Cancers

14 pages, 538 KiB

Open AccessReview

Lymph Node Involvement in Advanced Gastric Cancer in the Era of Multimodal Treatment—Oncological and Surgical Perspective

by Zuzanna Pelc, Magdalena Skórzewska, Karol Rawicz-Pruszyński and Wojciech P. Polkowski

Cancers 2021, 13(10), 2509; https://doi.org/10.3390/cancers13102509 - 20 May 2021

Cited by 12 | Viewed by 3612

Abstract

Gastric cancer (GC) continues to be one of the major oncological challenges on a global scale. The role of neoadjuvant chemotherapy (NAC) in GC is to downstage primary tumour, eliminate potential micrometastases, and increase the chance for radical resection. Although systemic treatment prolongs [...] Read more.

Gastric cancer (GC) continues to be one of the major oncological challenges on a global scale. The role of neoadjuvant chemotherapy (NAC) in GC is to downstage primary tumour, eliminate potential micrometastases, and increase the chance for radical resection. Although systemic treatment prolongs the survival in advanced GC, persistent lymph node (LN) metastases indicate poor prognosis. Further identification of prognostic factors after NAC is urgent and could positively influence clinical outcomes. This article aimed to review the actual trends and future perspectives in multimodal therapy of advanced GC, with a particular interest in the post-neoadjuvant pathological nodal stage. A favourable prognostic impact for ypN0 patients is observed, either due to truly negative LN before the start of therapy or because preoperative therapy achieved a pathologically complete nodal response. Ongoing trials investigating the extent of lymphadenectomy after neoadjuvant therapy will standardise the LN dissection from the multimodal therapy perspective. Since downstaged and primarily node-negative patients show a similar prognosis, the main target for NAC in advanced GC should be nodal clearance. Adequate staging and personalised perioperative therapy seem to be of great importance in the multimodal treatment of GC. Full article

(This article belongs to the Special Issue Advanced Gastric Cancer)

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20 pages, 41610 KiB

Open AccessArticle

The Interaction between Reactive Peritoneal Mesothelial Cells and Tumor Cells via Extracellular Vesicles Facilitates Colorectal Cancer Dissemination

by Simona Serratì, Letizia Porcelli, Francesco Fragassi, Marianna Garofoli, Roberta Di Fonte, Livia Fucci, Rosa Maria Iacobazzi, Antonio Palazzo, Francesca Margheri, Grazia Cristiani, Anna Albano, Raffaele De Luca, Donato Francesco Altomare, Michele Simone and Amalia Azzariti

Cancers 2021, 13(10), 2505; https://doi.org/10.3390/cancers13102505 - 20 May 2021

Cited by 10 | Viewed by 3123

Abstract

Advanced colorectal cancer (CRC) is highly metastatic and often results in peritoneal dissemination. The extracellular vesicles (EVs) released by cancer cells in the microenvironment are important mediators of tumor metastasis. We investigated the contribution of EV-mediated interaction between peritoneal mesothelial cells (MCs) and [...] Read more.

Advanced colorectal cancer (CRC) is highly metastatic and often results in peritoneal dissemination. The extracellular vesicles (EVs) released by cancer cells in the microenvironment are important mediators of tumor metastasis. We investigated the contribution of EV-mediated interaction between peritoneal mesothelial cells (MCs) and CRC cells in generating a pro-metastatic environment in the peritoneal cavity. Peritoneal MCs isolated from peritoneal lavage fluids displayed high CD44 expression, substantial mesothelial-to-mesenchymal transition (MMT) and released EVs that both directed tumor invasion and caused reprogramming of secretory profiles by increasing TGF-β1 and uPA/uPAR expression and MMP-2/9 activation in tumor cells. Notably, the EVs released by tumor cells induced apoptosis by activating caspase-3, peritoneal MC senescence, and MMT, thereby augmenting the tumor-promoting potential of these cells in the peritoneal cavity. By using pantoprazole, we reduced the biogenesis of EVs and their pro-tumor functions. In conclusion, our findings provided evidence of underlying mechanisms of CRC dissemination driven by the interaction of peritoneal MCs and tumor cells via the EVs released in the peritoneal cavity, which may have important implications for the clinical management of patients. Full article

(This article belongs to the Special Issue Targeting Therapy for Colon Cancer)

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20 pages, 6138 KiB

Open AccessArticle

Cell-Penetrating CEBPB and CEBPD Leucine Zipper Decoys as Broadly Acting Anti-Cancer Agents

by Qing Zhou, Xiotian Sun, Nicolas Pasquier, Parvaneh Jefferson, Trang T. T. Nguyen, Markus D. Siegelin, James M. Angelastro and Lloyd A. Greene

Cancers 2021, 13(10), 2504; https://doi.org/10.3390/cancers13102504 - 20 May 2021

Cited by 21 | Viewed by 4993

Abstract

Transcription factors are key players underlying cancer formation, growth, survival, metastasis and treatment resistance, yet few drugs exist to directly target them. Here, we characterized the in vitro and in vivo anti-cancer efficacy of novel synthetic cell-penetrating peptides (Bpep and Dpep) designed to [...] Read more.

Transcription factors are key players underlying cancer formation, growth, survival, metastasis and treatment resistance, yet few drugs exist to directly target them. Here, we characterized the in vitro and in vivo anti-cancer efficacy of novel synthetic cell-penetrating peptides (Bpep and Dpep) designed to interfere with the formation of active leucine-zipper-based dimers by CEBPB and CEBPD, transcription factors implicated in multiple malignancies. Both peptides similarly promoted apoptosis of multiple tumor lines of varying origins, without such effects on non-transformed cells. Combined with other treatments (radiation, Taxol, chloroquine, doxorubicin), the peptides acted additively to synergistically and were fully active on Taxol-resistant cells. The peptides suppressed expression of known direct CEBPB/CEBPD targets IL6, IL8 and asparagine synthetase (ASNS), supporting their inhibition of transcriptional activation. Mechanisms by which the peptides trigger apoptosis included depletion of pro-survival survivin and a required elevation of pro-apoptotic BMF. Bpep and Dpep significantly slowed tumor growth in mouse models without evident side effects. Dpep significantly prolonged survival in xenograft models. These findings indicate the efficacy and potential of Bpep and Dpep as novel agents to treat a variety of cancers as mono- or combination therapies. Full article

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15 pages, 524 KiB

Open AccessReview

CAR T-Cells for CNS Lymphoma: Driving into New Terrain?

by Philipp Karschnia, Jens Blobner, Nico Teske, Florian Schöberl, Esther Fitzinger, Martin Dreyling, Joerg-Christian Tonn, Niklas Thon, Marion Subklewe and Louisa von Baumgarten

Cancers 2021, 13(10), 2503; https://doi.org/10.3390/cancers13102503 - 20 May 2021

Cited by 15 | Viewed by 5259

Abstract

Primary CNS lymphomas (PCNSL) represent a group of extranodal non-Hodgkin lymphomas and secondary CNS lymphomas refer to secondary involvement of the neuroaxis by systemic disease. CNS lymphomas are associated with limited prognosis even after aggressive multimodal therapy. Chimeric antigen receptor (CAR) T-cells have [...] Read more.

