting in missed (micro-)metastases and incorrect staging of prostate cancer (PCa). One-step nucleic acid amplification (OSNA) analyzes the entire LN by detecting cytokeratin 19 (CK19) mRNA as a surrogate for LN metastases requiring less effort than conventional biomolecular techniques. We aimed to evaluate performance of OSNA in detecting sentinel LN (SLN) metastases in PCa. Methods: SLNs (n = 534) of 64 intermediate- or high-risk PCa patients undergoing radical prostatectomy with extended and sentinel-guided lymphadenectomy were cut into slices and alternatingly assigned to OSNA and histopathology (hematoxylin-eosin staining, CK19, and CK AE1/AE3 immunohistochemistry). Sensitivity and specificity of OSNA and concordance and measure of agreement (Cohen’s kappa (κ)) between OSNA and histopathology were assessed. Results: Histopathology revealed metastases in 76 SLNs. Sensitivity and specificity of OSNA were 84.2% and 96.1%, respectively. Discordant results were recorded for 30 of 534 SLNs, revealing high concordance (94.4%). Twenty-four discordant cases were classified as micrometastases, indicating a possible allocation bias. In 18 cases, positive results were conferred only by OSNA resulting in seven LN-positive patients who were missed by histopathology. Overall, the level of agreement was high (κ = 0.78). Conclusions: OSNA provided a diagnosis that was as least as accurate as detailed histological examination and might improve LN staging in PCa. Full article
(This article belongs to the Special Issue Bio-Pathological Markers in the Diagnosis and Therapy of Cancer)
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Article
Wilms’ Tumor 1 (WT1): A Novel Immunomarker of Dermatofibrosarcoma Protuberans—An Immunohistochemical Study on a Series of 114 Cases of Bland-Looking Mesenchymal Spindle Cell Lesions of the Dermis/Subcutaneous Tissues
Cancers 2021, 13(2), 252; https://doi.org/10.3390/cancers13020252 - 12 Jan 2021
Cited by 2 | Viewed by 712
Abstract
Purpose: to investigate the immunohistochemical expression and distribution of Wilms’ tumor 1 (WT1) (transcription factor produced by the tumor suppressor gene of the same name) in a series of 114 cases of bland-looking mesenchymal spindle cell lesions of the dermis/subcutaneous tissues to establish [...] Read more.
Purpose: to investigate the immunohistochemical expression and distribution of Wilms’ tumor 1 (WT1) (transcription factor produced by the tumor suppressor gene of the same name) in a series of 114 cases of bland-looking mesenchymal spindle cell lesions of the dermis/subcutaneous tissues to establish whether this immunomarker is differentially expressed in dermatofibrosarcoma protuberans (DFSP) versus its potential morphological mimickers. Methods: This retrospective multi-centric immunohistochemical study included 57 DFSP cases, 15 dermatofibromas, 5 deep fibrous histiocytomas, 8 neurofibromas, 5 spindle cell lipomas, 8 dermal scars, 6 nodular fasciitis, 5 cutaneous leiomyomas and 5 solitary fibrous tumors. Among the 57 DFSP cases, 11 were recurrent lesions; 2 non-recurrent cases exhibited an additional “fibrosarcomatous” overgrowth and 1 recurrent and 2 primary tumors contained a minority of “giant cell fibroblastoma” components. Results: Most DFSP (95% of cases) exhibited cytoplasmic staining for WT1; 11/11 residual/recurrent tumors showed diffuse and strong WT1 cytoplasmic immunoreactivity; apart from neurofibromas, WT1 expression was lacking in all the other cases studied. Conclusions: The cytoplasmic expression of WT1 may be exploitable as a complementary diagnostic immunomarker to CD34 in confirming the diagnosis of DFSP and to better evaluate the residual/recurrent tumor component. Full article
(This article belongs to the Special Issue Bio-Pathological Markers in the Diagnosis and Therapy of Cancer)
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Article
Loss of Tid1/DNAJA3 Co-Chaperone Promotes Progression and Recurrence of Hepatocellular Carcinoma after Surgical Resection: A Novel Model to Stratify Risk of Recurrence
Cancers 2021, 13(1), 138; https://doi.org/10.3390/cancers13010138 - 04 Jan 2021
Cited by 1 | Viewed by 1106
Abstract
Tid1, a mitochondrial co-chaperone protein, acts as a tumor suppressor in various cancer types. However, the role of Tid1 in hepatocellular carcinoma (HCC) remains unclear. First, we found that a low endogenous Tid1 protein level was observed in poorly differentiated HCC cell lines. [...] Read more.
