Editor’s Choice Articles

Editor’s Choice articles are based on recommendations by the scientific editors of MDPI journals from around the world. Editors select a small number of articles recently published in the journal that they believe will be particularly interesting to readers, or important in the respective research area. The aim is to provide a snapshot of some of the most exciting work published in the various research areas of the journal.

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17 pages, 9854 KiB  
Article
The First Cold Atmospheric Plasma Phase I Clinical Trial for the Treatment of Advanced Solid Tumors: A Novel Treatment Arm for Cancer
by Jerome Canady, Saravana R. K. Murthy, Taisen Zhuang, Steven Gitelis, Aviram Nissan, Lawan Ly, Olivia Z. Jones, Xiaoqian Cheng, Mohammad Adileh, Alan T. Blank, Matthew W. Colman, Keith Millikan, Cristina O’Donoghue, Kerstin M. Stenson, Karen Ohara, Gal Schtrechman, Michael Keidar and Giacomo Basadonna
Cancers 2023, 15(14), 3688; https://doi.org/10.3390/cancers15143688 - 20 Jul 2023
Cited by 13 | Viewed by 2751
Abstract
Local regional recurrence (LRR) remains the primary cause of treatment failure in solid tumors despite advancements in cancer therapies. Canady Helios Cold Plasma (CHCP) is a novel Cold Atmospheric Plasma device that generates an Electromagnetic Field and Reactive Oxygen and Nitrogen Species to [...] Read more.
Local regional recurrence (LRR) remains the primary cause of treatment failure in solid tumors despite advancements in cancer therapies. Canady Helios Cold Plasma (CHCP) is a novel Cold Atmospheric Plasma device that generates an Electromagnetic Field and Reactive Oxygen and Nitrogen Species to induce cancer cell death. In the first FDA-approved Phase I trial (March 2020–April 2021), 20 patients with stage IV or recurrent solid tumors underwent surgical resection combined with intra-operative CHCP treatment. Safety was the primary endpoint; secondary endpoints were non-LRR, survival, cancer cell death, and the preservation of surrounding healthy tissue. CHCP did not impact intraoperative physiological data (p > 0.05) or cause any related adverse events. Overall response rates at 26 months for R0 and R0 with microscopic positive margin (R0-MPM) patients were 69% (95% CI, 19–40%) and 100% (95% CI, 100–100.0%), respectively. Survival rates for R0 (n = 7), R0-MPM (n = 5), R1 (n = 6), and R2 (n = 2) patients at 28 months were 86%, 40%, 67%, and 0%, respectively. The cumulative overall survival rate was 24% at 31 months (n = 20, 95% CI, 5.3–100.0). CHCP treatment combined with surgery is safe, selective towards cancer, and demonstrates exceptional LRR control in R0 and R0-MPM patients. (Clinical Trials identifier: NCT04267575). Full article
(This article belongs to the Section Clinical Research of Cancer)
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11 pages, 261 KiB  
Article
Effectiveness of Opioid Switching in Advanced Cancer Pain: A Prospective Observational Cohort Study
by Aaron K. Wong, Andrew A. Somogyi, Justin Rubio, Tien Dung Pham, Brian Le, Pal Klepstad and Jennifer Philip
Cancers 2023, 15(14), 3676; https://doi.org/10.3390/cancers15143676 - 19 Jul 2023
Cited by 3 | Viewed by 1154
Abstract
Opioid switching is a common practice of substituting one opioid for another to improve analgesia or adverse effects; however, it has limited evidence. This study aimed to examine the effectiveness of opioid switching in advanced cancer. This multi-center prospective cohort study recruited patients [...] Read more.
Opioid switching is a common practice of substituting one opioid for another to improve analgesia or adverse effects; however, it has limited evidence. This study aimed to examine the effectiveness of opioid switching in advanced cancer. This multi-center prospective cohort study recruited patients assessed to switch opioids (opioid switch group) or to continue ongoing opioid treatment (control group). Clinical data (demographics, opioids) and validated instruments (pain and adverse effects) were collected over two timepoints seven days apart. Descriptive analyses were utilized. Non-parametric tests were used to determine differences. Fifty-four participants were recruited (23 control group, 31 switch group). At the follow-up, opioid switching reduced pain (worst, average, and now) (p < 0.05), uncontrolled breakthrough pain (3-fold reduction, p = 0.008), and psychological distress (48% to 16%, p < 0.005). The switch group had a ≥25% reduction in the reported frequency of seven moderate-to-severe adverse effects (score ≥ 4), compared to a reduction in only one adverse effect in the control group. The control group experienced no significant pain differences at the follow-up. Opioid switching is effective at reducing pain, adverse effects, and psychological distress in a population with advanced cancer pain, to levels of satisfactory symptom control in most patients within 1 week. Full article
(This article belongs to the Special Issue Strategies for Cancer Pain Management)
18 pages, 7061 KiB  
Article
Validation of a Novel EUS-FNB-Derived Organoid Co-Culture System for Drug Screening in Patients with Pancreatic Cancer
by Simon Ezban Grützmeier, Bojan Kovacevic, Peter Vilmann, Charlotte Vestrup Rift, Linea Cecilie Melchior, Morten Orebo Holmström, Lene Brink, Hazem Hassan, John Gásdal Karstensen, Hanne Grossjohann, Deepthi Chiranth, Anders Toxværd, Carsten Palnæs Hansen, Estrid Høgdall, Jane Preuss Hasselby and Pia Klausen
Cancers 2023, 15(14), 3677; https://doi.org/10.3390/cancers15143677 - 19 Jul 2023
Cited by 2 | Viewed by 1874
Abstract
Cancer-associated fibroblasts (CAFs) have been shown to impact the chemosensitivity of patient-derived tumor organoids (PDTOs). However, the published literature comparing PDTO response to clinical outcome does not include CAFs in the models. Here, a co-culture model was created using PDTOs and CAFs derived [...] Read more.
Cancer-associated fibroblasts (CAFs) have been shown to impact the chemosensitivity of patient-derived tumor organoids (PDTOs). However, the published literature comparing PDTO response to clinical outcome does not include CAFs in the models. Here, a co-culture model was created using PDTOs and CAFs derived from endoscopic ultrasound-guided fine-needle biopsies (EUS-FNBs) for potential use in drug screening applications. Co-cultures were established, and growth was compared to monocultures using image metrics and a commercially available assay. We were able to establish and expand validated malignant PDTOs from 19.2% of adenocarcinomas from EUS-FNBs. CAFs could be established from 25% of the samples. The viability of PDTOs in the mixed cell co-culture could be isolated using image metrics. The addition of CAFs promoted PDTO growth in half of the established co-cultures. These results show that co-cultures can be established from tiny amounts of tissue provided by EUS-FNB. An increased growth of PDTOs was shown in co-cultures, suggesting that the present setup successfully models CAF–PDTO interaction. Furthermore, we demonstrated that standard validation techniques may be insufficient to detect contamination with normal cells in PDTO cultures established from primary tumor core biopsies. Full article
(This article belongs to the Special Issue Endoscopic Ultrasound in Gastrointestinal Cancers)
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15 pages, 1784 KiB  
Article
Incidence and Mortality of Malignant Brain Tumors after 20 Years of Mobile Use
by Mohy Uddin, Rozy Dhanta, Thejkiran Pitti, Diana Barsasella, Jeremiah Scholl, Wen-Shan Jian, Yu-Chuan (Jack) Li, Min-Huei Hsu and Shabbir Syed-Abdul
Cancers 2023, 15(13), 3492; https://doi.org/10.3390/cancers15133492 - 04 Jul 2023
Viewed by 3090
Abstract
(1) Objective: This population-based study was performed to examine the trends of incidence and deaths due to malignant neoplasm of the brain (MNB) in association with mobile phone usage for a period of 20 years (January 2000–December 2019) in Taiwan. (2) Methods: Pearson [...] Read more.
(1) Objective: This population-based study was performed to examine the trends of incidence and deaths due to malignant neoplasm of the brain (MNB) in association with mobile phone usage for a period of 20 years (January 2000–December 2019) in Taiwan. (2) Methods: Pearson correlation, regression analysis, and joinpoint regression analysis were used to examine the trends of incidence of MNB and deaths due to MNB in association with mobile phone usage. (3) Results: The findings indicate a trend of increase in the number of mobile phone users over the study period, accompanied by a slight rise in the incidence and death rates of MNB. The compound annual growth rates further support these observations, highlighting consistent growth in mobile phone users and a corresponding increase in MNB incidences and deaths. (4) Conclusions: The results suggest a weaker association between the growing number of mobile phone users and the rising rates of MNB, and no significant correlation was observed between MNB incidences and deaths and mobile phone usage. Ultimately, it is important to acknowledge that conclusive results cannot be drawn at this stage and further investigation is required by considering various other confounding factors and potential risks to obtain more definitive findings and a clearer picture. Full article
(This article belongs to the Special Issue Brain Tumor: Recent Advances and Challenges)
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17 pages, 4920 KiB  
Article
Vitamin D Receptor Antagonist MeTC7 Inhibits PD-L1
by Negar Khazan, Emily R. Quarato, Niloy A. Singh, Cameron W. A. Snyder, Taylor Moore, John P. Miller, Masato Yasui, Yuki Teramoto, Takuro Goto, Sabeeha Reshi, Jennifer Hong, Naixin Zhang, Diya Pandey, Priyanka Srivastava, Alexandra Morell, Hiroki Kawano, Yuko Kawano, Thomas Conley, Deepak M. Sahasrabudhe, Naohiro Yano, Hiroshi Miyamoto, Omar Aljitawi, Jane Liesveld, Michael W. Becker, Laura M. Calvi, Alexander S. Zhovmer, Erdem D. Tabdanov, Nikolay V. Dokholyan, David C. Linehan, Jeanne N. Hansen, Scott A. Gerber, Ashoke Sharon, Manoj K. Khera, Peter W. Jurutka, Natacha Rochel, Kyu Kwang Kim, Rachael B. Rowswell-Turner, Rakesh K. Singh and Richard G. Mooreadd Show full author list remove Hide full author list
Cancers 2023, 15(13), 3432; https://doi.org/10.3390/cancers15133432 - 30 Jun 2023
Cited by 1 | Viewed by 3063
Abstract
Small-molecule inhibitors of PD-L1 are postulated to control immune evasion in tumors similar to antibodies that target the PD-L1/PD-1 immune checkpoint axis. However, the identity of targetable PD-L1 inducers is required to develop small-molecule PD-L1 inhibitors. In this study, using chromatin immunoprecipitation (ChIP) [...] Read more.
Small-molecule inhibitors of PD-L1 are postulated to control immune evasion in tumors similar to antibodies that target the PD-L1/PD-1 immune checkpoint axis. However, the identity of targetable PD-L1 inducers is required to develop small-molecule PD-L1 inhibitors. In this study, using chromatin immunoprecipitation (ChIP) assay and siRNA, we demonstrate that vitamin D/VDR regulates PD-L1 expression in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) cells. We have examined whether a VDR antagonist, MeTC7, can inhibit PD-L1. To ensure that MeTC7 inhibits VDR/PD-L1 without off-target effects, we examined competitive inhibition of VDR by MeTC7, utilizing ligand-dependent dimerization of VDR-RXR, RXR-RXR, and VDR-coactivators in a mammalian 2-hybrid (M2H) assay. MeTC7 inhibits VDR selectively, suppresses PD-L1 expression sparing PD-L2, and inhibits the cell viability, clonogenicity, and xenograft growth of AML cells. MeTC7 blocks AML/mesenchymal stem cells (MSCs) adhesion and increases the efferocytotic efficiency of THP-1 AML cells. Additionally, utilizing a syngeneic colorectal cancer model in which VDR/PD-L1 co-upregulation occurs in vivo under radiation therapy (RT), MeTC7 inhibits PD-L1 and enhances intra-tumoral CD8+T cells expressing lymphoid activation antigen-CD69. Taken together, MeTC7 is a promising small-molecule inhibitor of PD-L1 with clinical potential. Full article
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15 pages, 1562 KiB  
Article
Assessing the Performance of a Novel Stool-Based Microbiome Test That Predicts Response to First Line Immune Checkpoint Inhibitors in Multiple Cancer Types
by Irina Robinson, Maximilian Johannes Hochmair, Manuela Schmidinger, Gudrun Absenger, Martin Pichler, Van Anh Nguyen, Erika Richtig, Barbara Margaretha Rainer, Leyla Ay, Christian Jansen, Cátia Pacífico, Alexander Knabl, Barbara Sladek, Nikolaus Gasche and Arschang Valipour
Cancers 2023, 15(13), 3268; https://doi.org/10.3390/cancers15133268 - 21 Jun 2023
Cited by 2 | Viewed by 2230
Abstract
The intestinal microbiome is by now an undebatable key player in the clinical outcome of ICI therapies. However, no microbiome profiling method to aid therapy decision is yet validated. We conducted a multi-centric study in patients with stage III/IV melanoma, NSCLC, or RCC [...] Read more.
