Cancers

16 pages, 957 KiB

Open AccessReview

Incidence of Occult Lymph Node Metastasis in Primary Larynx Squamous Cell Carcinoma, by Subsite, T Classification and Neck Level: A Systematic Review

by Alvaro Sanabria, Jatin P. Shah, Jesus E. Medina, Kerry D. Olsen, K. Thomas Robbins, Carl E. Silver, Juan P. Rodrigo, Carlos Suárez, Andrés Coca-Pelaz, Ashok R. Shaha, Antti A. Mäkitie, Alessandra Rinaldo, Remco de Bree, Primož Strojan, Marc Hamoir, Robert P. Takes, Elisabeth V. Sjögren, Trinitia Cannon, Luiz P. Kowalski and Alfio Ferlito

Cancers 2020, 12(4), 1059; https://doi.org/10.3390/cancers12041059 - 24 Apr 2020

Cited by 39 | Viewed by 6682

Abstract

Background: Larynx cancer is a common site for tumors of the upper aerodigestive tract. In cases with a clinically negative neck, the indications for an elective neck treatment are still debated. The objective is to define the prevalence of occult metastasis based on [...] Read more.

Background: Larynx cancer is a common site for tumors of the upper aerodigestive tract. In cases with a clinically negative neck, the indications for an elective neck treatment are still debated. The objective is to define the prevalence of occult metastasis based on the subsite of the primary tumor, T classification and neck node levels involved. Methods: All studies included provided the rate of occult metastases in cN0 larynx squamous cell carcinoma patients. The main outcome was the incidence of occult metastasis. The pooled incidence was calculated with random effects analysis. Results: 36 studies with 3803 patients fulfilled the criteria. The incidence of lymph node metastases for supraglottic and glottic tumors was 19.9% (95% CI 16.4–23.4) and 8.0% (95% CI 2.7–13.3), respectively. The incidence of occult metastasis for level I, level IV and level V was 2.4% (95% CI 0–6.1%), 2.0% (95% CI 0.9–3.1) and 0.4% (95% CI 0–1.0%), respectively. For all tumors, the incidence for sublevel IIB was 0.5% (95% CI 0–1.3). Conclusions: The incidence of occult lymph node metastasis is higher in supraglottic and T3–4 tumors. Level I and V and sublevel IIB should not be routinely included in the elective neck treatment of cN0 laryngeal cancer and, in addition, level IV should not be routinely included in cases of supraglottic tumors. Full article

(This article belongs to the Special Issue Emerging Concepts in Treatment of Laryngeal Cancer)

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14 pages, 2384 KiB

Open AccessArticle

The Prognostic Value of the Detection of Microbial Translocation in the Blood of Colorectal Cancer Patients

by Ippokratis Messaritakis, Konstantinos Vogiatzoglou, Konstantina Tsantaki, Agapi Ntretaki, Maria Sfakianaki, Asimina Koulouridi, John Tsiaoussis, Dimitrios Mavroudis and John Souglakos

Cancers 2020, 12(4), 1058; https://doi.org/10.3390/cancers12041058 - 24 Apr 2020

Cited by 26 | Viewed by 3678

Abstract

Dysbiosis has been associated with various diseases and is of major health importance. Dysbiosis leads to microbial translocation, which is the passage of microorganisms, their fragments, or their metabolites from the intestinal lumen into the blood circulation and other sites. The aim of [...] Read more.

Dysbiosis has been associated with various diseases and is of major health importance. Dysbiosis leads to microbial translocation, which is the passage of microorganisms, their fragments, or their metabolites from the intestinal lumen into the blood circulation and other sites. The aim of the study was to determine whether microbial translocation occurs in stage II/III-IV colorectal cancer (CRC) patients. The aim was also to evaluate the usefulness of blood PCR for diagnosis of such translocation and correlate the presence of toll-like receptor/vitamin D receptor (TLR/VDR) gene polymorphisms with microbial DNA fragments detected in the blood of CRC patients. Three hundred and ninety-seven CRC patients enrolled in the study. Peripheral blood DNA was analyzed using PCR for the amplification of genomic DNA encoding 16S rRNA, the β-galactosidase gene of Escherichia coli, glutamine synthase gene of Bacteroides fragilis, and 5.8S rRNA of Candida albicans. Significantly higher rates of all microbial fragments, but E. coli, detected were observed in the CRC patients (p < 0.001); such detection of all four microbial fragments was also significantly associated with the metastatic disease (p < 0.001), leading to shorter survival rates (p < 0.001). Tumor location in the right colon also significantly correlated with shorter survival (p = 0.016). Individuals with homozygous mutant alleles of TLR/VDR polymorphisms had significantly higher detection rates of microbial DNA fragments. The detection of microbial DNA fragments in CRC patients highlighted the role of these microbes in cancer development, progression, and patients’ survival. Full article

(This article belongs to the Special Issue Microbiota in Colorectal Cancer)

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15 pages, 2896 KiB

Open AccessArticle

Unique Role of Histone Methyltransferase PRDM8 in the Tumorigenesis of Virus-Negative Merkel Cell Carcinoma

by Elias Orouji, Wiebke K. Peitsch, Azadeh Orouji, Roland Houben and Jochen Utikal

Cancers 2020, 12(4), 1057; https://doi.org/10.3390/cancers12041057 - 24 Apr 2020

Cited by 8 | Viewed by 2975

Abstract

Merkel cell carcinoma (MCC) is a deadly skin cancer, and about 80% of its cases have been shown to harbor integrated Merkel polyomavirus in the tumor cell genome. Viral oncoproteins expressed in the tumor cells are considered as the oncogenic factors of these [...] Read more.

Merkel cell carcinoma (MCC) is a deadly skin cancer, and about 80% of its cases have been shown to harbor integrated Merkel polyomavirus in the tumor cell genome. Viral oncoproteins expressed in the tumor cells are considered as the oncogenic factors of these virus-positive Merkel cell carcinoma (VP-MCC). In contrast, the molecular pathogenesis of virus-negative MCC (VN-MCC) is less well understood. Using gene expression analysis of MCC cell lines, we found histone methyltransferase PRDM8 to be elevated in VN-MCC. This finding was confirmed by immunohistochemical analysis of MCC tumors, revealing that increased PRDM8 expression in VN-MCC is also associated with increased H3K9 methylation. CRISPR-mediated silencing of PRDM8 in MCC cells further supported the histone methylating role of this protein in VN-MCC. We also identified miR-20a-5p as a negative regulator of PRDM8. Taken together, our findings provide insights into the role of PRDM8 as a histone methyltransferase in VN-MCC tumorigenesis. Full article

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14 pages, 3251 KiB

Open AccessArticle

Reduced Tumorigenicity of Mouse ES Cells and the Augmented Anti-Tumor Therapeutic Effects under Parg Deficiency

by Yuki Sonoda, Yuka Sasaki, Akemi Gunji, Hidenori Shirai, Tomonori Araki, Shoji Imamichi, Takae Onodera, Anna-Margareta Rydén, Masatoshi Watanabe, Jun Itami, Takuya Honda, Kazuto Ashizawa, Kazuhiko Nakao and Mitsuko Masutani

Cancers 2020, 12(4), 1056; https://doi.org/10.3390/cancers12041056 - 24 Apr 2020

Cited by 4 | Viewed by 2996

Abstract

PolyADP-ribosylation is a post-translational modification of proteins, and poly(ADP-ribose) (PAR) polymerase (PARP) family proteins synthesize PAR using NAD as a substrate. Poly(ADP-ribose) glycohydrolase (PARG) functions as the main enzyme for the degradation of PAR. In this study, we investigated the effects of Parg [...] Read more.