Tid1, a mitochondrial co-chaperone protein, acts as a tumor suppressor in various cancer types. However, the role of Tid1 in hepatocellular carcinoma (HCC) remains unclear. First, we found that a low endogenous Tid1 protein level was observed in poorly differentiated HCC cell lines. Further, upregulation/downregulation of Tid1 abrogated/promoted the malignancy of human HCC cell lines, respectively. Interestingly, Tid1 negatively modulated the protein level of Nrf2. Tissue assays from 210 surgically resected HCC patients were examined by immunohistochemistry (IHC) analyses. The protein levels of Tid1 in the normal and tumor part of liver tissues were correlated with the clinical outcome of the 210 HCC cases. In multivariate analysis, we discovered that tumor size > 5 cm, multiple tumors, presence of vascular invasion, low Tid1 expression in the non-tumor part, and high Nrf2 expression in the non-tumor part were significant factors associated with worse recurrence-free survival (RFS). A scoring system by integrating the five clinical and pathological factors predicts the RFS among HCC patients after surgical resection. Together, Tid1, serving as a tumor suppressor, has a prognostic role for surgically resected HCC to predict RFS. Full article
(This article belongs to the Special Issue Bio-Pathological Markers in the Diagnosis and Therapy of Cancer)
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Article
Restricted Water Diffusion in Diffusion-Weighted Magnetic Resonance Imaging in Pancreatic Cancer is Associated with Tumor Hypoxia
Cancers 2021, 13(1), 89; https://doi.org/10.3390/cancers13010089 - 30 Dec 2020
Cited by 3 | Viewed by 909
Abstract
Hypoxia is a hallmark of pancreatic cancer (PDAC) due to its compact and extensive fibrotic tumor stroma. Hypoxia contributes to high lethality of this disease, by inducing a more malignant phenotype and resistance to radiation and chemotherapy. Thus, non-invasive methods to quantify hypoxia [...] Read more.
Hypoxia is a hallmark of pancreatic cancer (PDAC) due to its compact and extensive fibrotic tumor stroma. Hypoxia contributes to high lethality of this disease, by inducing a more malignant phenotype and resistance to radiation and chemotherapy. Thus, non-invasive methods to quantify hypoxia could be helpful for treatment decisions, for monitoring, especially in non-resectable tumors, or to optimize personalized therapy. In the present study, we investigated whether tumor hypoxia in PDAC is reflected by diffusion-weighted magnetic resonance imaging (DW-MRI), a functional imaging technique, frequently used in clinical practice for identification and characterization of pancreatic lesions. DW-MRI assesses the tissue microarchitecture by measuring the diffusion of water molecules, which is more restricted in highly compact tissues. As reliable surrogate markers for hypoxia, we determined Blimp-1 (B-lymphocyte induced maturation protein), a transcription factor, as well as vascular endothelial growth factor (VEGF), which are up-regulated in response to hypoxia. In 42 PDAC patients, we observed a close association between restricted water diffusion in DW-MRI and tumor hypoxia in matched samples, as expressed by high levels of Blimp-1 and VEGF in tissue samples of the respective patients. In summary, our data show that DW-MRI is well suited for the evaluation of tumor hypoxia in PDAC and could potentially be used for the identification of lesions with a high hypoxic fraction, which are at high risk for failure of radiochemotherapy. Full article
(This article belongs to the Special Issue Bio-Pathological Markers in the Diagnosis and Therapy of Cancer)
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Article
Radiosensitivity of Cancer Stem Cells Has Potential Predictive Value for Individual Responses to Radiotherapy in Locally Advanced Rectal Cancer
Cancers 2020, 12(12), 3672; https://doi.org/10.3390/cancers12123672 - 07 Dec 2020
Cited by 2 | Viewed by 820
Abstract
Neo-adjuvant radiotherapy is frequently employed in the therapeutic management of locally advanced rectal cancer (LARC). Radiotherapy can both reduce local recurrence and improve the success of surgical procedures by reducing tumor mass size. However, some patients show a poor response to treatment, which [...] Read more.