The intestinal microbiome is by now an undebatable key player in the clinical outcome of ICI therapies. However, no microbiome profiling method to aid therapy decision is yet validated. We conducted a multi-centric study in patients with stage III/IV melanoma, NSCLC, or RCC receiving ICI treatment. The stool microbiome profile of 63 patients was analyzed with BiomeOne®, a microbiome-based algorithm that anticipates whether a patient will achieve clinical benefit with ICIs prior to therapy initiation. Classification of patient samples as Rs and NRs was achieved with a sensitivity of 81% and a specificity of 50% in this validation cohort. An ICI-favorable response was characterized by an intestinal microbiome rich in bacteria such as Oscillospira sp., Clostridia UCG-014, Lachnospiraceae UCG-010 sp., Prevotella copri, and a decrease in Sutterella sp., Lactobacillales, and Streptococcus sp. Patients who developed immune-related adverse events (irAEs) had an overall increased microbial diversity and richness, and a stool microbiome depleted in Agathobacter. When compared with the programmed death-ligand 1 (PD-L1) expression test in the subcohort of NSCLC patients (n = 38), BiomeOne® exhibited a numerically higher sensitivity (78.6%) in identifying responders when compared with the PD-L1 test (67.9%). This study provides an evaluation of BiomeOne®, the first microbiome-based test for prediction of ICI response, to achieve market authorization. Validation with further indications and expansion to other microbiome-based interventions will be essential to bring microbiome-based diagnostics into standard clinical practice. Full article
(This article belongs to the Special Issue Artificial Intelligence and Machine Learning in Precision Oncology)
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15 pages, 1033 KiB  
Review
New Approaches to Targeted Therapy in Melanoma
by Manuel Felipe Fernandez, Jacob Choi and Jeffrey Sosman
Cancers 2023, 15(12), 3224; https://doi.org/10.3390/cancers15123224 - 17 Jun 2023
Cited by 5 | Viewed by 2124
Abstract
It was just slightly more than a decade ago when metastatic melanoma carried a dismal prognosis with few, if any, effective therapies. Since then, the evolution of cancer immunotherapy has led to new and effective treatment approaches for melanoma. However, despite these advances, [...] Read more.
It was just slightly more than a decade ago when metastatic melanoma carried a dismal prognosis with few, if any, effective therapies. Since then, the evolution of cancer immunotherapy has led to new and effective treatment approaches for melanoma. However, despite these advances, a sizable portion of patients with advanced melanoma have de novo or acquired resistance to immune checkpoint inhibitors. At the same time, therapies (BRAF plus MEK inhibitors) targeting the BRAFV600 mutations found in 40–50% of cutaneous melanomas have also been critical for optimizing management and improving patient outcomes. Even though immunotherapy has been established as the initial therapy in most patients with cutaneous melanoma, subsequent effective therapy is limited to BRAFV600 melanoma. For all other melanoma patients, driver mutations have not been effectively targeted. Numerous efforts are underway to target melanomas with NRAS mutations, NF-1 LOF mutations, and other genetic alterations leading to activation of the MAP kinase pathway. In this era of personalized medicine, we will review the current genetic landscape, molecular classifications, emerging drug targets, and the potential for combination therapies for non-BRAFV600 melanoma. Full article
(This article belongs to the Collection Emerging Therapeutics in Advanced Melanoma)
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15 pages, 7002 KiB  
Article
Spatial Transcriptomics Identifies Expression Signatures Specific to Lacrimal Gland Adenoid Cystic Carcinoma Cells
by Acadia H. M. Moeyersoms, Ryan A. Gallo, Michelle G. Zhang, Vasileios Stathias, Michelle M. Maeng, Dawn Owens, Rayan Abou Khzam, Yoseph Sayegh, Cynthia Maza, Sander R. Dubovy, David T. Tse and Daniel Pelaez
Cancers 2023, 15(12), 3211; https://doi.org/10.3390/cancers15123211 - 16 Jun 2023
Cited by 2 | Viewed by 2084
Abstract
Although primary tumors of the lacrimal gland are rare, adenoid cystic carcinoma (ACC) is the most common and lethal epithelial lacrimal gland malignancy. Traditional management of lacrimal gland adenoid cystic carcinoma (LGACC) involves the removal of the eye and surrounding socket contents, followed [...] Read more.
Although primary tumors of the lacrimal gland are rare, adenoid cystic carcinoma (ACC) is the most common and lethal epithelial lacrimal gland malignancy. Traditional management of lacrimal gland adenoid cystic carcinoma (LGACC) involves the removal of the eye and surrounding socket contents, followed by chemoradiation. Even with this radical treatment, the 10-year survival rate for LGACC is 20% given the propensity for recurrence and metastasis. Due to the rarity of LGACC, its pathobiology is not well-understood, leading to difficulties in diagnosis, treatment, and effective management. Here, we integrate bulk RNA sequencing (RNA-seq) and spatial transcriptomics to identify a specific LGACC gene signature that can inform novel targeted therapies. Of the 3499 differentially expressed genes identified by bulk RNA-seq, the results of our spatial transcriptomic analysis reveal 15 upregulated and 12 downregulated genes that specifically arise from LGACC cells, whereas fibroblasts, reactive fibrotic tissue, and nervous and skeletal muscle account for the remaining bulk RNA-seq signature. In light of the analysis, we identified a transitional state cell or stem cell cluster. The results of the pathway analysis identified the upregulation of PI3K-Akt signaling, IL-17 signaling, and multiple other cancer pathways. This study provides insights into the molecular and cellular landscape of LGACC, which can inform new, targeted therapies to improve patient outcomes. Full article
(This article belongs to the Section Molecular Cancer Biology)
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24 pages, 3755 KiB  
Review
Tumor Microenvironment as a Therapeutic Target in Melanoma Treatment
by Naji Kharouf, Thomas W. Flanagan, Sofie-Yasmin Hassan, Hosam Shalaby, Marla Khabaz, Sarah-Lilly Hassan, Mosaad Megahed, Youssef Haikel, Simeon Santourlidis and Mohamed Hassan
Cancers 2023, 15(12), 3147; https://doi.org/10.3390/cancers15123147 - 11 Jun 2023
Cited by 2 | Viewed by 2504
Abstract
The role of the tumor microenvironment in tumor growth and therapy has recently attracted more attention in research and drug development. The ability of the microenvironment to trigger tumor maintenance, progression, and resistance is the main cause for treatment failure and tumor relapse. [...] Read more.
The role of the tumor microenvironment in tumor growth and therapy has recently attracted more attention in research and drug development. The ability of the microenvironment to trigger tumor maintenance, progression, and resistance is the main cause for treatment failure and tumor relapse. Accumulated evidence indicates that the maintenance and progression of tumor cells is determined by components of the microenvironment, which include stromal cells (endothelial cells, fibroblasts, mesenchymal stem cells, and immune cells), extracellular matrix (ECM), and soluble molecules (chemokines, cytokines, growth factors, and extracellular vesicles). As a solid tumor, melanoma is not only a tumor mass of monolithic tumor cells, but it also contains supporting stroma, ECM, and soluble molecules. Melanoma cells are continuously in interaction with the components of the microenvironment. In the present review, we focus on the role of the tumor microenvironment components in the modulation of tumor progression and treatment resistance as well as the impact of the tumor microenvironment as a therapeutic target in melanoma. Full article
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21 pages, 4028 KiB  
Review
Innovation in Radionuclide Therapy for the Treatment of Prostate Cancers: Radiochemical Perspective and Recent Therapeutic Practices
by Emmanuel Deshayes, Cyril Fersing, Constance Thibault, Mathieu Roumiguie, Philippe Pourquier and Nadine Houédé
Cancers 2023, 15(12), 3133; https://doi.org/10.3390/cancers15123133 - 10 Jun 2023
Cited by 3 | Viewed by 1972
Abstract
Prostate cancer represents the second cause of death by cancer in males in western countries. While early-stage diseases are accessible to surgery and/or external radiotherapy, advanced metastatic prostate cancers are primarily treated with androgen deprivation therapy, to which new generation androgen receptor antagonists [...] Read more.
Prostate cancer represents the second cause of death by cancer in males in western countries. While early-stage diseases are accessible to surgery and/or external radiotherapy, advanced metastatic prostate cancers are primarily treated with androgen deprivation therapy, to which new generation androgen receptor antagonists or taxane-based chemotherapies are added in the case of tumor relapse. Nevertheless, patients become invariably resistant to castration with a median survival that rarely exceeds 3 years. This fostered the search for alternative strategies, independent of the androgen receptor signaling pathway. In this line, radionuclide therapies may represent an interesting option as they could target either the microenvironment of sclerotic bone metastases with the use of radiopharmaceuticals containing samarium-153, strontium-89 or radium-223 or tumor cells expressing the prostate-specific membrane antigen (PSMA), a protein found at the surface of prostate cancer cells. This review gives highlights the chemical properties of radioligands targeting prostate cancer cells and recapitulates the clinical trials evaluating the efficacy of radionuclide therapies, alone or in combination with other approved treatments, in patients with castration-resistant prostate tumors. It discusses some of the encouraging results obtained, especially the benefit on overall survival that was reported with [177Lu]-PSMA-617. It also addresses the specific requirements for the use of this particular class of drugs, both in terms of medical staff coordination and adapted infrastructures for efficient radioprotection. Full article
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16 pages, 4543 KiB  
Article
Immuno-PET Imaging of Tumour PD-L1 Expression in Glioblastoma
by Gitanjali Sharma, Marta C. Braga, Chiara Da Pieve, Wojciech Szopa, Tatjana Starzetz, Karl H. Plate, Wojciech Kaspera and Gabriela Kramer-Marek
Cancers 2023, 15(12), 3131; https://doi.org/10.3390/cancers15123131 - 09 Jun 2023
Cited by 2 | Viewed by 2818
Abstract
There is no established method to assess the PD-L1 expression in brain tumours. Therefore, we investigated the suitability of affibody molecule (ZPD-L1) radiolabelled with F-18 (Al18F) and Ga-68 to measure the expression of PD-L1 in xenograft mouse models of [...] Read more.
There is no established method to assess the PD-L1 expression in brain tumours. Therefore, we investigated the suitability of affibody molecule (ZPD-L1) radiolabelled with F-18 (Al18F) and Ga-68 to measure the expression of PD-L1 in xenograft mouse models of GBM. Mice bearing subcutaneous and orthotopic tumours were imaged 1 h post-radioconjugate administration. Ex vivo biodistribution studies and immunohistochemistry (IHC) staining were performed. Tumoural PD-L1 expression and CD4+/CD8+ tumour-infiltrating lymphocytes were evaluated in human GBM specimens. ZPD-L1 was radiolabelled with radiochemical yields of 32.2 ± 4.4% (F-18) and 73.3 ± 1.8% (Ga-68). The cell-associated radioactivity in vitro was consistent with PD-L1 expression levels assessed with flow cytometry. In vivo imaging demonstrated that 18F-AlF-NOTA-ZPD-L1 can distinguish between PD-L1 high-expressing tumours (U87-MGvIII) and PD-L1-negative ones (H292PD-L1Ko). The radioconjugate was quickly cleared from the blood and normal tissues, allowing for high-contrast images of brain tumours as early as 1 h post-injection. 68Ga-NOTA-ZPD-L1 showed heterogeneous and diffuse accumulation that corresponded to the extensively infiltrating GCGR-E55 tumours involving contiguous lobes of the brain. Lastly, 39% of analysed GBM patient samples showed PD-L1+ staining of tumour cells that was associated with elevated levels of CD4+ and CD8+ lymphocytes. Our results suggest that the investigated radioconjugates are very promising agents with the potential to facilitate the future design of treatment regimens for GBM patients. Full article
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19 pages, 1853 KiB  
Review
Endoscopic Resection of Early Gastric Cancer and Pre-Malignant Gastric Lesions
by Ana Clara Vasconcelos, Mário Dinis-Ribeiro and Diogo Libânio
Cancers 2023, 15(12), 3084; https://doi.org/10.3390/cancers15123084 - 07 Jun 2023
Cited by 4 | Viewed by 3251
Abstract
Early gastric cancer comprises gastric malignancies that are confined to the mucosa or submucosa, irrespective of lymph node metastasis. Endoscopic resection is currently pivotal for the management of such early lesions, and it is the recommended treatment for tumors presenting a very low [...] Read more.