Primary CNS lymphomas (PCNSL) represent a group of extranodal non-Hodgkin lymphomas and secondary CNS lymphomas refer to secondary involvement of the neuroaxis by systemic disease. CNS lymphomas are associated with limited prognosis even after aggressive multimodal therapy. Chimeric antigen receptor (CAR) T-cells have proven as a promising therapeutic avenue in hematological B-cell malignancies including diffuse large B-cell lymphoma, B-cell acute lymphoblastic leukemia, and mantle-cell lymphoma. CARs endow an autologous T-cell population with MHC-unrestricted effectivity against tumor target antigens such as the pan B-cell marker CD19. In PCNSL, compelling and long-lasting anti-tumor effects of such therapy have been shown in murine immunocompromised models. In clinical studies on CAR T-cells for CNS lymphoma, only limited data are available and often include both patients with PCNSL but also patients with secondary CNS lymphoma. Several clinical trials on CAR T-cell therapy for primary and secondary CNS lymphoma are currently ongoing. Extrapolated from the available preliminary data, an overall acceptable safety profile with considerable anti-tumor effects might be expected. Whether these beneficial anti-tumor effects are as long-lasting as in animal models is currently in doubt; and the immunosuppressive tumor microenvironment of the brain may be among the most pivotal factors limiting efficacy of CAR T-cell therapy in CNS lymphoma. Based on an increasing understanding of CAR T-cell interactions with the tumor cells as well as the cerebral tissue, modifications of CAR design or the combination of CAR T-cell therapy with other therapeutic approaches may aid to release the full therapeutic efficiency of CAR T-cells. CAR T-cells may therefore emerge as a novel treatment strategy in primary and secondary CNS lymphoma. Full article

(This article belongs to the Special Issue Primary CNS Lymphomas: Diagnosis and Treatment)

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10 pages, 1373 KiB

Open AccessArticle

Evaluation of the Ginsburg Scheme: Where Is Significant Prostate Cancer Missed?

by August Sigle, Cordula A. Jilg, Timur H. Kuru, Nadine Binder, Jakob Michaelis, Markus Grabbert, Wolfgang Schultze-Seemann, Arkadiusz Miernik, Christian Gratzke, Matthias Benndorf and Rodrigo Suarez-Ibarrola

Cancers 2021, 13(10), 2502; https://doi.org/10.3390/cancers13102502 - 20 May 2021

Cited by 4 | Viewed by 2476

Abstract

Background: Systematic biopsy (SB) according to the Ginsburg scheme (GBS) is widely used to complement MRI-targeted biopsy (MR-TB) for optimizing the diagnosis of clinically significant prostate cancer (sPCa). Knowledge of the GBS’s blind sectors where sPCa is missed is crucial to improve biopsy [...] Read more.

Background: Systematic biopsy (SB) according to the Ginsburg scheme (GBS) is widely used to complement MRI-targeted biopsy (MR-TB) for optimizing the diagnosis of clinically significant prostate cancer (sPCa). Knowledge of the GBS’s blind sectors where sPCa is missed is crucial to improve biopsy strategies. Methods: We analyzed cancer detection rates in 1084 patients that underwent MR-TB and SB. Cancerous lesions that were missed or underestimated by GBS were re-localized onto a prostate map encompassing Ginsburg sectors and blind-sectors (anterior, central, basodorsal and basoventral). Logistic regression analysis (LRA) and prostatic configuration analysis were applied to identify predictors for missing sPCa with the GBS. Results: GBS missed sPCa in 39 patients (39/1084, 3.6%). In 27 cases (27/39, 69.2%), sPCa was missed within a blind sector, with 17/39 lesions localized in the anterior region (43.6%). Neither LRA nor prostatic configuration analysis identified predictors for missing sPCa with the GBS. Conclusions: This is the first study to analyze the distribution of sPCa missed by the GBS. GBS misses sPCa in few men only, with the majority localized in the anterior region. Adding blind sectors to GBS defined a new sector map of the prostate suited for reporting histopathological biopsy results. Full article

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

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14 pages, 2235 KiB

Open AccessArticle

The Impact of Illness Perceptions and Coping Strategies on Use of Supportive Care for Cancer

by Peta Stephenson, Eva Yuen, Gemma Skaczkowski, Evelien R. Spelten, Sheina Orbell and Carlene Wilson

Cancers 2021, 13(10), 2501; https://doi.org/10.3390/cancers13102501 - 20 May 2021

Cited by 7 | Viewed by 3547

Abstract

Despite evidence that survivorship support programmes enhance physical and psychosocial wellbeing, cancer patients and survivors often do not use these supportive care services. This study investigated the utility of the Common Sense Model of Self-Regulation for predicting supportive care use following cancer, and [...] Read more.

Despite evidence that survivorship support programmes enhance physical and psychosocial wellbeing, cancer patients and survivors often do not use these supportive care services. This study investigated the utility of the Common Sense Model of Self-Regulation for predicting supportive care use following cancer, and the mediating role of coping strategies. Cancer patients and survivors (n = 336 from Australia, n = 61 from the UK; 191 males, 206 females) aged 20–83 years (Mean (M) = 62.73, Standard Deviation (SD) = 13.28) completed an online questionnaire. Predictor variables were cognitive and emotional representations of cancer, as measured by the Illness Perception Questionnaire—Revised (IPQ-R), and problem- and emotion-focused coping strategies, as measured by the Brief-Coping Orientation to Problems Experienced inventory (Brief-COPE). The outcome variable was survivorship support programme use within the preceding month. Perceived personal control over cancer predicted supportive care use, but cancer-related emotional distress did not. Coping was an inconsistent mediator of the relationships. Problem-focused coping mediated the relationship between personal control and supportive care use; emotion-focused coping did not mediate between emotional responses to cancer and the uptake of survivorship support programmes. The Common Sense Model provides a useful framework for understanding survivorship support programme use. However, more clarity around the relationship between illness beliefs and coping is required. Full article

(This article belongs to the Special Issue Cancer Survivorship)

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24 pages, 1286 KiB

Open AccessReview

Harnessing CD16-Mediated NK Cell Functions to Enhance Therapeutic Efficacy of Tumor-Targeting mAbs

by Cristina Capuano, Chiara Pighi, Simone Battella, Davide De Federicis, Ricciarda Galandrini and Gabriella Palmieri

Cancers 2021, 13(10), 2500; https://doi.org/10.3390/cancers13102500 - 20 May 2021

Cited by 47 | Viewed by 9437

Abstract

Natural killer (NK) cells hold a pivotal role in tumor-targeting monoclonal antibody (mAb)-based activity due to the expression of CD16, the low-affinity receptor for IgG. Indeed, beyond exerting cytotoxic function, activated NK cells also produce an array of cytokines and chemokines, through which [...] Read more.

Natural killer (NK) cells hold a pivotal role in tumor-targeting monoclonal antibody (mAb)-based activity due to the expression of CD16, the low-affinity receptor for IgG. Indeed, beyond exerting cytotoxic function, activated NK cells also produce an array of cytokines and chemokines, through which they interface with and potentiate adaptive immune responses. Thus, CD16-activated NK cells can concur to mAb-dependent “vaccinal effect”, i.e., the development of antigen-specific responses, which may be highly relevant in maintaining long-term protection of treated patients. On this basis, the review will focus on strategies aimed at potentiating NK cell-mediated antitumor functions in tumor-targeting mAb-based regimens, represented by (a) mAb manipulation strategies, aimed at augmenting recruitment and efficacy of NK cells, such as Fc-engineering, and the design of bi- or trispecific NK cell engagers and (b) the possible exploitation of memory NK cells, whose distinctive characteristics (enhanced responsiveness to CD16 engagement, longevity, and intrinsic resistance to the immunosuppressive microenvironment) may maximize therapeutic mAb antitumor efficacy. Full article

(This article belongs to the Special Issue Antibodies in Cancer Treatment)

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16 pages, 4464 KiB

Open AccessArticle

Expression of Cancer Testis Antigens in Tumor-Adjacent Normal Liver Is Associated with Post-Resection Recurrence of Hepatocellular Carcinoma

by Lisanne Noordam, Zhouhong Ge, Hadiye Özturk, Michail Doukas, Shanta Mancham, Patrick P. C. Boor, Lucia Campos Carrascosa, Guoying Zhou, Thierry P. P. van den Bosch, Qiuwei Pan, Jan N. M. IJzermans, Marco J. Bruno, Dave Sprengers and Jaap Kwekkeboom

Cancers 2021, 13(10), 2499; https://doi.org/10.3390/cancers13102499 - 20 May 2021

Cited by 5 | Viewed by 2774

Abstract

High recurrence rates after resection of hepatocellular carcinoma (HCC) with curative intent impair clinical outcomes of HCC. Cancer/testis antigens (CTAs) are suitable targets for cancer immunotherapy if selectively expressed in tumor cells. The aims were to identify CTAs that are frequently and selectively [...] Read more.