Neo-adjuvant radiotherapy is frequently employed in the therapeutic management of locally advanced rectal cancer (LARC). Radiotherapy can both reduce local recurrence and improve the success of surgical procedures by reducing tumor mass size. However, some patients show a poor response to treatment, which results in primary resistance or relapse after apparent curative surgery. In this work, we report in vitro and in vivo models based on patient-derived cancer stem cells (CSCs); these models are able to predict individual responses to radiotherapy in LARC. CSCs isolated from colorectal cancer biopsies were subjected to in vitro irradiation with the same clinical protocol used for LARC patients. Animal models, generated by CSC xenotransplantation, were also obtained and treated with the same radiotherapy protocol. The results indicate that CSCs isolated from rectal cancer needle biopsies possess an intrinsic grade of sensitivity to treatment, which is also maintained in the animal model. Notably, the specific CSCs’ in vitro and in vivo sensitivity values correspond to patients’ responses to radiotherapy. This evidence suggests that an in vitro radiotherapy response predictivity assay could support clinical decisions for the management of LARC patients, thus avoiding radiation toxicity to resistant patients and reducing the treatment costs. Full article
(This article belongs to the Special Issue Bio-Pathological Markers in the Diagnosis and Therapy of Cancer)
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Review

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Review
Immune-Checkpoint Inhibition in the Treatment of Gastro-Esophageal Cancer: A Closer Look at the Emerging Evidence
Cancers 2021, 13(23), 5929; https://doi.org/10.3390/cancers13235929 - 25 Nov 2021
Viewed by 386
Abstract
To date, several trials have evaluated the safety and efficacy of immune-checkpoint inhibitors (ICI) for the treatment of gastroesophageal cancers (GEC). In the US, ICIs have established indications for second-line treatment of microsatellite unstable tumors, while their use in third-line settings was recently [...] Read more.
To date, several trials have evaluated the safety and efficacy of immune-checkpoint inhibitors (ICI) for the treatment of gastroesophageal cancers (GEC). In the US, ICIs have established indications for second-line treatment of microsatellite unstable tumors, while their use in third-line settings was recently withdrawn. Notably, the use of ICIs for first-line therapy of GEC is rapidly evolving, which currently includes high PD-L1 expressing tumors, irrespective of HER2 status, and in the adjuvant setting after neoadjuvant chemoradiotherapy in select patients. In this article, we review the results of studies that have evaluated the utility of ICI in the third-line, second-line, first-line, and peri-operative treatment settings of GECs. Considerations should be made before making any cross-trial comparisons since these trials vary in chemotherapy backbone, anatomical and histological eligibility, biomarker assessment, PD-L1 diagnostic antibodies, and definition of PD-L1 positivity. Regardless, the totality of the data suggest that first-line ICI use may most benefit GEC patients with high PD-L1 combined positivity score (CPS) ≥5 or ≥10, irrespective of histology or anatomy. Moreover, although PD-L1 by CPS has a good negative predictive value for significant benefit from ICIs, it has a low positive predictive value. Therefore, there is a pressing need to identify better biomarkers to predict benefit from ICIs among these patients. Full article
(This article belongs to the Special Issue Bio-Pathological Markers in the Diagnosis and Therapy of Cancer)
Review
Role of Cardiac Biomarkers in Cancer Patients
Cancers 2021, 13(21), 5426; https://doi.org/10.3390/cancers13215426 - 29 Oct 2021
Viewed by 471
Abstract
In patients with cancer—and especially some specific subtypes—the heart can be pathologically affected due to the direct action of the tumor or its secretion products or due to the toxicity of some oncological treatments. Cardiac biomarkers have been investigated as inexpensive and easily [...] Read more.