PolyADP-ribosylation is a post-translational modification of proteins, and poly(ADP-ribose) (PAR) polymerase (PARP) family proteins synthesize PAR using NAD as a substrate. Poly(ADP-ribose) glycohydrolase (PARG) functions as the main enzyme for the degradation of PAR. In this study, we investigated the effects of Parg deficiency on tumorigenesis and therapeutic efficacy of DNA damaging agents, using mouse ES cell-derived tumor models. To examine the effects of Parg deficiency on tumorigenesis, Parg^+/+ and Parg^−/− ES cells were subcutaneously injected into nude mice. The results showed that Parg deficiency delays early onset of tumorigenesis from ES cells. All the tumors were phenotypically similar to teratocarcinoma and microscopic findings indicated that differentiation spectrum was similar between the Parg genotypes. The augmented anti-tumor therapeutic effects of X-irradiation were observed under Parg deficiency. These results suggest that Parg deficiency suppresses early stages of tumorigenesis and that Parg inhibition, in combination with DNA damaging agents, may efficiently control tumor growth in particular types of germ cell tumors. Full article

(This article belongs to the Special Issue PARPs, PAR and NAD Metabolism and Their Inhibitors in Cancer)

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12 pages, 1702 KiB

Open AccessArticle

Cut-Off Analysis of CTC Change under Systemic Therapy for Defining Early Therapy Response in Metastatic Breast Cancer

by Thomas M. Deutsch, Stefan Stefanovic, Manuel Feisst, Chiara Fischer, Fabian Riedel, Carlo Fremd, Christoph Domschke, Klaus Pantel, Andreas D. Hartkopf, Marc Sutterlin, Sara Y. Brucker, Andreas Schneeweiss and Markus Wallwiener

Cancers 2020, 12(4), 1055; https://doi.org/10.3390/cancers12041055 - 24 Apr 2020

Cited by 21 | Viewed by 3545

Abstract

Detection of circulating tumor cells (CTC) can distinguish between aggressive and indolent metastatic disease in breast cancer patients and is thus considered an independent, negative prognostic factor. A clear decline in CTCs is observed in patients who respond to systemic therapy. Nevertheless, CTCs [...] Read more.

Detection of circulating tumor cells (CTC) can distinguish between aggressive and indolent metastatic disease in breast cancer patients and is thus considered an independent, negative prognostic factor. A clear decline in CTCs is observed in patients who respond to systemic therapy. Nevertheless, CTCs can decrease in patients experiencing disease progression during systemic therapy, too. This study aims to determine the differences between CTC decline in patients responding to therapy and those in whom disease is progressing. Therefore, CTC values were compared at the start and after one cycle of a new line of systemic therapy. In all, 108 initially CTC-positive patients (with ≥5 intact CTCs in 7.5 mL blood) were enrolled in this study and intact and apoptotic CTCs were measured via the CellSearch^® system. A cut-off analysis was performed using Youden’s J statistics to differentiate between CTC change in the two groups. Here, 64 (59.3%) patients showed stable disease or partial response vs. 44 (40.7%) presenting disease progression. Median overall survival was 23 (range: 4–92) vs. 7 (2–43) months (p < 0.001). Median intact CTC count at enrollment was 15.0 (5–2760) vs. 30.5 (5–200000) cells (p = 0.39) and 2.5 (0–420) vs. 8.5 (0–15000) cells after one cycle of systemic therapy (p = 0.001). Median apoptotic CTC count at enrollment was 10.5 (0–1500) vs. 9 (0–800) cells (p = 0.475) and 1 (0–200) vs. 3 (0–250) cells after one cycle of systemic therapy (p = 0.01). A 50% reduction in baseline apoptotic CTC count represents the optimal cut-off to differentiate between therapy response and disease progression. An apoptotic CTC reduction of ≤10% is 74% specific for early disease progression. Full article

(This article belongs to the Special Issue Circulating Tumor Cells' Heterogeneity and Precision Oncology)

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17 pages, 5159 KiB

Open AccessArticle

ALK Inhibitors-Induced M Phase Delay Contributes to the Suppression of Cell Proliferation

by Sirajam Munira, Ryuzaburo Yuki, Youhei Saito and Yuji Nakayama

Cancers 2020, 12(4), 1054; https://doi.org/10.3390/cancers12041054 - 24 Apr 2020

Cited by 6 | Viewed by 5197

Abstract

Anaplastic lymphoma kinase (ALK), a receptor-type tyrosine kinase, is involved in the pathogenesis of several cancers. ALK has been targeted with small molecule inhibitors for the treatment of different cancers, but absolute success remains elusive. In the present study, the effects of ALK [...] Read more.

Anaplastic lymphoma kinase (ALK), a receptor-type tyrosine kinase, is involved in the pathogenesis of several cancers. ALK has been targeted with small molecule inhibitors for the treatment of different cancers, but absolute success remains elusive. In the present study, the effects of ALK inhibitors on M phase progression were evaluated. Crizotinib, ceritinib, and TAE684 suppressed proliferation of neuroblastoma SH-SY5Y cells in a concentration-dependent manner. At approximate IC₅₀ concentrations, these inhibitors caused misorientation of spindles, misalignment of chromosomes and reduction in autophosphorylation. Similarly, knockdown of ALK caused M phase delay, which was rescued by re-expression of ALK. Time-lapse imaging revealed that anaphase onset was delayed. The monopolar spindle 1 (MPS1) inhibitor, AZ3146, and MAD2 knockdown led to a release from inhibitor-induced M phase delay, suggesting that spindle assembly checkpoint may be activated in ALK-inhibited cells. H2228 human lung carcinoma cells that express EML4-ALK fusion showed M phase delay in the presence of TAE684 at about IC₅₀ concentrations. These results suggest that ALK plays a role in M phase regulation and ALK inhibition may contribute to the suppression of cell proliferation in ALK-expressing cancer cells. Full article

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14 pages, 301 KiB

Open AccessReview

Self-Collection for Cervical Screening Programs: From Research to Reality

by David Hawkes, Marco H. T. Keung, Yanping Huang, Tracey L. McDermott, Joanne Romano, Marion Saville and Julia M. L. Brotherton

Cancers 2020, 12(4), 1053; https://doi.org/10.3390/cancers12041053 - 24 Apr 2020

Cited by 57 | Viewed by 9152

Abstract

In 2018, there were an estimated 570,000 new cases of cervical cancer globally, with most of them occurring in women who either had no access to cervical screening, or had not participated in screening in regions where programs are available. Where programs are [...] Read more.

In 2018, there were an estimated 570,000 new cases of cervical cancer globally, with most of them occurring in women who either had no access to cervical screening, or had not participated in screening in regions where programs are available. Where programs are in place, a major barrier for women across many cultures has been the requirement to undergo a speculum examination. With the emergence of HPV-based primary screening, the option of self-collection (where the woman takes the sample from the vagina herself) may overcome this barrier, given that such samples when tested using a PCR-based HPV assay have similar sensitivity for the detection of cervical pre-cancers as practitioner-collected cervical specimens. Other advantages of HPV-based screening using self-collection, beyond the increase in acceptability to women, include scalability, efficiency, and high negative predictive value, allowing for long intervals between negative tests. Self-collection will be a key strategy for the successful scale up of cervical screening programs globally in response to the WHO call for all countries to work towards the elimination of cervical cancer as a public health problem. This review will examine self-collection for HPV-based cervical screening including the collection devices, assays and possible routine laboratory processes considering how they can be utilized in cervical screening programs. Full article

(This article belongs to the Special Issue Human Papillomavirus and Cancers)

9 pages, 820 KiB

Open AccessBrief Report

Overexpression of Canonical Prefoldin Associates with the Risk of Mortality and Metastasis in Non-Small Cell Lung Cancer

by Xenia Peñate, Juan Manuel Praena-Fernández, Pedro Romero Pareja, María del Valle Enguix-Riego, Laura Payán-Bravo, Begoña Vieites, Lourdes Gomez-Izquierdo, Javier Jaen Olasolo, Eleonor Rivin del Campo, Jose Carlos Reyes, Sebastián Chávez and Jose Luis Lopez Guerra

Cancers 2020, 12(4), 1052; https://doi.org/10.3390/cancers12041052 - 24 Apr 2020

Cited by 8 | Viewed by 2923

Abstract

Canonical prefoldin is a protein cochaperone composed of six different subunits (PFDN1 to 6). PFDN1 overexpression promotes epithelial–mesenchymal transition (EMT) and increases the growth of xenograft lung cancer (LC) cell lines. We investigated whether this putative involvement of canonical PFDN in LC translates [...] Read more.