High recurrence rates after resection of hepatocellular carcinoma (HCC) with curative intent impair clinical outcomes of HCC. Cancer/testis antigens (CTAs) are suitable targets for cancer immunotherapy if selectively expressed in tumor cells. The aims were to identify CTAs that are frequently and selectively expressed in HCC-tumors, and to investigate whether CTAs could serve as biomarkers for occult metastasis. Tumor and paired tumor-free liver (TFL) tissues of HCC-patients and healthy tissues were assessed for mRNA expression of 49 CTAs by RT-qPCR and protein expression of five CTAs by immunohistochemistry. Twelve CTA-mRNAs were expressed in ≥10% of HCC-tumors and not in healthy tissues except testis. In tumors, mRNA and protein of ≥ 1 CTA was expressed in 78% and 71% of HCC-patients, respectively. In TFL, CTA mRNA and protein was found in 45% and 30% of HCC-patients, respectively. Interestingly, CTA-expression in TFL was an independent negative prognostic factor for post-resection HCC-recurrence and survival. We established a panel of 12 testis-restricted CTAs expressed in tumors of most HCC-patients. The increased risk of HCC-recurrence in patients with CTA expression in TFL, suggests that CTA-expressing (pre-)malignant cells may be a source of HCC-recurrence, reflecting the relevance of targeting these to prevent HCC-recurrence. Full article

(This article belongs to the Special Issue Assessing and Influencing Prognosis in Hepatocellular Carcinoma)

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15 pages, 2425 KiB

Open AccessArticle

Comparative Transcriptomics of Immune Checkpoint Inhibitor Myocarditis Identifies Guanylate Binding Protein 5 and 6 Dysregulation

by Daniel Finke, Markus B. Heckmann, Janek Salatzki, Johannes Riffel, Esther Herpel, Lucie M. Heinzerling, Benjamin Meder, Mirko Völkers, Oliver J. Müller, Norbert Frey, Hugo A. Katus, Florian Leuschner, Ziya Kaya and Lorenz H. Lehmann

Cancers 2021, 13(10), 2498; https://doi.org/10.3390/cancers13102498 - 20 May 2021

Cited by 28 | Viewed by 4541

Abstract

Immune checkpoint inhibitors (ICIs) are revolutionizing cancer treatment. Nevertheless, their increasing use leads to an increase of immune-related adverse events (irAEs). Among them, ICI-associated myocarditis (ICIM) is a rare irAE with a high mortality rate. We aimed to characterize the transcriptional changes of [...] Read more.

Immune checkpoint inhibitors (ICIs) are revolutionizing cancer treatment. Nevertheless, their increasing use leads to an increase of immune-related adverse events (irAEs). Among them, ICI-associated myocarditis (ICIM) is a rare irAE with a high mortality rate. We aimed to characterize the transcriptional changes of ICIM myocardial biopsies and their possible implications. Patients suspected for ICIM were assessed in the cardio-oncology units of University Hospitals Heidelberg and Kiel. Via RNA sequencing of myocardial biopsies, we compared transcriptional changes of ICIM (n = 9) with samples from dilated cardiomyopathy (DCM, n = 11), virus-induced myocarditis (VIM, n = 5), and with samples of patients receiving ICIs without any evidence of myocarditis (n = 4). Patients with ICIM (n = 19) showed an inconsistent clinical presentation, e.g., asymptomatic elevation of cardiac biomarkers (hs-cTnT, NT-proBNP, CK), a drop in left ventricular ejection fraction, or late gadolinium enhancement in cMRI. We found 3784 upregulated genes in ICIM (FDR < 0.05). In the overrepresented pathway ‘response to interferon-gamma’, we found guanylate binding protein 5 and 6 (compared with VIM: GBP5 (log2 fc 3.21), GBP6 (log2 fc 5.37)) to be significantly increased in ICIM on RNA- and protein-level. We conclude that interferon-gamma and inflammasome-regulating proteins, such as GBP5, may be of unrecognized significance in the pathophysiology of ICIM. Full article

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18 pages, 1286 KiB

Open AccessReview

Cyclin-Dependent Kinase Inhibitors in Hematological Malignancies—Current Understanding, (Pre-)Clinical Application and Promising Approaches

by Anna Richter, Nina Schoenwaelder, Sina Sender, Christian Junghanss and Claudia Maletzki

Cancers 2021, 13(10), 2497; https://doi.org/10.3390/cancers13102497 - 20 May 2021

Cited by 14 | Viewed by 3988

Abstract

Genetically altered stem or progenitor cells feature gross chromosomal abnormalities, inducing modified ability of self-renewal and abnormal hematopoiesis. Cyclin-dependent kinases (CDK) regulate cell cycle progression, transcription, DNA repair and are aberrantly expressed in hematopoietic malignancies. Incorporation of CDK inhibitors (CDKIs) into the existing [...] Read more.

Genetically altered stem or progenitor cells feature gross chromosomal abnormalities, inducing modified ability of self-renewal and abnormal hematopoiesis. Cyclin-dependent kinases (CDK) regulate cell cycle progression, transcription, DNA repair and are aberrantly expressed in hematopoietic malignancies. Incorporation of CDK inhibitors (CDKIs) into the existing therapeutic regimens therefore constitutes a promising strategy. However, the complex molecular heterogeneity and different clinical presentation is challenging for selecting the right target and defining the ideal combination to mediate long-term disease control. Preclinical and early clinical data suggest that specific CDKIs have activity in selected patients, dependent on the existing rearrangements and mutations, potentially acting as biomarkers. Indeed, CDK6, expressed in hematopoietic cells, is a direct target of MLL fusion proteins often observed in acute leukemia and thus contributes to leukemogenesis. The high frequency of aberrancies in the retinoblastoma pathway additionally warrants application of CDKIs in hematopoietic neoplasms. In this review, we describe the preclinical and clinical advances recently made in the use of CDKIs. These include the FDA-approved CDK4/6 inhibitors, traditional and novel pan-CDKIs, as well as dual kinase inhibitors. We additionally provide an overview on molecular mechanisms of response vs. resistance and discuss open questions. Full article

(This article belongs to the Special Issue Targeting Cyclin-Dependent Kinases in Human Cancers)

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14 pages, 3512 KiB

Open AccessSystematic Review

Differential Prognosis and Response of Denovo vs. Secondary Muscle-Invasive Bladder Cancer: An Updated Systematic Review and Meta-Analysis

by Mario Pones, David D’Andrea, Keiichiro Mori, Mohammad Abufraj, Marco Moschini, Eva Comperat and Shahrokh F. Shariat

Cancers 2021, 13(10), 2496; https://doi.org/10.3390/cancers13102496 - 20 May 2021

Cited by 11 | Viewed by 2381

Abstract

To evaluate oncological outcomes of primary versus secondary muscle-invasive bladder cancer treated with radical cystectomy. Medline, Embase, Scopus and Cochrane Library were searched for eligible studies. Hazard ratios for overall survival (OS), cancer specific survival (CSS) and progression free survival (PFS) were calculated [...] Read more.

To evaluate oncological outcomes of primary versus secondary muscle-invasive bladder cancer treated with radical cystectomy. Medline, Embase, Scopus and Cochrane Library were searched for eligible studies. Hazard ratios for overall survival (OS), cancer specific survival (CSS) and progression free survival (PFS) were calculated using survival data extracted from Kaplan-Meier curves. A total of 16 studies with 5270 patients were included. Pooled analysis showed similar 5-year and 10-year OS (HR 1, p = 0.96 and HR 1, p = 0.14) and CSS (HR 1.02, p = 0.85 and HR 0.99, p = 0.93) between primMIBC and secMIBC. Subgroup analyses according to starting point of follow-up and second-look transurethral resection revealed similar results. Subgroup analyses of studies in which neoadjuvant chemotherapy was administered demonstrated significantly worse 5-year CSS (HR 1.5, p = 0.04) but not 10-year CSS (HR 1.36, p = 0.13) in patients with secMIBC. Patients with secMIBC had significantly worse PFS at 5-year (HR 1.41, p = 0.002) but not at 10-year follow-up (HR 1.25, p = 0.34). This review found comparable oncologic outcomes between primMIBC and secMIBC patients treated with RC regarding OS and CSS. Subgroup analysis showed worse 5-year CSS but not 10-year CSS for neoadjuvant chemotherapy in the secMIBC group. Prospective clinical trials incorporating molecular markers, that allow precise risk stratification of secMIBC and further research uncovering underlying molecular and clinical drivers of the heterogeneous group of secMIBC is needed. Full article

(This article belongs to the Special Issue The Evolving Landscape of Tumor Microenvironment in Kidney and Bladder Cancers)

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20 pages, 1046 KiB

Open AccessFeature PaperReview

Recent Progress in Dendritic Cell-Based Cancer Immunotherapy

by Kazuhiko Matsuo, Osamu Yoshie, Kosuke Kitahata, Momo Kamei, Yuta Hara and Takashi Nakayama

Cancers 2021, 13(10), 2495; https://doi.org/10.3390/cancers13102495 - 20 May 2021

Cited by 33 | Viewed by 7504

Abstract

Cancer immunotherapy aims to treat cancer by enhancing cancer-specific host immune responses. Recently, cancer immunotherapy has been attracting much attention because of the successful clinical application of immune checkpoint inhibitors targeting the CTLA-4 and PD-1/PD-L1 pathways. However, although highly effective in some patients, [...] Read more.