In patients with cancer—and especially some specific subtypes—the heart can be pathologically affected due to the direct action of the tumor or its secretion products or due to the toxicity of some oncological treatments. Cardiac biomarkers have been investigated as inexpensive and easily accessible tools for prediction, early diagnosis, monitoring, or prognosis of various forms of cancer-related cardiac diseases. However, their clinical usefulness was not always clearly demonstrated in every area of cardioncology. For the identification of anthracycline related cardiotoxicity in the very early stages troponins proved to be more efficient detectors than imaging methods. Nevertheless, the lack of a standardized dosage methodology and of cardiotoxicity specific thresholds, do not yet allow to outline the precise way to employ them in clinical routine and to incorporate them into appropriate diagnostic or managing algorithms. Cardiac biomarkers proved also effective in patients with primary cardiac amyloidosis, in which both troponins and natriuretic peptides were able to predict adverse outcome, and carcinoid heart disease, where a precise diagnostic cut-off for N-terminal prohormone of brain natriuretic peptide (NT-proBNP) was identified to screen patients with valvular involvement. Likewise, NT-proBNP proved to be an excellent predictor of postoperative atrial fibrillation (POAF). On the contrary, evidence is still not sufficient to promote the routine use of cardiac biomarkers to early diagnose myocarditis due to immune check points inhibitors (ICIs), radiotherapy induced cardiotoxicity and cardiac complications related to androgenetic deprivation. In this review we present all the evidence gathered so far regarding the usefulness and limitations of these relatively inexpensive diagnostic tools in the field of cardio-oncology. Full article
(This article belongs to the Special Issue Bio-Pathological Markers in the Diagnosis and Therapy of Cancer)
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Review
Soluble Biomarkers with Prognostic and Predictive Value in Advanced Non-Small Cell Lung Cancer Treated with Immunotherapy
Cancers 2021, 13(17), 4280; https://doi.org/10.3390/cancers13174280 - 25 Aug 2021
Cited by 1 | Viewed by 675
Abstract
Numerous targeted therapies have been evaluated for the treatment of non-small cell lung cancer (NSCLC). To date, however, only a few agents have shown promising results. Recent advances in cancer immunotherapy, most notably immune checkpoint inhibitors (ICI), have transformed the treatment scenario for [...] Read more.
Numerous targeted therapies have been evaluated for the treatment of non-small cell lung cancer (NSCLC). To date, however, only a few agents have shown promising results. Recent advances in cancer immunotherapy, most notably immune checkpoint inhibitors (ICI), have transformed the treatment scenario for these patients. Although some patients respond well to ICIs, many patients do not benefit from ICIs, leading to disease progression and/or immune-related adverse events. New biomarkers capable of reliably predicting response to ICIs are urgently needed to improve patient selection. Currently available biomarkers—including programmed death protein 1 (PD-1) and its ligand (PD-L1), and tumor mutational burden (TMB)—have major limitations. At present, no well-validated, reliable biomarkers are available. Ideally, these biomarkers would be obtained through less invasive methods such as plasma determination or liquid biopsy. In the present review, we describe recent advances in the development of novel soluble biomarkers (e.g., circulating immune cells, TMB, circulating tumor cells, circulating tumor DNA, soluble factor PD-L1, tumor necrosis factor, etc.) for patients with NSCLC treated with ICIs. We also describe the potential use of these biomarkers as prognostic indicators of treatment response and toxicity. Full article
(This article belongs to the Special Issue Bio-Pathological Markers in the Diagnosis and Therapy of Cancer)
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Review
Novel Prognostic Immunohistochemical Markers in Uveal Melanoma-Literature Review
Cancers 2021, 13(16), 4031; https://doi.org/10.3390/cancers13164031 - 10 Aug 2021
Cited by 1 | Viewed by 579
Abstract
Uveal melanoma is the most common primary intraocular neoplasm in adults. As there are currently no effective methods of treating the disease in the metastatic stage, there is a need to search for new prognostic factors that would enable a reliable assessment of [...] Read more.
Uveal melanoma is the most common primary intraocular neoplasm in adults. As there are currently no effective methods of treating the disease in the metastatic stage, there is a need to search for new prognostic factors that would enable a reliable assessment of the patient’s condition and constitute a possible therapeutic target. In this review, we have prepared the results of English-language studies on new prognostic factors determined with immunohistochemical methods. We found 64 articles in which the expression of various proteins was associated in a statistically significant manner with the histopathological and clinical prognostic factors identified by AJCC. The results of our work clearly show that the biology of uveal melanoma is extraordinarily complex. Numerous studies have shed new light on the complexity of the processes involved in the development of this cancer. Moreover, a careful analysis of the expression of individual proteins may allow the identification of homogeneous groups of patients requiring different treatment regimens. Full article
(This article belongs to the Special Issue Bio-Pathological Markers in the Diagnosis and Therapy of Cancer)
Review
Metabolic Rewiring and the Characterization of Oncometabolites
Cancers 2021, 13(12), 2900; https://doi.org/10.3390/cancers13122900 - 10 Jun 2021
Cited by 2 | Viewed by 1111
Abstract
The study of low-molecular-weight metabolites that exist in cells and organisms is known as metabolomics and is often conducted using mass spectrometry laboratory platforms. Definition of oncometabolites in the context of the metabolic phenotype of cancer cells has been accomplished through metabolomics. Oncometabolites [...] Read more.