Early gastric cancer comprises gastric malignancies that are confined to the mucosa or submucosa, irrespective of lymph node metastasis. Endoscopic resection is currently pivotal for the management of such early lesions, and it is the recommended treatment for tumors presenting a very low risk of lymph node metastasis. In general, these lesions consist of two groups of differentiated mucosal adenocarcinomas: non-ulcerated lesions (regardless of their size) and small ulcerated lesions. Endoscopic submucosal dissection is the technique of choice in most cases. This procedure has high rates of complete histological resection while maintaining gastric anatomy and its functions, resulting in fewer adverse events than surgery and having a lesser impact on patient-reported quality of life. Nonetheless, approximately 20% of resected lesions do not fulfill curative criteria and demand further treatment, highlighting the importance of patient selection. Additionally, the preservation of the stomach results in a moderate risk of metachronous lesions, which underlines the need for surveillance. We review the current evidence regarding the endoscopic treatment of early gastric cancer, including the short-and long-term results and management after resection. Full article
(This article belongs to the Special Issue The Application of Endoscopy in Gastrointestinal Cancers)
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13 pages, 3868 KiB  
Article
Comparing Oncologic Outcomes and Toxicity for Combined Modality Therapy vs. Carbon-Ion Radiotherapy for Previously Irradiated Locally Recurrent Rectal Cancer
by Elizabeth B. Jeans, Daniel K. Ebner, Hirotoshi Takiyama, Kaitlin Qualls, Danielle A. Cunningham, Mark R. Waddle, Krishan R. Jethwa, William S. Harmsen, Joleen M. Hubbard, Eric J. Dozois, Kellie L. Mathis, Hiroshi Tsuji, Kenneth W. Merrell, Christopher L. Hallemeier, Anita Mahajan, Shigeru Yamada, Robert L. Foote and Michael G. Haddock
Cancers 2023, 15(11), 3057; https://doi.org/10.3390/cancers15113057 - 05 Jun 2023
Cited by 3 | Viewed by 1148
Abstract
No standard treatment paradigm exists for previously irradiated locally recurrent rectal cancer (PILRRC). Carbon-ion radiotherapy (CIRT) may improve oncologic outcomes and reduce toxicity compared with combined modality therapy (CMT). Eighty-five patients treated at Institution A with CIRT alone (70.4 Gy/16 fx) and eighty-six [...] Read more.
No standard treatment paradigm exists for previously irradiated locally recurrent rectal cancer (PILRRC). Carbon-ion radiotherapy (CIRT) may improve oncologic outcomes and reduce toxicity compared with combined modality therapy (CMT). Eighty-five patients treated at Institution A with CIRT alone (70.4 Gy/16 fx) and eighty-six at Institution B with CMT (30 Gy/15 fx chemoradiation, resection, intraoperative electron radiotherapy (IOERT)) between 2006 and 2019 were retrospectively compared. Overall survival (OS), pelvic re-recurrence (PR), distant metastasis (DM), or any disease progression (DP) were analyzed with the Kaplan–Meier model, with outcomes compared using the Cox proportional hazards model. Acute and late toxicities were compared, as was the 2-year cost. The median time to follow-up or death was 6.5 years. Median OS in the CIRT and CMT cohorts were 4.5 and 2.6 years, respectively (p ≤ 0.01). No difference was seen in the cumulative incidence of PR (p = 0.17), DM (p = 0.39), or DP (p = 0.19). Lower acute grade ≥ 2 skin and GI/GU toxicity and lower late grade ≥ 2 GU toxicities were associated with CIRT. Higher 2-year cumulative costs were associated with CMT. Oncologic outcomes were similar for patients treated with CIRT or CMT, although patient morbidity and cost were lower with CIRT, and CIRT was associated with longer OS. Prospective comparative studies are needed. Full article
(This article belongs to the Section Cancer Therapy)
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17 pages, 5649 KiB  
Article
deepPERFECT: Novel Deep Learning CT Synthesis Method for Expeditious Pancreatic Cancer Radiotherapy
by Hamed Hooshangnejad, Quan Chen, Xue Feng, Rui Zhang and Kai Ding
Cancers 2023, 15(11), 3061; https://doi.org/10.3390/cancers15113061 - 05 Jun 2023
Cited by 5 | Viewed by 1457
Abstract
Major sources of delay in the standard of care RT workflow are the need for multiple appointments and separate image acquisition. In this work, we addressed the question of how we can expedite the workflow by synthesizing planning CT from diagnostic CT. This [...] Read more.
Major sources of delay in the standard of care RT workflow are the need for multiple appointments and separate image acquisition. In this work, we addressed the question of how we can expedite the workflow by synthesizing planning CT from diagnostic CT. This idea is based on the theory that diagnostic CT can be used for RT planning, but in practice, due to the differences in patient setup and acquisition techniques, separate planning CT is required. We developed a generative deep learning model, deepPERFECT, that is trained to capture these differences and generate deformation vector fields to transform diagnostic CT into preliminary planning CT. We performed detailed analysis both from an image quality and a dosimetric point of view, and showed that deepPERFECT enabled the preliminary RT planning to be used for preliminary and early plan dosimetric assessment and evaluation. Full article
(This article belongs to the Special Issue Radiation Therapy for Pancreatic Cancer)
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17 pages, 1467 KiB  
Article
Analysis of the Gut Microbiome and Dietary Habits in Metastatic Melanoma Patients with a Complete and Sustained Response to Immunotherapy
by Marin Golčić, Luka Simetić, Davorin Herceg, Krešimir Blažičević, Gordana Kenđel Jovanović, Ivan Dražić, Andrej Belančić, Nataša Skočibušić, Dora Palčevski, Igor Rubinić, Vera Vlahović-Palčevski, Tea Majnarić, Renata Dobrila-Dintinjana and Stjepko Pleština
Cancers 2023, 15(11), 3052; https://doi.org/10.3390/cancers15113052 - 04 Jun 2023
Cited by 2 | Viewed by 1835
Abstract
Immunotherapy has improved the prognosis of metastatic melanoma patients, although most patients do not achieve a complete response. While specific gut microbiome and dietary habits might influence treatment success, there is a lack of concordance between the studies, potentially due to dichotomizing patients [...] Read more.
Immunotherapy has improved the prognosis of metastatic melanoma patients, although most patients do not achieve a complete response. While specific gut microbiome and dietary habits might influence treatment success, there is a lack of concordance between the studies, potentially due to dichotomizing patients only into responders and non-responders. The aim of this study was to elucidate whether metastatic melanoma patients with complete and sustained response to immunotherapy exhibit differences in gut microbiome composition among themselves, and whether those differences were associated with specific dietary habits. Shotgun metagenomic sequencing revealed that patients who exhibited a complete response after more than 9 months of treatment (late responders) exhibited a significantly higher beta-diversity (p = 0.02), with a higher abundance of Coprococcus comes (LDA 3.548, p = 0.010), Bifidobacterium pseudocatenulatum (LDA 3.392, p = 0.024), and lower abundance of Prevotellaceae (p = 0.04) compared to early responders. Furthermore, late responders exhibited a different diet profile, with a significantly lower intake of proteins and sweets and a higher intake of flavones (p < 0.05). The research showed that metastatic melanoma patients with a complete and sustained response to immunotherapy were a heterogeneous group. Patients with a late complete response exhibited microbiome and dietary habits which were previously associated with an improved response to immunotherapy. Full article
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18 pages, 4551 KiB  
Article
Follicular Helper and Regulatory T Cells Drive the Development of Spontaneous Epstein–Barr Virus Lymphoproliferative Disorder
by Elshafa Hassan Ahmed, Mark Lustberg, Claire Hale, Shelby Sloan, Charlene Mao, Xiaoli Zhang, Hatice Gulcin Ozer, Sarah Schlotter, Porsha L. Smith, Frankie Jeney, Wing Keung Chan, Bonnie K. Harrington, Christoph Weigel, Eric Brooks, Haley L. Klimaszewski, Christopher C. Oakes, Tamrat Abebe, Muntaser E. Ibrahim, Lapo Alinari, Gregory K. Behbehani, Polina Shindiapina, Michael A. Caligiuri and Robert A. Baiocchiadd Show full author list remove Hide full author list
Cancers 2023, 15(11), 3046; https://doi.org/10.3390/cancers15113046 - 03 Jun 2023
Cited by 1 | Viewed by 2457
Abstract
Epstein–Barr virus (EBV) is a ubiquitous herpes virus associated with various cancers. EBV establishes latency with life-long persistence in memory B-cells and can reactivate lytic infection placing immunocompromised individuals at risk for EBV-driven lymphoproliferative disorders (EBV-LPD). Despite the ubiquity of EBV, only a [...] Read more.
Epstein–Barr virus (EBV) is a ubiquitous herpes virus associated with various cancers. EBV establishes latency with life-long persistence in memory B-cells and can reactivate lytic infection placing immunocompromised individuals at risk for EBV-driven lymphoproliferative disorders (EBV-LPD). Despite the ubiquity of EBV, only a small percentage of immunocompromised patients (~20%) develop EBV-LPD. Engraftment of immunodeficient mice with peripheral blood mononuclear cells (PBMCs) from healthy EBV-seropositive donors leads to spontaneous, malignant, human B-cell EBV-LPD. Only about 20% of EBV+ donors induce EBV-LPD in 100% of engrafted mice (High-Incidence, HI), while another 20% of donors never generate EBV-LPD (No-Incidence, NI). Here, we report HI donors to have significantly higher basal T follicular helper (Tfh) and regulatory T-cells (Treg), and depletion of these subsets prevents/delays EBV-LPD. Transcriptomic analysis of CD4+ T cells from ex vivo HI donor PBMC revealed amplified cytokine and inflammatory gene signatures. HI vs. NI donors showed a marked reduction in IFNγ production to EBV latent and lytic antigen stimulation. In addition, we observed abundant myeloid-derived suppressor cells in HI donor PBMC that decreased CTL proliferation in co-cultures with autologous EBV+ lymphoblasts. Our findings identify potential biomarkers that may identify individuals at risk for EBV-LPD and suggest possible strategies for prevention. Full article
(This article belongs to the Special Issue Epstein-Barr Virus-Associated Cancers: From Pathogenesis to Treatment)
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16 pages, 1062 KiB  
Article
Cytogenetic Assessment and Risk Stratification in Myelofibrosis with Optical Genome Mapping
by Álvaro Díaz-González, Elvira Mora, Gayane Avetisyan, Santiago Furió, Rosalía De la Puerta, José Vicente Gil, Alessandro Liquori, Eva Villamón, Carmen García-Hernández, Marta Santiago, Cristian García-Ruiz, Marta Llop, Blanca Ferrer-Lores, Eva Barragán, Silvia García-Palomares, Empar Mayordomo, Irene Luna, Ana Vicente, Lourdes Cordón, Leonor Senent, Alberto Álvarez-Larrán, José Cervera, Javier De la Rubia, Juan Carlos Hernández-Boluda and Esperanza Suchadd Show full author list remove Hide full author list
Cancers 2023, 15(11), 3039; https://doi.org/10.3390/cancers15113039 - 02 Jun 2023
Viewed by 1898
Abstract
Cytogenetic assessment in myelofibrosis is essential for risk stratification and patient management. However, an informative karyotype is unavailable in a significant proportion of patients. Optical genome mapping (OGM) is a promising technique that allows for a high-resolution assessment of chromosomal aberrations (structural variants, [...] Read more.
Cytogenetic assessment in myelofibrosis is essential for risk stratification and patient management. However, an informative karyotype is unavailable in a significant proportion of patients. Optical genome mapping (OGM) is a promising technique that allows for a high-resolution assessment of chromosomal aberrations (structural variants, copy number variants, and loss of heterozygosity) in a single workflow. In this study, peripheral blood samples from a series of 21 myelofibrosis patients were analyzed via OGM. We assessed the clinical impact of the application of OGM for disease risk stratification using the DIPSS-plus, GIPSS, and MIPSS70+v2 prognostic scores compared with the standard-of-care approach. OGM, in combination with NGS, allowed for risk classification in all cases, compared to only 52% when conventional techniques were used. Cases with unsuccessful karyotypes (n = 10) using conventional techniques were fully characterized using OGM. In total, 19 additional cryptic aberrations were identified in 9 out of 21 patients (43%). No alterations were found via OGM in 4/21 patients with previously normal karyotypes. OGM upgraded the risk category for three patients with available karyotypes. This is the first study using OGM in myelofibrosis. Our data support that OGM is a valuable tool that can greatly contribute to improve disease risk stratification in myelofibrosis patients. Full article
(This article belongs to the Special Issue Diagnosis of Hematologic Malignancies)
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19 pages, 3798 KiB  
Article
An Aminosteroid Derivative Shows Higher In Vitro and In Vivo Potencies than Gold Standard Drugs in Androgen-Dependent Prostate Cancer Models
by Donald Poirier, Jenny Roy, René Maltais, Cindy Weidmann and Étienne Audet-Walsh
Cancers 2023, 15(11), 3033; https://doi.org/10.3390/cancers15113033 - 02 Jun 2023
Viewed by 4311
Abstract
The aminosteroid derivative RM-581 blocks with high potency the growth of androgen-dependent (AR+) prostate cancer VCaP, 22Rv1, and LAPC-4 cells. Notably, RM-581 demonstrated superior antiproliferative activity in LAPC-4 cells compared to enzalutamide and abiraterone, two drugs that exhibited a synergistic effect [...] Read more.
