Cancers

23 pages, 1703 KiB

Open AccessReview

NF-κB: A Druggable Target in Acute Myeloid Leukemia

by Barbara Di Francesco, Daniela Verzella, Daria Capece, Davide Vecchiotti, Mauro Di Vito Nolfi, Irene Flati, Jessica Cornice, Monica Di Padova, Adriano Angelucci, Edoardo Alesse and Francesca Zazzeroni

Cancers 2022, 14(14), 3557; https://doi.org/10.3390/cancers14143557 - 21 Jul 2022

Cited by 14 | Viewed by 3206

Abstract

Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy that relies on highly heterogeneous cytogenetic alterations. Although in the last few years new agents have been developed for AML treatment, the overall survival prospects for AML patients are still gloomy and new therapeutic [...] Read more.

Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy that relies on highly heterogeneous cytogenetic alterations. Although in the last few years new agents have been developed for AML treatment, the overall survival prospects for AML patients are still gloomy and new therapeutic options are still urgently needed. Constitutive NF-κB activation has been reported in around 40% of AML patients, where it sustains AML cell survival and chemoresistance. Given the central role of NF-κB in AML, targeting the NF-κB pathway represents an attractive strategy to treat AML. This review focuses on current knowledge of NF-κB’s roles in AML pathogenesis and summarizes the main therapeutic approaches used to treat NF-κB-driven AML. Full article

(This article belongs to the Collection Acute Myeloid Leukemia (AML))

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14 pages, 1230 KiB

Open AccessReview

Recent Advances in the Diagnosis and Management of High-Risk Cutaneous Squamous Cell Carcinoma

by Clio Dessinioti and Alexander J. Stratigos

Cancers 2022, 14(14), 3556; https://doi.org/10.3390/cancers14143556 - 21 Jul 2022

Cited by 7 | Viewed by 2723

Abstract

High-risk cSCC is defined as invasive cSCC staged as N0 (without detectable regional lymph nodes) and M0 (without distant metastasis), that has features associated with a higher risk of poorer prognosis. The focus of this review is on the recent advances in the [...] Read more.

High-risk cSCC is defined as invasive cSCC staged as N0 (without detectable regional lymph nodes) and M0 (without distant metastasis), that has features associated with a higher risk of poorer prognosis. The focus of this review is on the recent advances in the diagnosis and management of high-risk cSCC. The interest in high-risk cSCC relies on its higher risk of progression to advanced cSCC, as it represents the main pool of cSCCs that give rise to advanced tumors. Assessment of the risk is thus particularly relevant for common cSCC to identify the few with a high-risk risk of local recurrence, metastasis, or disease-specific death among all other low-risk tumors. The timely diagnosis and effective treatment of high-risk cSCCs may halt their further progression and aim to prevent and lower the incidence of advanced cSCCs. Clearance of the tumor with negative surgical margins is the main goal of surgery, which is the primary treatment of cSCC. It seems that it is difficult to discern the group of high-risk cSCCs that may benefit from adjuvant RT, as a universal beneficial effect for a cSCC with any high-risk factor which was resected with clear surgical margins has not been established. In the case of a high-risk cSCC with positive margins after surgery, and re-excision not feasible, post-operative radiotherapy is performed when possible. Recommendations on further management are discussed. Regarding the follow-up of patients diagnosed with high-risk cSCC, factors to consider regarding the frequency and intensity of the follow-up schedule include the risk and possible time of occurrence of metastasis from cSCC. Full article

(This article belongs to the Special Issue Recent Progress in the Diagnosis and Treatment of Melanoma and Other Skin Cancers)

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11 pages, 461 KiB

Open AccessFeature PaperArticle

Evaluation of the Perioperative and Postoperative Course of Surgery for Pineal Germinoma in the SIOP CNS GCT 96 Trial

by Ehab Shabo, Thomas Czech, James C. Nicholson, Conor Mallucci, Carmine Mottolese, Gianluca Piatelli, Didier Frappaz, Matthew Jonathan Murray, Cecile Faure-Conter, Maria Luisa Garrè, Sevgi Sarikaya-Seiwert, Leonie Weinhold, Hannes Haberl and Gabriele Calaminus

Cancers 2022, 14(14), 3555; https://doi.org/10.3390/cancers14143555 - 21 Jul 2022

Cited by 2 | Viewed by 1446

Abstract

Background: CNS germinoma, being marker-negative, are mainly diagnosed by histological examination. These tumors predominantly appear in the suprasellar and/or pineal region. In contrast to the suprasellar region, where biopsy is the standard procedure in case of a suspected germ-cell tumor to avoid mutilation [...] Read more.

Background: CNS germinoma, being marker-negative, are mainly diagnosed by histological examination. These tumors predominantly appear in the suprasellar and/or pineal region. In contrast to the suprasellar region, where biopsy is the standard procedure in case of a suspected germ-cell tumor to avoid mutilation to the endocrine structures, pineal tumors are more accessible to primary resection. We evaluated the perioperative course of patients with pineal germinoma who were diagnosed by primary biopsy or resection in the SIOP CNS GCT 96 trial. Methods: Overall, 235 patients had germinoma, with pineal localization in 113. The relationship between initial symptoms, tumor size, and postoperative complications was analyzed. Results: Of 111 evaluable patients, initial symptoms were headache (n = 98), hydrocephalus (n = 93), double vision (n = 62), Parinaud syndrome (n = 57), and papilledema (n = 44). There was no significant relationship between tumor size and primary symptoms. A total of 57 patients underwent primary resection and 54 underwent biopsy. Postoperative complications were reported in 43.2% of patients after resection and in 11.4% after biopsy (p < 0.008). Biopsy was significantly more commonly performed on larger tumors (p= 0.002). Conclusions: These results support the practice of biopsy over resection for histological confirmation of pineal germinoma. Full article

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17 pages, 2064 KiB

Open AccessArticle

Integrated Clinical and Genomic Models to Predict Optimal Cytoreduction in High-Grade Serous Ovarian Cancer

by Nicholas Cardillo, Eric J. Devor, Silvana Pedra Nobre, Andreea Newtson, Kimberly Leslie, David P. Bender, Brian J. Smith, Michael J. Goodheart and Jesus Gonzalez-Bosquet

Cancers 2022, 14(14), 3554; https://doi.org/10.3390/cancers14143554 - 21 Jul 2022

Cited by 4 | Viewed by 1763

Abstract

Advanced high-grade serous (HGSC) ovarian cancer is treated with either primary surgery followed by chemotherapy or neoadjuvant chemotherapy followed by interval surgery. The decision to proceed with surgery primarily or after chemotherapy is based on a surgeon’s clinical assessment and prediction of an [...] Read more.

Advanced high-grade serous (HGSC) ovarian cancer is treated with either primary surgery followed by chemotherapy or neoadjuvant chemotherapy followed by interval surgery. The decision to proceed with surgery primarily or after chemotherapy is based on a surgeon’s clinical assessment and prediction of an optimal outcome. Optimal and complete cytoreductive surgery are correlated with improved overall survival. This clinical assessment results in an optimal surgery approximately 70% of the time. We hypothesize that this prediction can be improved by using biological tumor data to predict optimal cytoreduction. With access to a large biobank of ovarian cancer tumors, we obtained genomic data on 83 patients encompassing gene expression, exon expression, long non-coding RNA, micro RNA, single nucleotide variants, copy number variation, DNA methylation, and fusion transcripts. We then used statistical learning methods (lasso regression) to integrate these data with pre-operative clinical information to create predictive models to discriminate which patient would have an optimal or complete cytoreductive outcome. These models were then validated within The Cancer Genome Atlas (TCGA) HGSC database and using machine learning methods (TensorFlow). Of the 124 models created and validated for optimal cytoreduction, 21 performed at least equal to, if not better than, our historical clinical rate of optimal debulking in advanced-stage HGSC as a control. Of the 89 models created to predict complete cytoreduction, 37 have the potential to outperform clinical decision-making. Prospective validation of these models could result in improving our ability to objectively predict which patients will undergo optimal cytoreduction and, therefore, improve our ovarian cancer outcomes. Full article

(This article belongs to the Special Issue Molecular Testing for Pathologic Diagnosis, Prediction and Prognostication in Gynecologic Cancers: Utility and Limitations)

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14 pages, 2446 KiB

Open AccessArticle

Individualized Selection Criteria Based on Tumor Burden in Future Remnant Liver for Staged Hepatectomy of Advanced CRLM: Conventional TSH or ALPPS

by Kun-Ming Chan, Hao-Chien Hung, Jin-Chiao Lee, Tsung-Han Wu, Yu-Chao Wang, Chih-Hsien Cheng, Chen-Fang Lee, Ting-Jung Wu, Hong-Shiue Chou and Wei-Chen Lee

Cancers 2022, 14(14), 3553; https://doi.org/10.3390/cancers14143553 - 21 Jul 2022

Viewed by 1451

Abstract

Staged hepatectomy is a promising strategy for curative resection of advanced colorectal liver metastasis (CRLM) to prevent inadequate future remnant liver (FRL). However, the selection criteria for conventional two-stage hepatectomy (cTSH) and associating liver partitioning and portal vein ligation for staged hepatectomy (ALPPS) [...] Read more.