The study of low-molecular-weight metabolites that exist in cells and organisms is known as metabolomics and is often conducted using mass spectrometry laboratory platforms. Definition of oncometabolites in the context of the metabolic phenotype of cancer cells has been accomplished through metabolomics. Oncometabolites result from mutations in cancer cell genes or from hypoxia-driven enzyme promiscuity. As a result, normal metabolites accumulate in cancer cells to unusually high concentrations or, alternatively, unusual metabolites are produced. The typical oncometabolites fumarate, succinate, (2R)-hydroxyglutarate and (2S)-hydroxyglutarate inhibit 2-oxoglutarate-dependent dioxygenases, such as histone demethylases and HIF prolyl-4-hydroxylases, together with DNA cytosine demethylases. As a result of the cancer cell acquiring this new metabolic phenotype, major changes in gene transcription occur and the modification of the epigenetic landscape of the cell promotes proliferation and progression of cancers. Stabilization of HIF1α through inhibition of HIF prolyl-4-hydroxylases by oncometabolites such as fumarate and succinate leads to a pseudohypoxic state that promotes inflammation, angiogenesis and metastasis. Metabolomics has additionally been employed to define the metabolic phenotype of cancer cells and patient biofluids in the search for cancer biomarkers. These efforts have led to the uncovering of the putative oncometabolites sarcosine, glycine, lactate, kynurenine, methylglyoxal, hypotaurine and (2R,3S)-dihydroxybutanoate, for which further research is required. Full article
(This article belongs to the Special Issue Bio-Pathological Markers in the Diagnosis and Therapy of Cancer)
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Review
From Biomarkers to Models in the Changing Landscape of Chronic Lymphocytic Leukemia: Evolve or Become Extinct
Cancers 2021, 13(8), 1782; https://doi.org/10.3390/cancers13081782 - 08 Apr 2021
Viewed by 722
Abstract
Chronic lymphocytic leukemia (CLL) is an extremely heterogeneous disease. With the advent of oral targeted agents (Tas) the treatment of CLL has undergone a revolution, which has been accompanied by an improvement in patient’s survival and quality of life. This paradigm shift also [...] Read more.
Chronic lymphocytic leukemia (CLL) is an extremely heterogeneous disease. With the advent of oral targeted agents (Tas) the treatment of CLL has undergone a revolution, which has been accompanied by an improvement in patient’s survival and quality of life. This paradigm shift also affects the value of prognostic and predictive biomarkers and prognostic models, most of them inherited from the chemoimmunotherapy era but with a different behavior with Tas. This review discusses: (i) the role of the most relevant prognostic and predictive biomarkers in the setting of Tas; and (ii) the validity of classic and new scoring systems in the context of Tas. In addition, a critical point of view about predictive biomarkers with special emphasis on 11q deletion, novel resistance mutations, TP53 abnormalities, IGHV mutational status, complex karyotype and NOTCH1 mutations is stated. We also go over prognostic models in early stage CLL such as IPS-E. Finally, we provide an overview of the applicability of the CLL-IPI for patients treated with Tas, as well as the emergence of new models, generated with data from patients treated with Tas. Full article
(This article belongs to the Special Issue Bio-Pathological Markers in the Diagnosis and Therapy of Cancer)
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Review
The Role of Hypoxia and SRC Tyrosine Kinase in Glioblastoma Invasiveness and Radioresistance
Cancers 2020, 12(10), 2860; https://doi.org/10.3390/cancers12102860 - 04 Oct 2020
Cited by 17 | Viewed by 957
Abstract
Advances in functional imaging are supporting neurosurgery and radiotherapy for glioblastoma, which still remains the most aggressive brain tumor with poor prognosis. The typical infiltration pattern of glioblastoma, which impedes a complete surgical resection, is coupled with a high rate of invasiveness and [...] Read more.