Cancer immunotherapy aims to treat cancer by enhancing cancer-specific host immune responses. Recently, cancer immunotherapy has been attracting much attention because of the successful clinical application of immune checkpoint inhibitors targeting the CTLA-4 and PD-1/PD-L1 pathways. However, although highly effective in some patients, immune checkpoint inhibitors are beneficial only in a limited fraction of patients, possibly because of the lack of enough cancer-specific immune cells, especially CD8⁺ cytotoxic T-lymphocytes (CTLs), in the host. On the other hand, studies on cancer vaccines, especially DC-based ones, have made significant progress in recent years. In particular, the identification and characterization of cross-presenting DCs have greatly advanced the strategy for the development of effective DC-based vaccines. In this review, we first summarize the surface markers and functional properties of the five major DC subsets. We then describe new approaches to induce antigen-specific CTLs by targeted delivery of antigens to cross-presenting DCs. In this context, the chemokine receptor XCR1 and its ligand XCL1, being selectively expressed by cross-presenting DCs and mainly produced by activated CD8⁺ T cells, respectively, provide highly promising molecular tools for this purpose. In the near future, CTL-inducing DC-based cancer vaccines may provide a new breakthrough in cancer immunotherapy alone or in combination with immune checkpoint inhibitors. Full article

(This article belongs to the Special Issue Cancer and Immune Cell Migration and Trafficking)

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14 pages, 2291 KiB

Open AccessArticle

Long-Term Survival Effect of the Interval between Postoperative Chemotherapy and Radiotherapy in Patients with Completely Resected Pathological N2 Non-Small-Cell Lung Cancer

by Shih-Min Lin, Hsiu-Ying Ku, Che-Yu Hsu, Chih-Liang Wang, Gee-Chen Chang, Cheng-Shyong Chang and Tsang-Wu Liu

Cancers 2021, 13(10), 2494; https://doi.org/10.3390/cancers13102494 - 20 May 2021

Cited by 2 | Viewed by 2463

Abstract

(1) Purpose: To investigate the effects of the time interval between initiation of adjuvant chemotherapy and radiotherapy on survival outcomes in patients with completely resected stage IIIA pN2 non-small-cell lung cancer (NSCLC); (2) Methods: Data on 2515 patients with completely resected stage IIIA [...] Read more.

(1) Purpose: To investigate the effects of the time interval between initiation of adjuvant chemotherapy and radiotherapy on survival outcomes in patients with completely resected stage IIIA pN2 non-small-cell lung cancer (NSCLC); (2) Methods: Data on 2515 patients with completely resected stage IIIA pN2 NSCLC in 2007–2017 were extracted from the Taiwan Cancer Registry Database. The survival outcomes in patients who underwent concurrent chemoradiotherapy (CCRT) and sequential chemotherapy and radiotherapy (SCRT) with either a short (SCRT1) or long (SCRT2) interval between treatments were estimated using Kaplan–Meier, Cox regression, and propensity score matching (PSM); (3) Results: Multivariate analyses of OS showed that SCRT2 (hazard ratio [HR] 0.64, p = 0.017) was associated with improved overall survival (OS). After PSM, the median OS periods were 64 and 75 months in the SCRT1 and SCRT2 groups, respectively, which differed significantly from that of 58 months in the CCRT group (p = 0.003). In elderly patients, SCRT2 significantly improved survival relative to CCRT before PSM (p = 0.024) and after PSM (p = 0.002); (4) Conclusions: A longer interval between initiation of adjuvant chemotherapy and postoperative radiotherapy (PORT; SCRT2) improved OS relative to CCRT; the benefits were greater in elderly patients (age >60 years). Full article

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21 pages, 3170 KiB

Open AccessArticle

Organoruthenium Complexes with Benzo-Fused Pyrithiones Overcome Platinum Resistance in Ovarian Cancer Cells

by Jerneja Kladnik, James P. C. Coverdale, Jakob Kljun, Hilke Burmeister, Petra Lippman, Francesca G. Ellis, Alan M. Jones, Ingo Ott, Isolda Romero-Canelón and Iztok Turel

Cancers 2021, 13(10), 2493; https://doi.org/10.3390/cancers13102493 - 20 May 2021

Cited by 22 | Viewed by 4424

Abstract

Drug resistance to existing anticancer agents is a growing clinical concern, with many first line treatments showing poor efficacy in treatment plans of some cancers. Resistance to platinum agents, such as cisplatin, is particularly prevalent in the treatment of ovarian cancer, one of [...] Read more.

Drug resistance to existing anticancer agents is a growing clinical concern, with many first line treatments showing poor efficacy in treatment plans of some cancers. Resistance to platinum agents, such as cisplatin, is particularly prevalent in the treatment of ovarian cancer, one of the most common cancers amongst women in the developing world. Therefore, there is an urgent need to develop next generation of anticancer agents which can overcome resistance to existing therapies. We report a new series of organoruthenium(II) complexes bearing structurally modified pyrithione ligands with extended aromatic scaffold, which overcome platinum and adriamycin resistance in human ovarian cancer cells. The mechanism of action of such complexes appears to be unique from that of cisplatin, involving G₁ cell cycle arrest without generation of cellular ROS, as is typically associated with similar ruthenium complexes. The complexes inhibit the enzyme thioredoxin reductase (TrxR) in a model system and reduce cell motility towards wound healing. Importantly, this work highlights further development in our understanding of the multi-targeting mechanism of action exhibited by transition metal complexes. Full article

(This article belongs to the Special Issue New Diagnostic and Therapeutic Tools Against Multidrug Resistant Tumors (STRATAGEM Special Issue, EU-COST CA17104))

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12 pages, 1404 KiB

Open AccessArticle

Patterns of Recurrence after Neoadjuvant Therapy in Early Breast Cancer, according to the Residual Cancer Burden Index and Reductions in Neoadjuvant Treatment Intensity

by Christoph Suppan, Florian Posch, Hannah Deborah Mueller, Nina Mischitz, Daniel Steiner, Eva Valentina Klocker, Lisa Setaffy, Ute Bargfrieder, Robert Hammer, Hubert Hauser, Philipp J. Jost, Nadia Dandachi, Sigurd Lax and Marija Balic

Cancers 2021, 13(10), 2492; https://doi.org/10.3390/cancers13102492 - 20 May 2021

Cited by 7 | Viewed by 3388

Abstract

Background: The prognostic performance of the residual cancer burden (RCB) score is a promising tool for breast cancer patients undergoing neoadjuvant therapy. We independently evaluated the prognostic value of RCB scores in an extended validation cohort. Additionally, we analyzed the association between chemotherapy [...] Read more.