Staged hepatectomy is a promising strategy for curative resection of advanced colorectal liver metastasis (CRLM) to prevent inadequate future remnant liver (FRL). However, the selection criteria for conventional two-stage hepatectomy (cTSH) and associating liver partitioning and portal vein ligation for staged hepatectomy (ALPPS) remain unclear. This study aimed to propose a selection criterion for determining the optimal staged hepatectomy for patients with advanced CRLM. A selection criterion based on the degree of metastatic tumors within the FRL was established to determine staged hepatectomy approaches. Generally, ALPPS is recommended for patients with ≤3 metastatic nodules and whose nodules do not measure >3 cm in the FRL. cTSH is performed for patients whose tumor burden in FRL beyond the selection criteria. Data of 37 patients who underwent staged hepatectomy and curative intent of CRLM were analyzed. The clinical characteristics and outcomes of the two approaches were compared. Overall, cTSH and ALPPS were performed for 27 (73.0%) and 10 (27.0%) patients, respectively. Of those, 20 patients in the cTSH group and all patients in the ALPPS group had completed staged hepatectomy. The 1-, 3-, and 5-year survival rates were 91.6%, 62.4%, and 45.4% for all patients, respectively. The outcomes of patients who had successfully completed the staged hepatectomy were significantly better than those of other patients who failed to achieve staged hepatectomy. However, no significant difference was observed in the overall survival of patients who underwent staged hepatectomy between the two groups, but those in the ALPPS group had 100% survival at the end of this study. The individualized selection criteria based on tumor burden in the FRL that could balance the operative risk and oncologic outcome appear to be a promising strategy for achieving complete staged hepatectomy in patients with advanced CRLM. Full article

(This article belongs to the Special Issue Colorectal Liver Metastasis (Volume II))

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16 pages, 2066 KiB

Open AccessReview

Effects of Exosomal Viral Components on the Tumor Microenvironment

by Jing Li, Yan Zhang and Bing Luo

Cancers 2022, 14(14), 3552; https://doi.org/10.3390/cancers14143552 - 21 Jul 2022

Cited by 8 | Viewed by 2703

Abstract

Exosomes are extracellular membrane vesicles with a diameter of 30–100 nm, produced by different eukaryotic cells that contain multitudinous lipids, nucleic acids, and proteins. They transfer membrane components and nucleic acids between cells, thereby performing an information exchange between cells. Many studies have [...] Read more.

Exosomes are extracellular membrane vesicles with a diameter of 30–100 nm, produced by different eukaryotic cells that contain multitudinous lipids, nucleic acids, and proteins. They transfer membrane components and nucleic acids between cells, thereby performing an information exchange between cells. Many studies have shown that a variety of tumor-associated viruses can exert their biological functions through exosomes. The tumor microenvironment (TME) is very important in the occurrence, development, and chemoresistance of tumors. It is composed of tumor cells, fibroblasts, endothelial cells, immune cells, stromal cells, and acellular components, such as exosomes and cytokines. This review focuses on the effects of virus-related components secreted by tumor cells over the TME in several virus-associated cancers. Full article

(This article belongs to the Special Issue Extracellular Vesicle in Cancer Biology)

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10 pages, 3703 KiB

Open AccessArticle

Clinical Usefulness of Monitoring Muscle Volume during Atezolizumab Plus Bevacizumab Therapy in Patients with Unresectable Hepatocellular Carcinoma

by Hiroaki Matsumoto, Kaoru Tsuchiya, Hiroyuki Nakanishi, Yuka Hayakawa, Yutaka Yasui, Naoki Uchihara, Keito Suzuki, Yuki Tanaka, Haruka Miyamoto, Shun Ishido, Michiko Yamada, Taisei Keitoku, Tsubasa Nobusawa, Mayu Higuchi, Kenta Takaura, Shohei Tanaka, Chiaki Maeyashiki, Nobuharu Tamaki, Yuka Takahashi, Masayuki Kurosaki, Yasuhiro Asahina, Ryuichi Okamoto and Namiki Izumi Show full author list Hide full author list

Cancers 2022, 14(14), 3551; https://doi.org/10.3390/cancers14143551 - 21 Jul 2022

Cited by 17 | Viewed by 1806

Abstract

Background: Sarcopenia is associated with overall survival in patients with hepatocellular carcinoma (HCC). However, it is not known whether muscle volume is associated with clinical outcomes during combination therapy with immune checkpoint inhibitors. We investigated the relationship between changes in muscle volume and [...] Read more.

Background: Sarcopenia is associated with overall survival in patients with hepatocellular carcinoma (HCC). However, it is not known whether muscle volume is associated with clinical outcomes during combination therapy with immune checkpoint inhibitors. We investigated the relationship between changes in muscle volume and treatment outcomes in patients treated with atezolizumab plus bevacizumab. Methods: Thirty-two patients with HCC who received atezolizumab plus bevacizumab as the first-line treatment between October 2020 and February 2022 were included. Skeletal muscle mass index (SMI) was calculated from the skeletal muscle area at the L3 level of the lumbar vertebrae. We compared pretreatment SMI and SMI at 6–14 weeks after administration. Results: Of the 32 patients, 18 had a decreased SMI, while 14 did not. Progression-free survival (PFS) was significantly longer in patients without SMI decrease than in patients with SMI decrease (8.5 vs. 5.8 months, p = 0.011). There were no significant differences in treatment-related adverse events between the patients with and without SMI. Presarcopenia at baseline was not significantly associated with PFS. Conclusions: Decreased SMI was significantly associated with PFS. Monitoring muscle volume during atezolizumab plus bevacizumab therapy is useful in clinical practice. Full article

(This article belongs to the Section Cancer Therapy)

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18 pages, 3052 KiB

Open AccessArticle

Pulmonary Delivery of Extracellular Vesicle-Encapsulated Dinaciclib as an Effective Lung Cancer Therapy

by Qian Yuan, Kui Su, Shuyi Li, Xinyi Long, Lang Liu, Minghui Yang, Xin Yuan, Jianwu Sun, Junhua Hu, Qin Li, Yu Zhao and Zhengqiang Yuan

Cancers 2022, 14(14), 3550; https://doi.org/10.3390/cancers14143550 - 21 Jul 2022

Cited by 6 | Viewed by 5281

Abstract

The clinical outcomes of lung cancer remain poor, mainly due to the chemoresistance and low bioavailability of systemically delivered drugs. Therefore, novel therapeutic strategies are urgently needed. The TNF-related apoptosis-inducing ligand (TRAIL)-armed extracellular vesicle (EV-T) has proven to be highly synergistic for the [...] Read more.