Advances in functional imaging are supporting neurosurgery and radiotherapy for glioblastoma, which still remains the most aggressive brain tumor with poor prognosis. The typical infiltration pattern of glioblastoma, which impedes a complete surgical resection, is coupled with a high rate of invasiveness and radioresistance, thus further limiting efficient therapy, leading to inevitable and fatal recurrences. Hypoxia is of crucial importance in gliomagenesis and, besides reducing radiotherapy efficacy, also induces cellular and molecular mediators that foster proliferation and invasion. In this review, we aimed at analyzing the biological mechanism of glioblastoma invasiveness and radioresistance in hypoxic niches of glioblastoma. We also discussed the link between hypoxia and radiation-induced radioresistance with activation of SRC proto-oncogene non-receptor tyrosine kinase, prospecting potential strategies to overcome the current limitation in glioblastoma treatment. Full article
(This article belongs to the Special Issue Bio-Pathological Markers in the Diagnosis and Therapy of Cancer)
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Other

Systematic Review
Performance of Narrow Band Imaging (NBI) and Photodynamic Diagnosis (PDD) Fluorescence Imaging Compared to White Light Cystoscopy (WLC) in Detecting Non-Muscle Invasive Bladder Cancer: A Systematic Review and Lesion-Level Diagnostic Meta-Analysis
Cancers 2021, 13(17), 4378; https://doi.org/10.3390/cancers13174378 - 30 Aug 2021
Viewed by 1076
Abstract
Despite early detection and regular surveillance of non-muscle invasive bladder cancer (NMIBC), recurrence and progression rates remain exceedingly high for this highly prevalent malignancy. Limited visualization of malignant lesions with standard cystoscopy and associated false-negative biopsy rates have been the driving force for [...] Read more.
Despite early detection and regular surveillance of non-muscle invasive bladder cancer (NMIBC), recurrence and progression rates remain exceedingly high for this highly prevalent malignancy. Limited visualization of malignant lesions with standard cystoscopy and associated false-negative biopsy rates have been the driving force for investigating alternative and adjunctive technologies for improved cystoscopy. The aim of our systematic review and meta-analysis was to compare the sensitivity, specificity, and oncologic outcomes of photodynamic diagnosis (PDD) fluorescence, narrow band imaging (NBI), and conventional white light cystoscopy (WLC) in detecting NMIBC. Out of 1,087 studies reviewed, 17 prospective non-randomized and randomized controlled trials met inclusion criteria for the study. We demonstrated that tumor resection with either PDD and NBI exhibited lower recurrence rates and greater diagnostic sensitivity compared to WLC alone. NBI demonstrated superior disease sensitivity and specificity as compared to WLC and an overall greater hierarchical summary receiver operative characteristic. Our findings are consistent with emerging guidelines and underscore the value of integrating these enhanced technologies as a part of the standard care for patients with suspected or confirmed NMIBC. Full article
(This article belongs to the Special Issue Bio-Pathological Markers in the Diagnosis and Therapy of Cancer)
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Study Protocol
Bone Pain in Multiple Myeloma (BPMM)—A Protocol for a Prospective, Longitudinal, Observational Study
Cancers 2021, 13(7), 1596; https://doi.org/10.3390/cancers13071596 - 30 Mar 2021
Cited by 1 | Viewed by 576
Abstract
Multiple myeloma (MM) is a bone marrow neoplasia that causes bone pain in 70% patients. While preclinical models of MM have suggested that both nerve sprouting and nerve injury may be causative for the pain, there is a lack of clinical data. Thus, [...] Read more.
Multiple myeloma (MM) is a bone marrow neoplasia that causes bone pain in 70% patients. While preclinical models of MM have suggested that both nerve sprouting and nerve injury may be causative for the pain, there is a lack of clinical data. Thus, the primary aims of this clinical study are: (1) to provide a deep characterization of the subjective experience of pain and quality of life in MM patients; (2) to investigate disturbances in the bone innervation of MM patients. Secondary aims include exploring correlations between pain and serum inflammatory and bone turnover biomarkers. In a prospective, observational study (clinicaltrials.gov: NCT04273425), patients with suspected MM requiring a diagnostic iliac crest biopsy at Sheffield Teaching Hospital (UK) are invited to participate. Consenting patients answer seven standardized questionnaires assessing pain, quality of life and catastrophizing. Bone turnover biomarkers and inflammatory cytokines are measured in fasting serum samples, and bone innervation is evaluated in diagnostic biopsies. MM patients are invited to a follow-up upon completion of first line treatment. This will be the first deep characterization of pain in MM patients and its correlation with disturbances in bone innervation. Understanding how bone turnover and inflammation correlate to pain in MM is crucial to identify novel analgesic targets for this condition. Full article
(This article belongs to the Special Issue Bio-Pathological Markers in the Diagnosis and Therapy of Cancer)
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