Background: The prognostic performance of the residual cancer burden (RCB) score is a promising tool for breast cancer patients undergoing neoadjuvant therapy. We independently evaluated the prognostic value of RCB scores in an extended validation cohort. Additionally, we analyzed the association between chemotherapy dose reduction and RCB scores. Methods: In this extended validation study, 367 breast cancer patients with available RCB scores were followed up for recurrence-free survival (RFS), distant disease-free survival (DDFS), and overall survival (OS). We also computed standardized cumulative doses of anthracyclines and taxanes (A/Ts) to investigate a potential interaction between neoadjuvant chemotherapy dose reduction and RCB scores. Results: Higher RCB scores were consistently associated with adverse clinical outcomes across different molecular subtypes (HR for RFS = 1.60, 95% CI 1.33–1.93, p < 0.0001; HR for DDFS = 1.70, 95% CI 1.39–2.05, p < 0.0001; HR for OS = 1.67, 95% CI 1.34–2.08, p < 0.0001). The adverse impact prevailed throughout 5 years of follow-up, with a peak for relapse risk between 1–2 years after surgery. Clinical outcomes of patients with RCB class 1 did not differ substantially at 5 years compared to RCB class 0. A total of 180 patients (49.1%) underwent dose reduction of neoadjuvant A/T chemotherapy. We observed a statistically significant interaction between dose reduction and higher RCB scores (interaction p-value = 0.042). Conclusion: Our results confirm RCB score as a prognostic marker for RFS, DDFS, and OS independent of the molecular subtype. Importantly, we show that lower doses of cumulative neoadjuvant A/T were associated with higher RCB scores in patients who required a dose reduction. Full article

(This article belongs to the Special Issue Neoadjuvant Systemic Therapy in Early Breast Cancer)

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15 pages, 1972 KiB

Open AccessReview

Cripto-1 as a Potential Target of Cancer Stem Cells for Immunotherapy

by Hiroko Ishii, Said M. Afify, Ghmkin Hassan, David S. Salomon and Masaharu Seno

Cancers 2021, 13(10), 2491; https://doi.org/10.3390/cancers13102491 - 20 May 2021

Cited by 12 | Viewed by 4245

Abstract

The immune system has been found to be suppressed in cancer patients. Cancer cells are extremely resistant to chemotherapeutic drugs, conventional immunotherapy, or cancer antigen vaccine therapy. Cancer immunotherapy, which is mainly based on immune checkpoint inhibitors, such as those for PD-1, PD-L1, [...] Read more.

The immune system has been found to be suppressed in cancer patients. Cancer cells are extremely resistant to chemotherapeutic drugs, conventional immunotherapy, or cancer antigen vaccine therapy. Cancer immunotherapy, which is mainly based on immune checkpoint inhibitors, such as those for PD-1, PD-L1, and CTLA4, is an effective treatment method. However, no immunotherapeutic target has been found that retains validity in the face of tumor diversity. The transforming growth factor (TGF)-β cytokine family possesses broad biological activity and is involved in the induction and/or transdifferentiation of helper T cells, which are important in immunotherapy. Nodal is a member of the TGF-β family playing important roles in tissue stem cells and cancer stem cells (CSCs), interacting with the co-receptor Cripto-1, as well as with Activin type IB (Alk4) and Activin typeIIreceptors, and maintaining stemness and Notch and Wnt/β-catenin signaling in CSCs. In recent years, it has been reported that Cripto-1 could be a potential therapeutic target in CSCs. Here, we review the accumulated literature on the molecular mechanisms by which Cripto-1 functions in CSCs and discuss the potential of Cripto-1 as an immunotherapeutic target in CSCs. Full article

(This article belongs to the Special Issue The Portrait of Cancer Immunotherapy: Tumor Microenvironment, Biomarkers and Immune Resistance)

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29 pages, 11484 KiB

Open AccessArticle

The Carcinogen Cadmium Activates Lysine 63 (K63)-Linked Ubiquitin-Dependent Signaling and Inhibits Selective Autophagy

by Abderrahman Chargui, Amine Belaid, Papa Diogop Ndiaye, Véronique Imbert, Michel Samson, Jean-Marie Guigonis, Michel Tauc, Jean-François Peyron, Philippe Poujeol, Patrick Brest, Paul Hofman and Baharia Mograbi

Cancers 2021, 13(10), 2490; https://doi.org/10.3390/cancers13102490 - 20 May 2021

Cited by 8 | Viewed by 3396

Abstract

Signaling, proliferation, and inflammation are dependent on K63-linked ubiquitination—conjugation of a chain of ubiquitin molecules linked via lysine 63. However, very little information is currently available about how K63-linked ubiquitination is subverted in cancer. The present study provides, for the first time, evidence [...] Read more.

Signaling, proliferation, and inflammation are dependent on K63-linked ubiquitination—conjugation of a chain of ubiquitin molecules linked via lysine 63. However, very little information is currently available about how K63-linked ubiquitination is subverted in cancer. The present study provides, for the first time, evidence that cadmium (Cd), a widespread environmental carcinogen, is a potent activator of K63-linked ubiquitination, independently of oxidative damage, activation of ubiquitin ligase, or proteasome impairment. We show that Cd induces the formation of protein aggregates that sequester and inactivate cylindromatosis (CYLD) and selective autophagy, two tumor suppressors that deubiquitinate and degrade K63-ubiquitinated proteins, respectively. The aggregates are constituted of substrates of selective autophagy—SQSTM1, K63-ubiquitinated proteins, and mitochondria. These protein aggregates also cluster double-membrane remnants, which suggests an impairment in autophagosome maturation. However, failure to eliminate these selective cargos is not due to alterations in the general autophagy process, as degradation of long-lived proteins occurs normally. We propose that the simultaneous disruption of CYLD and selective autophagy by Cd feeds a vicious cycle that further amplifies K63-linked ubiquitination and downstream activation of the NF-κB pathway, processes that support cancer progression. These novel findings link together impairment of selective autophagy, K63-linked ubiquitination, and carcinogenesis. Full article

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12 pages, 1378 KiB

Open AccessArticle

Response and Toxicity to the Second Course of 3 Cycles of ¹⁷⁷Lu-PSMA Therapy Every 4 Weeks in Patients with Metastatic Castration-Resistant Prostate Cancer

by Sazan Rasul, Tim Wollenweber, Lucia Zisser, Elisabeth Kretschmer-Chott, Bernhard Grubmüller, Gero Kramer, Shahrokh F. Shariat, Harald Eidherr, Markus Mitterhauser, Chrysoula Vraka, Werner Langsteger, Marcus Hacker and Alexander R. Haug

Cancers 2021, 13(10), 2489; https://doi.org/10.3390/cancers13102489 - 20 May 2021

Cited by 6 | Viewed by 2987

Abstract

Background: We investigated the response rate and degree of toxicity of a second course of three cycles of [¹⁷⁷Lu]Lu-PSMA radioligand therapy (PSMA-RLT) every 4 weeks in mCRPC patients. Methods: Forty-three men (71.5 ± 6.6 years, median PSA 40.8 (0.87–1358 µg/L)) were [...] Read more.

Background: We investigated the response rate and degree of toxicity of a second course of three cycles of [¹⁷⁷Lu]Lu-PSMA radioligand therapy (PSMA-RLT) every 4 weeks in mCRPC patients. Methods: Forty-three men (71.5 ± 6.6 years, median PSA 40.8 (0.87–1358 µg/L)) were studied. The response was based on the PSA level 4 weeks after the third cycle. The laboratory parameters before and one month after the last cycle were compared. Kaplan–Meier methods were used to estimate the progression-free survival (PFS) and overall survival (OS), and the Cox regression model was performed to find predictors of survival. Results: Twenty-six patients (60.5%) exhibited a PSA reduction (median PSA declined from 40.8 to 20.2, range 0.6–1926 µg/L, p = 0.002); 18 (42%) and 8 (19%) patients showed a PSA decline of ≥50% and ≥80%, respectively. The median OS and PFS were 136 and 31 weeks, respectively. The patients with only lymph node metastases survived longer (p = 0.02), whereas the patients with bone metastases had a shorter survival (p = 0.03). In the multivariate analysis, only the levels of PSA prior to the therapy remained significant for OS (p < 0.05, hazard ratio 2.43, 95% CI 1.01–5.87). The levels of hemoglobin (11.5 ± 1.7 g/dL vs. 11 ± 1.6 g/dL, p = 0.006) and platelets (208 ± 63 g/L vs. 185 ± 63 g/L, p = 0.002) significantly decreased one month after cycle three, though only two grade 3 anemia and one grade 3 thrombocytopenia were recorded. Conclusion: A further intensive PSMA-RLT course is well tolerated in mCRPC patients and associated with promising response rates and OS. Full article

(This article belongs to the Special Issue Urological Cancer 2021)

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2 pages, 147 KiB

Open AccessEditorial

RKIP: A Pivotal Gene Product in the Pathogenesis of Cancer

by Benjamin Bonavida

Cancers 2021, 13(10), 2488; https://doi.org/10.3390/cancers13102488 - 20 May 2021

Cited by 3 | Viewed by 1655

Abstract

Since its original cloning by Yeung et al [...] Full article

(This article belongs to the Special Issue RKIP: A Pivotal Gene Product in the Pathogenesis of Cancer)

19 pages, 2327 KiB

Open AccessArticle

Inactivating Mutations of the IK Gene Weaken Ku80/Ku70-Mediated DNA Repair and Sensitize Endometrial Cancer to Chemotherapy

by Chao Gao, Guangxu Jin, Elizabeth Forbes, Lingegowda S. Mangala, Yingmei Wang, Cristian Rodriguez-Aguayo, Paola Amero, Emine Bayraktar, Ye Yan, Gabriel Lopez-Berestein, Russell R. Broaddus, Anil K. Sood, Fengxia Xue and Wei Zhang

Cancers 2021, 13(10), 2487; https://doi.org/10.3390/cancers13102487 - 20 May 2021

Cited by 1 | Viewed by 3394

Abstract

IK is a mitotic factor that promotes cell cycle progression. Our previous investigation of 271 endometrial cancer (EC) samples from the Cancer Genome Atlas (TCGA) dataset showed IK somatic mutations were enriched in a cluster of patients with high-grade and high-stage cancers, and [...] Read more.