The aminosteroid derivative RM-581 blocks with high potency the growth of androgen-dependent (AR+) prostate cancer VCaP, 22Rv1, and LAPC-4 cells. Notably, RM-581 demonstrated superior antiproliferative activity in LAPC-4 cells compared to enzalutamide and abiraterone, two drugs that exhibited a synergistic effect in combination with RM-581. These findings suggest that RM-581 may have an action that is not directly associated with the hormonal pathway of androgens. Furthermore, RM-581 completely blocks tumor growth in LAPC-4 xenografts when given orally at 3, 10, and 30 mg/kg in non-castrated (intact) nude mice. During this study, an accumulation of RM-581 was observed in tumors compared to plasma (3.3–10 folds). Additionally, the level of fatty acids (FA) increased in the tumors and livers of mice treated with RM-581 but not in plasma. The increase was greater in unsaturated FA (21–28%) than in saturated FA (7–11%). The most affected FA were saturated palmitic acid (+16%), monounsaturated oleic acid (+34%), and di-unsaturated linoleic acid (+56%), i.e., the 3 most abundant FA, with a total of 55% of the 56 FA measured. For cholesterol levels, there was no significant difference in the tumor, liver, or plasma of mice treated or not with RM-581. Another important result was the innocuity of RM-581 in mice during a 28-day xenograft experiment and a 7-week dose-escalation study, suggesting a favorable safety window for this new promising drug candidate when given orally. Full article
(This article belongs to the Special Issue Novel Drugs for Prostate Cancer)
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13 pages, 1789 KiB  
Article
Plasma Metabolomics Predicts Chemotherapy Response in Advanced Pancreatic Cancer
by Hayato Muranaka, Andrew Hendifar, Arsen Osipov, Natalie Moshayedi, Veronica Placencio-Hickok, Nicholas Tatonetti, Aleksandr Stotland, Sarah Parker, Jennifer Van Eyk, Stephen J. Pandol, Neil A. Bhowmick and Jun Gong
Cancers 2023, 15(11), 3020; https://doi.org/10.3390/cancers15113020 - 01 Jun 2023
Cited by 3 | Viewed by 1471
Abstract
Pancreatic cancer (PC) is one of the deadliest cancers. Developing biomarkers for chemotherapeutic response prediction is crucial for improving the dismal prognosis of advanced-PC patients (pts). To evaluate the potential of plasma metabolites as predictors of the response to chemotherapy for PC patients, [...] Read more.
Pancreatic cancer (PC) is one of the deadliest cancers. Developing biomarkers for chemotherapeutic response prediction is crucial for improving the dismal prognosis of advanced-PC patients (pts). To evaluate the potential of plasma metabolites as predictors of the response to chemotherapy for PC patients, we analyzed plasma metabolites using high-performance liquid chromatography–mass spectrometry from 31 cachectic, advanced-PC subjects enrolled into the PANCAX-1 (NCT02400398) prospective trial to receive a jejunal tube peptide-based diet for 12 weeks and who were planned for palliative chemotherapy. Overall, there were statistically significant differences in the levels of intermediates of multiple metabolic pathways in pts with a partial response (PR)/stable disease (SD) vs. progressive disease (PD) to chemotherapy. When stratified by the chemotherapy regimen, PD after 5-fluorouracil-based chemotherapy (e.g., FOLFIRINOX) was associated with decreased levels of amino acids (AAs). For gemcitabine-based chemotherapy (e.g., gemcitabine/nab-paclitaxel), PD was associated with increased levels of intermediates of glycolysis, the TCA cycle, nucleoside synthesis, and bile acid metabolism. These results demonstrate the feasibility of plasma metabolomics in a prospective cohort of advanced-PC patients for assessing the effect of enteral feeding as their primary source of nutrition. Metabolic signatures unique to FOLFIRINOX or gemcitabine/nab-paclitaxel may be predictive of a patient’s response and warrant further study. Full article
(This article belongs to the Special Issue Lipids and Small Metabolites in Cancer)
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19 pages, 1166 KiB  
Systematic Review
Drug Repurposing in Oncology: A Systematic Review of Randomized Controlled Clinical Trials
by Ignatios Ioakeim-Skoufa, Natalia Tobajas-Ramos, Enrica Menditto, Mercedes Aza-Pascual-Salcedo, Antonio Gimeno-Miguel, Valentina Orlando, Francisca González-Rubio, Ana Fanlo-Villacampa, Carmen Lasala-Aza, Ewelina Ostasz and Jorge Vicente-Romero
Cancers 2023, 15(11), 2972; https://doi.org/10.3390/cancers15112972 - 30 May 2023
Cited by 5 | Viewed by 2509
Abstract
Quality pharmacological treatment can improve survival in many types of cancer. Drug repurposing offers advantages in comparison with traditional drug development procedures, reducing time and risk. This systematic review identified the most recent randomized controlled clinical trials that focus on drug repurposing in [...] Read more.
Quality pharmacological treatment can improve survival in many types of cancer. Drug repurposing offers advantages in comparison with traditional drug development procedures, reducing time and risk. This systematic review identified the most recent randomized controlled clinical trials that focus on drug repurposing in oncology. We found that only a few clinical trials were placebo-controlled or standard-of-care-alone-controlled. Metformin has been studied for potential use in various types of cancer, including prostate, lung, and pancreatic cancer. Other studies assessed the possible use of the antiparasitic agent mebendazole in colorectal cancer and of propranolol in multiple myeloma or, when combined with etodolac, in breast cancer. We were able to identify trials that study the potential use of known antineoplastics in other non-oncological conditions, such as imatinib for severe coronavirus disease in 2019 or a study protocol aiming to assess the possible repurposing of leuprolide for Alzheimer’s disease. Major limitations of these clinical trials were the small sample size, the high clinical heterogeneity of the participants regarding the stage of the neoplastic disease, and the lack of accounting for multimorbidity and other baseline clinical characteristics. Drug repurposing possibilities in oncology must be carefully examined with well-designed trials, considering factors that could influence prognosis. Full article
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14 pages, 1409 KiB  
Article
Efficacy of Tango Argentino for Cancer-Associated Fatigue and Quality of Life in Breast Cancer Survivors: A Randomized Controlled Trial
by Friedemann Schad, Thomas Rieser, Sarah Becker, Jessica Groß, Harald Matthes, Shiao Li Oei and Anja Thronicke
Cancers 2023, 15(11), 2920; https://doi.org/10.3390/cancers15112920 - 26 May 2023
Cited by 3 | Viewed by 2757
Abstract
Background: Persistent impairments of quality of life—in particular, cancer-associated fatigue—are a major limitation for breast cancer survivors. As physical activity and mindfulness interventions have been shown to be effective in reducing fatigue symptoms, we investigated the efficacy of a six-week Argentine tango program. [...] Read more.
Background: Persistent impairments of quality of life—in particular, cancer-associated fatigue—are a major limitation for breast cancer survivors. As physical activity and mindfulness interventions have been shown to be effective in reducing fatigue symptoms, we investigated the efficacy of a six-week Argentine tango program. Methods: A randomized controlled trial was conducted with 60 breast cancer survivors diagnosed with stage I-III tumors 12–48 months prior to study enrollment and who had increased symptoms of fatigue. The participants were randomly assigned with a 1:1 allocation to either the tango or the waiting group. The treatment consisted of six weeks of supervised weekly one-hour tango group-sessions. Self-reported fatigue and further quality of life parameters were assessed at baseline and six weeks post-baseline. Longitudinal changes, correlations, Cohen’s D (d) effect sizes, and association factors were also calculated. Results: Superiority of the tango intervention over the waiting list control was found in terms of improvement in fatigue (d = −0.64; 95%CI, −1.2 to −0.08; p = 0.03), especially cognitive fatigue. In addition, a superiority of the tango intervention over the waiting list was found in the improvement of diarrhea (d = −0.69; 95%CI, −1.25 to −0.13; p = 0.02). A pooled pre-post analysis of the 50 participants completing the six-week tango program revealed a close to 10% improvement of fatigue (p = 0.0003), insomnia (p = 0.008) and further quality of life outcomes. Adjusted multivariate linear regression analyses revealed the greatest improvements for participants who were more active in sports. In particular, survivors who received endocrine therapies, were obese, or had no prior dance experience seemed to especially benefit from the tango program. Conclusions: This randomized controlled trial demonstrated that a six-week Argentine tango program improves fatigue in breast cancer survivors. Further trials are warranted to determine whether such improvements lead to better long-term clinical outcomes. Trial registration: trial registration number DRKS00021601. Retrospectively registered on 21 August 2020. Full article
(This article belongs to the Special Issue Breast Cancer Survivors and Supportive Therapies)
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26 pages, 2938 KiB  
Review
PDAC, the Influencer Cancer: Cross-Talk with Tumor Microenvironment and Connected Potential Therapy Strategies
by Leonardo Mercanti, Maria Sindaco, Mariangela Mazzone, Maria Carmela Di Marcantonio, Mariagrazia Piscione, Raffaella Muraro and Gabriella Mincione
Cancers 2023, 15(11), 2923; https://doi.org/10.3390/cancers15112923 - 26 May 2023
Cited by 6 | Viewed by 2867
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is among the leading causes of death by cancer in the world. What makes this pathological condition particularly lethal is a combination of clinical and molecular heterogeneity, lack of early diagnostic indexes, and underwhelming results from current therapeutic protocols. [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is among the leading causes of death by cancer in the world. What makes this pathological condition particularly lethal is a combination of clinical and molecular heterogeneity, lack of early diagnostic indexes, and underwhelming results from current therapeutic protocols. A major cause of PDAC chemoresistance seems to lie in the ability of cancer cells to spread out and fill the pancreatic parenchyma, exchanging nutrients, substrates, and even genetic material with cells from the surrounding tumor microenvironment (TME). Several components can be found in the TME ultrastructure, including collagen fibers, cancer-associated fibroblasts, macrophages, neutrophils, mast cells, and lymphocytes. Cross-talk between PDAC and TME cells results in the latter being converted into cancer-favoring phenotypes; this behavior could be compared to an influencer guiding followers into supporting his activity. Moreover, TME could be a potential target for some of the newest therapeutic strategies; these include the use of pegvorhyaluronidase-α and CAR-T lymphocytes against HER2, FAP, CEA, MLSN, PSCA, and CD133. Other experimental therapy options are being currently studied, aiming to interfere with the KRAS pathway, DNA-repairing proteins, and apoptosis resistance in PDAC cells. Hopefully these new approaches will grant better clinical outcomes in future patients. Full article
(This article belongs to the Collection Recent Advances in Pancreatic Ductal Adenocarcinoma)
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22 pages, 1193 KiB  
Review
Hope and Hype around Immunotherapy in Triple-Negative Breast Cancer
by Flavia Jacobs, Elisa Agostinetto, Chiara Miggiano, Rita De Sanctis, Alberto Zambelli and Armando Santoro
Cancers 2023, 15(11), 2933; https://doi.org/10.3390/cancers15112933 - 26 May 2023
Cited by 4 | Viewed by 2358
Abstract
Triple-negative breast cancer (TNBC) holds a poor prognosis compared to other breast cancer subtypes, and the development of new effective treatment strategies is an unmet medical need. TNBC has traditionally been considered not amenable to treatment with targeted agents due to a lack [...] Read more.
Triple-negative breast cancer (TNBC) holds a poor prognosis compared to other breast cancer subtypes, and the development of new effective treatment strategies is an unmet medical need. TNBC has traditionally been considered not amenable to treatment with targeted agents due to a lack of actionable targets. Therefore, chemotherapy has remained the mainstay of systemic treatment for many decades. The advent of immunotherapy raised very hopeful expectations in TNBC, possibly due to higher levels of tumor-infiltrating lymphocytes, PD-L1 expression and tumor mutational burden compared to other breast cancer subtypes, that predict an effective anti-tumor immune-engagement. The results of clinical trials testing immunotherapy in TNBC led to the approval of the combination of immune checkpoint inhibitors and chemotherapy in both early and advanced settings. However, some open questions about the use of immunotherapy in TNBC still exist. These include a deeper understanding of the heterogeneity of the disease, identification of reliable predictive biomarkers of response, determination of the most appropriate chemotherapy backbone and appropriate management of potential long-term immune-related adverse events. In this review we aim to examine the available evidence on the use of immunotherapy strategies in both early and advanced TNBC, to critically discuss some of the limitations encountered in clinical research and to summarize data on novel promising immunotherapeutic strategies beyond PD-(L)1 blockade that have been investigated in the most recent trials. Full article
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25 pages, 2621 KiB  
Review
Emerging Targeted Therapies in Advanced Non-Small-Cell Lung Cancer
by Shenduo Li, Guilherme Sacchi de Camargo Correia, Jing Wang, Rami Manochakian, Yujie Zhao and Yanyan Lou
Cancers 2023, 15(11), 2899; https://doi.org/10.3390/cancers15112899 - 24 May 2023
Cited by 6 | Viewed by 2966
Abstract
Lung cancer remains the leading cause of cancer-related mortality worldwide. Non-small-cell lung cancer (NSCLC) is the most common type and is still incurable for most patients at the advanced stage. Targeted therapy is an effective treatment that has significantly improved survival in NSCLC [...] Read more.
