Cancers

19 pages, 938 KiB

Open AccessReview

Clinical Characterisation and Management of the Main Treatment-Induced Toxicities in Patients with Hepatocellular Carcinoma and Cirrhosis

by Fausto Meriggi and Massimo Graffeo

Cancers 2021, 13(3), 584; https://doi.org/10.3390/cancers13030584 - 2 Feb 2021

Cited by 7 | Viewed by 2550

Abstract

The incidence of hepatocellular carcinoma (HCC) continues to increase worldwide, particularly in Western countries. In almost all cases, HCC develops in subjects with hepatic cirrhosis, often as the result of hepatitis B or C virus infection, alcohol abuse or metabolic forms secondary to [...] Read more.

The incidence of hepatocellular carcinoma (HCC) continues to increase worldwide, particularly in Western countries. In almost all cases, HCC develops in subjects with hepatic cirrhosis, often as the result of hepatitis B or C virus infection, alcohol abuse or metabolic forms secondary to non-alcoholic steatohepatitis. Patients with HCC and hepatic symptoms can therefore present symptoms that are attributable to both conditions. These patients require multidisciplinary management, calling for close interaction between the hepatologist and the oncologist. Indeed, the treatment of HCC requires, depending on the disease stage and the degree of hepatic impairment, locoregional therapies that can in turn be broken down into surgical and nonsurgical treatments and systemic treatments used in the event of progression after the administration of locoregional treatments. The past decade has seen the publication of countless papers of great interest that have radically changed the scenario of treatment for HCC. Novel therapies with biological agents and immunotherapy have come to be standard options in the approach to treatment of this cancer, obtaining very promising results where in the past chemotherapy was almost never able to have an impact on the course of the disease. However, in addition to being costly, these drugs are not devoid of adverse effects and their management cannot forgo the consideration of the underlying hepatic impairment. Patients with HCC and cirrhosis therefore require special attention, starting from the initial characterisation needed for an appropriate selection of those to be referred for treatment, as these patients are almost never fit. In this chapter, we will attempt to investigate and clarify the key points of the management of the main toxicities induced by locoregional and systemic treatments for HCC secondary to cirrhosis. Full article

(This article belongs to the Special Issue Hepatocellular Carcinoma)

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12 pages, 273 KiB

Open AccessGuidelines

Bringing Onco-Innovation to Europe’s Healthcare Systems: The Potential of Biomarker Testing, Real World Evidence, Tumour Agnostic Therapies to Empower Personalised Medicine

by Denis Horgan, Gennaro Ciliberto, Pierfranco Conte, Giuseppe Curigliano, Luis Seijo, Luis M. Montuenga, Marina Garassino, Frederique Penault-Llorca, Fabrizia Galli, Isabelle Ray-Coquard, Denis Querleu, Peter Riegman, Keith Kerr, Hein Van Poppel, Anders Bjartell, Giovanni Codacci-Pisanelli, Jasmina Koeva-Balabanova, Angelo Paradiso, Zorana Maravic, Vassiliki Fotaki, Nuria Malats, Chiara Bernini, Simonetta Buglioni, Alastair Kent, Elisabetta Munzone, Ivica Belina, Jan Van Meerbeeck, Michael Duffy, Beata Jagielska and Ettore Capoluongo Show full author list Hide full author list

Cancers 2021, 13(3), 583; https://doi.org/10.3390/cancers13030583 - 2 Feb 2021

Cited by 15 | Viewed by 4392

Abstract

Rapid and continuing advances in biomarker testing are not being matched by uptake in health systems, and this is hampering both patient care and innovation. It also risks costing health systems the opportunity to make their services more efficient and, over time, more [...] Read more.

Rapid and continuing advances in biomarker testing are not being matched by uptake in health systems, and this is hampering both patient care and innovation. It also risks costing health systems the opportunity to make their services more efficient and, over time, more economical. The potential that genomics has brought to biomarker testing in diagnosis, prediction and research is being realised, pre-eminently in many cancers, but also in an ever-wider range of conditions—notably BRCA1/2 testing in ovarian, breast, pancreatic and prostate cancers. Nevertheless, the implementation of genetic testing in clinical routine setting is still challenging. Development is impeded by country-related heterogeneity, data deficiencies, and lack of policy alignment on standards, approval—and the role of real-world evidence in the process—and reimbursement. The acute nature of the problem is compellingly illustrated by the particular challenges facing the development and use of tumour agnostic therapies, where the gaps in preparedness for taking advantage of this innovative approach to cancer therapy are sharply exposed. Europe should already have in place a guarantee of universal access to a minimum suite of biomarker tests and should be planning for an optimum testing scenario with a wider range of biomarker tests integrated into a more sophisticated health system articulated around personalised medicine. Improving healthcare and winning advantages for Europe’s industrial competitiveness and innovation require an appropriate policy framework—starting with an update to outdated recommendations. We show herein the main issues and proposals that emerged during the previous advisory boards organised by the European Alliance for Personalized Medicine which mainly focus on possible scenarios of harmonisation of both oncogenetic testing and management of cancer patients. Full article

(This article belongs to the Special Issue The Long Journey into BRCA1/2 Genes Goes On: The Emerging Landscape in BRCA-Mediated Tumors)

33 pages, 19007 KiB

Open AccessReview

Epidemiology, Diagnosis, Staging and Multimodal Therapy of Esophageal and Gastric Tumors

by Donelle Cummings, Joyce Wong, Russell Palm, Sarah Hoffe, Khaldoun Almhanna and Shivakumar Vignesh

Cancers 2021, 13(3), 582; https://doi.org/10.3390/cancers13030582 - 2 Feb 2021

Cited by 25 | Viewed by 9168

Abstract

Gastric and esophageal tumors are diverse neoplasms that involve mucosal and submucosal tissue layers and include squamous cell carcinomas, adenocarcinomas, spindle cell neoplasms, neuroendocrine tumors, marginal B cell lymphomas, along with less common tumors. The worldwide burden of esophageal and gastric malignancies is [...] Read more.

Gastric and esophageal tumors are diverse neoplasms that involve mucosal and submucosal tissue layers and include squamous cell carcinomas, adenocarcinomas, spindle cell neoplasms, neuroendocrine tumors, marginal B cell lymphomas, along with less common tumors. The worldwide burden of esophageal and gastric malignancies is significant, with esophageal and gastric cancer representing the ninth and fifth most common cancers, respectively. The approach to diagnosis and staging of these lesions is multimodal and includes a combination of gastrointestinal endoscopy, endoscopic ultrasound, and cross-sectional imaging. Likewise, therapy is multidisciplinary and combines therapeutic endoscopy, surgery, radiotherapy, and systemic chemotherapeutic tools. Future directions for diagnosis of esophageal and gastric malignancies are evolving rapidly and will involve advances in endoscopic and endosonographic techniques including tethered capsules, optical coherence tomography, along with targeted cytologic and serological analyses. Full article

(This article belongs to the Special Issue Multimodal Therapy of Upper Gastrointestinal Malignancies)

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16 pages, 2856 KiB

Open AccessArticle

BMI1-Inhibitor PTC596 in Combination with MCL1 Inhibitor S63845 or MEK Inhibitor Trametinib in the Treatment of Acute Leukemia

by Katja Seipel, Basil Kopp, Ulrike Bacher and Thomas Pabst

Cancers 2021, 13(3), 581; https://doi.org/10.3390/cancers13030581 - 2 Feb 2021

Cited by 14 | Viewed by 3603

Abstract

Purpose: Prognosis for acute myeloid leukemia (AML) patients is poor, particularly in TP53 mutated AML, secondary, relapsed, and refractory AML, and in patients unfit for intensive treatment, thus highlighting an unmet need for novel therapeutic approaches. The combined use of compounds targeting the [...] Read more.