Canonical prefoldin is a protein cochaperone composed of six different subunits (PFDN1 to 6). PFDN1 overexpression promotes epithelial–mesenchymal transition (EMT) and increases the growth of xenograft lung cancer (LC) cell lines. We investigated whether this putative involvement of canonical PFDN in LC translates into the clinic. First, the mRNA expression of 518 non-small cell LC (NSCLC) cases from The Cancer Genome Atlas (TCGA) database was evaluated. Patients with PFDN1 overexpression had lower overall survival (OS; 45 vs. 86 months; p = 0.034). We then assessed the impact of PFDN expression on outcome in 58 NSCLC patients with available tumor tissue samples. PFDN1, 3, and 5 overexpression were found in 38% (n = 22), 53% (n = 31), and 41% (n = 24) of tumor samples. PFDN1, 3, and 5 overexpression were significantly associated with lower OS, lower disease-free survival (DFS), and lower distant metastasis-free survival (DMFS) for PFDN1 and 3 with a trend for PFDN5. In multivariate analysis, PFDN5 retained significance for OS (hazard ratio (HR) 2.56; p = 0.007) and PFDN1 for DFS (HR 2.53; p = 0.010) and marginally for DMFS (HR 2.32; p = 0.053). Our results indicate that protein response markers, such as PFDN1, 3, and 5, may complement mRNA signatures and be useful for determining the most appropriate therapy for NSCLC patients. Full article

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12 pages, 2839 KiB

Open AccessArticle

Radiomics-Based Outcome Prediction for Pancreatic Cancer Following Stereotactic Body Radiotherapy

by Elsa Parr, Qian Du, Chi Zhang, Chi Lin, Ahsan Kamal, Josiah McAlister, Xiaoying Liang, Kyle Bavitz, Gerard Rux, Michael Hollingsworth, Michael Baine and Dandan Zheng

Cancers 2020, 12(4), 1051; https://doi.org/10.3390/cancers12041051 - 24 Apr 2020

Cited by 45 | Viewed by 4641

Abstract

(1) Background: Radiomics use high-throughput mining of medical imaging data to extract unique information and predict tumor behavior. Currently available clinical prediction models poorly predict treatment outcomes in pancreatic adenocarcinoma. Therefore, we used radiomic features of primary pancreatic tumors to develop outcome prediction [...] Read more.

(1) Background: Radiomics use high-throughput mining of medical imaging data to extract unique information and predict tumor behavior. Currently available clinical prediction models poorly predict treatment outcomes in pancreatic adenocarcinoma. Therefore, we used radiomic features of primary pancreatic tumors to develop outcome prediction models and compared them to traditional clinical models. (2) Methods: We extracted and analyzed radiomic data from pre-radiation contrast-enhanced CTs of 74 pancreatic cancer patients undergoing stereotactic body radiotherapy. A panel of over 800 radiomic features was screened to create overall survival and local-regional recurrence prediction models, which were compared to clinical prediction models and models combining radiomic and clinical information. (3) Results: A 6-feature radiomic signature was identified that achieved better overall survival prediction performance than the clinical model (mean concordance index: 0.66 vs. 0.54 on resampled cross-validation test sets), and the combined model improved the performance slightly further to 0.68. Similarly, a 7-feature radiomic signature better predicted recurrence than the clinical model (mean AUC of 0.78 vs. 0.66). (4) Conclusion: Overall survival and recurrence can be better predicted with models based on radiomic features than with those based on clinical features for pancreatic cancer. Full article

(This article belongs to the Special Issue Radiomics and Cancers)

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22 pages, 1743 KiB

Open AccessReview

DNA Damage/Repair Management in Cancers

by Jehad F. Alhmoud, John F. Woolley, Ala-Eddin Al Moustafa and Mohammed Imad Malki

Cancers 2020, 12(4), 1050; https://doi.org/10.3390/cancers12041050 - 23 Apr 2020

Cited by 203 | Viewed by 17456

Abstract

DNA damage is well recognized as a critical factor in cancer development and progression. DNA lesions create an abnormal nucleotide or nucleotide fragment, causing a break in one or both chains of the DNA strand. When DNA damage occurs, the possibility of generated [...] Read more.

DNA damage is well recognized as a critical factor in cancer development and progression. DNA lesions create an abnormal nucleotide or nucleotide fragment, causing a break in one or both chains of the DNA strand. When DNA damage occurs, the possibility of generated mutations increases. Genomic instability is one of the most important factors that lead to cancer development. DNA repair pathways perform the essential role of correcting the DNA lesions that occur from DNA damaging agents or carcinogens, thus maintaining genomic stability. Inefficient DNA repair is a critical driving force behind cancer establishment, progression and evolution. A thorough understanding of DNA repair mechanisms in cancer will allow for better therapeutic intervention. In this review we will discuss the relationship between DNA damage/repair mechanisms and cancer, and how we can target these pathways. Full article

(This article belongs to the Special Issue DNA Damage and Repair in Cancers)

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20 pages, 4038 KiB

Open AccessReview

Nanoparticles to Improve the Efficacy of Peptide-Based Cancer Vaccines

by Anna Lucia Tornesello, Maria Tagliamonte, Maria Lina Tornesello, Franco M. Buonaguro and Luigi Buonaguro

Cancers 2020, 12(4), 1049; https://doi.org/10.3390/cancers12041049 - 23 Apr 2020

Cited by 54 | Viewed by 6627

Abstract

Nanoparticles represent a potent antigen presentation and delivery system to elicit an optimal immune response by effector cells targeting tumor-associated antigens expressed by cancer cells. Many types of nanoparticles have been developed, such as polymeric complexes, liposomes, micelles and protein-based structures such as [...] Read more.

Nanoparticles represent a potent antigen presentation and delivery system to elicit an optimal immune response by effector cells targeting tumor-associated antigens expressed by cancer cells. Many types of nanoparticles have been developed, such as polymeric complexes, liposomes, micelles and protein-based structures such as virus like particles. All of them show promising results for immunotherapy approaches. In particular, the immunogenicity of peptide-based cancer vaccines can be significantly potentiated by nanoparticles. Indeed, nanoparticles are able to enhance the targeting of antigen-presenting cells (APCs) and trigger cytokine production for optimal T cell response. The present review summarizes the categories of nanoparticles and peptide cancer vaccines which are currently under pre-clinical evaluation. Full article

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13 pages, 2501 KiB

Open AccessArticle

TrkB-Induced Inhibition of R-SMAD/SMAD4 Activation is Essential for TGF-β-Mediated Tumor Suppressor Activity

by Min Soo Kim and Wook Jin

Cancers 2020, 12(4), 1048; https://doi.org/10.3390/cancers12041048 - 23 Apr 2020

Cited by 10 | Viewed by 3746

Abstract

TrkB-mediated activation of the IL6/JAK2/STAT3 signaling pathway is associated with the induction of the epithelial–mesenchymal transition (EMT) program and the acquisition of metastatic potential by tumors. Conversely, the transforming of growth factor-β (TGF-β) is implicated in tumor suppression through the canonical SMAD-dependent signaling [...] Read more.