Lung cancer remains the leading cause of cancer-related mortality worldwide. Non-small-cell lung cancer (NSCLC) is the most common type and is still incurable for most patients at the advanced stage. Targeted therapy is an effective treatment that has significantly improved survival in NSCLC patients with actionable mutations. However, therapy resistance occurs widely among patients leading to disease progression. In addition, many oncogenic driver mutations in NSCLC still lack targeted agents. New drugs are being developed and tested in clinical trials to overcome these challenges. This review aims to summarize emerging targeted therapy that have been conducted or initiated through first-in-human clinical trials in the past year. Full article
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21 pages, 7124 KiB  
Review
Novel Targets, Novel Treatments: The Changing Landscape of Non-Small Cell Lung Cancer
by Dorine de Jong, Jeeban P. Das, Hong Ma, Jacienta Pailey Valiplackal, Conor Prendergast, Tina Roa, Brian Braumuller, Aileen Deng, Laurent Dercle, Randy Yeh, Mary M. Salvatore and Kathleen M. Capaccione
Cancers 2023, 15(10), 2855; https://doi.org/10.3390/cancers15102855 - 21 May 2023
Cited by 5 | Viewed by 2992
Abstract
Treatment of non-small cell lung cancer (NSCLC) has undergone a paradigm shift. Once a disease with limited potential therapies, treatment options for patients have exploded with the availability of molecular testing to direct management and targeted therapies to treat tumors with specific driver [...] Read more.
Treatment of non-small cell lung cancer (NSCLC) has undergone a paradigm shift. Once a disease with limited potential therapies, treatment options for patients have exploded with the availability of molecular testing to direct management and targeted therapies to treat tumors with specific driver mutations. New in vitro diagnostics allow for the early and non-invasive detection of disease, and emerging in vivo imaging techniques allow for better detection and monitoring. The development of checkpoint inhibitor immunotherapy has arguably been the biggest advance in lung cancer treatment, given that the vast majority of NSCLC tumors can be treated with these therapies. Specific targeted therapies, including those against KRAS, EGFR, RTK, and others have also improved the outcomes for those individuals bearing an actionable mutation. New and emerging therapies, such as bispecific antibodies, CAR T cell therapy, and molecular targeted radiotherapy, offer promise to patients for whom none of the existing therapies have proved effective. In this review, we provide the most up-to-date survey to our knowledge regarding emerging diagnostic and therapeutic strategies for lung cancer to provide clinicians with a comprehensive reference of the options for treatment available now and those which are soon to come. Full article
(This article belongs to the Special Issue Lung Cancer - Molecular Insights and Targeted Therapies)
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32 pages, 907 KiB  
Review
Beyond CTLA-4 and PD-1 Inhibition: Novel Immune Checkpoint Molecules for Melanoma Treatment
by Dimitrios C. Ziogas, Charalampos Theocharopoulos, Panagiotis-Petros Lialios, Dimitra Foteinou, Ioannis-Alexios Koumprentziotis, Georgios Xynos and Helen Gogas
Cancers 2023, 15(10), 2718; https://doi.org/10.3390/cancers15102718 - 11 May 2023
Cited by 9 | Viewed by 4960
Abstract
More than ten years after the approval of ipilimumab, immune checkpoint inhibitors (ICIs) against PD-1 and CTLA-4 have been established as the most effective treatment for locally advanced or metastatic melanoma, achieving durable responses either as monotherapies or in combinatorial regimens. However, a [...] Read more.
More than ten years after the approval of ipilimumab, immune checkpoint inhibitors (ICIs) against PD-1 and CTLA-4 have been established as the most effective treatment for locally advanced or metastatic melanoma, achieving durable responses either as monotherapies or in combinatorial regimens. However, a considerable proportion of patients do not respond or experience early relapse, due to multiple parameters that contribute to melanoma resistance. The expression of other immune checkpoints beyond the PD-1 and CTLA-4 molecules remains a major mechanism of immune evasion. The recent approval of anti-LAG-3 ICI, relatlimab, in combination with nivolumab for metastatic disease, has capitalized on the extensive research in the field and has highlighted the potential for further improvement of melanoma prognosis by synergistically blocking additional immune targets with new ICI-doublets, antibody–drug conjugates, or other novel modalities. Herein, we provide a comprehensive overview of presently published immune checkpoint molecules, including LAG-3, TIGIT, TIM-3, VISTA, IDO1/IDO2/TDO, CD27/CD70, CD39/73, HVEM/BTLA/CD160 and B7-H3. Beginning from their immunomodulatory properties as co-inhibitory or co-stimulatory receptors, we present all therapeutic modalities targeting these molecules that have been tested in melanoma treatment either in preclinical or clinical settings. Better understanding of the checkpoint-mediated crosstalk between melanoma and immune effector cells is essential for generating more effective strategies with augmented immune response. Full article
(This article belongs to the Special Issue Immunotherapy in Melanoma: Recent Advances and Future Directions)
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27 pages, 4387 KiB  
Article
Development and Validation of Blood-Based Predictive Biomarkers for Response to PD-1/PD-L1 Checkpoint Inhibitors: Evidence of a Universal Systemic Core of 3D Immunogenetic Profiling across Multiple Oncological Indications
by Ewan Hunter, Matthew Salter, Ryan Powell, Ann Dring, Tarun Naithani, Maria Eleni Chatziioannou, Abel Gebregzabhar, Mutaz Issa, Jayne Green, Serene Ng, Chun Ren Lim, Cheah Soon Keat, Ang Tick Suan, Rakesh Raman, Ho Kean Fatt, Fabian Lee Wei Luen, Heba Alshaker, Dmitri Pchejetski, Dave Blum, Thomas Guiel, Robert Heaton, Jr., Jedd Levine and Alexandre Akoulitchevadd Show full author list remove Hide full author list
Cancers 2023, 15(10), 2696; https://doi.org/10.3390/cancers15102696 - 10 May 2023
Cited by 3 | Viewed by 3431
Abstract
Background: Unprecedented advantages in cancer treatment with immune checkpoint inhibitors (ICIs) remain limited to only a subset of patients. Systemic analyses of the regulatory 3D genome architecture linked to individual epigenetic and immunogenetic controls associated with tumour immune evasion mechanisms and immune checkpoint [...] Read more.
Background: Unprecedented advantages in cancer treatment with immune checkpoint inhibitors (ICIs) remain limited to only a subset of patients. Systemic analyses of the regulatory 3D genome architecture linked to individual epigenetic and immunogenetic controls associated with tumour immune evasion mechanisms and immune checkpoint pathways reveal a highly prevalent molecular profile predictive of response to PD-1/PD-L1 ICIs. A clinical blood test based on a set of eight (8) 3D genomic biomarkers has been developed and validated on the basis of an observational trial to predict response to ICI therapy. Methods: The predictive eight biomarker set is derived from prospective observational clinical trials, representing 280 treatments with Pembrolizumab, Atezolizumab, Durvalumab, Nivolumab, and Avelumab in a broad range of indications: melanoma, lung, hepatocellular, renal, breast, bladder, colon, head and neck, bone, brain, lymphoma, prostate, vulvar, and cervical cancers. Results: The 3D genomic eight biomarker panel for response to immune checkpoint therapy achieved a high accuracy of 85%, sensitivity of 93%, and specificity of 82%. Conclusions: This study demonstrates that a 3D genomic approach can be used to develop a predictive clinical assay for response to PD-1/PD-L1 checkpoint inhibition in cancer patients. Full article
(This article belongs to the Topic Biomarker Development and Application)
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12 pages, 1034 KiB  
Review
HER2 Intratumoral Heterogeneity in Breast Cancer, an Evolving Concept
by Yanjun Hou, Hiroaki Nitta and Zaibo Li
Cancers 2023, 15(10), 2664; https://doi.org/10.3390/cancers15102664 - 09 May 2023
Cited by 9 | Viewed by 2681
Abstract
Amplification and/or overexpression of human epidermal growth factor receptor 2 (HER2) in breast cancer is associated with an adverse prognosis. The introduction of anti-HER2 targeted therapy has dramatically improved the clinical outcomes of patients with HER2-positive breast cancer. Unfortunately, a significant number of [...] Read more.
Amplification and/or overexpression of human epidermal growth factor receptor 2 (HER2) in breast cancer is associated with an adverse prognosis. The introduction of anti-HER2 targeted therapy has dramatically improved the clinical outcomes of patients with HER2-positive breast cancer. Unfortunately, a significant number of patients eventually relapse and develop distant metastasis. HER2 intratumoral heterogeneity (ITH) has been reported to be associated with poor prognosis in patients with anti-HER2 targeted therapies and was proposed to be a potential mechanism for anti-HER2 resistance. In this review, we described the current definition, common types of HER2 ITH in breast cancer, the challenge in interpretation of HER2 status in cases showing ITH and the clinical applications of anti-HER2 agents in breast cancer showing heterogeneous HER2 expression. Digital image analysis has emerged as an objective and reproducible scoring method and its role in the assessment of HER2 status with ITH remains to be demonstrated. Full article
(This article belongs to the Special Issue Biomarkers in Breast Cancer: Recent Advances and Challenges)
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12 pages, 272 KiB  
Review
The Role of HER2 Status in the Biliary Tract Cancers
by Ruveyda Ayasun, Muhammet Ozer and Ilyas Sahin
Cancers 2023, 15(9), 2628; https://doi.org/10.3390/cancers15092628 - 05 May 2023
Cited by 5 | Viewed by 2647
Abstract
Despite recent advances, biliary tract cancer (BTC) is traditionally known as being hard to treat with a poor prognosis. Recent state-of-the-art genomic technologies such as next-generation sequencing (NGS) revolutionized cancer management and shed light on the genomic landscape of BTCs. There are ongoing [...] Read more.
Despite recent advances, biliary tract cancer (BTC) is traditionally known as being hard to treat with a poor prognosis. Recent state-of-the-art genomic technologies such as next-generation sequencing (NGS) revolutionized cancer management and shed light on the genomic landscape of BTCs. There are ongoing clinical trials to assess the efficacy of HER2-blocking antibodies or drug conjugates in BTCs with HER2 amplifications. However, HER2 amplifications may not be the sole eligibility factor for these clinical trials. In this review, we aimed to comprehensively examine the role of somatic HER2 alterations and amplifications in patient stratification and provide an overview of the current state of ongoing clinical trials. Full article
(This article belongs to the Special Issue Recent Advances in Hepatobiliary Cancers: From Diagnosis to Treatment)
48 pages, 7853 KiB  
Review
Regulation of Autophagy via Carbohydrate and Lipid Metabolism in Cancer
by Javad Alizadeh, Mahboubeh Kavoosi, Navjit Singh, Shahrokh Lorzadeh, Amir Ravandi, Biniam Kidane, Naseer Ahmed, Fatima Mraiche, Michael R. Mowat and Saeid Ghavami
Cancers 2023, 15(8), 2195; https://doi.org/10.3390/cancers15082195 - 07 Apr 2023
Cited by 11 | Viewed by 3373
Abstract
Metabolic changes are an important component of tumor cell progression. Tumor cells adapt to environmental stresses via changes to carbohydrate and lipid metabolism. Autophagy, a physiological process in mammalian cells that digests damaged organelles and misfolded proteins via lysosomal degradation, is closely associated [...] Read more.
Metabolic changes are an important component of tumor cell progression. Tumor cells adapt to environmental stresses via changes to carbohydrate and lipid metabolism. Autophagy, a physiological process in mammalian cells that digests damaged organelles and misfolded proteins via lysosomal degradation, is closely associated with metabolism in mammalian cells, acting as a meter of cellular ATP levels. In this review, we discuss the changes in glycolytic and lipid biosynthetic pathways in mammalian cells and their impact on carcinogenesis via the autophagy pathway. In addition, we discuss the impact of these metabolic pathways on autophagy in lung cancer. Full article
(This article belongs to the Special Issue Autophagy–EMT Interrelations: At the Core of Tumor Transformation)
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20 pages, 1020 KiB  
Review
Detection and Molecular Characterization of Circulating Tumour Cells: Challenges for the Clinical Setting
by Areti Strati, Athina Markou, Evgenia Kyriakopoulou and Evi Lianidou
Cancers 2023, 15(7), 2185; https://doi.org/10.3390/cancers15072185 - 06 Apr 2023
Cited by 7 | Viewed by 2678
Abstract
Over the last decade, liquid biopsy has gained much attention as a powerful tool in personalized medicine since it enables monitoring cancer evolution and follow-up of cancer patients in real time. Through minimally invasive procedures, liquid biopsy provides important information through the analysis [...] Read more.