The clinical outcomes of lung cancer remain poor, mainly due to the chemoresistance and low bioavailability of systemically delivered drugs. Therefore, novel therapeutic strategies are urgently needed. The TNF-related apoptosis-inducing ligand (TRAIL)-armed extracellular vesicle (EV-T) has proven to be highly synergistic for the killing of cancer cells with the potent cyclin-dependent kinase (CDK) inhibitor Dinaciclib (Dina). However, both optimal drug formulations and delivery strategies are yet to be established to facilitate the clinical application of the combination of EV-T and Dina. We hypothesize that Dina can be encapsulated into EV-T to produce a complexed formulation, designated EV-T-Dina, which can be nebulized for pulmonary delivery to treat lung cancer with potentially improved efficacy and safety. The prepared EV-T-Dina shows good stability both in vitro and in vivo and is very efficient at killing two highly TRAIL-resistant cancer lines. The ability to overcome TRAIL resistance is associated with the concomitant downregulation of the expression of cFLIP, MCL-1, and Survivin by Dina. The EV-T-Dina solution is nebulized for inhalation, showing unique deposition in animal lungs and importantly it demonstrates a significant suppression of the growth of orthotopic A549 tumors without any detectable adverse side events. In conclusion, the aerosolized EV-T-Dina constitutes a novel therapy, which is highly effective and safe for the treatment of lung cancers. Full article

(This article belongs to the Special Issue CDK Targeting in Cancer Therapy)

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24 pages, 7426 KiB

Open AccessArticle

3D Disease Modelling of Hard and Soft Cancer Using PHA-Based Scaffolds

by Akanksha Tomar, Pinar Uysal-Onganer, Pooja Basnett, Uttam Pati and Ipsita Roy

Cancers 2022, 14(14), 3549; https://doi.org/10.3390/cancers14143549 - 21 Jul 2022

Cited by 4 | Viewed by 2195

Abstract

Tumour cells are shown to change shape and lose polarity when they are cultured in 3D, a feature typically associated with tumour progression in vivo, thus making it significant to study cancer cells in an environment that mimics the in vivo milieu. In [...] Read more.

Tumour cells are shown to change shape and lose polarity when they are cultured in 3D, a feature typically associated with tumour progression in vivo, thus making it significant to study cancer cells in an environment that mimics the in vivo milieu. In this study we established hard (MCF7 and MDA-MB-231, breast cancer) and soft (HCT116, colon cancer) 3D cancer tumour models utilizing a blend of P(3HO-co-3HD) and P(3HB). P(3HO-co-3HD) and P(3HB) belong to a group of natural biodegradable polyesters, PHAs, that are synthesised by microorganisms. The 3D PHA scaffolds produced, with a pore size of 30 to 300 µm, allow for nutrients to diffuse within the scaffold and provide the cells with the flexibility to distribute evenly within the scaffold and grow within the pores. Interestingly, by Day 5, MDA-MB-231 showed dispersed growth in clusters, and MCF7 cells formed an evenly dispersed dense layer, while HCT116 formed large colonies within the pockets of the 3D PHA scaffolds. Our results show Epithelial Mesenchymal Transition (EMT) marker gene expression profiles in the hard tumour cancer models. In the 3D-based PHA scaffolds, MDA-MB-231 cells expressed higher levels of Wnt-11 and mesenchymal markers, such as Snail and its downstream gene Vim mRNAs, while MCF7 cells exhibited no change in their expression. On the other hand, MCF7 cells exhibited a significantly increased E-Cadherin expression as compared to MDA-MB-231 cells. The expression levels of EMT markers were comparative to their expression reported in the tumour samples, making them good representative of cancer models. In future these models will be helpful in mimicking hypoxic tumours, in studying gene expression, cellular signalling, angiogenesis and drug response more accurately than 2D and perhaps other 3D models. Full article

(This article belongs to the Special Issue Biomaterial-Assisted 3D In Vitro Tumor Models: From Organoid towards Cancer Tissue Engineering Approaches)

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17 pages, 3381 KiB

Open AccessArticle

A Face-To-Face Comparison of Tumor Chicken Chorioallantoic Membrane (TCAM) In Ovo with Murine Models for Early Evaluation of Cancer Therapy and Early Drug Toxicity

by Tristan Rupp, Christophe Legrand, Marion Hunault, Laurie Genest, David Babin, Guillaume Froget and Vincent Castagné

Cancers 2022, 14(14), 3548; https://doi.org/10.3390/cancers14143548 - 21 Jul 2022

Cited by 5 | Viewed by 2480

Abstract

Ethical considerations, cost, and time constraints have highlighted the need to develop alternatives to rodent in vivo models for evaluating drug candidates for cancer. The tumor chicken chorioallantoic membrane (TCAM) model provides an affordable and fast assay that permits direct visualization of tumor [...] Read more.

Ethical considerations, cost, and time constraints have highlighted the need to develop alternatives to rodent in vivo models for evaluating drug candidates for cancer. The tumor chicken chorioallantoic membrane (TCAM) model provides an affordable and fast assay that permits direct visualization of tumor progression. Tumors from multiple species including rodents and human cell lines can be engrafted. In this study, we engrafted several tumor models onto the CAM and demonstrated that the TCAM model is an alternative to mouse models for preliminary cancer drug efficacy testing and toxicity analysis. Tumor cells were deposited onto CAM, and then grown for up to an additional 10 days before chronic treatments were administered. The drug response of anticancer therapies was screened in 12 tumor cell lines including glioblastoma, melanoma, breast, prostate, colorectal, liver, and lung cancer. Tumor-bearing eggs and tumor-bearing mice had a similar chemotherapy response (cisplatin and temozolomide) in four human and mouse tumor models. We also demonstrated that lethality observed in chicken embryos following chemotherapies such as cisplatin and cyclophosphamide were associated with corresponding side-effects in mice with body weight loss. According to our work, TCAM represents a relevant alternative model to mice in early preclinical oncology screening, providing insights for both the efficacy and the toxicity of anticancer drugs. Full article

(This article belongs to the Special Issue The Chorioallantoic Membrane (CAM) Model – Traditional and State-of–the Art Applications: The 1st International CAM Conference)

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24 pages, 2291 KiB

Open AccessReview

Deubiquitinases in Cancers: Aspects of Proliferation, Metastasis, and Apoptosis

by Jiaqi LIU, Chi Tim LEUNG, Luyun LIANG, Yuqin WANG, Jian CHEN, Keng Po LAI and William Ka Fai TSE

Cancers 2022, 14(14), 3547; https://doi.org/10.3390/cancers14143547 - 21 Jul 2022

Cited by 12 | Viewed by 3158

Abstract

Deubiquitinases (DUBs) deconjugate ubiquitin (UBQ) from ubiquitylated substrates to regulate its activity and stability. They are involved in several cellular functions. In addition to the general biological regulation of normal cells, studies have demonstrated their critical roles in various cancers. In this review, [...] Read more.

Deubiquitinases (DUBs) deconjugate ubiquitin (UBQ) from ubiquitylated substrates to regulate its activity and stability. They are involved in several cellular functions. In addition to the general biological regulation of normal cells, studies have demonstrated their critical roles in various cancers. In this review, we evaluated and grouped the biological roles of DUBs, including proliferation, metastasis, and apoptosis, in the most common cancers in the world (liver, breast, prostate, colorectal, pancreatic, and lung cancers). The current findings in these cancers are summarized, and the relevant mechanisms and relationship between DUBs and cancers are discussed. In addition to highlighting the importance of DUBs in cancer biology, this study also provides updated information on the roles of DUBs in different types of cancers. Full article

(This article belongs to the Special Issue The Role of the Ubiquitin-Proteasome-System in Human Cancer)

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13 pages, 1427 KiB

Open AccessReview

Dynamic CD8⁺ T Cell Cooperation with Macrophages and Monocytes for Successful Cancer Immunotherapy

by Anaïs Vermare, Marion V. Guérin, Elisa Peranzoni and Nadège Bercovici

Cancers 2022, 14(14), 3546; https://doi.org/10.3390/cancers14143546 - 21 Jul 2022

Cited by 6 | Viewed by 6836

Abstract

The essential roles endorsed by macrophages and monocytes are well established in response to infections, where they contribute to launching the differentiation of specific T-lymphocytes for long-term protection. This knowledge is the result of dynamic studies that can inspire the cancer field, particularly [...] Read more.