Purpose: Prognosis for acute myeloid leukemia (AML) patients is poor, particularly in TP53 mutated AML, secondary, relapsed, and refractory AML, and in patients unfit for intensive treatment, thus highlighting an unmet need for novel therapeutic approaches. The combined use of compounds targeting the stem cell oncoprotein BMI1 and activating the tumor suppressor protein p53 may represent a promising novel treatment option for poor risk AML patients. Experimental Design: The BMI1 inhibitor PTC596, MCL1 inhibitor S63845, and MEK inhibitor trametinib, as well as the p53 activator APR-246 were assessed as single agents and in combination for their ability to induce apoptosis and cell death in leukemic cells. AML cells represented all major morphologic and molecular subtypes including FLT3-ITD and FLT3 wild type, NPM1 mutant and wild type, as well as TP53 mutant and wild type AML cell lines and a variety of patient derived AML cells. Results: AML cell lines were variably susceptible to PTC596 and to combination treatments with PTC596 and MCL1 inhibitor S63845, MEK inhibitor trametinib, or TP53 activator APR-246, independent of TP53 mutational status. Susceptibility of patient samples for PTC596 in combination with S63845 or trametinib was significant for the majority of adverse risk primary and secondary AML with minimal efficacy in favorable risk AML, and correlated significantly with CD34 positivity of the samples. BMI1 and MN1 gene expression, and MCL1 and MEK1 protein levels were identified as biomarkers for response to PTC596 combination treatments. Conclusions: The combination of PTC596 and S63845 may be an effective treatment in CD34+ adverse risk AML with elevated MN1 gene expression and MCL1 protein levels, while PTC596 and trametinib may be more effective in CD34+ adverse risk AML with elevated BMI1 gene expression and MEK protein levels. Full article

(This article belongs to the Special Issue Recent Developments of Hematologic Diagnostics in the Interplay with Evolving Treatment Developments)

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15 pages, 750 KiB

Open AccessReview

Molecular and Metabolic Mechanisms Underlying Selective 5-Aminolevulinic Acid-Induced Fluorescence in Gliomas

by Jeffrey I. Traylor, Mark N. Pernik, Alex C. Sternisha, Samuel K. McBrayer and Kalil G. Abdullah

Cancers 2021, 13(3), 580; https://doi.org/10.3390/cancers13030580 - 2 Feb 2021

Cited by 48 | Viewed by 6028

Abstract

5-aminolevulinic acid (5-ALA) is a porphyrin precursor in the heme synthesis pathway. When supplied exogenously, certain cancers consume 5-ALA and convert it to the fluorogenic metabolite protoporphyrin IX (PpIX), causing tumor-specific tissue fluorescence. Preoperative administration of 5-ALA is used to aid neurosurgical resection [...] Read more.

5-aminolevulinic acid (5-ALA) is a porphyrin precursor in the heme synthesis pathway. When supplied exogenously, certain cancers consume 5-ALA and convert it to the fluorogenic metabolite protoporphyrin IX (PpIX), causing tumor-specific tissue fluorescence. Preoperative administration of 5-ALA is used to aid neurosurgical resection of high-grade gliomas such as glioblastoma, allowing for increased extent of resection and progression free survival for these patients. A subset of gliomas, especially low-grade tumors, do not accumulate PpIX intracellularly or readily fluoresce upon 5-ALA administration, making gross total resection difficult to achieve in diffuse lesions. We review existing literature on 5-ALA metabolism and PpIX accumulation to explore potential mechanisms of 5-ALA-induced glioma tissue fluorescence. Targeting the heme synthesis pathway and understanding its dysregulation in malignant tissues could aid the development of adjunct therapies to increase intraoperative fluorescence after 5-ALA treatment. Full article

(This article belongs to the Section Molecular Cancer Biology)

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15 pages, 3499 KiB

Open AccessArticle

Oxidation of Innate Immune Checkpoint CD47 on Cancer Cells with Non-Thermal Plasma

by Abraham Lin, Jamoliddin Razzokov, Hanne Verswyvel, Angela Privat-Maldonado, Joey De Backer, Maksudbek Yusupov, Edgar Cardenas De La Hoz, Peter Ponsaerts, Evelien Smits and Annemie Bogaerts

Cancers 2021, 13(3), 579; https://doi.org/10.3390/cancers13030579 - 2 Feb 2021

Cited by 27 | Viewed by 4207

Abstract

Non-thermal plasma (NTP) therapy has been emerging as a promising cancer treatment strategy, and recently, its ability to locally induce immunogenic cancer cell death is being unraveled. We hypothesized that the chemical species produced by NTP reduce immunosuppressive surface proteins and checkpoints that [...] Read more.

Non-thermal plasma (NTP) therapy has been emerging as a promising cancer treatment strategy, and recently, its ability to locally induce immunogenic cancer cell death is being unraveled. We hypothesized that the chemical species produced by NTP reduce immunosuppressive surface proteins and checkpoints that are overexpressed on cancerous cells. Here, 3D in vitro tumor models, an in vivo mouse model, and molecular dynamics simulations are used to investigate the effect of NTP on CD47, a key innate immune checkpoint. CD47 is immediately modulated after NTP treatment and simulations reveal the potential oxidized salt-bridges responsible for conformational changes. Umbrella sampling simulations of CD47 with its receptor, signal-regulatory protein alpha (SIRPα), demonstrate that the induced-conformational changes reduce its binding affinity. Taken together, this work provides new insight into fundamental, chemical NTP-cancer cell interaction mechanisms and a previously overlooked advantage of present NTP cancer therapy: reducing immunosuppressive signals on the surface of cancer cells. Full article

(This article belongs to the Special Issue Advances in Plasma Oncology toward Clinical Translation)

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21 pages, 18440 KiB

Open AccessArticle

Increased Expression of AKT3 in Neuroendocrine Differentiated Prostate Cancer Cells Alters the Response Towards Anti-Androgen Treatment

by Marc Wiesehöfer, Elena Dilara Czyrnik, Martin Spahn, Saskia Ting, Henning Reis, Jaroslaw Thomas Dankert and Gunther Wennemuth

Cancers 2021, 13(3), 578; https://doi.org/10.3390/cancers13030578 - 2 Feb 2021

Cited by 8 | Viewed by 2900

Abstract

Patients with advanced prostate carcinoma are often treated with an androgen deprivation therapy but long-term treatment can result in a metastatic castration-resistant prostate cancer. This is a more aggressive, untreatable tumor recurrence often containing areas of neuroendocrine differentiated prostate cancer cells. Using an [...] Read more.

Patients with advanced prostate carcinoma are often treated with an androgen deprivation therapy but long-term treatment can result in a metastatic castration-resistant prostate cancer. This is a more aggressive, untreatable tumor recurrence often containing areas of neuroendocrine differentiated prostate cancer cells. Using an in vitro model of NE-like cancer cells, it could previously be shown that neuroendocrine differentiation of LNCaP cells leads to a strong deregulation of mRNA and miRNA expression. We observe elevated RNA and protein levels of AKT Serine/Threonine Kinase 3 (AKT3) in neuroendocrine-like LNCaP cells. We used prostate resections from patients with neuroendocrine prostate cancer to validate these results and detect a co-localization of neuroendocrine marker genes with AKT3. Analysis of downstream target genes FOXO3A and GSK3 strengthens the assumption AKT3 may play a role in neuroendocrine differentiation. Overexpression of AKT3 shows an increased survival rate of LNCaP cells after apoptosis induction, which in turn reflects the significance in vivo or for treatment. Furthermore, miR-17, −20b and −106b, which are decreased in neuroendocrine-like LNCaP cells, negatively regulate AKT3 biosynthesis. Our findings demonstrate AKT3 as a potential therapeutic target and diagnostic tool in advanced neuroendocrine prostate cancer and a new mRNA–miRNA interaction with a potential role in neuroendocrine differentiation of prostate cancer. Full article

(This article belongs to the Special Issue Diagnosis of Prostate Cancer)

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23 pages, 5213 KiB

Open AccessArticle

Optimizing the Procedure to Manufacture Clinical-Grade NK Cells for Adoptive Immunotherapy

by Adrián Fernández, Alfonso Navarro-Zapata, Adela Escudero, Nerea Matamala, Beatriz Ruz-Caracuel, Isabel Mirones, Alicia Pernas, Marta Cobo, Gema Casado, Diego Lanzarot, Carlos Rodríguez-Antolín, María Vela, Cristina Ferreras, Carmen Mestre, Aurora Viejo, Alejandra Leivas, Joaquín Martínez, Lucía Fernández and Antonio Pérez-Martínez

Cancers 2021, 13(3), 577; https://doi.org/10.3390/cancers13030577 - 2 Feb 2021

Cited by 17 | Viewed by 9535

Abstract

Natural killer (NK) cells represent promising tools for cancer immunotherapy. We report the optimization of an NK cell activation–expansion process and its validation on clinical-scale. Methods: RPMI-1640, stem cell growth medium (SCGM), NK MACS and TexMACS were used as culture mediums. Activated and [...] Read more.