IK is a mitotic factor that promotes cell cycle progression. Our previous investigation of 271 endometrial cancer (EC) samples from the Cancer Genome Atlas (TCGA) dataset showed IK somatic mutations were enriched in a cluster of patients with high-grade and high-stage cancers, and this group had longer survival. This study provides insight into how IK somatic mutations contribute to EC pathophysiology. We analyzed the somatic mutational landscape of IK gene in 547 EC patients using expanded TCGA dataset. Co-immunoprecipitation and mass spectrometry were used to identify protein interactions. In vitro and in vivo experiments were used to evaluate IK’s role in EC. The patients with IK-inactivating mutations had longer survival during 10-year follow-up. Frameshift and stop-gain were common mutations and were associated with decreased IK expression. IK knockdown led to enrichment of G2/M phase cells, inactivation of DNA repair signaling mediated by heterodimerization of Ku80 and Ku70, and sensitization of EC cells to cisplatin treatment. IK/Ku80 mutations were accompanied by higher mutation rates and associated with significantly better overall survival. Inactivating mutations of IK gene and loss of IK protein expression were associated with weakened Ku80/Ku70-mediated DNA repair, increased mutation burden, and better response to chemotherapy in patients with EC. Full article

(This article belongs to the Special Issue Cellular Plasticity and the Untapped Therapeutic Potential in Cancer)

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23 pages, 7639 KiB

Open AccessArticle

Estetrol Combined to Progestogen for Menopause or Contraception Indication Is Neutral on Breast Cancer

by Anne Gallez, Silvia Blacher, Erik Maquoi, Erika Konradowski, Marc Joiret, Irina Primac, Céline Gérard, Mélanie Taziaux, René Houtman, Liesbet Geris, Françoise Lenfant, Elisabetta Marangoni, Nor Eddine Sounni, Jean-Michel Foidart, Agnès Noël and Christel Péqueux

Cancers 2021, 13(10), 2486; https://doi.org/10.3390/cancers13102486 - 20 May 2021

Cited by 22 | Viewed by 5239

Abstract

Given the unequivocal benefits of menopause hormone therapies (MHT) and combined oral contraceptives (COC), there is a clinical need for new formulations devoid of any risk of breast cancer promotion. Accumulating data from preclinical and clinical studies support that estetrol (E4) is a [...] Read more.

Given the unequivocal benefits of menopause hormone therapies (MHT) and combined oral contraceptives (COC), there is a clinical need for new formulations devoid of any risk of breast cancer promotion. Accumulating data from preclinical and clinical studies support that estetrol (E4) is a promising natural estrogen for MHT and COC. Nevertheless, we report here that E4 remains active on the endometrium, even under a dose that is neutral on breast cancer growth and lung metastasis dissemination. This implies that a progestogen should be combined with E4 to protect the endometrium of non-hysterectomized women from hyperplasia and cancer. Through in vivo observations and transcriptomic analyses, our work provides evidence that combining a progestogen to E4 is neutral on breast cancer growth and dissemination, with very limited transcriptional impact. The assessment of breast cancer risk in patients during the development of new MHT or COC is not possible given the requirement of long-term studies in large populations. This translational preclinical research provides new evidence that a therapeutic dose of E4 for MHT or COC, combined with progesterone or drospirenone, may provide a better benefit/risk profile towards breast cancer risk compared to hormonal treatments currently available for patients. Full article

(This article belongs to the Special Issue Nuclear Receptors and Cancer)

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22 pages, 1572 KiB

Open AccessReview

HCV Proteins Modulate the Host Cell miRNA Expression Contributing to Hepatitis C Pathogenesis and Hepatocellular Carcinoma Development

by Devis Pascut, Minh Hoang, Nhu N. Q. Nguyen, Muhammad Yogi Pratama and Claudio Tiribelli

Cancers 2021, 13(10), 2485; https://doi.org/10.3390/cancers13102485 - 19 May 2021

Cited by 16 | Viewed by 4163

Abstract

Hepatitis C virus (HCV) genome encodes for one long polyprotein that is processed by cellular and viral proteases to generate 10 polypeptides. The viral structural proteins include the core protein, and the envelope glycoproteins E1 and E2, present at the surface of HCV [...] Read more.

Hepatitis C virus (HCV) genome encodes for one long polyprotein that is processed by cellular and viral proteases to generate 10 polypeptides. The viral structural proteins include the core protein, and the envelope glycoproteins E1 and E2, present at the surface of HCV particles. Non-structural (NS) proteins consist of NS1, NS2, NS3, NS4A, NS4B, NS5a, and NS5b and have a variable function in HCV RNA replication and particle assembly. Recent findings evidenced the capacity of HCV virus to modulate host cell factors to create a favorable environment for replication. Indeed, increasing evidence has indicated that the presence of HCV is significantly associated with aberrant miRNA expression in host cells, and HCV structural and non-structural proteins may be responsible for these alterations. In this review, we summarize the recent findings on the role of HCV structural and non-structural proteins in the modulation of host cell miRNAs, with a focus on the molecular mechanisms responsible for the cell re-programming involved in viral replication, immune system escape, as well as the oncogenic process. In this regard, structural and non-structural proteins have been shown to modulate the expression of several onco-miRNAs or tumor suppressor miRNAs. Full article

(This article belongs to the Special Issue Hepatitis C Virus and Hepatocellular Carcinoma (HCV & HCC))

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17 pages, 1734 KiB

Open AccessArticle

Diagnostic and Prognostic Value of miR-16, miR-146a, miR-192 and miR-221 in Exosomes of Hepatocellular Carcinoma and Liver Cirrhosis Patients

by Thorben Fründt, Linda Krause, Elaine Hussey, Bettina Steinbach, Daniel Köhler, Johann von Felden, Kornelius Schulze, Ansgar W. Lohse, Henning Wege and Heidi Schwarzenbach

Cancers 2021, 13(10), 2484; https://doi.org/10.3390/cancers13102484 - 19 May 2021

Cited by 26 | Viewed by 3025

Abstract

We aimed to identify a specific microRNA (miRNA) pattern to determine diagnostic and prognostic value in plasma exosomes of hepatocellular carcinoma (HCC) patients. A two-stage study was carried out: exosomal miRNAs were quantified in plasma of HCC patients and healthy individuals by PCR-based [...] Read more.