The essential roles endorsed by macrophages and monocytes are well established in response to infections, where they contribute to launching the differentiation of specific T-lymphocytes for long-term protection. This knowledge is the result of dynamic studies that can inspire the cancer field, particularly now that cancer immunotherapies elicit some tumor regression. Indeed, immune responses to cancer have mainly been studied after tumors have escaped immune attacks. In particular, the suppressive functions of macrophages were revealed in this context, introducing an obvious bias across the literature. In this review, we will focus on the ways inwhich monocytes and macrophages cooperate with T-lymphocytes, leading to successful immune responses. We will bring together the preclinical studies that have revealed the existence of such positive cooperation in the cancer field, and we will place particular emphasis on proposing the underlying mechanisms. Finally, we will give some perspectives to decipher the functional roles of such T-cell and myeloid cell interactions in the frame of human cancer immunotherapy. Full article

(This article belongs to the Special Issue Tumor, Tumor-Associated Macrophages, and Therapy)

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21 pages, 813 KiB

Open AccessReview

Plasmacytoid Dendritic Cells, a Novel Target in Myeloid Neoplasms

by Xavier Roussel, Francine Garnache Ottou and Florian Renosi

Cancers 2022, 14(14), 3545; https://doi.org/10.3390/cancers14143545 - 21 Jul 2022

Cited by 4 | Viewed by 2981

Abstract

Plasmacytoid dendritic cells (pDC) are the main type I interferon producing cells in humans and are able to modulate innate and adaptive immune responses. Tumor infiltration by plasmacytoid dendritic cells is already well described and is associated with poor outcomes in cancers due [...] Read more.

Plasmacytoid dendritic cells (pDC) are the main type I interferon producing cells in humans and are able to modulate innate and adaptive immune responses. Tumor infiltration by plasmacytoid dendritic cells is already well described and is associated with poor outcomes in cancers due to the tolerogenic activity of pDC. In hematological diseases, Blastic Plasmacytoid Dendritic Cells Neoplasm (BPDCN), aggressive leukemia derived from pDCs, is well described, but little is known about tumor infiltration by mature pDC described in Myeloid Neoplasms (MN). Recently, mature pDC proliferation (MPDCP) has been described as a differential diagnosis of BPDCN associated with acute myeloid leukemia (pDC-AML), myelodysplastic syndrome (pDC-MDS) and chronic myelomonocytic leukemia (pDC-CMML). Tumor cells are myeloid blasts and/or mature myeloid cells from related myeloid disorders and pDC derived from a clonal proliferation. The poor prognosis associated with MPDCP requires a better understanding of pDC biology, MN oncogenesis and immune response. This review provides a comprehensive overview about the biological aspects of pDCs, the description of pDC proliferation in MN, and an insight into putative therapies in pDC-AML regarding personalized medicine. Full article

(This article belongs to the Special Issue Blastic Dendritic Cell Neoplasms (BPDCNs) and AML Associated with an Excess of pDC (AML-pDC))

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13 pages, 1512 KiB

Open AccessArticle

Tumor Location in the Head/Uncinate Process and Presence of Fibrosis Impair the Adequacy of Endoscopic Ultrasound-Guided Tissue Acquisition of Solid Pancreatic Tumors

by Thomas Togliani, Andrea Lisotti, Rosa Rinaldi, Adele Fornelli, Stefano Pilati, Nicola Passigato and Pietro Fusaroli

Cancers 2022, 14(14), 3544; https://doi.org/10.3390/cancers14143544 - 21 Jul 2022

Cited by 4 | Viewed by 1331

Abstract

Endoscopic ultrasound-guided tissue acquisition (EUS-TA) of solid pancreatic tumors shows optimal specificity despite fair sensitivity, with an overall suboptimal diagnostic yield. We aim to quantify the adequacy and accuracy of EUS-TA and assess predictive factors for success, focusing on the presence and degree [...] Read more.

Endoscopic ultrasound-guided tissue acquisition (EUS-TA) of solid pancreatic tumors shows optimal specificity despite fair sensitivity, with an overall suboptimal diagnostic yield. We aim to quantify the adequacy and accuracy of EUS-TA and assess predictive factors for success, focusing on the presence and degree of specimen fibrosis. All consecutive EUS-TA procedures were retrieved, and the specimens were graded for sample adequacy and fibrosis. The results were evaluated according to patients’ and tumor characteristics and the EUS-TA technique. In total, 407 patients (59% male, 70 [63–77] year old) were included; sample adequacy and diagnostic accuracy were 90.2% and 94.7%, respectively. Fibrosis was significantly more represented in tumors located in the head/uncinate process (p = 0.001). Tumor location in the head/uncinate (OR 0.37 [0.14–0.99]), number of needle passes ≥ 3 (OR 4.53 [2.22–9.28]), and the use of cell block (OR 8.82 [3.23–23.8]) were independently related to adequacy. Severe fibrosis was independently related to false negative results (OR 8.37 [2.33–30.0]). Pancreatic tumors located in the head/uncinate process showed higher fibrosis, resulting in EUS-TA with lower sample adequacy and diagnostic accuracy. We maintain that three or more needle passes and cell block should be done to increase the diagnostic yield. Full article

(This article belongs to the Special Issue Endoscopic Management of Liver and Pancreatic Cancer)

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20 pages, 3173 KiB

Open AccessArticle

NPC1 Confers Metabolic Flexibility in Triple Negative Breast Cancer

by Kathleen I. O’Neill, Li-Wei Kuo, Michelle M. Williams, Hanne Lind, Lyndsey S. Crump, Nia G. Hammond, Nicole S. Spoelstra, M. Cecilia Caino and Jennifer K. Richer

Cancers 2022, 14(14), 3543; https://doi.org/10.3390/cancers14143543 - 21 Jul 2022

Cited by 8 | Viewed by 3033

Abstract

Triple-negative breast cancer (TNBC) often undergoes at least partial epithelial-to-mesenchymal transition (EMT) to facilitate metastasis. Identifying EMT-associated characteristics can reveal novel dependencies that may serve as therapeutic vulnerabilities in this aggressive breast cancer subtype. We found that NPC1, which encodes the lysosomal [...] Read more.

Triple-negative breast cancer (TNBC) often undergoes at least partial epithelial-to-mesenchymal transition (EMT) to facilitate metastasis. Identifying EMT-associated characteristics can reveal novel dependencies that may serve as therapeutic vulnerabilities in this aggressive breast cancer subtype. We found that NPC1, which encodes the lysosomal cholesterol transporter Niemann–Pick type C1 is highly expressed in TNBC as compared to estrogen receptor-positive (ER+) breast cancer, and is significantly elevated in high-grade disease. We demonstrated that NPC1 is directly targeted by microRNA-200c (miR-200c), a potent suppressor of EMT, providing a mechanism for its differential expression in breast cancer subtypes. The silencing of NPC1 in TNBC causes an accumulation of cholesterol-filled lysosomes, and drives decreased growth in soft agar and invasive capacity. Conversely, overexpression of NPC1 in an ER+ cell line increases invasion and growth in soft agar. We further identified TNBC cell lines as cholesterol auxotrophs, however, they do not solely depend on NPC1 for adequate cholesterol supply. The silencing of NPC1 in TNBC cell lines led to altered mitochondrial function and morphology, suppression of mTOR signaling, and accumulation of autophagosomes. A small molecule inhibitor of NPC1, U18666A, decreased TNBC proliferation and synergized with the chemotherapeutic drug, paclitaxel. This work suggests that NPC1 promotes aggressive characteristics in TNBC, and identifies NPC1 as a potential therapeutic target. Full article

(This article belongs to the Special Issue New Insights into Targeted Drugs for Breast Cancer)

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21 pages, 2060 KiB

Open AccessArticle

Oleocanthal Attenuates Metastatic Castration-Resistant Prostate Cancer Progression and Recurrence by Targeting SMYD2

by Abu Bakar Siddique, Hassan Y. Ebrahim, Afsana Tajmim, Judy Ann King, Khaldoun S. Abdelwahed, Zakaria Y. Abd Elmageed and Khalid A. El Sayed

Cancers 2022, 14(14), 3542; https://doi.org/10.3390/cancers14143542 - 21 Jul 2022

Cited by 6 | Viewed by 3635

Abstract

Metastatic castration-resistant prostate cancer (mCRPC) is the most aggressive prostate cancer (PC) phenotype. Cellular lysine methylation is driven by protein lysine methyltransferases (PKMTs), such as those in the SET- and MYND-containing protein (SMYD) family, including SMYD2 methylate, and several histone and non-histone proteins. [...] Read more.