Over the last decade, liquid biopsy has gained much attention as a powerful tool in personalized medicine since it enables monitoring cancer evolution and follow-up of cancer patients in real time. Through minimally invasive procedures, liquid biopsy provides important information through the analysis of circulating tumour cells (CTCs) and circulating tumour-derived material, such as circulating tumour DNA (ctDNA), circulating miRNAs (cfmiRNAs) and extracellular vehicles (EVs). CTC analysis has already had an important impact on the prognosis, detection of minimal residual disease (MRD), treatment selection and monitoring of cancer patients. Numerous clinical trials nowadays include a liquid biopsy arm. CTC analysis is now an exponentially expanding field in almost all types of solid cancers. Functional studies, mainly based on CTC-derived cell-lines and CTC-derived explants (CDx), provide important insights into the metastatic process. The purpose of this review is to summarize the latest findings on the clinical significance of CTCs for the management of cancer patients, covering the last four years. This review focuses on providing a comprehensive overview of CTC analysis in breast, prostate and non-small-cell lung cancer. The unique potential of CTC single-cell analysis for understanding metastasis biology, and the importance of quality control and standardization of methodologies used in this field, is also discussed. Full article
(This article belongs to the Special Issue The 5th ACTC: “Liquid Biopsy in Its Best”)
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25 pages, 1410 KiB  
Review
The Cell Biology of Metastatic Invasion in Pancreatic Cancer: Updates and Mechanistic Insights
by Vidhu B. Joshi, Omar L. Gutierrez Ruiz and Gina L. Razidlo
Cancers 2023, 15(7), 2169; https://doi.org/10.3390/cancers15072169 - 06 Apr 2023
Cited by 4 | Viewed by 2867
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related mortality worldwide. This is largely due to the lack of routine screening protocols, an absence of symptoms in early-stage disease leading to late detection, and a paucity of effective treatment options. [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related mortality worldwide. This is largely due to the lack of routine screening protocols, an absence of symptoms in early-stage disease leading to late detection, and a paucity of effective treatment options. Critically, the majority of patients either present with metastatic disease or rapidly develop metastatic disease. Thus, there is an urgent need to deepen our understanding of metastasis in PDAC. During metastasis, tumor cells escape from the primary tumor, enter the circulation, and travel to a distant site to form a secondary tumor. In order to accomplish this relatively rare event, tumor cells develop an enhanced ability to detach from the primary tumor, migrate into the surrounding matrix, and invade across the basement membrane. In addition, cancer cells interact with the various cell types and matrix proteins that comprise the tumor microenvironment, with some of these factors working to promote metastasis and others working to suppress it. In PDAC, many of these processes are not well understood. The purpose of this review is to highlight recent advances in the cell biology of the early steps of the metastatic cascade in pancreatic cancer. Specifically, we will examine the regulation of epithelial-to-mesenchymal transition (EMT) in PDAC and its requirement for metastasis, summarize our understanding of how PDAC cells invade and degrade the surrounding matrix, and discuss how migration and adhesion dynamics are regulated in PDAC to optimize cancer cell motility. In addition, the role of the tumor microenvironment in PDAC will also be discussed for each of these invasive processes. Full article
(This article belongs to the Collection Recent Advances in Pancreatic Ductal Adenocarcinoma)
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58 pages, 2391 KiB  
Review
DNA-Based Nanomaterials as Drug Delivery Platforms for Increasing the Effect of Drugs in Tumors
by Anastasiya N. Shishparenok, Vitalina V. Furman and Dmitry D. Zhdanov
Cancers 2023, 15(7), 2151; https://doi.org/10.3390/cancers15072151 - 05 Apr 2023
Cited by 4 | Viewed by 3219
Abstract
DNA nanotechnology has significantly advanced and might be used in biomedical applications, drug delivery, and cancer treatment during the past few decades. DNA nanomaterials are widely used in biomedical research involving biosensing, bioimaging, and drug delivery since they are remarkably addressable and biocompatible. [...] Read more.
DNA nanotechnology has significantly advanced and might be used in biomedical applications, drug delivery, and cancer treatment during the past few decades. DNA nanomaterials are widely used in biomedical research involving biosensing, bioimaging, and drug delivery since they are remarkably addressable and biocompatible. Gradually, modified nucleic acids have begun to be employed to construct multifunctional DNA nanostructures with a variety of architectural designs. Aptamers are single-stranded nucleic acids (both DNAs and RNAs) capable of self-pairing to acquire secondary structure and of specifically binding with the target. Diagnosis and tumor therapy are prospective fields in which aptamers can be applied. Many DNA nanomaterials with three-dimensional structures have been studied as drug delivery systems for different anticancer medications or gene therapy agents. Different chemical alterations can be employed to construct a wide range of modified DNA nanostructures. Chemically altered DNA-based nanomaterials are useful for drug delivery because of their improved stability and inclusion of functional groups. In this work, the most common oligonucleotide nanomaterials were reviewed as modern drug delivery systems in tumor cells. Full article
(This article belongs to the Special Issue Nanoplatforms Based Cancers Therapy 2.0)
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37 pages, 1753 KiB  
Review
Mechanisms of Resistance and Current Treatment Options for Glioblastoma Multiforme (GBM)
by Satya Siva Kishan Yalamarty, Nina Filipczak, Xiang Li, Md Abdus Subhan, Farzana Parveen, Janaína Artem Ataide, Bharat Ashok Rajmalani and Vladimir P. Torchilin
Cancers 2023, 15(7), 2116; https://doi.org/10.3390/cancers15072116 - 01 Apr 2023
Cited by 16 | Viewed by 6115
Abstract
Glioblastoma multiforme (GBM) is a highly aggressive form of brain cancer that is difficult to treat due to its resistance to both radiation and chemotherapy. This resistance is largely due to the unique biology of GBM cells, which can evade the effects of [...] Read more.
Glioblastoma multiforme (GBM) is a highly aggressive form of brain cancer that is difficult to treat due to its resistance to both radiation and chemotherapy. This resistance is largely due to the unique biology of GBM cells, which can evade the effects of conventional treatments through mechanisms such as increased resistance to cell death and rapid regeneration of cancerous cells. Additionally, the blood–brain barrier makes it difficult for chemotherapy drugs to reach GBM cells, leading to reduced effectiveness. Despite these challenges, there are several treatment options available for GBM. The standard of care for newly diagnosed GBM patients involves surgical resection followed by concurrent chemoradiotherapy and adjuvant chemotherapy. Emerging treatments include immunotherapy, such as checkpoint inhibitors, and targeted therapies, such as bevacizumab, that attempt to attack specific vulnerabilities in GBM cells. Another promising approach is the use of tumor-treating fields, a type of electric field therapy that has been shown to slow the growth of GBM cells. Clinical trials are ongoing to evaluate the safety and efficacy of these and other innovative treatments for GBM, intending to improve with outcomes for patients. Full article
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14 pages, 3978 KiB  
Article
Pediatric Patients with Stage IV Rhabdomyosarcoma Significantly Benefit from Long-Term Maintenance Therapy: Results of the CWS-IV 2002 and the CWS DOK IV 2004-Trials
by Lars Tramsen, Konrad Bochennek, Monika Sparber-Sauer, Emilia Salzmann-Manrique, Monika Scheer, Tobias Dantonello, Arndt Borkhardt, Uta Dirksen, Anne Thorwarth, Jeanette Greiner, Martin Ebinger, Jadwiga Weclawek-Tompol, Ruth Ladenstein, Gustaf Ljungman, Erika Hallmen, Thomas Lehrnbecher, Ewa Koscielniak and Thomas Klingebiel
Cancers 2023, 15(7), 2050; https://doi.org/10.3390/cancers15072050 - 30 Mar 2023
Cited by 4 | Viewed by 1985
Abstract
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma (STS) in childhood. Whereas more than 90% of patients with localized low-risk RMS can be cured, metastatic RMS have a dismal outcome, with survival rates of less than 30%. The HD CWS-96 trial showed [...] Read more.
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma (STS) in childhood. Whereas more than 90% of patients with localized low-risk RMS can be cured, metastatic RMS have a dismal outcome, with survival rates of less than 30%. The HD CWS-96 trial showed an improved outcome for patients receiving maintenance therapy after completing intensive chemotherapy. Consequently, the international clinical trials CWS-IV 2002 and CWS DOK IV 2004 on metastatic disease of STS of the Cooperative Weichteilsarkom Studiengruppe (CWS) were designed in addition to the CWS-2002P trial for localized RMS disease. All patients received a multimodal intensive treatment regimen. To maintain remission, three options were compared: long-term maintenance therapy (LTMT) versus allogeneic hematopoietic stem cell transplantation (alloHSCT) versus high-dose chemotherapy (HDCT). A total of 176 pediatric patients with a histologically confirmed diagnosis of metastatic RMS or RMS-like tumor were included. A total of 89 patients receiving LTML showed a significantly better outcome, with an event-free survival (EFS) of 41% and an overall survival (OS) of 53%, than alloHSCT (n = 21, EFS 19%, p = 0.02, OS 24%, p = 0.002). The outcome of LTML was slightly improved compared to HDCT (n = 13, EFS 35%, OS 34%). In conclusion, our data suggest that in patients suffering from metastatic RMS, long-term maintenance therapy is a superior strategy in terms of EFS and OS compared to alloHSCT. EFS and OS of HDCT are similar in these strategies; however, the therapeutic burden of LTMT is much lower. Full article
(This article belongs to the Special Issue Rhabdomyosarcoma: Still Unresolved Questions but New Perspectives)
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30 pages, 1692 KiB  
Review
The Glioma Immune Landscape: A Double-Edged Sword for Treatment Regimens
by Sukrit Mahajan, Mirko H. H. Schmidt and Ulrike Schumann
Cancers 2023, 15(7), 2024; https://doi.org/10.3390/cancers15072024 - 28 Mar 2023
Cited by 8 | Viewed by 2464
Abstract
Immune cells constitute a major part of the tumor microenvironment, thereby playing an important role in regulating tumor development. They interact with tumor cells, resulting in the suppression or promotion of glioma development. Therefore, in recent years, scientists have focused on immunotherapy that [...] Read more.
Immune cells constitute a major part of the tumor microenvironment, thereby playing an important role in regulating tumor development. They interact with tumor cells, resulting in the suppression or promotion of glioma development. Therefore, in recent years, scientists have focused on immunotherapy that involves enhancing the immune response to fight the battle against cancer more effectively. While it has shown success against different cancer types, immunotherapy faces major roadblocks in glioma treatment. These involve the blood brain barrier, tumor heterogeneity and an immunosuppressive glioma microenvironment, among other factors. Additionally, the interaction of the peripheral immune system with the central nervous system provides another challenge for immunotherapeutic regimens. For modulating different immune cell populations to counter glioma cells, it is important to expand our knowledge about their role within the glioma microenvironment; therefore, herein, we review the different immune cell populations found in the glioma microenvironment and navigate through the various shortcomings of current immunotherapies for glioma. We conclude by providing an insight into ongoing pre-clinical and clinical trials for glioma therapies. Full article
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20 pages, 576 KiB  
Article
Mathematical Model of Clonal Evolution Proposes a Personalised Multi-Modal Therapy for High-Risk Neuroblastoma
by Matteo Italia, Kenneth Y. Wertheim, Sabine Taschner-Mandl, Dawn Walker and Fabio Dercole
Cancers 2023, 15(7), 1986; https://doi.org/10.3390/cancers15071986 - 26 Mar 2023
Cited by 4 | Viewed by 2324
Abstract
Neuroblastoma is the most common extra-cranial solid tumour in children. Despite multi-modal therapy, over half of the high-risk patients will succumb. One contributing factor is the one-size-fits-all nature of multi-modal therapy. For example, during the first step (induction chemotherapy), the standard regimen (rapid [...] Read more.
Neuroblastoma is the most common extra-cranial solid tumour in children. Despite multi-modal therapy, over half of the high-risk patients will succumb. One contributing factor is the one-size-fits-all nature of multi-modal therapy. For example, during the first step (induction chemotherapy), the standard regimen (rapid COJEC) administers fixed doses of chemotherapeutic agents in eight two-week cycles. Perhaps because of differences in resistance, this standard regimen results in highly heterogeneous outcomes in different tumours. In this study, we formulated a mathematical model comprising ordinary differential equations. The equations describe the clonal evolution within a neuroblastoma tumour being treated with vincristine and cyclophosphamide, which are used in the rapid COJEC regimen, including genetically conferred and phenotypic drug resistance. The equations also describe the agents’ pharmacokinetics. We devised an optimisation algorithm to find the best chemotherapy schedules for tumours with different pre-treatment clonal compositions. The optimised chemotherapy schedules exploit the cytotoxic difference between the two drugs and intra-tumoural clonal competition to shrink the tumours as much as possible during induction chemotherapy and before surgical removal. They indicate that induction chemotherapy can be improved by finding and using personalised schedules. More broadly, we propose that the overall multi-modal therapy can be enhanced by employing targeted therapies against the mutations and oncogenic pathways enriched and activated by the chemotherapeutic agents. To translate the proposed personalised multi-modal therapy into clinical use, patient-specific model calibration and treatment optimisation are necessary. This entails a decision support system informed by emerging medical technologies such as multi-region sequencing and liquid biopsies. The results and tools presented in this paper could be the foundation of this decision support system. Full article
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15 pages, 2281 KiB  
Article
Immune Checkpoint and EMT-Related Molecules in Circulating Tumor Cells (CTCs) from Triple Negative Breast Cancer Patients and Their Clinical Impact
by Vasileios Vardas, Anastasios Tolios, Athina Christopoulou, Vassilis Georgoulias, Anastasia Xagara, Filippos Koinis, Athanasios Kotsakis and Galatea Kallergi
Cancers 2023, 15(7), 1974; https://doi.org/10.3390/cancers15071974 - 25 Mar 2023
Cited by 4 | Viewed by 1456
Abstract
Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype. There are few targeted therapies for these patients, leading to an unmet need for new biomarkers. The present study aimed to investigate the expression of PD-L1, CTLA-4, GLU, and VIM in [...] Read more.
Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype. There are few targeted therapies for these patients, leading to an unmet need for new biomarkers. The present study aimed to investigate the expression of PD-L1, CTLA-4, GLU, and VIM in CTCs of TNBC patients. Ninety-five patients were enrolled in this study: sixty-four TNBC and thirty-one luminal. Of these patients, 60 were in the early stage, while 35 had metastatic disease. Protein expression was identified by immunofluorescence staining experiments and VyCAP analysis. All the examined proteins were upregulated in TNBC patients. The expression of the GLU+VIM+CK+ phenotype was higher (50%) in metastatic TNBC compared to early TNBC patients (17%) (p = 0.005). Among all the BC patients, a significant correlation was found between PD-L1+CD45CK+ and CTLA-4+CD45CK+ phenotypes (Spearman test, p = 0.024), implying an important role of dual inhibition in BC. Finally, the phenotypes GLU+VIM+CK+ and PD-L1+CD45CK+ were associated with shorter OS in TNBC patients (OS: log-rank p = 0.048, HR = 2.9, OS: log-rank p < 0.001, HR = 8.7, respectively). Thus, PD-L1, CTLA-4, GLU, and VIM constitute significant biomarkers in TNBC associated with patients’ outcome, providing new therapeutic targets for this difficult breast cancer subtype. Full article
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21 pages, 5153 KiB  
Article
From Head and Neck Tumour and Lymph Node Segmentation to Survival Prediction on PET/CT: An End-to-End Framework Featuring Uncertainty, Fairness, and Multi-Region Multi-Modal Radiomics
by Zohaib Salahuddin, Yi Chen, Xian Zhong, Henry C. Woodruff, Nastaran Mohammadian Rad, Shruti Atul Mali and Philippe Lambin
Cancers 2023, 15(7), 1932; https://doi.org/10.3390/cancers15071932 - 23 Mar 2023
Cited by 4 | Viewed by 2365
Abstract
Automatic delineation and detection of the primary tumour (GTVp) and lymph nodes (GTVn) using PET and CT in head and neck cancer and recurrence-free survival prediction can be useful for diagnosis and patient risk stratification. We used data from nine different centres, with [...] Read more.
Automatic delineation and detection of the primary tumour (GTVp) and lymph nodes (GTVn) using PET and CT in head and neck cancer and recurrence-free survival prediction can be useful for diagnosis and patient risk stratification. We used data from nine different centres, with 524 and 359 cases used for training and testing, respectively. We utilised posterior sampling of the weight space in the proposed segmentation model to estimate the uncertainty for false positive reduction. We explored the prognostic potential of radiomics features extracted from the predicted GTVp and GTVn in PET and CT for recurrence-free survival prediction and used SHAP analysis for explainability. We evaluated the bias of models with respect to age, gender, chemotherapy, HPV status, and lesion size. We achieved an aggregate Dice score of 0.774 and 0.760 on the test set for GTVp and GTVn, respectively. We observed a per image false positive reduction of 19.5% and 7.14% using the uncertainty threshold for GTVp and GTVn, respectively. Radiomics features extracted from GTVn in PET and from both GTVp and GTVn in CT are the most prognostic, and our model achieves a C-index of 0.672 on the test set. Our framework incorporates uncertainty estimation, fairness, and explainability, demonstrating the potential for accurate detection and risk stratification. Full article
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14 pages, 1976 KiB  
Article
Exact Probability Distribution for the ROC Area under Curve
by Joakim Ekström, Jim Åkerrén Ögren and Tobias Sjöblom
Cancers 2023, 15(6), 1788; https://doi.org/10.3390/cancers15061788 - 15 Mar 2023
Cited by 4 | Viewed by 1385
Abstract
The Receiver Operating Characteristic (ROC) is a de facto standard for determining the accuracy of in vitro diagnostic (IVD) medical devices, and thus the exactness in its probability distribution is crucial toward accurate statistical inference. We show the exact probability distribution of the [...] Read more.
The Receiver Operating Characteristic (ROC) is a de facto standard for determining the accuracy of in vitro diagnostic (IVD) medical devices, and thus the exactness in its probability distribution is crucial toward accurate statistical inference. We show the exact probability distribution of the ROC AUC-value, hence exact critical values and p-values are readily obtained. Because the exact calculations are computationally intense, we demonstrate a method of geometric interpolation, which is exact in a special case but generally an approximation, vastly increasing computational speeds. The method is illustrated through open access data, demonstrating superiority of 26 composite biomarkers relative to a predicate device. Especially under correction for testing of multiple hypotheses, traditional asymptotic approximations are encumbered by considerable imprecision, adversely affecting IVD device development. The ability to obtain exact p-values will allow more efficient IVD device development. Full article
(This article belongs to the Section Cancer Informatics and Big Data)
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85 pages, 4243 KiB  
Review
The Role of Different Immunocompetent Cell Populations in the Pathogenesis of Head and Neck Cancer—Regulatory Mechanisms of Pro- and Anti-Cancer Activity and Their Impact on Immunotherapy
by Katarzyna Starska-Kowarska
Cancers 2023, 15(6), 1642; https://doi.org/10.3390/cancers15061642 - 07 Mar 2023
Cited by 3 | Viewed by 6315
Abstract
Head and neck squamous cell carcinoma (HNSCC) is one of the most aggressive and heterogeneous groups of human neoplasms. HNSCC is characterized by high morbidity, accounting for 3% of all cancers, and high mortality with ~1.5% of all cancer deaths. It was the [...] Read more.
Head and neck squamous cell carcinoma (HNSCC) is one of the most aggressive and heterogeneous groups of human neoplasms. HNSCC is characterized by high morbidity, accounting for 3% of all cancers, and high mortality with ~1.5% of all cancer deaths. It was the most common cancer worldwide in 2020, according to the latest GLOBOCAN data, representing the seventh most prevalent human malignancy. Despite great advances in surgical techniques and the application of modern combinations and cytotoxic therapies, HNSCC remains a leading cause of death worldwide with a low overall survival rate not exceeding 40–60% of the patient population. The most common causes of death in patients are its frequent nodal metastases and local neoplastic recurrences, as well as the relatively low response to treatment and severe drug resistance. Much evidence suggests that the tumour microenvironment (TME), tumour infiltrating lymphocytes (TILs) and circulating various subpopulations of immunocompetent cells, such regulatory T cells (CD4+CD25+Foxp3+Tregs), cytotoxic CD3+CD8+ T cells (CTLs) and CD3+CD4+ T helper type 1/2/9/17 (Th1/Th2/Th9/Th17) lymphocytes, T follicular helper cells (Tfh) and CD56dim/CD16bright activated natural killer cells (NK), carcinoma-associated fibroblasts (CAFs), myeloid-derived suppressor cells (MDSCs), tumour-associated neutrophils (N1/N2 TANs), as well as tumour-associated macrophages (M1/M2 phenotype TAMs) can affect initiation, progression and spread of HNSCC and determine the response to immunotherapy. Rapid advances in the field of immuno-oncology and the constantly growing knowledge of the immunosuppressive mechanisms and effects of tumour cancer have allowed for the use of effective and personalized immunotherapy as a first-line therapeutic procedure or an essential component of a combination therapy for primary, relapsed and metastatic HNSCC. This review presents the latest reports and molecular studies regarding the anti-tumour role of selected subpopulations of immunocompetent cells in the pathogenesis of HNSCC, including HPV+ve (HPV+) and HPV−ve (HPV) tumours. The article focuses on the crucial regulatory mechanisms of pro- and anti-tumour activity, key genetic or epigenetic changes that favour tumour immune escape, and the strategies that the tumour employs to avoid recognition by immunocompetent cells, as well as resistance mechanisms to T and NK cell-based immunotherapy in HNSCC. The present review also provides an overview of the pre- and clinical early trials (I/II phase) and phase-III clinical trials published in this arena, which highlight the unprecedented effectiveness and limitations of immunotherapy in HNSCC, and the emerging issues facing the field of HNSCC immuno-oncology. Full article
(This article belongs to the Special Issue Molecular Signatures in Head and Neck Cancer)
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18 pages, 3732 KiB  
Review
Treatment Strategies for KRAS-Mutated Non-Small-Cell Lung Cancer
by Éabha O’Sullivan, Anna Keogh, Brian Henderson, Stephen P. Finn, Steven G. Gray and Kathy Gately
Cancers 2023, 15(6), 1635; https://doi.org/10.3390/cancers15061635 - 07 Mar 2023
Cited by 10 | Viewed by 5848
Abstract
Activating mutations in KRAS are highly prevalent in solid tumours and are frequently found in 35% of lung, 45% of colorectal, and up to 90% of pancreatic cancers. Mutated KRAS is a prognostic factor for disease-free survival (DFS) and overall survival (OS) in [...] Read more.
Activating mutations in KRAS are highly prevalent in solid tumours and are frequently found in 35% of lung, 45% of colorectal, and up to 90% of pancreatic cancers. Mutated KRAS is a prognostic factor for disease-free survival (DFS) and overall survival (OS) in NSCLC and is associated with a more aggressive clinical phenotype, highlighting the need for KRAS-targeted therapy. Once considered undruggable due to its smooth shallow surface, a breakthrough showed that the activated G12C-mutated KRAS isozyme can be directly inhibited via a newly identified switch II pocket. This discovery led to the development of a new class of selective small-molecule inhibitors against the KRAS G12C isoform. Sotorasib and adagrasib are approved in locally advanced or metastatic NSCLC patients who have received at least one prior systemic therapy. Currently, there are at least twelve KRAS G12C inhibitors being tested in clinical trials, either as a single agent or in combination. In this study, KRAS mutation prevalence, subtypes, rates of occurrence in treatment-resistant invasive mucinous adenocarcinomas (IMAs), and novel drug delivery options are reviewed. Additionally, the current status of KRAS inhibitors, multiple resistance mechanisms that limit efficacy, and their use in combination treatment strategies and novel multitargeted approaches in NSCLC are discussed. Full article
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35 pages, 1829 KiB  
Review
Immunotargeting of Cancer Stem Cells
by Ayse Sedef Köseer, Simona Di Gaetano, Claudia Arndt, Michael Bachmann and Anna Dubrovska
Cancers 2023, 15(5), 1608; https://doi.org/10.3390/cancers15051608 - 05 Mar 2023
Cited by 3 | Viewed by 3200
Abstract
The generally accepted view is that CSCs hijack the signaling pathways attributed to normal stem cells that regulate the self-renewal and differentiation processes. Therefore, the development of selective targeting strategies for CSC, although clinically meaningful, is associated with significant challenges because CSC and [...] Read more.
The generally accepted view is that CSCs hijack the signaling pathways attributed to normal stem cells that regulate the self-renewal and differentiation processes. Therefore, the development of selective targeting strategies for CSC, although clinically meaningful, is associated with significant challenges because CSC and normal stem cells share many important signaling mechanisms for their maintenance and survival. Furthermore, the efficacy of this therapy is opposed by tumor heterogeneity and CSC plasticity. While there have been considerable efforts to target CSC populations by the chemical inhibition of the developmental pathways such as Notch, Hedgehog (Hh), and Wnt/β-catenin, noticeably fewer attempts were focused on the stimulation of the immune response by CSC-specific antigens, including cell-surface targets. Cancer immunotherapies are based on triggering the anti-tumor immune response by specific activation and targeted redirecting of immune cells toward tumor cells. This review is focused on CSC-directed immunotherapeutic approaches such as bispecific antibodies and antibody-drug candidates, CSC-targeted cellular immunotherapies, and immune-based vaccines. We discuss the strategies to improve the safety and efficacy of the different immunotherapeutic approaches and describe the current state of their clinical development. Full article
(This article belongs to the Special Issue Cancer Stem Cells and Targeted Therapy)
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20 pages, 4420 KiB  
Systematic Review
A Systematic Review of High-Dose Methotrexate for Adults with Primary Central Nervous System Lymphoma
by Gabriela Villanueva, Martin Guscott, Paula Schaiquevich, Claudia Sampor, Ryan Combs, Nicolás Tentoni, Miriam Hwang, Jennifer Lowe and Scott Howard
Cancers 2023, 15(5), 1459; https://doi.org/10.3390/cancers15051459 - 25 Feb 2023
Cited by 6 | Viewed by 2348
Abstract
Primary central nervous system lymphoma (PCNSL) is a highly aggressive non-Hodgkin lymphoma that is confined within the CNS. Due to its ability to cross the blood–brain barrier, high-dose methotrexate (HDMTX) is the backbone for induction chemotherapy. This systematic review was conducted to observe [...] Read more.