We aimed to identify a specific microRNA (miRNA) pattern to determine diagnostic and prognostic value in plasma exosomes of hepatocellular carcinoma (HCC) patients. A two-stage study was carried out: exosomal miRNAs were quantified in plasma of HCC patients and healthy individuals by PCR-based microarray cards containing 45 different miRNAs (training cohort). Then, four deregulated miRNAs (miR-16, miR-146a, miR-192, and miR-221) were quantified in the validation analysis using exosomes derived from 85 HCC patients, 50 liver cirrhosis patients, and 20 healthy individuals. Exosomal miR-146a (p = 0.0001), miR-192 (p = 0.002) and miR-221 (p = 0.032) were upregulated only in HCC patients. Repeated 10-fold cross validation showed that miR-146a differentiated HCC from liver cirrhosis patients with AUC of 0.80 ± 0.14 (sensitivity: 81 ± 13%, specificity: 58 ± 22%) in a logistic regression model. High miR-192 presence is associated with poor overall survival (OS) in all HCC patients (p = 0.027) and was predictor of OS in HCC patients in an uni- and multivariate Cox regression model. Moreover, decreased miR-16 levels correlated with OS in liver cirrhosis patients (p = 0.034). Our results emphasized that exosomes secreted into the plasma carry differentially expressed miRNAs of which in particular, miR-192, miR-146, and miR-16 are promising diagnostic and prognostic markers for both HCC and liver cirrhosis patients. Full article

(This article belongs to the Special Issue Primary Hepatobiliary Tumor)

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16 pages, 3605 KiB

Open AccessArticle

Multimodal Imaging Techniques to Evaluate the Anticancer Effect of Cold Atmospheric Pressure Plasma

by Marcel Kordt, Isabell Trautmann, Christin Schlie, Tobias Lindner, Jan Stenzel, Anna Schildt, Lars Boeckmann, Sander Bekeschus, Jens Kurth, Bernd J. Krause, Brigitte Vollmar and Eberhard Grambow

Cancers 2021, 13(10), 2483; https://doi.org/10.3390/cancers13102483 - 19 May 2021

Cited by 10 | Viewed by 2850

Abstract

Background: Skin cancer is the most frequent cancer worldwide and is divided into non-melanoma skin cancer, including basal cell carcinoma, as well as squamous cell carcinoma (SCC) and malignant melanoma (MM). Methods: This study evaluates the effects of cold atmospheric pressure plasma (CAP) [...] Read more.

Background: Skin cancer is the most frequent cancer worldwide and is divided into non-melanoma skin cancer, including basal cell carcinoma, as well as squamous cell carcinoma (SCC) and malignant melanoma (MM). Methods: This study evaluates the effects of cold atmospheric pressure plasma (CAP) on SCC and MM in vivo, employing a comprehensive approach using multimodal imaging techniques. Longitudinal MR and PET/CT imaging were performed to determine the anatomic and metabolic tumour volume over three-weeks in vivo. Additionally, the formation of reactive species after CAP treatment was assessed by non-invasive chemiluminescence imaging of L-012. Histological analysis and immunohistochemical staining for Ki-67, ApopTag^®, F4/80, CAE, and CD31, as well as protein expression of PCNA, caspase-3 and cleaved-caspase-3, were performed to study proliferation, apoptosis, inflammation, and angiogenesis in CAP-treated tumours. Results: As the main result, multimodal in vivo imaging revealed a substantial reduction in tumour growth and an increase in reactive species after CAP treatment, in comparison to untreated tumours. In contrast, neither the markers for apoptosis, nor the metabolic activity of both tumour entities was affected by CAP. Conclusions: These findings propose CAP as a potential adjuvant therapy option to established standard therapies of skin cancer. Full article

(This article belongs to the Special Issue Clinical Experience with Cold Atmospheric Pressure Plasma (CAP) in Cancer Treatment)

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12 pages, 3894 KiB

Open AccessSystematic Review

Impact of Previous Irradiation on Wound Healing after Negative Pressure Wound Therapy in Head and Neck Cancer Patients—A Systematic Review

by Muhammad Faisal, Peter D. Berend, Rudolf Seemann, Stefan Janik, Stefan Grasl, Andrea Ritzengruber, Herbert Mendel, Arif Jamshed, Raza Hussain and Boban M. Erovic

Cancers 2021, 13(10), 2482; https://doi.org/10.3390/cancers13102482 - 19 May 2021

Cited by 9 | Viewed by 4955

Abstract

(1) Background: Negative pressure wound therapy (NPWT) has been effectively used for wound management in comparison to traditional dressings. The purpose of this study was to provide an evidence-based review of NPWT in head and neck cancer patients, as well as the impact [...] Read more.

(1) Background: Negative pressure wound therapy (NPWT) has been effectively used for wound management in comparison to traditional dressings. The purpose of this study was to provide an evidence-based review of NPWT in head and neck cancer patients, as well as the impact of previous irradiation and other risk factors on wound healing. (2) Material and Methods: We conducted a comprehensive search in PubMed, Medline, Embase, Web of Science, and Cochrane Library databases for relevant literature. (3) Results: 15 studies fulfilled the inclusion criteria. The most common etiologies requiring NPWT were defects post tumor resection and flap reconstruction and oro/pharyngo-cutaneous fistulas. The neck was found to be the most common site of involvement (47.3%). The overall wound healing response rate was 87.5%. The median negative pressure recorded was 125 mm of Hg, with a median dressing change time of three days. Previous irradiation (p = 0.01; OR = 4.07) and diabetes mellitus (DM) (p = 0.001; OR = 5.62) were found to be significantly associated with delayed wound healing after NPWT. (4) Conclusion: NPWT treats complex wounds in head and neck cancer patients and should represent a significant armamentarium in head and neck cancers. Previous irradiation and DM have detrimental effects on wound healing after NPWT. Full article

(This article belongs to the Special Issue Surgical Treatment of Head and Neck Squamous Cell Carcinomas (HNSCC))

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23 pages, 2335 KiB

Open AccessReview

Enhancing Clinical Translation of Cancer Using Nanoinformatics

by Madjid Soltani, Farshad Moradi Kashkooli, Mohammad Souri, Samaneh Zare Harofte, Tina Harati, Atefeh Khadem, Mohammad Haeri Pour and Kaamran Raahemifar

Cancers 2021, 13(10), 2481; https://doi.org/10.3390/cancers13102481 - 19 May 2021

Cited by 34 | Viewed by 4607

Abstract

Application of drugs in high doses has been required due to the limitations of no specificity, short circulation half-lives, as well as low bioavailability and solubility. Higher toxicity is the result of high dosage administration of drug molecules that increase the side effects [...] Read more.

Application of drugs in high doses has been required due to the limitations of no specificity, short circulation half-lives, as well as low bioavailability and solubility. Higher toxicity is the result of high dosage administration of drug molecules that increase the side effects of the drugs. Recently, nanomedicine, that is the utilization of nanotechnology in healthcare with clinical applications, has made many advancements in the areas of cancer diagnosis and therapy. To overcome the challenge of patient-specificity as well as time- and dose-dependency of drug administration, artificial intelligence (AI) can be significantly beneficial for optimization of nanomedicine and combinatorial nanotherapy. AI has become a tool for researchers to manage complicated and big data, ranging from achieving complementary results to routine statistical analyses. AI enhances the prediction precision of treatment impact in cancer patients and specify estimation outcomes. Application of AI in nanotechnology leads to a new field of study, i.e., nanoinformatics. Besides, AI can be coupled with nanorobots, as an emerging technology, to develop targeted drug delivery systems. Furthermore, by the advancements in the nanomedicine field, AI-based combination therapy can facilitate the understanding of diagnosis and therapy of the cancer patients. The main objectives of this review are to discuss the current developments, possibilities, and future visions in naoinformatics, for providing more effective treatment for cancer patients. Full article

(This article belongs to the Collection Artificial Intelligence in Oncology)

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16 pages, 1391 KiB

Open AccessArticle

Liver Transplantation for Hepatocellular Carcinoma: A Real-Life Comparison of Milan Criteria and AFP Model

by Bleuenn Brusset, Jerome Dumortier, Daniel Cherqui, Georges-Philippe Pageaux, Emmanuel Boleslawski, Ludivine Chapron, Jean-Louis Quesada, Sylvie Radenne, Didier Samuel, Francis Navarro, Sebastien Dharancy and Thomas Decaens

Cancers 2021, 13(10), 2480; https://doi.org/10.3390/cancers13102480 - 19 May 2021

Cited by 7 | Viewed by 2331

Abstract

Purpose: To compare the agreement for the criteria on the explant and the results of liver transplantation (LT) before and after adoption of the AFP (α-fetoprotein) model. Methods: 523 patients consecutively listed in five French centers were reviewed to compare results of the [...] Read more.