Metastatic castration-resistant prostate cancer (mCRPC) is the most aggressive prostate cancer (PC) phenotype. Cellular lysine methylation is driven by protein lysine methyltransferases (PKMTs), such as those in the SET- and MYND-containing protein (SMYD) family, including SMYD2 methylate, and several histone and non-histone proteins. SMYD2 is dysregulated in metastatic PC patients with high Gleason score and shorter survival. The Mediterranean, extra-virgin-olive-oil-rich diet ingredient S-(-)-oleocanthal (OC) inhibited SMYD2 in biochemical assays and suppressed viability, migration, invasion, and colony formation of PC-3, CWR-R1ca, PC-3M, and DU-145 PC cell lines with IC₅₀ range from high nM to low µM. OC’s in vitro antiproliferative effect was comparable to standard anti-PC chemotherapies or hormone therapies. A daily, oral 10 mg/kg dose of OC for 11 days effectively suppressed the progression of the mCRPC CWR-R1ca cells engrafted into male nude mice. Daily, oral OC treatment for 30 days suppressed tumor locoregional and distant recurrences after the primary tumors’ surgical excision. Collected OC-treated animal tumors showed marked SMYD2 reduction. OC-treated mice showed significant serum PSA reduction. For the first time, this study showed SMYD2 as novel molecular target in mCRPC, and OC emerged as a specific SMYD2 lead inhibitor. OC prevailed over previously reported SMYD2 inhibitors, with validated in vivo potency and high safety profile, and, therefore, is proposed as a novel nutraceutical for mCRPC progression and recurrence control. Full article

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10 pages, 533 KiB

Open AccessArticle

[68Ga]Ga-DOTANOC Uptake at Pancreatic Head/Uncinate Process: Is It a Persistent Diagnostic Pitfall Over Time?

by Elena Tabacchi, Emilia Fortunati, Giulia Argalia, Lucia Zanoni, Diletta Calabrò, Silvi Telo, Davide Campana, Giuseppe Lamberti, Claudio Ricci, Riccardo Casadei, Stefano Fanti and Valentina Ambrosini

Cancers 2022, 14(14), 3541; https://doi.org/10.3390/cancers14143541 - 21 Jul 2022

Cited by 6 | Viewed by 1768

Abstract

Purpose: [68Ga]Ga-DOTA-peptide uptake in the pancreatic head/uncinate process (UP) is a frequent PET/CT finding. Although mostly physiologic, it can represent a pitfall in PET/CT reading, especially when focal. An increased frequency of UP uptake has been reported in patients (pts) affected by diabetes [...] Read more.

Purpose: [68Ga]Ga-DOTA-peptide uptake in the pancreatic head/uncinate process (UP) is a frequent PET/CT finding. Although mostly physiologic, it can represent a pitfall in PET/CT reading, especially when focal. An increased frequency of UP uptake has been reported in patients (pts) affected by diabetes mellitus (DM). The aim of the study is to describe the frequency of [68Ga]Ga-DOTANOC UP uptake to evaluate its variations over time and its possible correlation with DM. Methods: In September 2017, a monocentric prospective observational electronic archive was initiated at our center to collect clinical and imaging data of pts undergoing [68Ga]Ga-DOTANOC PET/CT. Among the pts enrolled in the first 6 months (Sept 2017 to Feb 2018), those presenting [68Ga]Ga-DOTANOC PET/CT uptake at UP level were included. Pts with UP lesions already documented on CT/MRI or those that underwent surgical excision of UP before PET/CT were excluded from the analysis. [68Ga]Ga-DOTANOC UP uptake was classified as diffuse or focal and compared with the pattern observed in previous PET/CT scans performed at our center. An increased frequency of UP uptake was also correlated with the presence of DM. Results: In the first 6 months, 253 pts were enrolled in the archive and 172 out of them were included in the analysis. UP increased uptake was frequently observed (77/172, 44.8%) and was mostly diffuse (62/77). In 75/172 pts (43.6%), previous [68Ga]Ga-DOTANOC PET/CT scans were available (overall 268 scans; number of previous PET per pt range: 1–20) and were retrospectively reviewed. Despite the fact that, in most pts, the uptake pattern was stable over time (54/75 pts, 72%), it changed in approximately one third of cases (21/75, 28%). Among DM pts (29/172), only 10/29 (34.4%) presented increased UP uptake. Conclusions: UP [68Ga]Ga-DOTANOC uptake is a frequent non-malignant finding (slightly higher than previously reported), mostly presenting with a diffuse pattern. However, contrary to previous reports, our data show that the pattern of uptake may vary over time in approximately one third of the cases and it is not more frequently observed in pts with DM. Full article

(This article belongs to the Special Issue Heterogeneity of Neuroendocrine Tumors: Impact on Biology and Response to Treatments)

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18 pages, 3356 KiB

Open AccessArticle

Brassinin Promotes the Degradation of Tie2 and FGFR1 in Endothelial Cells and Inhibits Triple-Negative Breast Cancer Angiogenesis

by Yuan Gu, Vivien Becker, Moqin Qiu, Tianci Tang, Emmanuel Ampofo, Michael D. Menger and Matthias W. Laschke

Cancers 2022, 14(14), 3540; https://doi.org/10.3390/cancers14143540 - 21 Jul 2022

Cited by 5 | Viewed by 1810

Abstract

Brassinin, a phytoalexin derived from cruciferous vegetables, has been reported to exhibit anti-cancer activity in multiple cancer types. However, its effects on triple-negative breast cancer (TNBC) development and the underlying mechanisms have not been elucidated so far. In this study, we demonstrated in [...] Read more.

Brassinin, a phytoalexin derived from cruciferous vegetables, has been reported to exhibit anti-cancer activity in multiple cancer types. However, its effects on triple-negative breast cancer (TNBC) development and the underlying mechanisms have not been elucidated so far. In this study, we demonstrated in vitro that brassinin preferentially reduces the viability of endothelial cells (ECs) when compared to other cell types of the tumor microenvironment, including TNBC cells, pericytes, and fibroblasts. Moreover, brassinin at non-cytotoxic doses significantly suppressed the proliferation, migration, tube formation, and spheroid sprouting of ECs. It also efficiently inhibited angiogenesis in an ex-vivo aortic ring assay and an in-vivo Matrigel plug assay. Daily intraperitoneal injection of brassinin significantly reduced tumor size, microvessel density, as well as the perfusion of tumor microvessels in a dorsal skinfold chamber model of TNBC. Mechanistic analyses showed that brassinin selectively stimulates the degradation of Tie2 and fibroblast growth factor receptor 1 in ECs, leading to the down-regulation of the AKT and extracellular signal-regulated kinase pathways. These findings demonstrate a preferential and potent anti-angiogenic activity of brassinin, which may be the main mechanism of its anti-tumor action. Accordingly, this phytochemical represents a promising candidate for the future anti-angiogenic treatment of TNBC. Full article

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5 pages, 216 KiB

Open AccessEditorial

Involvement of the Substance P/Neurokinin-1 Receptor System in Cancer

by Rafael Coveñas and Miguel Muñoz

Cancers 2022, 14(14), 3539; https://doi.org/10.3390/cancers14143539 - 21 Jul 2022

Cited by 10 | Viewed by 1513

Abstract

New, promising molecular targets to block tumor development and new compounds capable of specifically destroying cancer cells must be urgently investigated [...] Full article

(This article belongs to the Special Issue Involvement of the Substance P/Neurokinin-1 Receptor System in Cancer)

21 pages, 5897 KiB

Open AccessArticle

Overexpression of NNMT in Glioma Aggravates Tumor Cell Progression: An Emerging Therapeutic Target

by Wei Sun, Yongxiang Zou, Zheng Cai, Jinxiang Huang, Xinjie Hong, Qiang Liang and Weilin Jin

Cancers 2022, 14(14), 3538; https://doi.org/10.3390/cancers14143538 - 21 Jul 2022

Cited by 7 | Viewed by 2345

Abstract

Purpose: Increasing evidence has revealed that nicotinamide N-methyltransferase (NNMT) is a key factor influencing the prognosis of tumors. The present study aimed to investigate the role of NNMT in glioma and to elucidate the associated functional mechanisms. Methods: Clinical samples were analyzed [...] Read more.