TrkB-mediated activation of the IL6/JAK2/STAT3 signaling pathway is associated with the induction of the epithelial–mesenchymal transition (EMT) program and the acquisition of metastatic potential by tumors. Conversely, the transforming of growth factor-β (TGF-β) is implicated in tumor suppression through the canonical SMAD-dependent signaling pathway. Hence, TrkB could play a role in disrupting the potent TGF-β-mediated growth inhibition, a concept that has not been fully explored. Here, we identified TrkB to be a crucial regulator of the TGF-β signaling pathway as it inhibits the TGF-β-mediated tumor suppression and the activation of TrkB kinase. We further show that the interactions between TrkB and SMADs inhibit TGF-β-mediated R-SMAD/SMAD4 complex formation and suppress TGF-β-induced nuclear translocation and target gene expression. Additionally, the knockdown of TrkB restored the tumor inhibitory activity of TGF-β signaling. These observations suggest that interactions between TrkB and SMADs are critical for the inhibition of TGF-β tumor suppressor activity in cancer cells. Full article

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38 pages, 1760 KiB

Open AccessEditor’s ChoiceReview

Current Approaches for Combination Therapy of Cancer: The Role of Immunogenic Cell Death

by Zahra Asadzadeh, Elham Safarzadeh, Sahar Safaei, Ali Baradaran, Ali Mohammadi, Khalil Hajiasgharzadeh, Afshin Derakhshani, Antonella Argentiero, Nicola Silvestris and Behzad Baradaran

Cancers 2020, 12(4), 1047; https://doi.org/10.3390/cancers12041047 - 23 Apr 2020

Cited by 164 | Viewed by 10139

Abstract

Cell death resistance is a key feature of tumor cells. One of the main anticancer therapies is increasing the susceptibility of cells to death. Cancer cells have developed a capability of tumor immune escape. Hence, restoring the immunogenicity of cancer cells can be [...] Read more.

Cell death resistance is a key feature of tumor cells. One of the main anticancer therapies is increasing the susceptibility of cells to death. Cancer cells have developed a capability of tumor immune escape. Hence, restoring the immunogenicity of cancer cells can be suggested as an effective approach against cancer. Accumulating evidence proposes that several anticancer agents provoke the release of danger-associated molecular patterns (DAMPs) that are determinants of immunogenicity and stimulate immunogenic cell death (ICD). It has been suggested that ICD inducers are two different types according to their various activities. Here, we review the well-characterized DAMPs and focus on the different types of ICD inducers and recent combination therapies that can augment the immunogenicity of cancer cells. Full article

(This article belongs to the Special Issue Immunogenic Cell Death and Immunotherapy in Cancers)

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13 pages, 1351 KiB

Open AccessArticle

Oligoprogressive Non-Small-Cell Lung Cancer under Treatment with PD-(L)1 Inhibitors

by Stephan Rheinheimer, Claus-Peter Heussel, Philipp Mayer, Lena Gaissmaier, Farastuk Bozorgmehr, Hauke Winter, Felix J. Herth, Thomas Muley, Stephan Liersch, Helge Bischoff, Mark Kriegsmann, Rami A. El Shafie, Albrecht Stenzinger, Michael Thomas, Hans-Ulrich Kauczor and Petros Christopoulos

Cancers 2020, 12(4), 1046; https://doi.org/10.3390/cancers12041046 - 23 Apr 2020

Cited by 57 | Viewed by 5096

Abstract

Oligoprogression (OPD) of non-small-cell lung cancer (NSCLC) occurs in approximately half of patients under targeted compounds (TKI) and facilitates use of regional therapies that can prolong survival. In order to characterize OPD in immunotherapy (IO)-treated NSCLC, we analyzed the failure pattern under PD-1/PD-L1 [...] Read more.

Oligoprogression (OPD) of non-small-cell lung cancer (NSCLC) occurs in approximately half of patients under targeted compounds (TKI) and facilitates use of regional therapies that can prolong survival. In order to characterize OPD in immunotherapy (IO)-treated NSCLC, we analyzed the failure pattern under PD-1/PD-L1 inhibitors (n = 297) or chemoimmunotherapy (n = 75). Under IO monotherapy, OPD was more frequent (20% vs. 10%, p < 0.05), occurred later (median 11 vs. 5 months, p < 0.01), affected fewer sites (mean 1.1 vs. 1.5, p < 0.05), and involved fewer lesions (1.4 vs. 2.3, p < 0.05) in the first compared to later lines. Lymph nodes (42%, mainly mediastinal) and the brain (39%) were mostly affected, followed by the lung (24%) and other organs. Compared to multifocal progression, OPD occurred later (11 vs. 4 months, p < 0.001) and was associated with longer survival (26 vs. 13 months, p < 0.001) and higher tumor PD-L1 expression (p < 0.001). Chemoimmunotherapy showed a similar incidence of OPD as IO monotherapy (13% vs. 11% at 2 years). Local treatments were applied regularly for brain but only in 50% for extracranial lesions. Thus, NSCLC oligoprogression is less common under IO than under TKI, but also favorable. Since its frequency drops later in the disease, regular restaging and multidisciplinary evaluation are essential in order to exploit the full therapeutic potential. Full article

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14 pages, 1686 KiB

Open AccessReview

Transmembrane Activator and CAML Interactor (TACI): Another Potential Target for Immunotherapy of Multiple Myeloma?

by Shengli Xu and Kong-Peng Lam

Cancers 2020, 12(4), 1045; https://doi.org/10.3390/cancers12041045 - 23 Apr 2020

Cited by 9 | Viewed by 7960

Abstract

Multiple myeloma (MM) has emerged as the next most likely oncological or hematological disease indication amenable for cellular immunotherapy. Much of the attention has been focused on B cell maturation antigen (BCMA) as a unique cell surface protein on myeloma cells that is [...] Read more.

Multiple myeloma (MM) has emerged as the next most likely oncological or hematological disease indication amenable for cellular immunotherapy. Much of the attention has been focused on B cell maturation antigen (BCMA) as a unique cell surface protein on myeloma cells that is available for monoclonal antibodies, antibody drug conjugates (ADCs), T-cell redirecting bispecific molecules, and chimeric antigen receptor (CAR) T cell targeting. BCMA is a member of the tumor necrosis factor receptor (TNFR) superfamily that binds two ligands B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) and mediates the growth and survival of plasma and MM cells. Interestingly, transmembrane activator and CAML interactor (TACI), another TNFR superfamily member, also binds the same ligands and plays largely overlapping roles as BCMA in normal plasma and malignant MM cells. In this article, we review the biology of TACI, focusing on its role in normal B and plasma cells and malignant MM cells, and also discuss various ways to incorporate TACI as a potential target for immunotherapies against MM. Full article

(This article belongs to the Special Issue Cellular Immunotherapies for Multiple Myeloma)

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17 pages, 1047 KiB

Open AccessArticle

Identification of Dietary Pattern Networks Associated with Gastric Cancer Using Gaussian Graphical Models: A Case-Control Study

by Madhawa Gunathilake, Jeonghee Lee, Il Ju Choi, Young-Il Kim and Jeongseon Kim

Cancers 2020, 12(4), 1044; https://doi.org/10.3390/cancers12041044 - 23 Apr 2020

Cited by 10 | Viewed by 2956

Abstract

Gaussian graphical models (GGMs) are novel approaches to deriving dietary patterns that assess how foods are consumed in relation to one another. We aimed to apply GGMs to identify dietary patterns and to investigate the associations between dietary patterns and gastric cancer (GC) [...] Read more.