Natural killer (NK) cells represent promising tools for cancer immunotherapy. We report the optimization of an NK cell activation–expansion process and its validation on clinical-scale. Methods: RPMI-1640, stem cell growth medium (SCGM), NK MACS and TexMACS were used as culture mediums. Activated and expanded NK cells (NKAE) were obtained by coculturing total peripheral blood mononuclear cells (PBMC) or CD45RA⁺ cells with irradiated K562mbIL15-41BBL or K562mbIL21-41BBL. Fold increase, NK cell purity, activation status, cytotoxicity and transcriptome profile were analyzed. Clinical-grade NKAE cells were manufactured in CliniMACS Prodigy. Results: NK MACS and TexMACs achieved the highest NK cell purity and lowest T cell contamination. Obtaining NKAE cells from CD45RA⁺ cells was feasible although PBMC yielded higher total cell numbers and NK cell purity than CD45RA⁺ cells. The highest fold expansion and NK purity were achieved by using PBMC and K562mbIL21-41BBL cells. However, no differences in activation and cytotoxicity were found when using either NK cell source or activating cell line. Transcriptome profile showed to be different between basal NK cells and NKAE cells expanded with K562mbIL21-41BBL or K562mbIL15-41BBL. Clinical-grade manufactured NKAE cells complied with the specifications from the Spanish Regulatory Agency. Conclusions: GMP-grade NK cells for clinical use can be obtained by using different starting cells and aAPC. Full article

(This article belongs to the Special Issue The Role of NK and T Cells in Cancer)

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27 pages, 3788 KiB

Open AccessArticle

Cooperative Blockade of CK2 and ATM Kinases Drives Apoptosis in VHL-Deficient Renal Carcinoma Cells through ROS Overproduction

by Sofia Giacosa, Catherine Pillet, Irinka Séraudie, Laurent Guyon, Yann Wallez, Caroline Roelants, Christophe Battail, Bertrand Evrard, Frédéric Chalmel, Caroline Barette, Emmanuelle Soleilhac, Marie-Odile Fauvarque, Quentin Franquet, Clément Sarrazin, Nicolas Peilleron, Gaëlle Fiard, Jean-Alexandre Long, Jean-Luc Descotes, Claude Cochet and Odile Filhol

Cancers 2021, 13(3), 576; https://doi.org/10.3390/cancers13030576 - 2 Feb 2021

Cited by 18 | Viewed by 4578

Abstract

Kinase-targeted agents demonstrate antitumor activity in advanced metastatic clear cell renal cell carcinoma (ccRCC), which remains largely incurable. Integration of genomic approaches through small-molecules and genetically based high-throughput screening holds the promise of improved discovery of candidate targets for cancer therapy. The 786-O [...] Read more.

Kinase-targeted agents demonstrate antitumor activity in advanced metastatic clear cell renal cell carcinoma (ccRCC), which remains largely incurable. Integration of genomic approaches through small-molecules and genetically based high-throughput screening holds the promise of improved discovery of candidate targets for cancer therapy. The 786-O cell line represents a model for most ccRCC that have a loss of functional pVHL (von Hippel-Lindau). A multiplexed assay was used to study the cellular fitness of a panel of engineered ccRCC isogenic 786-O VHL⁻ cell lines in response to a collection of targeted cancer therapeutics including kinase inhibitors, allowing the interrogation of over 2880 drug–gene pairs. Among diverse patterns of drug sensitivities, investigation of the mechanistic effect of one selected drug combination on tumor spheroids and ex vivo renal tumor slice cultures showed that VHL-defective ccRCC cells were more vulnerable to the combined inhibition of the CK2 and ATM kinases than wild-type VHL cells. Importantly, we found that HIF-2α acts as a key mediator that potentiates the response to combined CK2/ATM inhibition by triggering ROS-dependent apoptosis. Importantly, our findings reveal a selective killing of VHL-deficient renal carcinoma cells and provide a rationale for a mechanism-based use of combined CK2/ATM inhibitors for improved patient care in metastatic VHL-ccRCC. Full article

(This article belongs to the Section Cancer Therapy)

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17 pages, 940 KiB

Open AccessReview

The Role of BRCA1/2-Mutated Tumor Microenvironment in Breast Cancer

by Svetlana Miklikova, Lenka Trnkova, Jana Plava, Martin Bohac, Marcela Kuniakova and Marina Cihova

Cancers 2021, 13(3), 575; https://doi.org/10.3390/cancers13030575 - 2 Feb 2021

Cited by 12 | Viewed by 5523

Abstract

Taking into account the factors of high incidence rate, prevalence and mortality, breast cancer represents a crucial social and economic burden. Most cases of breast cancer develop as a consequence of somatic mutations accumulating in mammary epithelial cells throughout lifetime and approximately 5–10% [...] Read more.

Taking into account the factors of high incidence rate, prevalence and mortality, breast cancer represents a crucial social and economic burden. Most cases of breast cancer develop as a consequence of somatic mutations accumulating in mammary epithelial cells throughout lifetime and approximately 5–10% can be ascribed to monogenic predispositions. Even though the role of genetic predispositions in breast cancer is well described in the context of genetics, very little is known about the role of the microenvironment carrying the same aberrant cells impaired by the germline mutation in the breast cancer development and progression. Based on the clinical observations, carcinomas carrying mutations in hereditary tumor-suppressor genes involved in maintaining genome integrity such as BRCA1/2 have worse prognosis and aggressive behavior. One of the mechanisms clarifying the aggressive nature of BRCA-associated tumors implies alterations within the surrounding adipose tissue itself. The objective of this review is to look at the role of BRCA1/2 mutations in the context of breast tumor microenvironment and plausible mechanisms by which it contributes to the aggressive behavior of the tumor cells. Full article

(This article belongs to the Special Issue The Long Journey into BRCA1/2 Genes Goes On: The Emerging Landscape in BRCA-Mediated Tumors)

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Graphical abstract

24 pages, 1648 KiB

Open AccessReview

Challenges in Crohn’s Disease Management after Gastrointestinal Cancer Diagnosis

by Claudio Fiorillo, Carlo Alberto Schena, Giuseppe Quero, Vito Laterza, Daniela Pugliese, Giuseppe Privitera, Fausto Rosa, Tommaso Schepis, Lisa Salvatore, Brunella Di Stefano, Luigi Larosa, Laura Maria Minordi, Luigi Natale, Giampaolo Tortora, Alessandro Armuzzi and Sergio Alfieri

Cancers 2021, 13(3), 574; https://doi.org/10.3390/cancers13030574 - 2 Feb 2021

Cited by 8 | Viewed by 4897

Abstract

Crohn’s disease (CD) is a chronic inflammatory bowel disease with a progressive course, potentially affecting the entire gastrointestinal tract from mouth to anus. Several studies have shown an increased risk of both intestinal and extra-intestinal cancer in patients with CD, due to long-standing [...] Read more.