Primary central nervous system lymphoma (PCNSL) is a highly aggressive non-Hodgkin lymphoma that is confined within the CNS. Due to its ability to cross the blood–brain barrier, high-dose methotrexate (HDMTX) is the backbone for induction chemotherapy. This systematic review was conducted to observe outcomes among different HDMTX doses (low, <3 g/m2; intermediate, 3–4.9 g/m2; high, ≥5 g/m2) and regimens used in the treatment of PCNSL. A PubMed search resulted in 26 articles reporting clinical trials using HDMTX for PCNSL, from which 35 treatment cohorts were identified for analysis. The median dose of HDMTX used for induction was 3.5 g/m2 (interquartile range IQR, 3–3.5); the intermediate dose was most frequently used in the studies examined (24 cohorts, 69%). Five cohorts used HDMTX monotherapy, 19 cohorts used HDMTX + polychemotherapy, and 11 cohorts used HDMTX + rituximab ± polychemotherapy. Pooled overall response rate (ORR) estimates for low, intermediate, and high dose HDMTX cohorts were 71%, 76%, and 76%, respectively. Pooled 2-year progression-free survival (PFS) estimates for low, intermediate, and high HDMTX dose cohorts were 50%, 51%, and 55%, respectively. Regimens that included rituximab showed a tendency to have higher ORR and 2-year PFS than those that did not include rituximab. These findings indicate that current protocols utilizing 3–4 g/m2 of HDMTX in combination with rituximab provide therapeutic efficacy in PCNSL. Full article
(This article belongs to the Section Systematic Review or Meta-Analysis in Cancer Research)
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23 pages, 370 KiB  
Review
Bispecific T-Cell Engagers Therapies in Solid Tumors: Focusing on Prostate Cancer
by Diana C. Simão, Kevin K. Zarrabi, José L. Mendes, Ricardo Luz, Jorge A. Garcia, William K. Kelly and Pedro C. Barata
Cancers 2023, 15(5), 1412; https://doi.org/10.3390/cancers15051412 - 23 Feb 2023
Cited by 6 | Viewed by 4481
Abstract
Over the past decade, immunotherapy has demonstrated an impressive improvement in treatment outcomes for multiple cancers. Following the landmark approvals for use of immune checkpoint inhibitors, new challenges emerged in various clinical settings. Not all tumor types harbor immunogenic characteristics capable of triggering [...] Read more.
Over the past decade, immunotherapy has demonstrated an impressive improvement in treatment outcomes for multiple cancers. Following the landmark approvals for use of immune checkpoint inhibitors, new challenges emerged in various clinical settings. Not all tumor types harbor immunogenic characteristics capable of triggering responses. Similarly, many tumors’ immune microenvironment allows them to become evasive, leading to resistance and, thus, limiting the durability of responses. To overcome this limitation, new T-cell redirecting strategies such as bispecific T-cell engager (BiTE) have become attractive and promising immunotherapies. Our review provides a comprehensive perspective of the current evidence of BiTE therapies in solid tumors. Considering that immunotherapy has shown modest results in advanced prostate cancer to date, we review the biologic rationale and promising results of BiTE therapy in this clinical setting and discuss potential tumor-associated antigens that may be integrated into BiTE construct designs. Our review also aims to evaluate the advances of BiTE therapies in prostate cancer, illustrate the major obstacles and underlying limitations, and discuss directions for future research. Full article
(This article belongs to the Collection Urological Cancer)
16 pages, 1929 KiB  
Review
Unlocking the Resistance to Anti-HER2 Treatments in Breast Cancer: The Issue of HER2 Spatial Distribution
by Federica Giugliano, Ambra Carnevale Schianca, Chiara Corti, Mariia Ivanova, Nadia Bianco, Silvia Dellapasqua, Carmen Criscitiello, Nicola Fusco, Giuseppe Curigliano and Elisabetta Munzone
Cancers 2023, 15(5), 1385; https://doi.org/10.3390/cancers15051385 - 22 Feb 2023
Cited by 5 | Viewed by 3469
Abstract
Approximately 15% of breast cancers are classified as HER2-positive, with an amplification of the ERBB2 gene and/or an overexpression of the HER2 protein. Up to 30% of HER2-positive breast cancers shows heterogeneity in HER2 expression and different patterns of spatial distribution, i.e., the [...] Read more.
Approximately 15% of breast cancers are classified as HER2-positive, with an amplification of the ERBB2 gene and/or an overexpression of the HER2 protein. Up to 30% of HER2-positive breast cancers shows heterogeneity in HER2 expression and different patterns of spatial distribution, i.e., the variability in the distribution and expression of the HER2 protein within a single tumour. Spatial heterogeneity may potentially affect treatment, response, assessment of HER2 status and consequently, may impact on the best treatment strategy. Understanding this feature can help clinicians to predict response to HER2-targeted therapies and patient outcomes, and to fine tune treatment decisions. This review summarizes the available evidence on HER2 heterogeneity and spatial distribution and how this may affect current available treatment choices, exploring possible opportunities for overcoming this issue, such as novel pharmacological agents, belonging to the group of antibody–drug conjugates. Full article
(This article belongs to the Special Issue Anti-HER2 Therapy Resistance in Breast Cancer)
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14 pages, 1198 KiB  
Review
The Gut-Prostate Axis: A New Perspective of Prostate Cancer Biology through the Gut Microbiome
by Kazutoshi Fujita, Makoto Matsushita, Marco A. De Velasco, Koji Hatano, Takafumi Minami, Norio Nonomura and Hirotsugu Uemura
Cancers 2023, 15(5), 1375; https://doi.org/10.3390/cancers15051375 - 21 Feb 2023
Cited by 7 | Viewed by 3123
Abstract
Obesity and a high-fat diet are risk factors associated with prostate cancer, and lifestyle, especially diet, impacts the gut microbiome. The gut microbiome plays important roles in the development of several diseases, such as Alzheimer’s disease, rheumatoid arthritis, and colon cancer. The analysis [...] Read more.
Obesity and a high-fat diet are risk factors associated with prostate cancer, and lifestyle, especially diet, impacts the gut microbiome. The gut microbiome plays important roles in the development of several diseases, such as Alzheimer’s disease, rheumatoid arthritis, and colon cancer. The analysis of feces from patients with prostate cancer by 16S rRNA sequencing has uncovered various associations between altered gut microbiomes and prostate cancer. Gut dysbiosis caused by the leakage of gut bacterial metabolites, such as short-chain fatty acids and lipopolysaccharide results in prostate cancer growth. Gut microbiota also play a role in the metabolism of androgen which could affect castration-resistant prostate cancer. Moreover, men with high-risk prostate cancer share a specific gut microbiome and treatments such as androgen-deprivation therapy alter the gut microbiome in a manner that favors prostate cancer growth. Thus, implementing interventions aiming to modify lifestyle or altering the gut microbiome with prebiotics or probiotics may curtail the development of prostate cancer. From this perspective, the “Gut–Prostate Axis” plays a fundamental bidirectional role in prostate cancer biology and should be considered when screening and treating prostate cancer patients. Full article
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23 pages, 1809 KiB  
Review
Downstream Targets of VHL/HIF-α Signaling in Renal Clear Cell Carcinoma Progression: Mechanisms and Therapeutic Relevance
by Sonia Mazumder, Paul J. Higgins and Rohan Samarakoon
Cancers 2023, 15(4), 1316; https://doi.org/10.3390/cancers15041316 - 19 Feb 2023
Cited by 11 | Viewed by 4591
Abstract
The clear cell variant of renal cell carcinoma (ccRCC) is the most common renal epithelial malignancy and responsible for most of the deaths from kidney cancer. Patients carrying inactivating mutations in the Von Hippel-Lindau (VHL) gene have an increased proclivity to develop several [...] Read more.
The clear cell variant of renal cell carcinoma (ccRCC) is the most common renal epithelial malignancy and responsible for most of the deaths from kidney cancer. Patients carrying inactivating mutations in the Von Hippel-Lindau (VHL) gene have an increased proclivity to develop several types of tumors including ccRCC. Normally, the Hypoxia Inducible Factor alpha (HIF-α) subunits of the HIF heterodimeric transcription factor complex are regulated by oxygen-dependent prolyl-hydroxylation, VHL-mediated ubiquitination and proteasomal degradation. Loss of pVHL function results in elevated levels of HIF-α due to increased stability, leading to RCC progression. While HIF-1α acts as a tumor suppressor, HIF-2α promotes oncogenic potential by driving tumor progression and metastasis through activation of hypoxia-sensitive signaling pathways and overexpression of HIF-2α target genes. One strategy to suppress ccRCC aggressiveness is directed at inhibition of HIF-2α and the associated molecular pathways leading to cell proliferation, angiogenesis, and metastasis. Indeed, clinical and pre-clinical data demonstrated the effectiveness of HIF-2α targeted therapy in attenuating ccRCC progression. This review focuses on the signaling pathways and the involved genes (cyclin D, c-Myc, VEGF-a, EGFR, TGF-α, GLUT-1) that confer oncogenic potential downstream of the VHL-HIF-2α signaling axis in ccRCC. Discussed as well are current treatment options (including receptor tyrosine kinase inhibitors such as sunitinib), the medical challenges (high prevalence of metastasis at the time of diagnosis, refractory nature of advanced disease to current treatment options), scientific challenges and future directions. Full article
(This article belongs to the Special Issue Cancers Driven by HIF)
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12 pages, 293 KiB  
Review
Evolving Treatment Landscape of HER2-mutant Non-Small Cell Lung Cancer: Trastuzumab Deruxtecan and Beyond
by Ioannis A. Vathiotis, Dimitrios Bafaloukos, Konstantinos N. Syrigos and George Samonis
Cancers 2023, 15(4), 1286; https://doi.org/10.3390/cancers15041286 - 17 Feb 2023
Cited by 6 | Viewed by 2577
Abstract
Successful targeting of HER2-activating mutations in DESTINY-Lung02 phase II study has led to the approval of the antibody–drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) as second-line treatment in patients with non-small cell lung cancer (NSCLC). Despite the impressive results, several matters need to [...] Read more.
Successful targeting of HER2-activating mutations in DESTINY-Lung02 phase II study has led to the approval of the antibody–drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) as second-line treatment in patients with non-small cell lung cancer (NSCLC). Despite the impressive results, several matters need to be addressed, including the clinical activity of T-DXd in patients with disease in the central nervous system as well as the role of T-DXd in the context of HER2 overexpression. Additionally, data regarding novel agents used to target HER2 continue to accumulate. This review highlights the challenges and unanswered questions that have emerged after the approval of T-DXd in patients with HER2-mutant NSCLC. Full article
(This article belongs to the Special Issue World Lung Cancer Awareness Month)
12 pages, 1341 KiB  
Review
Mechanisms of Resistance to Antibody–Drug Conjugates
by Rachel Occhiogrosso Abelman, Bogang Wu, Laura M. Spring, Leif W. Ellisen and Aditya Bardia
Cancers 2023, 15(4), 1278; https://doi.org/10.3390/cancers15041278 - 17 Feb 2023
Cited by 10 | Viewed by 4123
Abstract
Antibody–drug conjugates (ADCs), with antibodies targeted against specific antigens linked to cytotoxic payloads, offer the opportunity for a more specific delivery of chemotherapy and other bioactive payloads to minimize side effects. First approved in the setting of HER2+ breast cancer, more recent ADCs [...] Read more.
Antibody–drug conjugates (ADCs), with antibodies targeted against specific antigens linked to cytotoxic payloads, offer the opportunity for a more specific delivery of chemotherapy and other bioactive payloads to minimize side effects. First approved in the setting of HER2+ breast cancer, more recent ADCs have been developed for triple-negative breast cancer (TNBC) and, most recently, hormone receptor-positive (HR+) breast cancer. While antibody–drug conjugates have compared favorably against traditional chemotherapy in some settings, patients eventually progress on these therapies and require a change in treatment. Mechanisms to explain the resistance to ADCs are highly sought after, in hopes of developing next-line treatment options and expanding the therapeutic windows of existing therapies. These resistance mechanisms are categorized as follows: change in antigen expression, change in ADC processing and resistance, and efflux of the ADC payload. This paper reviews the recently published literature on these mechanisms as well as potential options to overcome these barriers. Full article
(This article belongs to the Special Issue Resistance in Breast Cancer)
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