Gaussian graphical models (GGMs) are novel approaches to deriving dietary patterns that assess how foods are consumed in relation to one another. We aimed to apply GGMs to identify dietary patterns and to investigate the associations between dietary patterns and gastric cancer (GC) risk in a Korean population. In this case-control study of 415 GC cases and 830 controls, food intake was assessed using a 106-item semiquantitative food frequency questionnaire that captured 33 food groups. The dietary pattern networks corresponding to the total population contained a main network and four subnetworks. For the vegetable and seafood network, those who were in the highest tertile of the network-specific score showed a significantly reduced risk of GC both in the total population (OR = 0.66, 95% CI = 0.47–0.93, p for trend = 0.018) and in males (OR = 0.55, 95% CI = 0.34–0.89, p for trend = 0.012). Most importantly, the fruit pattern network was inversely associated with the risk of GC for the highest tertile (OR = 0.56, 95% CI = 0.38–0.81, p for trend = 0.002). The identified vegetable and seafood network and the fruit network showed a protective effect against GC development in Koreans. Full article

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19 pages, 9347 KiB

Open AccessArticle

The Efficiency of Gene Electrotransfer in Breast-Cancer Cell Lines Cultured on a Novel Collagen-Free 3D Scaffold

by Elisabetta Sieni, Monica Dettin, Mariangela De Robertis, Bianca Bazzolo, Maria Teresa Conconi, Annj Zamuner, Ramona Marino, Flavio Keller, Luca Giovanni Campana and Emanuela Signori

Cancers 2020, 12(4), 1043; https://doi.org/10.3390/cancers12041043 - 23 Apr 2020

Cited by 17 | Viewed by 4739

Abstract

Gene Electro-Transfer (GET) is a powerful method of DNA delivery with great potential for medical applications. Although GET has been extensively studied in vitro and in vivo, the optimal parameters remain controversial. 2D cell cultures have been widely used to investigate GET protocols, [...] Read more.

Gene Electro-Transfer (GET) is a powerful method of DNA delivery with great potential for medical applications. Although GET has been extensively studied in vitro and in vivo, the optimal parameters remain controversial. 2D cell cultures have been widely used to investigate GET protocols, but have intrinsic limitations, whereas 3D cultures may represent a more reliable model thanks to the capacity of reproducing the tumor architecture. Here we applied two GET protocols, using a plate or linear electrode, on 3D-cultured HCC1954 and MDA-MB231 breast cancer cell lines grown on a novel collagen-free 3D scaffold and compared results with conventional 2D cultures. To evaluate the electrotransfer efficiency, we used the plasmid pEGFP-C3 encoding the enhanced green fluorescent protein (EGFP) reporter gene. The novel 3D scaffold promoted extracellular matrix deposition, which particularly influences cell behavior in both in vitro cell cultures and in vivo tumor tissue. While the transfection efficiency was similar in the 2D-cultures, we observed significant differences in the 3D-model. The transfection efficiency in the 3D vs 2D model was 44% versus 15% (p < 0.01) and 24% versus 17% (p < 0.01) in HCC1954 and MDA-MB231 cell cultures, respectively. These findings suggest that the novel 3D scaffold allows reproducing, at least partially, the peculiar morphology of the original tumor tissues, thus allowing us to detect meaningful differences between the two cell lines. Following GET with plate electrodes, cell viability was higher in 3D-cultured HCC1954 (66%) and MDA-MB231 (96%) cell lines compared to their 2D counterpart (53% and 63%, respectively, p < 0.001). Based on these results, we propose the novel 3D scaffold as a reliable support for the preparation of cell cultures in GET studies. It may increase the reliability of in vitro assays and allow the optimization of GET parameters of in vivo protocols. Full article

(This article belongs to the Special Issue Electric Field Based Therapies in Cancer Treatment: a Selection of Studies Presented at the 3rd World Congress on Electroporation)

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12 pages, 3919 KiB

Open AccessArticle

¹⁸F-FDG and ¹¹C-Methionine PET/CT in Newly Diagnosed Multiple Myeloma Patients: Comparison of Volume-Based PET Biomarkers

by Maria I Morales-Lozano, Oliver Viering, Samuel Samnick, Paula Rodriguez-Otero, Andreas K Buck, Maria Marcos-Jubilar, Leo Rasche, Elena Prieto, K Martin Kortüm, Jesus San-Miguel, Maria J. Garcia-Velloso and Constantin Lapa

Cancers 2020, 12(4), 1042; https://doi.org/10.3390/cancers12041042 - 23 Apr 2020

Cited by 25 | Viewed by 4737

Abstract

¹¹C-methionine (¹¹C-MET) is a new positron emission tomography (PET) tracer for the assessment of disease activity in multiple myeloma (MM) patients, with preliminary data suggesting higher sensitivity and specificity than ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG). However, the value of tumor [...] Read more.

¹¹C-methionine (¹¹C-MET) is a new positron emission tomography (PET) tracer for the assessment of disease activity in multiple myeloma (MM) patients, with preliminary data suggesting higher sensitivity and specificity than ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG). However, the value of tumor burden biomarkers has yet to be investigated. Our goals were to corroborate the superiority of ¹¹C-MET for MM staging and to compare its suitability for the assessment of metabolic tumor burden biomarkers in comparison to ¹⁸F-FDG. Twenty-two patients with newly diagnosed, treatment-naïve symptomatic MM who had undergone ¹¹C-MET and ¹⁸F-FDG PET/CT were evaluated. Standardized uptake values (SUV) were determined and compared with total metabolic tumor volume (TMTV) for both tracers: total lesion glycolysis (TLG) and total lesion ¹¹C-MET uptake (TLMU). PET-derived values were compared to Revised International Staging System (R-ISS), cytogenetic, and serologic MM markers such as M component, beta 2 microglobulin (B2M), serum free light chains (FLC), albumin, and lactate dehydrogenase (LDH). In 11 patients (50%), ¹¹C-MET detected more focal lesions (FL) than FDG (p < 0.01). SUVmax, SUVmean, SUVpeak, TMTV, and TLMU were also significantly higher in ¹¹C-MET than in ¹⁸F-FDG (p < 0.05, respectively). ¹¹C-MET PET biomarkers had a better correlation with tumor burden (bone marrow plasma cell infiltration, M component; p < 0.05 versus p = n.s. respectively). This pilot study suggests that ¹¹C-MET PET/CT is a more sensitive marker for the assessment of myeloma tumor burden than ¹⁸F-FDG. Its implications for prognosis evaluation need further investigation. Full article

(This article belongs to the Special Issue PET/CT in Multiple Myeloma Patients)

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13 pages, 629 KiB

Open AccessReview

Functional and Clinical Impact of CircRNAs in Oral Cancer

by Ion Cristóbal, Cristina Caramés, Jaime Rubio, Marta Sanz-Alvarez, Melani Luque, Juan Madoz-Gúrpide, Federico Rojo and Jesús García-Foncillas

Cancers 2020, 12(4), 1041; https://doi.org/10.3390/cancers12041041 - 23 Apr 2020

Cited by 16 | Viewed by 3157

Abstract

The increasing number of recently published works regarding the role of circular RNAs (circRNAs) in oral cancer highlights the key contribution of this novel class of endogenous noncoding RNAs as regulators of critical signaling pathways and their clinical value as novel biomarkers. This [...] Read more.

The increasing number of recently published works regarding the role of circular RNAs (circRNAs) in oral cancer highlights the key contribution of this novel class of endogenous noncoding RNAs as regulators of critical signaling pathways and their clinical value as novel biomarkers. This review summarizes and puts into context the existing literature in order to clarify the relevance of circRNAs as novel mediators of oral cancer pathogenesis as well as their potential usefulness as predictors of clinical outcome and response to therapy in this disease. Full article

(This article belongs to the Special Issue Circular RNAs in Cancer)

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15 pages, 4229 KiB

Open AccessArticle

Enhancing Antitumor Efficacy of Heavily Vascularized Tumors by RAMBO Virus through Decreased Tumor Endothelial Cell Activation

by Mitra Nair, Maninder Khosla, Yoshihiro Otani, Margaret Yeh, Flora Park, Toshihiko Shimizu, Jin Muk Kang, Chelsea Bolyard, Jun-Ge Yu, Yeshavanth Kumar Banasavadi-Siddegowda, Gonzalo Lopez, Balveen Kaur, Raphael E. Pollock, Tae Jin Lee, Matthew Old and Ji Young Yoo

Cancers 2020, 12(4), 1040; https://doi.org/10.3390/cancers12041040 - 23 Apr 2020

Cited by 11 | Viewed by 3514

Abstract

Vascularization is a common pathology for many solid tumors, and therefore anti-angiogenic strategies are being investigated as a therapeutic target for treatment. Numerous studies are also being conducted regarding the effects of oncolytic viruses, including Imlygic^TM, an FDA approved oncolytic herpes [...] Read more.