Crohn’s disease (CD) is a chronic inflammatory bowel disease with a progressive course, potentially affecting the entire gastrointestinal tract from mouth to anus. Several studies have shown an increased risk of both intestinal and extra-intestinal cancer in patients with CD, due to long-standing transmural inflammation and damage accumulation. The similarity of symptoms among CD, its related complications and the de novo onset of gastrointestinal cancer raises difficulties in the differential diagnosis. In addition, once a cancer diagnosis in CD patients is made, selecting the appropriate treatment can be particularly challenging. Indeed, both surgical and oncological treatments are not always the same as that of the general population, due to the inflammatory context of the gastrointestinal tract and the potential exacerbation of gastrointestinal symptoms of patients with CD; moreover, the overlap of the neoplastic disease could lead to adjustments in the pharmacological treatment of the underlying CD, especially with regard to immunosuppressive drugs. For these reasons, a case-by-case analysis in a multidisciplinary approach is often appropriate for the best diagnostic and therapeutic evaluation of patients with CD after gastrointestinal cancer onset. Full article

(This article belongs to the Special Issue Intestinal Cancers and Surgery in Inflammatory Bowel Diseases)

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11 pages, 600 KiB

Open AccessSystematic Review

Computed Tomography Based Radiomics as a Predictor of Survival in Ovarian Cancer Patients: A Systematic Review

by Stefania Rizzo, Lucia Manganaro, Miriam Dolciami, Maria Luisa Gasparri, Andrea Papadia and Filippo Del Grande

Cancers 2021, 13(3), 573; https://doi.org/10.3390/cancers13030573 - 2 Feb 2021

Cited by 30 | Viewed by 3914

Abstract

The objective of this systematic review was to assess the results of radiomics for prediction of overall survival (OS) and progression free survival (PFS) in ovarian cancer (OC) patients. A secondary objective was to evaluate the findings of papers that based their analyses [...] Read more.

The objective of this systematic review was to assess the results of radiomics for prediction of overall survival (OS) and progression free survival (PFS) in ovarian cancer (OC) patients. A secondary objective was to evaluate the findings of papers that based their analyses on inter-site heterogeneity. This systematic review was conducted according to the PRISMA statement. After the initial retrieval of 145 articles, the final systematic review comprised six articles. Association between radiomic features and OS was evaluated in 3/6 studies (50%); all articles showed a significant association between radiomic features and OS. Association with PFS was evaluated in 5/6 (83%) articles; the period of follow-up ranged between six and 36 months. All the articles showed significant association between radiomic models and PFS. Inter-site textural features were used for analysis in 2/6 (33%) articles. They demonstrated that high levels of inter-site textural heterogeneity were significantly associated with incomplete surgical resection in breast cancer gene-negative patients, and that lower heterogeneity was associated with complete resectability. There were some differences among papers in methodology; for example, only 3/6 (50%) articles included validation cohorts. In conclusion, radiomic models have demonstrated promising results as predictors of survival in OC patients, although larger studies are needed to allow clinical applicability. Full article

(This article belongs to the Special Issue Omics in Ovarian Cancer)

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18 pages, 894 KiB

Open AccessArticle

Long-Term Outcome and Role of Biology within Risk-Adapted Treatment Strategies: The Austrian Neuroblastoma Trial A-NB94

by Stefan Fiedler, Inge M. Ambros, Evgenia Glogova, Martin Benesch, Christian Urban, Marlene Mayer, Georg Ebetsberger-Dachs, Edit Bardi, Neil Jones, Agnes Gamper, Bernhard Meister, Roman Crazzolara, Gabriele Amann, Karin Dieckmann, Ernst Horcher, Reinhold Kerbl, Bettina Brunner-Herglotz, Andrea Ziegler, Peter F. Ambros and Ruth Ladenstein

Cancers 2021, 13(3), 572; https://doi.org/10.3390/cancers13030572 - 2 Feb 2021

Cited by 1 | Viewed by 2664

Abstract

We evaluated long-term outcome and genomic profiles in the Austrian Neuroblastoma Trial A-NB94 which applied a risk-adapted strategy of treatment (RAST) using stage, age and MYCN amplification (MNA) status for stratification. RAST ranged from surgery only to intensity-adjusted chemotherapy, single or multiple courses [...] Read more.

We evaluated long-term outcome and genomic profiles in the Austrian Neuroblastoma Trial A-NB94 which applied a risk-adapted strategy of treatment (RAST) using stage, age and MYCN amplification (MNA) status for stratification. RAST ranged from surgery only to intensity-adjusted chemotherapy, single or multiple courses of high-dose chemotherapy (HDT) followed by autologous stem cell rescue depending on response to induction chemotherapy, and irradiation to the primary tumor site. Segmental chromosomal alterations (SCAs) were investigated retrospectively using multi- and pan-genomic techniques. The A-NB94 trial enrolled 163 patients. Patients with localized disease had an excellent ten-year (10y) event free survival (EFS) and overall survival (OS) of 99 ± 1% and 93 ± 2% whilst it was 80 ± 13% and 90 ± 9% for infants with stage 4S and for infants with stage 4 non-MNA disease both 83 ± 15%. Stage 4 patients either >12 months or ≤12 months but with MNA had a 10y-EFS and OS of 45 ± 8% and 47 ± 8%, respectively. SCAs were present in increasing frequencies according to stage and age: in 29% of localized tumors but in 92% of stage 4 tumors (p < 0.001), and in 39% of patients ≤ 12 months but in 63% of patients > 12 months (p < 0.001). RAST successfully reduced chemotherapy exposure in low- and intermediate-risk patients with excellent long-term results while the outcome of high-risk disease met contemporary trials. Full article

(This article belongs to the Section Clinical Research of Cancer)

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18 pages, 2077 KiB

Open AccessArticle

The Protein Secretome Is Altered in Rectal Cancer Tissue Compared to Normal Rectal Tissue, and Alterations in the Secretome Induce Enhanced Innate Immune Responses

by Aisling B. Heeran, Margaret R. Dunne, Maria E. Morrissey, Croí E. Buckley, Niamh Clarke, Aoife Cannon, Noel E. Donlon, Timothy S. Nugent, Michael Durand, Cara Dunne, John O. Larkin, Brian Mehigan, Paul McCormick, Niamh Lynam-Lennon and Jacintha O’Sullivan

Cancers 2021, 13(3), 571; https://doi.org/10.3390/cancers13030571 - 2 Feb 2021

Cited by 11 | Viewed by 2740

Abstract

Locally advanced rectal cancer is treated with neoadjuvant-chemoradiotherapy; however, only ~22% of patients achieve a complete response, and resistance mechanisms are poorly understood. The role of inflammation and immune cell biology in this setting is under-investigated. In this study, we profiled the inflammatory [...] Read more.

Locally advanced rectal cancer is treated with neoadjuvant-chemoradiotherapy; however, only ~22% of patients achieve a complete response, and resistance mechanisms are poorly understood. The role of inflammation and immune cell biology in this setting is under-investigated. In this study, we profiled the inflammatory protein secretome of normal (non-cancer) (n = 8) and malignant rectal tissue (n = 12) pre- and post-radiation in human ex vivo explant models and examined the influence of these untreated and treated secretomes on dendritic cell biology (n = 8 for cancer and normal). These resultant profiles were correlated with patient clinical characteristics. Nineteen factors were secreted at significantly higher levels from the rectal cancer secretome when compared to the normal rectal secretome; Flt-1, P1GF, IFN-γ, IL-6, IL-10, CCL20, CCL26, CCL22, CCL3, CCL4, CCL17, GM-CSF, IL-12/IL-23p40, IL-17A, IL-1α, IL-17A/F, IL-1RA, TSLP and CXCL10 (p < 0.05). Radiation was found to have differential effects on normal rectal tissue and rectal cancer tissue with increased IL-15 and CCL22 secretion following radiation from normal rectal tissue explants (p < 0.05), while no significant alterations were observed in the irradiated rectal cancer tissue. Interestingly, however, the irradiated rectal cancer secretome induced the most potent effect on dendritic cell maturation via upregulation of CD80 and PD-L1. Patient’s visceral fat area correlated with secreted factors including CCL20, suggesting that obesity status may alter the tumour microenvironment (TME). These results suggest that radiation does not have a negative effect on the ability of the rectal cancer TME to induce an immune response. Understanding these responses may unveil potential therapeutic targets to enhance radiation response and mitigate normal tissue injury. Tumour irradiation in this cohort enhances innate immune responses, which may be harnessed to improve patient treatment outcome. Full article

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22 pages, 792 KiB

Open AccessReview

Functional Interaction among lncRNA HOTAIR and MicroRNAs in Cancer and Other Human Diseases

by Monica Cantile, Maurizio Di Bonito, Maura Tracey De Bellis and Gerardo Botti

Cancers 2021, 13(3), 570; https://doi.org/10.3390/cancers13030570 - 2 Feb 2021

Cited by 66 | Viewed by 6117

Abstract

LncRNAs are a class of non-coding RNAs mostly involved in regulation of cancer initiation, metastatic progression, and drug resistance, through participation in post-transcription regulatory processes by interacting with different miRNAs. LncRNAs are able to compete with endogenous RNAs by binding and sequestering miRNAs [...] Read more.