Purpose: Increasing evidence has revealed that nicotinamide N-methyltransferase (NNMT) is a key factor influencing the prognosis of tumors. The present study aimed to investigate the role of NNMT in glioma and to elucidate the associated functional mechanisms. Methods: Clinical samples were analyzed by immunohistochemical staining and Western blotting to evaluate NNMT expression in glioma and normal brain tissues. The correlation between NNMT expression and glioma was analyzed using the Cancer Genome Atlas (TCGA) database. Additionally, NNMT was knocked down in two types of glioma cells, U87 and U251, to evaluate the invasive ability of these cells. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate NNMT knockdown in the cells. Furthermore, ELISA was used to determine the balance between nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide hydrogen (NAD/NADH ratio), which verified the altered methylation patterns in the cells. The glioma xenograft mouse models were used to verify the regulatory role of NNMT, GAP43, and SIRT1. Results: Analysis based on our clinical glioma samples and TCGA database revealed that overexpression of NNMT was associated with poor prognosis of patients. Knockdown of NNMT reduced the invasive ability of glioma cells, and downregulation of its downstream protein GAP43 occurred due to altered cellular methylation caused by NNMT overexpression. Gene Set Enrichment Analysis confirmed that NNMT modulated the NAD-related signaling pathway and showed a negative association between NNMT and SIRT1. Moreover, the regulatory roles of NNMT, GAP43, and SIRT1 were confirmed in glioma xenograft mouse models. Conclusion: Overexpression of NNMT causes abnormal DNA methylation through regulation of the NAD/NADH ratio, which in turn leads to the downregulation of GAP43 and SIRT1, eventually altering the biological behavior of tumor cells. Full article

(This article belongs to the Special Issue New Strategies in Diagnosis and Treatments for Brain Tumors)

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13 pages, 1896 KiB

Open AccessArticle

Urine Cellular DNA Point Mutation and Methylation for Identifying Upper Tract Urinary Carcinoma

by Wei Ouyang, Lufeng Luo, Junjie Zhang, Ran Xu, Qiang Lu, Zhenzhou Xu, Jianye Liu, Pei Li, Yaqun Zhang, Chuanchi Zhou, Wei Tang, Zhenting Wang, Manman Cao, Genming Xu and Long Wang

Cancers 2022, 14(14), 3537; https://doi.org/10.3390/cancers14143537 - 21 Jul 2022

Cited by 3 | Viewed by 1831

Abstract

Background: To improve the selection of patients for ureteroscopy, avoid excessive testing and reduce costs, we aimed to develop and validate a diagnostic urine assay for upper tract urinary carcinoma (UTUC). Methods: In this cohort study we recruited 402 patients from six Hunan [...] Read more.

Background: To improve the selection of patients for ureteroscopy, avoid excessive testing and reduce costs, we aimed to develop and validate a diagnostic urine assay for upper tract urinary carcinoma (UTUC). Methods: In this cohort study we recruited 402 patients from six Hunan hospitals who underwent ureteroscopy for hematuria, including 95 patients with UTUC and 307 patients with non-UTUC findings. Midstream morning urine samples were collected before ureteroscopy and surgery. DNA was extracted and qPCR was used to analyze mutations in TERT and FGFR3 and the methylation of NRN1. In the training set, the random forest algorithm was used to build an optimal panel. Lastly, the Beijing cohort (n = 76) was used to validate the panel. Results: The panel combining the methylation with mutation markers led to an AUC of 0.958 (95% CI: 0.933–0.975) with a sensitivity of 91.58% and a specificity of 94.79%. The panel presented a favorable diagnostic value for UTUC vs. other malignant tumors (AUC = 0.920) and UTUC vs. benign disease (AUC = 0.975). Furthermore, combining the panel with age revealed satisfactory results, with 93.68% sensitivity, 94.44% specificity, AUC = 0.970 and NPV = 98.6%. In the external validation process, the model showed an AUC of 0.971, a sensitivity of 95.83% and a specificity of 92.31, respectively. Conclusions: A novel diagnostic model for analyzing hematuria patients for the risk of UTUC was developed, which could lead to a reduction in the need for invasive examinations. Combining NRN1 methylation and gene mutation (FGFR3 and TERT) with age resulted in a validated accurate prediction model. Full article

(This article belongs to the Special Issue Advances and Updates in Prognostic and Predictive Biomarkers of Urologic Malignancy)

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16 pages, 1670 KiB

Open AccessArticle

Endometrial Carcinoma: Molecular Cytogenetics and Transcriptomic Profile

by Marta Brunetti, Ioannis Panagopoulos, Valeria Vitelli, Kristin Andersen, Tarjei S. Hveem, Ben Davidson, Ane Gerda Z. Eriksson, Pernille Kristina Bjerre Trent, Sverre Heim and Francesca Micci

Cancers 2022, 14(14), 3536; https://doi.org/10.3390/cancers14143536 - 20 Jul 2022

Cited by 3 | Viewed by 2362

Abstract

Endometrial carcinomas (ECs) are histologically classified as endometrioid and nonendometrioid tumors, with each subgroup displaying different molecular profiles and clinical outcomes. Considerable biological and clinical heterogeneity exists within this scheme, however, reflecting its imperfection. We aimed to gather additional data that might help [...] Read more.

Endometrial carcinomas (ECs) are histologically classified as endometrioid and nonendometrioid tumors, with each subgroup displaying different molecular profiles and clinical outcomes. Considerable biological and clinical heterogeneity exists within this scheme, however, reflecting its imperfection. We aimed to gather additional data that might help clarify the tumors’ pathogenesis and contribute toward a more meaningful classification scheme. In total, 33 ECs were examined for the presence of chromosomal aberrations, genomic imbalances, pathogenic variants, microsatellite instability, and expression profiles at both gene and miRNA levels. Chromosome 1 was the most frequently rearranged chromosome, showing a gain of all or part of the long arm. Pathogenic variants were found for PTEN (53%), PDGFRA (37%), PIK3CA (34%), and KIT (31%). High microsatellite instability was identified in 15 ECs. Comparing tumors and controls, we identified 23 differentially expressed genes of known importance in carcinogenesis, 15 genes involved in innate and adaptative immune responses, and altered expression of 7 miRNAs. miR-32-5p was the most upregulated. Our series showed a high degree of heterogeneity. Tumors were well-separated from controls, but there was no clear-cut separation between endometrioid and nonendometrioid ECs. Whether this means that the current phenotypic classification is of little relevance or if one still has not detected which genomic parameters to enter into correlation analyses remains unknown. Full article

(This article belongs to the Section Molecular Cancer Biology)

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33 pages, 10631 KiB

Open AccessReview

3D Bioprinting: An Enabling Technology to Understand Melanoma

by Samantha Fernandes, Cian Vyas, Peggy Lim, Rúben F. Pereira, Amaya Virós and Paulo Bártolo

Cancers 2022, 14(14), 3535; https://doi.org/10.3390/cancers14143535 - 20 Jul 2022

Cited by 8 | Viewed by 2875

Abstract

Melanoma is a potentially fatal cancer with rising incidence over the last 50 years, associated with enhanced sun exposure and ultraviolet radiation. Its incidence is highest in people of European descent and the ageing population. There are multiple clinical and epidemiological variables affecting [...] Read more.