Vascularization is a common pathology for many solid tumors, and therefore anti-angiogenic strategies are being investigated as a therapeutic target for treatment. Numerous studies are also being conducted regarding the effects of oncolytic viruses, including Imlygic^TM, an FDA approved oncolytic herpes simplex virus-1 (oHSV) for the treatment of highly vascularized tumors such as Kaposi sarcoma (NCT04065152), and brain tumors. To our knowledge, the effects of combining oncolytic HSV with angiogenesis inhibition on endothelial cell activation has not been previously described. Here, we tested the effects of Rapid Antiangiogenesis Mediated By Oncolytic Virus (RAMBO), an oHSV which expresses a potent anti-angiogenic gene Vasculostatin on endothelial cell activation in heavily vascularized solid tumors. oHSV treatment induces endothelial cell activation, which inhibits virus propagation and oncolysis in adjacent tumor cells in vitro. Consistently, this was also observed in intravital imaging of intracranial tumor-bearing mice in vivo where infected tumor endothelial cells could efficiently clear the virus without cell lysis. Quantitative real-time PCR (Q-PCR), leukocyte adhesion assay, and fluorescent microscopy imaging data, however, revealed that RAMBO virus significantly decreased expression of endothelial cell activation markers and leukocyte adhesion, which in turn increased virus replication and cytotoxicity in endothelial cells. In vivo RAMBO treatment of subcutaneously implanted sarcoma tumors significantly reduced tumor growth in mice bearing sarcoma compared to rHSVQ. In addition, histological analysis of RAMBO-treated tumor tissues revealed large areas of necrosis and a statistically significant reduction in microvessel density (MVD). This study provides strong preclinical evidence of the therapeutic benefit for the use of RAMBO virus as a treatment option for highly vascularized tumors. Full article

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15 pages, 1061 KiB

Open AccessArticle

Targeted Next-Generation Sequencing of 117 Routine Clinical Samples Provides Further Insights into the Molecular Landscape of Uveal Melanoma

by Sophie Thornton, Sarah E. Coupland, Lisa Olohan, Julie S. Sibbring, John G. Kenny, Christiane Hertz-Fowler, Xuan Liu, Sam Haldenby, Heinrich Heimann, Rumana Hussain, Natalie Kipling, Azzam Taktak and Helen Kalirai

Cancers 2020, 12(4), 1039; https://doi.org/10.3390/cancers12041039 - 23 Apr 2020

Cited by 37 | Viewed by 5758

Abstract

Uveal melanoma (UM) has well-characterised somatic copy number alterations (SCNA) in chromosomes 1, 3, 6 and 8, in addition to mutations in GNAQ, GNA11, CYSLTR2, PLCB4, BAP1, SF3B1 and EIF1AX, most being linked to metastatic-risk. To gain further insight into the molecular [...] Read more.

Uveal melanoma (UM) has well-characterised somatic copy number alterations (SCNA) in chromosomes 1, 3, 6 and 8, in addition to mutations in GNAQ, GNA11, CYSLTR2, PLCB4, BAP1, SF3B1 and EIF1AX, most being linked to metastatic-risk. To gain further insight into the molecular landscape of UM, we designed a targeted next-generation sequencing (NGS) panel to detect SCNA and mutations in routine clinical UM samples. We compared hybrid-capture and amplicon-based target enrichment methods and tested a larger cohort of primary UM samples on the best performing panel. UM clinical samples processed either as fresh-frozen, formalin-fixed paraffin embedded (FFPE), small intraocular biopsies or following irradiation were successfully profiled using NGS, with hybrid capture outperforming the PCR-based enrichment methodology. We identified monosomy 3 (M3)-UM that were wild-type for BAP1 but harbored SF3B1 mutations, novel frameshift deletions in SF3B1 and EIF1AX, as well as a PLCB4 mutation outside of the hotspot on exon 20 coinciding with a GNAQ mutation in some UM. We observed samples that harboured mutations in both BAP1 and SF3B1, and SF3B1 and EIF1AX, respectively. Novel mutations were also identified in TTC28, KTN1, CSMD1 and TP53BP1. NGS can simultaneously assess SCNA and mutation data in UM, in a reliable and reproducible way, irrespective of sample type or previous processing. BAP1 and SF3B1 mutations, in addition to 8q copy number, are of added importance when determining UM patient outcome. Full article

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14 pages, 1484 KiB

Open AccessCommunication

β-Caryophyllene Inhibits Cell Proliferation through a Direct Modulation of CB2 Receptors in Glioblastoma Cells

by Natasha Irrera, Angela D’Ascola, Giovanni Pallio, Alessandra Bitto, Federica Mannino, Vincenzo Arcoraci, Michelangelo Rottura, Antonio Ieni, Letteria Minutoli, Daniela Metro, Mario Vaccaro, Domenica Altavilla and Francesco Squadrito

Cancers 2020, 12(4), 1038; https://doi.org/10.3390/cancers12041038 - 23 Apr 2020

Cited by 49 | Viewed by 5654

Abstract

Glioblastomas are aggressive cancers characterized by uncontrolled proliferation and inflammation. b-caryophyllene (BCP) is a cannabinoid receptor 2 (CB2) agonist that showed an important anti-inflammatory effect through the interaction of CB2 and peroxisome proliferator-activated receptor gamma (PPARg) receptors. BCP effects were investigated in an [...] Read more.

Glioblastomas are aggressive cancers characterized by uncontrolled proliferation and inflammation. b-caryophyllene (BCP) is a cannabinoid receptor 2 (CB2) agonist that showed an important anti-inflammatory effect through the interaction of CB2 and peroxisome proliferator-activated receptor gamma (PPARg) receptors. BCP effects were investigated in an in vitro model of glioblastoma. U-373 and U87, derived from a human glioblastoma, and human glioma stem-like cells (GSCs) were treated with BCP at different doses and time-points. AM360, a specific CB2 antagonist, was added 2 h before BCP treatment. BCP showed a significant anti-proliferative effect, reducing cell viability, inhibiting cell cycle, and increasing apoptosis, as demonstrated by Tunel assay, caspase-3 and caspase -9 activation. In addition, the pro-apoptotic BAX expression was increased, whereas the anti-apoptotic Bcl-2 expression was reduced. Treatment with BCP decreased Beclin-1, LC3 and p62/SQSTM1 expression, indicating a possible switch of autophagy to apoptosis. BCP’s anti-inflammatory effect was demonstrated by NF-κB reduction, PPARg activation and TNF-a decrease; BCP significantly reduced Jun N-Terminal Kinase (JNK) expression as a consequence of TNF-α inhibition. AM360 abrogated BCP effects, thus demonstrating the BCP mechanism of action through the CB2 receptor. These findings let us hypothesize that BCP may act as a tumor suppressor in glioblastoma, acting on CB2 receptor and modulating JNK. Full article

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15 pages, 1642 KiB

Open AccessArticle

Cancer-Selective Treatment of Cancerous and Non-Cancerous Human Cervical Cell Models by a Non-Thermally Operated Electrosurgical Argon Plasma Device

by Lukas Feil, André Koch, Raphael Utz, Michael Ackermann, Jakob Barz, Matthias Stope, Bernhard Krämer, Diethelm Wallwiener, Sara Y. Brucker and Martin Weiss

Cancers 2020, 12(4), 1037; https://doi.org/10.3390/cancers12041037 - 23 Apr 2020

Cited by 24 | Viewed by 3709

Abstract

Cold atmospheric plasma (CAP) treatment is developing as a promising option for local anti-neoplastic treatment of dysplastic lesions and early intraepithelial cancer. Currently, high-frequency electrosurgical argon plasma sources are available and well established for clinical use. In this study, we investigated the effects [...] Read more.