LncRNAs are a class of non-coding RNAs mostly involved in regulation of cancer initiation, metastatic progression, and drug resistance, through participation in post-transcription regulatory processes by interacting with different miRNAs. LncRNAs are able to compete with endogenous RNAs by binding and sequestering miRNAs and thereby regulating the expression of their target genes, often represented by oncogenes. The lncRNA HOX transcript antisense RNA (HOTAIR) represents a diagnostic, prognostic, and predictive biomarker in many human cancers, and its functional interaction with miRNAs has been described as crucial in the modulation of different cellular processes during cancer development. The aim of this review is to highlight the relation between lncRNA HOTAIR and different microRNAs in human diseases, discussing the contribution of these functional interactions, especially in cancer development and progression. Full article

(This article belongs to the Collection The Role of Non-coding RNA in Cancer)

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24 pages, 1813 KiB

Open AccessArticle

In Vitro and In Vivo Characterization of MCT1 Inhibitor AZD3965 Confirms Preclinical Safety Compatible with Breast Cancer Treatment

by Zohra Benyahia, Marine C. N. M. Blackman, Loïc Hamelin, Luca X. Zampieri, Tania Capeloa, Marie L. Bedin, Thibaut Vazeille, Olivier Schakman and Pierre Sonveaux

Cancers 2021, 13(3), 569; https://doi.org/10.3390/cancers13030569 - 2 Feb 2021

Cited by 17 | Viewed by 4924

Abstract

To survive and proliferate in solid tumors, cancer cells adapt and evolve rapidly in microenvironments where oxygen and substrate bioavailability fluctuates over time and space. This creates metabolic heterogeneity. Cancer cells can further cooperate metabolically, for example by swapping glycolytic end-product lactate for [...] Read more.

To survive and proliferate in solid tumors, cancer cells adapt and evolve rapidly in microenvironments where oxygen and substrate bioavailability fluctuates over time and space. This creates metabolic heterogeneity. Cancer cells can further cooperate metabolically, for example by swapping glycolytic end-product lactate for blood-borne glucose. This type of cooperation can be targeted therapeutically, since transmembrane lactate exchanges are facilitated by lactate-proton symporters of the monocarboxylate (MCT) family. Among new drugs, AZD3965 is a first-in-class selective MCT1 inhibitor currently tested in Phase I/II clinical trials for patients with different types of cancers. Because MCT1 can function bidirectionally, we tested here whether and how malignant and nonmalignant cells adapt their metabolism and MCT repertoire when AZD3965 inhibits either lactate import or export. Using breast-associated malignant and nonmalignant cell lines as models, we report that AZD3965 is not directly cytotoxic. In the presence of glucose and glutamine, oxidative cells can survive when lactate uptake is blocked, and proliferating cells compensate MCT1 inhibition by overexpressing MCT4, a specialized facilitator of lactate export. Phenotypic characterization of mice focusing on metabolism, muscle and brain physiology found partial and transient memory retention defect as sole consequence of MCT1 inhibition by AZD3965. We therefore conclude that AZD3965 is compatible with anticancer therapy. Full article

(This article belongs to the Special Issue Novel Perspectives on Hypoxia in Cancer)

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14 pages, 938 KiB

Open AccessArticle

An Observational Cohort Study on 194 Supraglottic Cancer Patients: Implications for Laser Surgery and Adjuvant Treatment

by Gerhard Dyckhoff, Rolf Warta, Christel Herold-Mende, Elisabeth Rudolph, Peter K. Plinkert and Heribert Ramroth

Cancers 2021, 13(3), 568; https://doi.org/10.3390/cancers13030568 - 2 Feb 2021

Cited by 8 | Viewed by 2198

Abstract

Supraglottic laryngeal cancer is characterized by poor prognosis. In contrast, excellent outcomes have been published in early-stage supraglottic cancers after laser surgery in single-institutional series in centers of excellence. Are these results reproducible in the normal clinical practice of less specialized facilities? As [...] Read more.

Supraglottic laryngeal cancer is characterized by poor prognosis. In contrast, excellent outcomes have been published in early-stage supraglottic cancers after laser surgery in single-institutional series in centers of excellence. Are these results reproducible in the normal clinical practice of less specialized facilities? As part of an observational cohort study, the outcomes of 194 supraglottic cancer patients were assessed after treatment by larynx-preserving surgery (transoral laser microsurgery [TLM] or open partial laryngectomy [OPL]) or total laryngectomy (TL), with each having risk-adopted adjuvant treatment, or primary (chemo-)radiotherapy (pCRT or pRT). In early-stage supraglottic cancers, TLM achieved a 5-year overall survival (5-year OS) of 62.0%. No significant survival difference could be discerned between patients with and without adjuvant treatment (HR 1.47; 95% CI: 0.80 2.69). The comparison between pCRT and pRT patients suggests that CRT is more effective in supraglottic cancer. The 5-year OS rate achieved in our multiinstitutional setting is comparable to that reached in laser surgery centers of excellence (59.4–76.0%). According to our data and supported by the literature, adjuvant RT (aRT) is not sufficiently effective in supraglottic cancers. In case adjuvant therapy is indicated, adjuvant chemoradiation (aCRT) could be recommended. Full article

(This article belongs to the Special Issue Larynx Cancer: From Diagnosis to Treatment and Rehabilitation)

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2 pages, 175 KiB

Open AccessEditorial

Ultrasound: The Extension of Our Hands to Improve the Management of Thyroid Patients

by Pierpaolo Trimboli

Cancers 2021, 13(3), 567; https://doi.org/10.3390/cancers13030567 - 2 Feb 2021

Cited by 5 | Viewed by 1776

Abstract

Ultrasonography (US) was introduced in the thyroid field in the 1980s to guide the biopsy of palpable, scintigraphically cold nodules [...] Full article

(This article belongs to the Special Issue Risk Stratification of Thyroid Nodule: From Ultrasound Features to TIRADS)

10 pages, 1315 KiB

Open AccessArticle

Evaluation of the Temporal Muscle Thickness as an Independent Prognostic Biomarker in Patients with Primary Central Nervous System Lymphoma

by Julia Furtner, Karl-Heinz Nenning, Thomas Roetzer, Johanna Gesperger, Lukas Seebrecht, Michael Weber, Astrid Grams, Stefan L. Leber, Franz Marhold, Camillo Sherif, Johannes Trenkler, Barbara Kiesel, Georg Widhalm, Ulrika Asenbaum, Ramona Woitek, Anna S. Berghoff, Daniela Prayer, Georg Langs, Matthias Preusser and Adelheid Wöhrer

Cancers 2021, 13(3), 566; https://doi.org/10.3390/cancers13030566 - 2 Feb 2021

Cited by 24 | Viewed by 2513

Abstract

In this study, we assessed the prognostic relevance of temporal muscle thickness (TMT), likely reflecting patient’s frailty, in patients with primary central nervous system lymphoma (PCNSL). In 128 newly diagnosed PCNSL patients TMT was analyzed on cranial magnetic resonance images. Predefined sex-specific TMT [...] Read more.