Melanoma is a potentially fatal cancer with rising incidence over the last 50 years, associated with enhanced sun exposure and ultraviolet radiation. Its incidence is highest in people of European descent and the ageing population. There are multiple clinical and epidemiological variables affecting melanoma incidence and mortality, such as sex, ethnicity, UV exposure, anatomic site, and age. Although survival has improved in recent years due to advances in targeted and immunotherapies, new understanding of melanoma biology and disease progression is vital to improving clinical outcomes. Efforts to develop three-dimensional human skin equivalent models using biofabrication techniques, such as bioprinting, promise to deliver a better understanding of the complexity of melanoma and associated risk factors. These 3D skin models can be used as a platform for patient specific models and testing therapeutics. Full article

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11 pages, 1273 KiB

Open AccessArticle

LncRNA HOXC-AS1 Sponges miR-99a-3p and Upregulates MMP8, Ultimately Promoting Gastric Cancer

by Yue Jiang, Xiangpan Li, Yu Yang, Jiajun Luo, Xunshan Ren, Jingwen Yuan and Qiang Tong

Cancers 2022, 14(14), 3534; https://doi.org/10.3390/cancers14143534 - 20 Jul 2022

Cited by 4 | Viewed by 1504

Abstract

Gastric cancer (GC) is among the most lethal tumors worldwide. Long noncoding RNAs (lncRNAs) are reported to be critical during the occurrence and progression of malignancies. The HOXC cluster antisense RNA 1 (HOXC-AS1) has been suggested to participate in the genesis and development [...] Read more.

Gastric cancer (GC) is among the most lethal tumors worldwide. Long noncoding RNAs (lncRNAs) are reported to be critical during the occurrence and progression of malignancies. The HOXC cluster antisense RNA 1 (HOXC-AS1) has been suggested to participate in the genesis and development of GC. Therefore, we examined GC cells and tissues for the expression of HOXC-AS1 and correlated the expression levels with the disease specific survival of the patients, finding that HOXC-AS1 was overexpressed and probably had a tendency of leading to a poor prognosis. The Cell Counting Kit-8 assay and colony formation assay were then performed under knockdown of HOXC-AS1, revealing that cell proliferation of GC was distinctly decreased. Afterwards, miR-99a-3p was predicted to bind with HOXC-AS1 by DIANA tools. We carried out dual-luciferase reporter gene assays to identify the interaction between them. After knockdown of HOXC-AS1, miR-99a-3p was clearly overexpressed in GC cells. In addition, matrix metalloproteinase 8 (MMP8) was shown to be combined with miR-99a-3p using TargetScan. Similar experiments, along with western blot, were conducted to validate the correlation between miR-99a-3p and MMP8. Finally, rescue experiments for CCK-8 were completed, disclosing that HOXC-AS1 promoted cell progression of GC through sponging miR-99a-3p followed by subsequent upregulation of MMP8. Full article

(This article belongs to the Special Issue Signaling Pathway in Gastrointestinal Cancer)

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9 pages, 1515 KiB

Open AccessCommentary

The “Balloon-Like” Sign: Differential Diagnosis between Postoperative Air Leak and Residual Pleural Space: Radiological Findings and Clinical Implications of the Young–Laplace Equation

by Francesco Petrella, Stefania Rizzo, Luca Bertolaccini, Monica Casiraghi, Lara Girelli, Giorgio Lo Iacono, Antonio Mazzella and Lorenzo Spaggiari

Cancers 2022, 14(14), 3533; https://doi.org/10.3390/cancers14143533 - 20 Jul 2022

Viewed by 1566

Abstract

In this paper, we propose a radiological sign for an appropriate differential diagnosis between postoperative pleural space and active air leak after lung resection. In the case of residual pleural space without any active air leak, the lung takes the form of a [...] Read more.

In this paper, we propose a radiological sign for an appropriate differential diagnosis between postoperative pleural space and active air leak after lung resection. In the case of residual pleural space without any active air leak, the lung takes the form of a round balloon due to the hyperinflation condition, which is governed by the Young–Laplace equation describing the capillary pressure difference sustained across the interface between two static fluids, such as water and air, due to the phenomenon of wall tension. The two principal mechanisms by which a lung forms a spherical image are shear-controlled detachment induced by shear stress on the membrane surface, and spontaneous detachment induced by a gradient in Young–Laplace pressure. On the contrary, the lung maintains its tapered shape in the case of an active air leak because the continuous air refill does not allow a complete parenchyma re-expansion. Full article

(This article belongs to the Special Issue The Role of Surgery in Lung Cancer Treatment: Present Indications and Future Perspectives)

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6 pages, 227 KiB

Open AccessOpinion

Treatment Planning in Intraoperative Radiation Therapy (IORT): Where Should We Go?

by Carlo Cavedon and Renzo Mazzarotto

Cancers 2022, 14(14), 3532; https://doi.org/10.3390/cancers14143532 - 20 Jul 2022

Cited by 3 | Viewed by 1343

Abstract

As opposed to external beam radiation therapy (EBRT), treatment planning systems (TPS) dedicated to intraoperative radiation therapy (IORT) were not subject to radical modifications in the last two decades. However, new treatment regimens such as ultrahigh dose rates and combination with multiple treatment [...] Read more.

As opposed to external beam radiation therapy (EBRT), treatment planning systems (TPS) dedicated to intraoperative radiation therapy (IORT) were not subject to radical modifications in the last two decades. However, new treatment regimens such as ultrahigh dose rates and combination with multiple treatment modalities, as well as the prospected availability of dedicated in-room imaging, call for important new features in the next generation of treatment planning systems in IORT. Dosimetric accuracy should be guaranteed by means of advanced dose calculation algorithms, capable of modelling complex scattering phenomena and accounting for the non-tissue equivalent materials used to shape and compensate electron beams. Kilovoltage X-ray based IORT also presents special needs, including the correct description of extremely steep dose gradients and the accurate simulation of applicators. TPSs dedicated to IORT should also allow real-time imaging to be used for treatment adaptation at the time of irradiation. Other features implemented in TPSs should include deformable registration and capability of radiobiological planning, especially if unconventional irradiation schemes are used. Finally, patient safety requires that the multiple features be integrated in a comprehensive system in order to facilitate control of the whole process. Full article

(This article belongs to the Special Issue Intraoperative Radiation Therapy in the Treatment of Cancer)

9 pages, 1759 KiB

Open AccessArticle

Chemotherapy Shows a Better Efficacy Than Endocrine Therapy in Metastatic Breast Cancer Patients with a Heterogeneous Estrogen Receptor Expression Assessed by ¹⁸F-FES PET

by Yizhao Xie, Xinyue Du, Yannan Zhao, Chengcheng Gong, Shihui Hu, Shuhui You, Shaoli Song, Xichun Hu, Zhongyi Yang and Biyun Wang

Cancers 2022, 14(14), 3531; https://doi.org/10.3390/cancers14143531 - 20 Jul 2022

Cited by 8 | Viewed by 2136

Abstract

Background: The heterogeneity of estrogen receptor (ER) expression has long been a challenge for the diagnosis and treatment strategy of metastatic breast cancer (MBC). A novel convenient method of ER detection using ¹⁸F-fluoroestradiol positron emission tomography/computed tomography (¹⁸F-FES PET/CT) offers [...] Read more.

Background: The heterogeneity of estrogen receptor (ER) expression has long been a challenge for the diagnosis and treatment strategy of metastatic breast cancer (MBC). A novel convenient method of ER detection using ¹⁸F-fluoroestradiol positron emission tomography/computed tomography (¹⁸F-FES PET/CT) offers a chance to screen and analyze MBC patients with ER uncertainty. Methods: MBC patients who received ¹⁸F-FES PET/CT were screened and patients with both FES positive (FES+) and negative (FES-) lesions were enrolled in this study. Progression-free survival (PFS) was estimated using the Kaplan–Meier method and was compared using the log-rank test. Results: A total of 635 patients were screened and 75 of 635 (11.8%) patients showed ER uncertainty; 51 patients received further treatment and were enrolled in this study. Among them, 20 (39.2%) patients received chemotherapy (CT), 21 (41.2%) patients received endocrine-based therapy (ET), and 10 (19.6%) patients received combined therapy (CT + ET). CT showed a better progression-free survival (PFS) compared with ET (mPFS 7.1 vs. 4.6 months, HR 0.44, 95% CI 0.20–0.93, p = 0.03). CT + ET did not improve PFS compared with either CT or ET alone (mPFS 4.4 months, p > 0.2). All three treatment options were well tolerated. Conclusions: ¹⁸F-FES PET/CT could identify patients with ER heterogeneity. Patients with bone metastasis are more likely to have ER heterogeneity. Patients with ER heterogeneity showed better sensitivity to CT rather than ET. Combined therapy of CT + ET did not improve the treatment outcome. Full article

(This article belongs to the Collection Breast Cancer—Therapeutic Challenges, Research Strategies and Novel Diagnostics)

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15 pages, 317 KiB

Open AccessArticle

Effect of Condom Use after CIN Treatment on Cervical HPV Biomarkers Positivity: Prolonged Follow Up Study

by George Valasoulis, Georgios Michail, Abraham Pouliakis, Georgios Androutsopoulos, Ioannis. G. Panayiotides, Maria Kyrgiou, Alexandros Daponte and Evangelos Paraskevaidis

Cancers 2022, 14(14), 3530; https://doi.org/10.3390/cancers14143530 - 20 Jul 2022

Cited by 5 | Viewed by 2064

Abstract

Background: Several factors contribute in the cervical healing process following local surgical treatment; in a previous work our group has documented a beneficial mid-term role of regular condom use immediately postoperatively in terms of CIN relapse prevention and expression of active viral biomarkers. [...] Read more.