Cold atmospheric plasma (CAP) treatment is developing as a promising option for local anti-neoplastic treatment of dysplastic lesions and early intraepithelial cancer. Currently, high-frequency electrosurgical argon plasma sources are available and well established for clinical use. In this study, we investigated the effects of treatment with a non-thermally operated electrosurgical argon plasma source, a Martin Argon Plasma Beamer System (MABS), on cell proliferation and metabolism of a tissue panel of human cervical cancer cell lines as well as on non-cancerous primary cells of the cervix uteri. Similar to conventional CAP sources, we were able to show that MABS was capable of causing antiproliferative and cytotoxic effects on cervical squamous cell and adenocarcinoma as well as on non-neoplastic cervical tissue cells due to the generation of reactive species. Notably, neoplastic cells were more sensitive to the MABS treatment, suggesting a promising new and non-invasive application for in vivo treatment of precancerous and cancerous cervical lesions with non-thermally operated electrosurgical argon plasma sources. Full article

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

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Graphical abstract

18 pages, 2864 KiB

Open AccessReview

The Role of CCL21/CCR7 Chemokine Axis in Breast Cancer Progression

by Balsam Rizeq and Mohammed Imad Malki

Cancers 2020, 12(4), 1036; https://doi.org/10.3390/cancers12041036 - 23 Apr 2020

Cited by 64 | Viewed by 11087

Abstract

Breast cancer is a leading cause of cancer-related deaths worldwide, predominantly caused by metastasis. It is generally accepted that the pattern of breast cancer metastasis is largely determined by the interaction between the chemokine receptors on cancer cells and the chemokines expressed at [...] Read more.

Breast cancer is a leading cause of cancer-related deaths worldwide, predominantly caused by metastasis. It is generally accepted that the pattern of breast cancer metastasis is largely determined by the interaction between the chemokine receptors on cancer cells and the chemokines expressed at the sites of metastatic disease. Chemokine receptors belong to the G-protein-coupled receptors (GPCRs) family that appear to be implicated in inflammatory diseases, tumor growth and metastasis. One of its members, C-C Chemokine receptor 7 (CCR7), binds chemokines CCL19 and CCL21, which are important for tissue homeostasis, immune surveillance and tumorigenesis. These receptors have been shown to induce the pathobiology of breast cancer due to their ability to induce cellular proliferation and migration upon the binding of the cognate chemokine receptors. The underlying signaling pathways and exact cellular interactions within this biological system are not fully understood and need further insights. Thus, in this review, we summarize the essential roles of CCR7 and its receptors in breast cancer progression. Furthermore, we discuss the mechanisms of regulation that may lead to novel opportunities for therapeutic intervention. Despite the enormous advances in our knowledge of the nature of the chemokines in breast cancer metastasis, research about the involvement of CCR7 in cancer progression is still limited. Therefore, further studies are essential to illustrate the distinct roles of CCR7 in cancer progression and validate its potential as a preventive bio-factor for human breast cancer metastasis by targeting chemokine receptor genes. Full article

(This article belongs to the Special Issue Chemokines and Chemokine Receptors: New Targets for Cancer Therapy)

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13 pages, 888 KiB

Open AccessArticle

Carfilzomib Based Treatment Strategies in the Management of Relapsed/Refractory Multiple Myeloma with Extramedullary Disease

by Xiang Zhou, Patricia Flüchter, Katharina Nickel, Katharina Meckel, Janin Messerschmidt, David Böckle, Sebastian Knorz, Maximilian Johannes Steinhardt, Franziska Krummenast, Sophia Danhof, Hermann Einsele, K. Martin Kortüm and Leo Rasche

Cancers 2020, 12(4), 1035; https://doi.org/10.3390/cancers12041035 - 23 Apr 2020

Cited by 33 | Viewed by 4435

Abstract

Published experience with carfilzomib in patients with relapsed/refractory multiple myeloma (RRMM) and extramedullary disease (EMD) is still limited. The current study aimed to assess the efficacy and safety of carfilzomib containing therapy regimens in EMD. We retrospectively analyzed 45 patients with extramedullary RRMM [...] Read more.

Published experience with carfilzomib in patients with relapsed/refractory multiple myeloma (RRMM) and extramedullary disease (EMD) is still limited. The current study aimed to assess the efficacy and safety of carfilzomib containing therapy regimens in EMD. We retrospectively analyzed 45 patients with extramedullary RRMM treated with carfilzomib from June 2013 to September 2019. The median age at the start of carfilzomib was 64 (range 40–80) years. Twenty (44%) and 25 (56%) patients had paraosseous manifestation and EMD without adjacency to bone, respectively. The serological overall response rate (ORR) was 59%. Extramedullary response was evaluable in 33 patients, nine (27%) of them achieved partial remission (PR) (ORR = 27%). In 15 (33%) patients, we observed no extramedullary response despite serological response. The median progression-free survival (PFS) and overall survival (OS) were five (95% CI, 3.5–6.5) and ten (95% CI, 7.5–12.5) months, respectively. EMD without adjacency to bone was associated with a significantly inferior PFS (p = 0.004) and OS (p = 0.04) compared to paraosseous lesions. Carfilzomib based treatment strategies showed some efficacy in heavily pretreated patients with extramedullary RRMM but could not overcome the negative prognostic value of EMD. Due to the discrepancy between serological and extramedullary response, evaluation of extramedullary response using imaging is mandatory in these patients. Full article

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18 pages, 628 KiB

Open AccessReview

Effect of Transgene Location, Transcriptional Control Elements and Transgene Features in Armed Oncolytic Adenoviruses

by Martí Farrera-Sal, Cristina Fillat and Ramon Alemany

Cancers 2020, 12(4), 1034; https://doi.org/10.3390/cancers12041034 - 23 Apr 2020

Cited by 17 | Viewed by 3910

Abstract

Clinical results with oncolytic adenoviruses (OAds) used as antitumor monotherapies show limited efficacy. To increase OAd potency, transgenes have been inserted into their genome, a strategy known as “arming OAds”. Here, we review different parameters that affect the outcome of armed OAds. Recombinant [...] Read more.

Clinical results with oncolytic adenoviruses (OAds) used as antitumor monotherapies show limited efficacy. To increase OAd potency, transgenes have been inserted into their genome, a strategy known as “arming OAds”. Here, we review different parameters that affect the outcome of armed OAds. Recombinant adenovirus used in gene therapy and vaccination have been the basis for the design of armed OAds. Hence, early region 1 (E1) and early region 3 (E3) have been the most commonly used transgene insertion sites, along with partially or complete E3 deletions. Besides transgene location and orientation, transcriptional control elements, transgene function, either virocentric or immunocentric, and even the codons encoding it, greatly impact on transgene levels and virus fitness. Full article

(This article belongs to the Special Issue The Role of Adenovirus in Cancer Therapy)

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27 pages, 1854 KiB

Open AccessReview

Can Hemp Help? Low-THC Cannabis and Non-THC Cannabinoids for the Treatment of Cancer

by Farjana Afrin, Mengna Chi, Andrew L. Eamens, Ryan J. Duchatel, Alicia M. Douglas, Jennifer Schneider, Craig Gedye, Ameha S. Woldu and Matthew D. Dun

Cancers 2020, 12(4), 1033; https://doi.org/10.3390/cancers12041033 - 23 Apr 2020

Cited by 43 | Viewed by 17620

Abstract

Cannabis has been used to relieve the symptoms of disease for thousands of years. However, social and political biases have limited effective interrogation of the potential benefits of cannabis and polarised public opinion. Further, the medicinal and clinical utility of cannabis is limited [...] Read more.