In this study, we assessed the prognostic relevance of temporal muscle thickness (TMT), likely reflecting patient’s frailty, in patients with primary central nervous system lymphoma (PCNSL). In 128 newly diagnosed PCNSL patients TMT was analyzed on cranial magnetic resonance images. Predefined sex-specific TMT cutoff values were used to categorize the patient cohort. Survival analyses, using a log-rank test as well as Cox models adjusted for further prognostic parameters, were performed. The risk of death was significantly increased for PCNSL patients with reduced muscle thickness (hazard ratio of 3.189, 95% CI: 2–097–4.848, p < 0.001). Importantly, the results confirmed that TMT could be used as an independent prognostic marker upon multivariate Cox modeling (hazard ratio of 2.504, 95% CI: 1.608–3.911, p < 0.001) adjusting for sex, age at time of diagnosis, deep brain involvement of the PCNSL lesions, Eastern Cooperative Oncology Group (ECOG) performance status, and methotrexate-based chemotherapy. A TMT value below the sex-related cutoff value at the time of diagnosis is an independent adverse marker in patients with PCNSL. Thus, our results suggest the systematic inclusion of TMT in further translational and clinical studies designed to help validate its role as a prognostic biomarker. Full article

(This article belongs to the Special Issue Clinical Studies on Imaging Biomarkers)

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12 pages, 1229 KiB

Open AccessArticle

Association of RERG Expression with Female Survival Advantage in Malignant Pleural Mesothelioma

by Assunta De Rienzo, Melissa H. Coleman, Beow Y. Yeap, David T. Severson, Benjamin Wadowski, Corinne E. Gustafson, Roderick V. Jensen, Lucian R. Chirieac, William G. Richards and Raphael Bueno

Cancers 2021, 13(3), 565; https://doi.org/10.3390/cancers13030565 - 2 Feb 2021

Cited by 6 | Viewed by 5467

Abstract

Sex differences in incidence, prognosis, and treatment response have been described for many cancers. In malignant pleural mesothelioma (MPM), a lethal disease associated with asbestos exposure, men outnumber women 4 to 1, but women consistently live longer than men following surgery-based therapy. This [...] Read more.

Sex differences in incidence, prognosis, and treatment response have been described for many cancers. In malignant pleural mesothelioma (MPM), a lethal disease associated with asbestos exposure, men outnumber women 4 to 1, but women consistently live longer than men following surgery-based therapy. This study investigated whether tumor expression of genes associated with estrogen signaling could potentially explain observed survival differences. Two microarray datasets of MPM tumors were analyzed to discover estrogen-related genes associated with survival. A validation cohort of MPM tumors was selected to balance the numbers of men and women and control for competing prognostic influences. The RAS like estrogen regulated growth inhibitor (RERG) gene was identified as the most differentially-expressed estrogen-related gene in these tumors and predicted prognosis in discovery datasets. In the sex-matched validation cohort, low RERG expression was significantly associated with increased risk of death among women. No association between RERG expression and survival was found among men, and no relationship between estrogen receptor protein or gene expression and survival was found for either sex. Additional investigations are needed to elucidate the molecular mechanisms underlying this association and its sex specificity. Full article

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33 pages, 1094 KiB

Open AccessEditor’s ChoiceReview

Harnessing Tumor Necrosis Factor Alpha to Achieve Effective Cancer Immunotherapy

by María Florencia Mercogliano, Sofía Bruni, Florencia Mauro, Patricia Virginia Elizalde and Roxana Schillaci

Cancers 2021, 13(3), 564; https://doi.org/10.3390/cancers13030564 - 2 Feb 2021

Cited by 61 | Viewed by 7382

Abstract

Tumor necrosis factor alpha (TNFα) is a pleiotropic cytokine known to have contradictory roles in oncoimmunology. Indeed, TNFα has a central role in the onset of the immune response, inducing both activation and the effector function of macrophages, dendritic cells, natural killer (NK) [...] Read more.

Tumor necrosis factor alpha (TNFα) is a pleiotropic cytokine known to have contradictory roles in oncoimmunology. Indeed, TNFα has a central role in the onset of the immune response, inducing both activation and the effector function of macrophages, dendritic cells, natural killer (NK) cells, and B and T lymphocytes. Within the tumor microenvironment, however, TNFα is one of the main mediators of cancer-related inflammation. It is involved in the recruitment and differentiation of immune suppressor cells, leading to evasion of tumor immune surveillance. These characteristics turn TNFα into an attractive target to overcome therapy resistance and tackle cancer. This review focuses on the diverse molecular mechanisms that place TNFα as a source of resistance to immunotherapy such as monoclonal antibodies against cancer cells or immune checkpoints and adoptive cell therapy. We also expose the benefits of TNFα blocking strategies in combination with immunotherapy to improve the antitumor effect and prevent or treat adverse immune-related effects. Full article

(This article belongs to the Special Issue Challenges and Opportunities for Effective Cancer Immunotherapies)

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27 pages, 3629 KiB

Open AccessArticle

Cysteine-Rich Angiogenic Inducer 61: Pro-Survival Function and Role as a Biomarker for Disseminating Breast Cancer Cells

by Kai Bartkowiak, Isabel Heidrich, Marcel Kwiatkowski, Tobias M. Gorges, Antje Andreas, Maria Geffken, Karl Verpoort, Volkmar Müller, Hartmut Schlüter and Klaus Pantel

Cancers 2021, 13(3), 563; https://doi.org/10.3390/cancers13030563 - 2 Feb 2021

Cited by 7 | Viewed by 3575

Abstract

(1) Background: the early detection of cancer cells in the blood or bone marrow of breast cancer patients improves the understanding of metastasis. Disseminating tumor cells in the bone marrow with a pronounced manifestation of mesenchymal markers (mDTC) are difficult to detect by [...] Read more.

(1) Background: the early detection of cancer cells in the blood or bone marrow of breast cancer patients improves the understanding of metastasis. Disseminating tumor cells in the bone marrow with a pronounced manifestation of mesenchymal markers (mDTC) are difficult to detect by epithelial markers, but they are relevant in the initiation of metastasis. (2) Methods: the breast cancer mDTC cell line BC-M1 was analyzed by mass spectrometry, which revealed high levels of the protein-cysteine–rich angiogenic inducer 61 (Cyr61). The function of Cyr61 was investigated using shRNA and hypoxia. Peripheral blood samples from 35 breast cancer patients were investigated for CTCs defined as cytokeratin-positive/CD45-negative cells. (3) Results: the Cyr61 levels are elevated in mDTC lines from breast, lung, and prostate cancer patients. The loss of Cyr61 resulted in the diminished expression of hypoxia-inducible factor 1-alpha, and increased apoptosis. Cyr61 was present in 47 (43%) of the 109 detected circulating tumor cells (CTCs), while the blood and bone marrow cells from healthy controls were Cyr61-negative. (4) Conclusions: Cyr61 is expressed in mDTC lines, supports the viability of cancer cells, and classifies a new subset of cytokeratin-positive CTCs, which deserves further investigation. Full article

(This article belongs to the Special Issue Liquid Biopsy: Latest Advances and Future Challenges)

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10 pages, 697 KiB

Open AccessReview

Value and Unmet Needs in Non-Invasive Human Papillomavirus (HPV) Testing for Oropharyngeal Cancer

by Alec J. Kacew and Glenn J. Hanna

Cancers 2021, 13(3), 562; https://doi.org/10.3390/cancers13030562 - 2 Feb 2021

Cited by 4 | Viewed by 3177

Abstract

The burden of human papillomavirus (HPV)-related oropharyngeal cancer (OPC) has risen, now representing the most common HPV-related malignancy. For years, researchers have explored the utility of measuring HPV-related markers from mouth, throat, and blood samples, often with the aim of gathering more information [...] Read more.

The burden of human papillomavirus (HPV)-related oropharyngeal cancer (OPC) has risen, now representing the most common HPV-related malignancy. For years, researchers have explored the utility of measuring HPV-related markers from mouth, throat, and blood samples, often with the aim of gathering more information about an existing HPV-related tumor in a given patient. We review the widely varying methods for collecting and testing saliva and blood samples and offer guidance for standardizing these practices. We then review an array of clinical contexts in which non-invasive testing holds the most promise for potentially addressing unmet needs. In particular, such testing could help clinicians and researchers monitor the effects of vaccination and treatment. Meanwhile, due to the currently incomplete understanding of how carrying HPV relates to infection and subsequent oncogenesis, non-invasive testing methods may not be suitable for the screening setting at this time. Full article

(This article belongs to the Special Issue Human Papillomavirus (HPV) Associated Head and Neck Cancers: From Basic Biology to Clinical Challenges)

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15 pages, 18325 KiB

Open AccessArticle

Role of Epstein–Barr Virus C Promoter Deletion in Diffuse Large B Cell Lymphoma

by Seiyo Mabuchi, Fumiya Hijioka, Takahiro Watanabe, Yusuke Yanagi, Yusuke Okuno, H. M. Abdullah Al Masud, Yoshitaka Sato, Takayuki Murata and Hiroshi Kimura

Cancers 2021, 13(3), 561; https://doi.org/10.3390/cancers13030561 - 1 Feb 2021

Cited by 12 | Viewed by 4079

Abstract

The Epstein–Barr virus (EBV) is the cause of several malignancies, including diffuse large B cell lymphoma (DLBCL). We recently found that EBV genomes in EBV-positive cancer specimens have various deletions (Okuno et al. Nat Microbiol. 2019). Here, we focus on the deletion of [...] Read more.