Purpose: To compare the agreement for the criteria on the explant and the results of liver transplantation (LT) before and after adoption of the AFP (α-fetoprotein) model. Methods: 523 patients consecutively listed in five French centers were reviewed to compare results of the Milan criteria period (MilanCP, n = 199) (before 2013) and the AFP score period (AFPscP, n = 324) (after 2013). (NCT03156582). Results: During AFPscP, there was a significantly longer waiting time on the list (12.3 vs. 7.7 months, p < 0.001) and higher rate of bridging therapies (84 vs. 75%, p = 0.012) compared to the MilanCP. Dropout rate was slightly higher in the AFPscP (31 vs. 24%, p = 0.073). No difference was found in the histological AFP score between groups (p = 0.838) with a global agreement in 88% of patients. Post-LT recurrence was 9.2% in MilanCP vs. 13.2% in AFPscP (p = 0.239) and predictive factors were AFP > 2 on the last imaging, downstaging policy and salvage transplantation. Post-LT survival was similar (83 vs. 87% after 2 years, p = 0.100), but after propensity score analysis, the post-listing overall survival (OS) was worse in the AFPscP (HR 1.45, p = 0.045). Conclusions: Agreement for the AFP model on explant analysis (≤2) did not significantly change. AFP score > 2 was the major prognostic factor for recurrence. Graft allocation policy has a major impact on prognosis, with a post-listing OS significantly decreased, probably due to the increase in waiting time, increase in bridging therapies, downstaging policy and salvage transplantation. Full article

(This article belongs to the Special Issue Hepatocellular Carcinoma: Updates in Pathogenesis, Detection and Treatment)

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13 pages, 2268 KiB

Open AccessArticle

COVID-19 Risk Factors for Cancer Patients: A First Report with Comparator Data from COVID-19 Negative Cancer Patients

by Beth Russell, Charlotte L. Moss, Kieran Palmer, Rushan Sylva, Andrea D’Souza, Harriet Wylie, Anna Haire, Fidelma Cahill, Renee Steel, Angela Hoyes, Isabelle Wilson, Alyson Macneil, Belul Shifa, Maria J Monroy-Iglesias, Sophie Papa, Sheeba Irshad, Paul Ross, James Spicer, Shahram Kordasti, Danielle Crawley, Kamarul Zaki, Ailsa Sita-Lumsden, Debra Josephs, Deborah Enting, Angela Swampillai, Elinor Sawyer, Paul Fields, David Wrench, Anne Rigg, Richard Sullivan, Mieke Van Hemelrijck and Saoirse Dolly Show full author list Hide full author list

Cancers 2021, 13(10), 2479; https://doi.org/10.3390/cancers13102479 - 19 May 2021

Cited by 10 | Viewed by 3689

Abstract

Very few studies investigating COVID-19 in cancer patients have included cancer patients as controls. We aimed to identify factors associated with the risk of testing positive for SARS CoV2 infection in a cohort of cancer patients. We analyzed data from all cancer patients [...] Read more.

Very few studies investigating COVID-19 in cancer patients have included cancer patients as controls. We aimed to identify factors associated with the risk of testing positive for SARS CoV2 infection in a cohort of cancer patients. We analyzed data from all cancer patients swabbed for COVID-19 between 1^st March and 31^st July 2020 at Guy’s Cancer Centre. We conducted logistic regression analyses to identify which factors were associated with a positive COVID-19 test. Results: Of the 2152 patients tested for COVID-19, 190 (9%) tested positive. Male sex, black ethnicity, and hematological cancer type were positively associated with risk of COVID-19 (OR = 1.85, 95%CI:1.37–2.51; OR = 1.93, 95%CI:1.31–2.84; OR = 2.29, 95%CI:1.45–3.62, respectively) as compared to females, white ethnicity, or solid cancer type, respectively. Male, Asian ethnicity, and hematological cancer type were associated with an increased risk of severe COVID-19 (OR = 3.12, 95%CI:1.58–6.14; OR = 2.97, 95%CI:1.00–8.93; OR = 2.43, 95%CI:1.00–5.90, respectively). This study is one of the first to compare the risk of COVID-19 incidence and severity in cancer patients when including cancer patients as controls. Results from this study have echoed those of previous reports, that patients who are male, of black or Asian ethnicity, or with a hematological malignancy are at an increased risk of COVID-19. Full article

(This article belongs to the Section Cancer Epidemiology and Prevention)

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27 pages, 1292 KiB

Open AccessReview

The Role of IGF/IGF-IR-Signaling and Extracellular Matrix Effectors in Bone Sarcoma Pathogenesis

by George N. Tzanakakis, Eirini-Maria Giatagana, Aikaterini Berdiaki, Ioanna Spyridaki, Kyoko Hida, Monica Neagu, Aristidis M. Tsatsakis and Dragana Nikitovic

Cancers 2021, 13(10), 2478; https://doi.org/10.3390/cancers13102478 - 19 May 2021

Cited by 25 | Viewed by 4158

Abstract

Bone sarcomas, mesenchymal origin tumors, represent a substantial group of varying neoplasms of a distinct entity. Bone sarcoma patients show a limited response or do not respond to chemotherapy. Notably, developing efficient chemotherapy approaches, dealing with chemoresistance, and preventing metastasis pose unmet challenges [...] Read more.

Bone sarcomas, mesenchymal origin tumors, represent a substantial group of varying neoplasms of a distinct entity. Bone sarcoma patients show a limited response or do not respond to chemotherapy. Notably, developing efficient chemotherapy approaches, dealing with chemoresistance, and preventing metastasis pose unmet challenges in sarcoma therapy. Insulin-like growth factors 1 and 2 (IGF-1 and -2) and their respective receptors are a multifactorial system that significantly contributes to bone sarcoma pathogenesis. Whereas failures have been registered in creating novel targeted therapeutics aiming at the IGF pathway, new agent development should continue, evaluating combinatorial strategies for enhancing antitumor responses and better classifying the patients that could best benefit from these therapies. A plausible approach for developing a combinatorial strategy is to focus on the tumor microenvironment (TME) and processes executed therein. Herewith, we will discuss how the interplay between IGF-signaling and the TME constituents affects sarcomas’ basal functions and their response to therapy. This review highlights key studies focusing on IGF signaling in bone sarcomas, specifically studies underscoring novel properties that make this system an attractive therapeutic target and identifies new relationships that may be exploited. Potential direct and adjunct therapeutical implications of the extracellular matrix (ECM) effectors will also be summarized. Full article

(This article belongs to the Collection Matrix Effectors and Cancer)

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10 pages, 1479 KiB

Open AccessCommunication

Proof of Concept of a Binary Blood Assay for Predicting Radiosensitivity

by Sophie Deneuve, Céline Mirjolet, Thierry Bastogne, Mirlande Duclos, Paul Retif, Philippe Zrounba, Pierre-Eric Roux, Marc Poupart, Guillaume Vogin, Nicolas Foray and Sandrine Pereira

Cancers 2021, 13(10), 2477; https://doi.org/10.3390/cancers13102477 - 19 May 2021

Cited by 10 | Viewed by 2849

Abstract

Radiation therapy (RT), either alone or in combination with surgery and/or chemotherapy is a keystone of cancers treatment. Early toxicity is common, sometimes leading to discontinuation of treatment. Recent studies stressed the role of the phosphorylated ATM (pATM) protein in RT-toxicity genesis and [...] Read more.

Radiation therapy (RT), either alone or in combination with surgery and/or chemotherapy is a keystone of cancers treatment. Early toxicity is common, sometimes leading to discontinuation of treatment. Recent studies stressed the role of the phosphorylated ATM (pATM) protein in RT-toxicity genesis and its ability in predicting individual radiosensitivity (IRS) in fibroblasts. Here we assessed the reliability of the pATM quantification in lymphocytes to predict IRS. A first retrospective study was performed on 150 blood lymphocytes of patients with several cancer types. Patients were divided into 2 groups, according to the grade of experienced toxicity. The global quantity of pATM molecules was assessed by ELISA on lymphocytes to determine the best threshold value. Then, the binary assay was assessed on a validation cohort of 36 patients with head and neck cancers. The quantity of pATM molecules in each sample of the training cohort was found in agreement with the observed Common Terminology Criteria for Adverse Events (CTCAE) grades with an AUC = 0.71 alone and of 0.77 combined to chemotherapy information. In the validation cohort, the same test was conducted with the following performances: sensitivity = 0.84, specificity = 0.54, AUC = 0.70 and 0.72 combined to chemotherapy. This study provides the basis of an easy to perform assay for clinical use. Full article

(This article belongs to the Section Cancer Therapy)

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