Background: Several factors contribute in the cervical healing process following local surgical treatment; in a previous work our group has documented a beneficial mid-term role of regular condom use immediately postoperatively in terms of CIN relapse prevention and expression of active viral biomarkers. Materials and Methods: Aiming to investigate whether the favorable contribution of consistent condom use could be extrapolated in the longer term, we conducted a prospective single center observational study including women scheduled to undergo conservative excisional treatment for CIN (LLETZ procedure). In all women a strong recommendation for consistent use for the first 6 months was given. For 204 women who underwent the procedure and completed successfully the two-year follow up a complete dataset of HPV biomarkers’ results obtained six months and two years postoperatively was available. Patients were asked to complete a questionnaire to assess condom use compliance. A 90% compliance rate represented the threshold for consistent use. An LBC sample was obtained and tested for HPV genotyping, E6 & E7 mRNA by NASBA technique as well as flow cytometry, and p16 at 0 (pre-treatment), 6 and 24 months. HPV DNA and other related biomarkers status at 6 and 24 months, treatment failures at 24 months and condom use compliance rates represented study outcomes. Results: Six months post-operatively we documented a reduction in the rates of HPV DNA positivity, which was detected in only 23.2% of compliant condom users in comparison to 61.9% in the non-compliant group (p < 0.001, OR: 0.19, 95%CI: 0.1–0.36). For the HPV mRNA test, either assessed with the NASBA method or with flow cytometry, reduced positivity percentages were observed in the compliant group, in particular 1.6% vs. 8% for NASBA and 7.1% vs. 16.4% using flow cytometry, although these differences were not statistically significant (p = 0.1039 and 0.0791, respectively). Finally, reduced p16 positivity rates were documented in the compliant group. At the two year follow up, a more pronounced difference in HPV DNA positivity rates was observed, specifically only 13% positivity among the compliant women compared with 71% of the non-compliant (p < 0.0001); this illustrates a further decreasing trend compared with the 6th month in the compliant group as opposed to an increasing tendency in the non-compliant group, respectively (difference: 9.0%, 95% CI: 0% to 20.6%, p = 0.1523). At that time, 80% of the failed treatments were HPV mRNA positive compared to 10% positivity for the cases treated successfully (OR: 34, 95%CI: 6.8–173, p < 0.0001), a finding indicative that HPV mRNA E6 & E7 positivity accurately predicts treatment failure; p16 positivity was also observed at higher rates in cases with treatment failure. Conclusions: Consistent condom use following conservative excisional CIN treatment appears to significantly reduce rates of CIN recurrence and biomarkers of HPV expression. Additional HPV vaccination at the time of treatment could further enhance the positive effect of consistent condom use. Full article

(This article belongs to the Special Issue Therapies in Cervical Cancer)

23 pages, 5881 KiB

Open AccessSystematic Review

Recent Application of Artificial Intelligence in Non-Gynecological Cancer Cytopathology: A Systematic Review

by Nishant Thakur, Mohammad Rizwan Alam, Jamshid Abdul-Ghafar and Yosep Chong

Cancers 2022, 14(14), 3529; https://doi.org/10.3390/cancers14143529 - 20 Jul 2022

Cited by 13 | Viewed by 2594

Abstract

State-of-the-art artificial intelligence (AI) has recently gained considerable interest in the healthcare sector and has provided solutions to problems through automated diagnosis. Cytological examination is a crucial step in the initial diagnosis of cancer, although it shows limited diagnostic efficacy. Recently, AI applications [...] Read more.

State-of-the-art artificial intelligence (AI) has recently gained considerable interest in the healthcare sector and has provided solutions to problems through automated diagnosis. Cytological examination is a crucial step in the initial diagnosis of cancer, although it shows limited diagnostic efficacy. Recently, AI applications in the processing of cytopathological images have shown promising results despite the elementary level of the technology. Here, we performed a systematic review with a quantitative analysis of recent AI applications in non-gynecological (non-GYN) cancer cytology to understand the current technical status. We searched the major online databases, including MEDLINE, Cochrane Library, and EMBASE, for relevant English articles published from January 2010 to January 2021. The searched query terms were: “artificial intelligence”, “image processing”, “deep learning”, “cytopathology”, and “fine-needle aspiration cytology.” Out of 17,000 studies, only 26 studies (26 models) were included in the full-text review, whereas 13 studies were included for quantitative analysis. There were eight classes of AI models treated of according to target organs: thyroid (n = 11, 39%), urinary bladder (n = 6, 21%), lung (n = 4, 14%), breast (n = 2, 7%), pleural effusion (n = 2, 7%), ovary (n = 1, 4%), pancreas (n = 1, 4%), and prostate (n = 1, 4). Most of the studies focused on classification and segmentation tasks. Although most of the studies showed impressive results, the sizes of the training and validation datasets were limited. Overall, AI is also promising for non-GYN cancer cytopathology analysis, such as pathology or gynecological cytology. However, the lack of well-annotated, large-scale datasets with Z-stacking and external cross-validation was the major limitation found across all studies. Future studies with larger datasets with high-quality annotations and external validation are required. Full article

(This article belongs to the Special Issue Artificial Intelligence and Advanced Medical Imaging in Cancer Diagnosis and Precision Care)

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45 pages, 3007 KiB

Open AccessReview

Autophagy: A Key Player in Pancreatic Cancer Progression and a Potential Drug Target

by Josef Gillson, Yomna S. Abd El-Aziz, Lionel Y. W. Leck, Patric J. Jansson, Nick Pavlakis, Jaswinder S. Samra, Anubhav Mittal and Sumit Sahni

Cancers 2022, 14(14), 3528; https://doi.org/10.3390/cancers14143528 - 20 Jul 2022

Cited by 11 | Viewed by 3791

Abstract

Pancreatic cancer is known to have the lowest survival outcomes among all major cancers, and unfortunately, this has only been marginally improved over last four decades. The innate characteristics of pancreatic cancer include an aggressive and fast-growing nature from powerful driver mutations, a [...] Read more.

Pancreatic cancer is known to have the lowest survival outcomes among all major cancers, and unfortunately, this has only been marginally improved over last four decades. The innate characteristics of pancreatic cancer include an aggressive and fast-growing nature from powerful driver mutations, a highly defensive tumor microenvironment and the upregulation of advantageous survival pathways such as autophagy. Autophagy involves targeted degradation of proteins and organelles to provide a secondary source of cellular supplies to maintain cell growth. Elevated autophagic activity in pancreatic cancer is recognized as a major survival pathway as it provides a plethora of support for tumors by supplying vital resources, maintaining tumour survival under the stressful microenvironment and promoting other pathways involved in tumour progression and metastasis. The combination of these features is unique to pancreatic cancer and present significant resistance to chemotherapeutic strategies, thus, indicating a need for further investigation into therapies targeting this crucial pathway. This review will outline the autophagy pathway and its regulation, in addition to the genetic landscape and tumor microenvironment that contribute to pancreatic cancer severity. Moreover, this review will also discuss the mechanisms of novel therapeutic strategies that inhibit autophagy and how they could be used to suppress tumor progression. Full article

(This article belongs to the Collection Recent Advances in Pancreatic Ductal Adenocarcinoma)

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