The Epstein–Barr virus (EBV) is the cause of several malignancies, including diffuse large B cell lymphoma (DLBCL). We recently found that EBV genomes in EBV-positive cancer specimens have various deletions (Okuno et al. Nat Microbiol. 2019). Here, we focus on the deletion of C promoter (Cp), which transcribes EBV nuclear antigen (EBNA) genes in type III latency. The Cp deletion found in a DLBCL patient (332 bp) was introduced into EBV-BAC of the B95-8 strain. Interestingly, the dCp virus transformed B cells more efficiently than WT and revertant strains. Deletion of Cp also promoted tumor formation and severe pathogenicity in a mouse xenograft model. RNA sequencing and qRT–PCR analyses revealed that Cp transcription was undetectable in the dCp cells. Instead, transcription from the W promoter (Wp), an alternative promoter for EBNA, was activated in the dCp mutant. We also found that the expression of latent membrane protein 2A (LMP2A) was somehow induced in the dCp mutant. Double knockout of Cp and LMP2A indicated that LMP2A is crucial for B cell transformation, but the increased transformation induced by Cp deletion cannot be explained by LMP2A alone. We also tested the effect of an anti-apoptotic viral BCL2 homolog, BHRF1, because its expression was reportedly induced more efficiently by that of Wp. However, increased growth transformation via Cp deletion was not due to the BHRF1 gene. Taken together, the results indicated that deletion of a specific region in Cp increased in vitro transformation and the rate of progression of EBV-positive lymphoproliferative disorders in vivo. Our data suggest that genomic alteration not only of the host but also the virus promotes EBV-positive tumor generation and expansion, although the molecular mechanism underlying this phenomenon is still unclear. However, LMP2A and BHRF1 are not involved. Full article

(This article belongs to the Special Issue Molecular Advances in Diffuse Large B-Cell Lymphoma)

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16 pages, 7743 KiB

Open AccessArticle

⁸⁹Zr-Labeled Domain II-Specific scFv-Fc ImmunoPET Probe for Imaging Epidermal Growth Factor Receptor In Vivo

by Elahe Alizadeh, Khan Behlol Ayaz Ahmed, Viswas Raja Solomon, Vijay Gaja, Wendy Bernhard, Amal Makhlouf, Carolina Gonzalez, Kris Barreto, Angel Casaco, C. Ronald Geyer and Humphrey Fonge

Cancers 2021, 13(3), 560; https://doi.org/10.3390/cancers13030560 - 1 Feb 2021

Cited by 8 | Viewed by 3224

Abstract

Epidermal growth factor receptor I (EGFR) is overexpressed in many cancers. The extracellular domain of EGFR has four binding epitopes (domains I- IV). All clinically approved anti-EGFR antibodies bind to domain III. Imaging agents that bind to domains other than domain III of [...] Read more.

Epidermal growth factor receptor I (EGFR) is overexpressed in many cancers. The extracellular domain of EGFR has four binding epitopes (domains I- IV). All clinically approved anti-EGFR antibodies bind to domain III. Imaging agents that bind to domains other than domain III of EGFR are needed for accurate quantification of EGFR, patient selection for anti-EGFR therapeutics and monitoring of response to therapies. We recently developed a domain II-specific antibody fragment 8709. In this study, we have evaluated the in vitro and in vivo properties of ⁸⁹Zr-8709-scFv-Fc (105 kDa). We conjugated 8709-scFv-Fc with the deferoxamine (DFO) chelator and radiolabeled the DFO-8970-scFv with ⁸⁹Zr. We evaluated the binding of ⁸⁹Zr-DFO-8709-scFv-Fc in EGFR positive and negative cell lines DLD-1, MDA-MB-231 and MDA-MB-435, respectively, and in mouse xenograft models. Simultaneously, we have compared the binding of ⁸⁹Zr-8709-scFv-Fc with ¹¹¹In-nimotuzumab, a domain III anti-EGFR antibody. DFO-8709-scFv-Fc displayed similar cell binding specificity as 8709-scFv-Fc. Saturation cell binding assay and immunoreactive fraction showed that radiolabeling did not alter the binding of 8709-scFv-Fc. Biodistribution and microPET showed good uptake of ⁸⁹Zr-8709-scFv-Fc in xenografts after 120 h post injection (p.i). and was domain-specific to EGFR domain II. ⁸⁹Zr-8709-scFv-Fc did not compete for binding in vitro and in vivo with a known domain III binder nimotuzumab. The results show that ⁸⁹Zr-8709-scFv-Fc is specific to domain II of EGFR making it favorable for quantification of EGFR in vivo, hence, patient selection and monitoring of response to treatment with anti-EGFR antibodies. Full article

(This article belongs to the Special Issue Monoclonal Antibodies: Applications in Diagnosis and Immunotherapy of Cancer)

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16 pages, 2888 KiB

Open AccessEditor’s ChoiceArticle

Type 2 Innate Lymphoid Cells Protect against Colorectal Cancer Progression and Predict Improved Patient Survival

by Qiutong Huang, Nicolas Jacquelot, Adele Preaudet, Soroor Hediyeh-zadeh, Fernando Souza-Fonseca-Guimaraes, Andrew N. J. McKenzie, Philip M. Hansbro, Melissa J. Davis, Lisa A. Mielke, Tracy L. Putoczki and Gabrielle T. Belz

Cancers 2021, 13(3), 559; https://doi.org/10.3390/cancers13030559 - 1 Feb 2021

Cited by 34 | Viewed by 5220

Abstract

Chronic inflammation of the gastrointestinal (GI) tract contributes to colorectal cancer (CRC) progression. While the role of adaptive T cells in CRC is now well established, the role of innate immune cells, specifically innate lymphoid cells (ILCs), is not well understood. To define [...] Read more.

Chronic inflammation of the gastrointestinal (GI) tract contributes to colorectal cancer (CRC) progression. While the role of adaptive T cells in CRC is now well established, the role of innate immune cells, specifically innate lymphoid cells (ILCs), is not well understood. To define the role of ILCs in CRC we employed complementary heterotopic and chemically-induced CRC mouse models. We discovered that ILCs were abundant in CRC tumours and contributed to anti-tumour immunity. We focused on ILC2 and showed that ILC2-deficient mice developed a higher tumour burden compared with littermate wild-type controls. We generated an ILC2 gene signature and using machine learning models revealed that CRC patients with a high intratumor ILC2 gene signature had a favourable clinical prognosis. Collectively, our results highlight a critical role for ILC2 in CRC, suggesting a potential new avenue to improve clinical outcomes through ILC2-agonist based therapeutic approaches. Full article

(This article belongs to the Special Issue NK/ILCs in Tumors)

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13 pages, 632 KiB

Open AccessEditor’s ChoiceReview

PD-L1, TMB, MSI, and Other Predictors of Response to Immune Checkpoint Inhibitors in Biliary Tract Cancer

by Alessandro Rizzo, Angela Dalia Ricci and Giovanni Brandi

Cancers 2021, 13(3), 558; https://doi.org/10.3390/cancers13030558 - 1 Feb 2021

Cited by 189 | Viewed by 9429

Abstract

Biliary tract cancer (BTC) represents the second most frequently diagnosed primary liver cancer worldwide following hepatocellular carcinoma, and the overall survival of patients with unresectable disease remains poor. In recent years, the advent of immune checkpoint inhibitors (ICIs) has revolutionized the therapeutic landscape [...] Read more.