Cannabis has been used to relieve the symptoms of disease for thousands of years. However, social and political biases have limited effective interrogation of the potential benefits of cannabis and polarised public opinion. Further, the medicinal and clinical utility of cannabis is limited by the psychotropic side effects of ∆⁹-tetrahydrocannabinol (∆⁹-THC). Evidence is emerging for the therapeutic benefits of cannabis in the treatment of neurological and neurodegenerative diseases, with potential efficacy as an analgesic and antiemetic for the management of cancer-related pain and treatment-related nausea and vomiting, respectively. An increasing number of preclinical studies have established that ∆⁹-THC can inhibit the growth and proliferation of cancerous cells through the modulation of cannabinoid receptors (CB1R and CB2R), but clinical confirmation remains lacking. In parallel, the anti-cancer properties of non-THC cannabinoids, such as cannabidiol (CBD), are linked to the modulation of non-CB1R/CB2R G-protein-coupled receptors, neurotransmitter receptors, and ligand-regulated transcription factors, which together modulate oncogenic signalling and redox homeostasis. Additional evidence has also demonstrated the anti-inflammatory properties of cannabinoids, and this may prove relevant in the context of peritumoural oedema and the tumour immune microenvironment. This review aims to document the emerging mechanisms of anti-cancer actions of non-THC cannabinoids. Full article

(This article belongs to the Special Issue Cannabinoids and Cancer)

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16 pages, 875 KiB

Open AccessReview

The Effect of Higher Level Computerized Clinical Decision Support Systems on Oncology Care: A Systematic Review

by Sosse E. Klarenbeek, Harm H.A. Weekenstroo, J.P. Michiel Sedelaar, Jurgen J. Fütterer, Mathias Prokop and Marcia Tummers

Cancers 2020, 12(4), 1032; https://doi.org/10.3390/cancers12041032 - 22 Apr 2020

Cited by 43 | Viewed by 5133

Abstract

Background: To deal with complexity in cancer care, computerized clinical decision support systems (CDSSs) are developed to support quality of care and improve decision-making. We performed a systematic review to explore the value of CDSSs using automated clinical guidelines, Artificial Intelligence, datamining or [...] Read more.

Background: To deal with complexity in cancer care, computerized clinical decision support systems (CDSSs) are developed to support quality of care and improve decision-making. We performed a systematic review to explore the value of CDSSs using automated clinical guidelines, Artificial Intelligence, datamining or statistical methods (higher level CDSSs) on the quality of care in oncology. Materials and Methods: The search strategy combined synonyms for ‘CDSS’ and ‘cancer.’ Pubmed, Embase, The Cochrane Library, Institute of Electrical and Electronics Engineers, Association of Computing Machinery digital library and Web of Science were systematically searched from January 2000 to December 2019. Included studies evaluated the impact of higher level CDSSs on process outcomes, guideline adherence and clinical outcomes. Results: 11,397 studies were selected for screening, after which 61 full-text articles were assessed for eligibility. Finally, nine studies were included in the final analysis with a total population size of 7985 patients. Types of cancer included breast cancer (63.1%), lung cancer (27.8%), prostate cancer (4.1%), colorectal cancer (3.1%) and other cancer types (1.9%). The included studies demonstrated significant improvements of higher level CDSSs on process outcomes and guideline adherence across diverse settings in oncology. No significant differences were reported for clinical outcomes. Conclusion: Higher level CDSSs seem to improve process outcomes and guidelines adherence but not clinical outcomes. It should be noticed that the included studies primarily focused on breast and lung cancer. To further explore the impact of higher level CDSSs on quality of care, high-quality research is required. Full article

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25 pages, 2314 KiB

Open AccessFeature PaperArticle

The Mitochondrial Protein VDAC1 at the Crossroads of Cancer Cell Metabolism: The Epigenetic Link

by Zohar Amsalem, Tasleem Arif, Anna Shteinfer-Kuzmine, Vered Chalifa-Caspi and Varda Shoshan-Barmatz

Cancers 2020, 12(4), 1031; https://doi.org/10.3390/cancers12041031 - 22 Apr 2020

Cited by 25 | Viewed by 5255

Abstract

Carcinogenesis is a complicated process that involves the deregulation of epigenetics, resulting in cellular transformational events, such as proliferation, differentiation, and metastasis. Most chromatin-modifying enzymes utilize metabolites as co-factors or substrates and thus are directly dependent on such metabolites as acetyl-coenzyme A, S-adenosylmethionine, [...] Read more.

Carcinogenesis is a complicated process that involves the deregulation of epigenetics, resulting in cellular transformational events, such as proliferation, differentiation, and metastasis. Most chromatin-modifying enzymes utilize metabolites as co-factors or substrates and thus are directly dependent on such metabolites as acetyl-coenzyme A, S-adenosylmethionine, and NAD+. Here, we show that using specific siRNA to deplete a tumor of VDAC1 not only led to reprograming of the cancer cell metabolism but also altered several epigenetic-related enzymes and factors. VDAC1, in the outer mitochondrial membrane, controls metabolic cross-talk between the mitochondria and the rest of the cell, thus regulating the metabolic and energetic functions of mitochondria, and has been implicated in apoptotic-relevant events. We previously demonstrated that silencing VDAC1 expression in glioblastoma (GBM) U-87MG cell-derived tumors, resulted in reprogramed metabolism leading to inhibited tumor growth, angiogenesis, epithelial–mesenchymal transition and invasiveness, and elimination of cancer stem cells, while promoting the differentiation of residual tumor cells into neuronal-like cells. These VDAC1 depletion-mediated effects involved alterations in transcription factors regulating signaling pathways associated with cancer hallmarks. As the epigenome is sensitive to cellular metabolism, this study was designed to assess whether depleting VDAC1 affects the metabolism–epigenetics axis. Using DNA microarrays, q-PCR, and specific antibodies, we analyzed the effects of si-VDAC1 treatment of U-87MG-derived tumors on histone modifications and epigenetic-related enzyme expression levels, as well as the methylation and acetylation state, to uncover any alterations in epigenetic properties. Our results demonstrate that metabolic rewiring of GBM via VDAC1 depletion affects epigenetic modifications, and strongly support the presence of an interplay between metabolism and epigenetics. Full article

(This article belongs to the Special Issue Mitochondrial function and dysfunction in cancer and their potential as anti-cancer targets)

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10 pages, 2739 KiB

Open AccessCommunication

PET-FDG: Impetus

by Cristina Nanni

Cancers 2020, 12(4), 1030; https://doi.org/10.3390/cancers12041030 - 22 Apr 2020

Cited by 19 | Viewed by 5678

Abstract

The International Myeloma Working Group (IMWG)recommends FDG PET/CT (Fluoro-Deoxy-glucose Positron Emission Tomography/Computed Tomography) as the gold standard imaging modality for initial evaluation and response to therapy assessment in multiple myeloma. In fact, FDG PET/CT, provides multiple useful indexes to risk-stratify patients and has [...] Read more.

The International Myeloma Working Group (IMWG)recommends FDG PET/CT (Fluoro-Deoxy-glucose Positron Emission Tomography/Computed Tomography) as the gold standard imaging modality for initial evaluation and response to therapy assessment in multiple myeloma. In fact, FDG PET/CT, provides multiple useful indexes to risk-stratify patients and has significant prognostic value. However, multiple myeloma remains a complex disease to interpret on imaging. The Italian myeloma criteria for PET use (IMPeTUs) were proposed to standardize FDG PET/CT reading in multiple myeloma. In this communication an overview on IMPeTUs is provided as well as some examples of application. Full article

(This article belongs to the Special Issue PET/CT in Multiple Myeloma Patients)

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