Biliary tract cancer (BTC) represents the second most frequently diagnosed primary liver cancer worldwide following hepatocellular carcinoma, and the overall survival of patients with unresectable disease remains poor. In recent years, the advent of immune checkpoint inhibitors (ICIs) has revolutionized the therapeutic landscape of several malignancies with these agents, which have also been explored in advanced BTC, as monotherapy or in combination with other anticancer agents. However, clinical trials evaluating ICIs in BTC have shown conflicting results, and the clinical benefit provided by immunotherapy seems limited to a small subgroup of BTC patients. Thus, the identification of reliable predictors of the response to immunotherapy represents a significant challenge in this setting. This review provides an overview of the available evidence on the biomarkers predictive of the response to ICIs in patients with advanced BTC, especially focusing on programmed death-ligand 1 (PD-L1), tumor mutational burden (TMB), microsatellite instability (MSI), and other emerging biomarkers. Full article

(This article belongs to the Special Issue Surgical Treatment of Cholangiocarcinoma)

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27 pages, 908 KiB

Open AccessSystematic Review

Candidate Biomarkers for Specific Intraoperative Near-Infrared Imaging of Soft Tissue Sarcomas: A Systematic Review

by Zeger Rijs, A. Naweed Shifai, Sarah E. Bosma, Peter J. K. Kuppen, Alexander L. Vahrmeijer, Stijn Keereweer, Judith V. M. G. Bovée, Michiel A. J. van de Sande, Cornelis F. M. Sier and Pieter B. A. A. van Driel

Cancers 2021, 13(3), 557; https://doi.org/10.3390/cancers13030557 - 1 Feb 2021

Cited by 10 | Viewed by 4425

Abstract

Surgery is the mainstay of treatment for localized soft tissue sarcomas (STS). The curative treatment highly depends on complete tumor resection, as positive margins are associated with local recurrence (LR) and prognosis. However, determining the tumor margin during surgery is challenging. Real-time tumor-specific [...] Read more.

Surgery is the mainstay of treatment for localized soft tissue sarcomas (STS). The curative treatment highly depends on complete tumor resection, as positive margins are associated with local recurrence (LR) and prognosis. However, determining the tumor margin during surgery is challenging. Real-time tumor-specific imaging can facilitate complete resection by visualizing tumor tissue during surgery. Unfortunately, STS specific tracers are presently not clinically available. In this review, STS-associated cell surface-expressed biomarkers, which are currently already clinically targeted with monoclonal antibodies for therapeutic purposes, are evaluated for their use in near-infrared fluorescence (NIRF) imaging of STS. Clinically targeted biomarkers in STS were extracted from clinical trial registers and a PubMed search was performed. Data on biomarker characteristics, sample size, percentage of biomarker-positive STS samples, pattern of biomarker expression, biomarker internalization features, and previous applications of the biomarker in imaging were extracted. The biomarkers were ranked utilizing a previously described scoring system. Eleven cell surface-expressed biomarkers were identified from which 7 were selected as potential biomarkers for NIRF imaging: TEM1, VEGFR-1, EGFR, VEGFR-2, IGF-1R, PDGFRα, and CD40. Promising biomarkers in common and aggressive STS subtypes are TEM1 for myxofibrosarcoma, TEM1, and PDGFRα for undifferentiated soft tissue sarcoma and EGFR for synovial sarcoma. Full article

(This article belongs to the Special Issue Novel Therapeutic Considerations in Bone and Soft Tissue Sarcoma)

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17 pages, 4146 KiB

Open AccessArticle

ESR1 NAPA Assay: Development and Analytical Validation of a Highly Sensitive and Specific Blood-Based Assay for the Detection of ESR1 Mutations in Liquid Biopsies

by Dimitra Stergiopoulou, Athina Markou, Eleni Tzanikou, Ioannis Ladas, G. Mike Makrigiorgos, Vassilis Georgoulias and Evi Lianidou

Cancers 2021, 13(3), 556; https://doi.org/10.3390/cancers13030556 - 1 Feb 2021

Cited by 11 | Viewed by 3613

Abstract

A considerable number of estrogen receptor-positive breast cancer (ER⁺ BrCa) patients develop resistance to endocrine treatment. One of the most important resistance mechanisms is the presence of ESR1 mutations. We developed and analytically validated a highly sensitive and specific NaME-PrO-assisted ARMS (NAPA) [...] Read more.

A considerable number of estrogen receptor-positive breast cancer (ER⁺ BrCa) patients develop resistance to endocrine treatment. One of the most important resistance mechanisms is the presence of ESR1 mutations. We developed and analytically validated a highly sensitive and specific NaME-PrO-assisted ARMS (NAPA) assay for the detection of four ESR1 mutations (Y537S, Y537C, Y537N and D538G) in circulating tumour cells (CTCs) and paired plasma circulating tumour DNA (ctDNA) in patients with ER⁺ BrCa. The analytical specificity, analytical sensitivity and reproducibility of the assay were validated using synthetic oligos standards. We further applied the developed ESR1 NAPA assay in 13 ER⁺ BrCa primary tumour tissues, 13 non-cancerous breast tissues (mammoplasties) and 64 liquid biopsy samples: 32 EpCAM-positive cell fractions and 32 paired plasma ctDNA samples obtained at different time points from 8 ER+ metastatic breast cancer patients, during a 5-year follow-up period. Peripheral blood from 11 healthy donors (HD) was used as a control. The developed assay is highly sensitive (a detection of mutation-allelic-frequency (MAF) of 0.5% for D538G and 0.1% for Y537S, Y537C, Y537N), and highly specific (0/13 mammoplasties and 0/11 HD for all mutations). In the plasma ctDNA, ESR1 mutations were not identified at the baseline, whereas the D538G mutation was detected in five sequential ctDNA samples during the follow-up period in the same patient. In the EpCAM-isolated cell fractions, only the Y537C mutation was detected in one patient sample at the baseline. A direct comparison of the ESR1 NAPA assay with the drop-off ddPCR using 32 identical plasma ctDNA samples gave a concordance of 90.6%. We present a low cost, highly specific, sensitive and robust assay for blood-based ESR1 profiling. The clinical performance of the ESR1 NAPA assay will be prospectively evaluated in a large number of well-characterized patient cohorts. Full article

(This article belongs to the Special Issue Strategies for Isolation and Phenotypic, Genetic, and Functional Characterization of Circulating Tumor Cells)

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15 pages, 2669 KiB

Open AccessArticle

PD-L1 Is an Independent Prognostic Marker in Middle Eastern PTC and Its Expression Is Upregulated by BRAFV600E Mutation

by Abdul K. Siraj, Sandeep Kumar Parvathareddy, Poyil Pratheeshkumar, Sasidharan Padmaja Divya, Saif S. Al-Sobhi, Fouad Al-Dayel and Khawla S. Al-Kuraya

Cancers 2021, 13(3), 555; https://doi.org/10.3390/cancers13030555 - 1 Feb 2021

Cited by 21 | Viewed by 2615

Abstract

PD-L1 inhibition is a promising therapeutic target whose efficacy has been demonstrated in several cancers. Immunohistochemistry was performed to assess PD-L1 protein expression in PTC. We further conducted in vitro analysis to investigate the role of PD-L1 in regulating BRAFV600E in PTC cell [...] Read more.

PD-L1 inhibition is a promising therapeutic target whose efficacy has been demonstrated in several cancers. Immunohistochemistry was performed to assess PD-L1 protein expression in PTC. We further conducted in vitro analysis to investigate the role of PD-L1 in regulating BRAFV600E in PTC cell lines. PD-L1 over-expression was noted in 32.4% (473/1458) of cases and significantly associated with aggressive clinico-pathological parameters. Importantly, PD-L1 was found to be an independent poorer prognostic marker. We also found PD-L1 to be significantly associated with BRAF mutation and patients with co-existing PD-L1 over-expression and BRAF mutation had a poor disease-free survival compared to patients with BRAF mutation alone. In vitro analysis showed high expression of PD-L1 in BRAF-mutated PTC cell lines compared to a BRAF wild-type cell line. Inhibition of BRAF using vemurafenib induced PD-L1 expression in BRAF-mutated cell lines without affecting cell growth. Knockdown of PD-L1 in BRAF-mutated cell lines significantly decreased the cell growth and induced apoptosis. Our data suggest that PD-L1 might represent a useful prognostic marker in Middle Eastern PTC and PD-L1 inhibition could be a potential therapeutic option for aggressive PTC cancers, such as the tall cell variant, BRAF mutation-positive patients that are unresponsive to standard treatment. Full article

(This article belongs to the Collection Mechanism of Immunotherapy in Cancers)

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