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Cancers, Volume 15, Issue 10 (May-2 2023) – 206 articles

Cover Story (view full-size image): The quest for more augmented and durable responses to melanoma immunotherapy has fueled recent efforts toward identifying novel immune checkpoint (IC) molecules that could be potentially targeted. The dynamic crosstalk between melanoma and immune effector cells is based on a complex network of many implicated IC molecules beyond PD-1 and CTLA-4, including LAG-3, TIGIT, TIM-3, VISTA, IDO1-2/TDO, CD27/70, CD39/73, HVEM/BTLA/CD160 and B7-H3. This paper explores all emerging IC molecules with emphasis on their co-inhibitory or co-stimulatory properties, with the aim of presenting all currently available clinical and preclinical data on their therapeutic potential. Understanding these IC-mediated pathways presents a unique opportunity to get a step closer to realizing “personalized immunotherapy”. View this paper
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9 pages, 656 KiB  
Article
A Retrospective Study Comparing Olaparib and Bevacizumab as a Maintenance Therapy for Platinum-Sensitive Recurrent Ovarian Cancer: Impact on Recurrence-Free Survival in Japanese and Asian Populations
by Kazuho Nakanishi, Masafumi Toyoshima, Yuta Ueno and Shunji Suzuki
Cancers 2023, 15(10), 2869; https://doi.org/10.3390/cancers15102869 - 22 May 2023
Cited by 1 | Viewed by 1441
Abstract
The use of angiogenesis inhibitors and poly ADP-ribose polymerase inhibitors following multi-agent chemotherapy, including platinum-based agents, has become the standard treatment for platinum-sensitive recurrent ovarian cancer (PSROC). However, the optimal maintenance therapy and selection criteria for these patients remain unclear. Thus, this study [...] Read more.
The use of angiogenesis inhibitors and poly ADP-ribose polymerase inhibitors following multi-agent chemotherapy, including platinum-based agents, has become the standard treatment for platinum-sensitive recurrent ovarian cancer (PSROC). However, the optimal maintenance therapy and selection criteria for these patients remain unclear. Thus, this study aimed to optimize the treatment options and selection criteria for patients with PSROC. The clinical data of 51 patients with PSROC admitted to Nippon Medical School Chiba Hokusoh Hospital and Nippon Medical School Hospital were retrospectively collected. The log-rank test was used for the survival analysis, and Cox proportional hazard regression analysis was used for the multivariate survival analysis. Of the 51 patients, 17 received maintenance therapy with bevacizumab (Bev), and 34 received olaparib (Ola). Recurrence-free survival (RFS) was significantly prolonged in the Ola group (27 months; 95% confidence interval (CI), 19–NA months) compared with that in the Bev group (9 months; 95% CI, 5–22 months; p = 0.000103). The efficacy of Ola was independent of background factors, including response to previous chemotherapy, homologous recombination status, histological type, or laboratory data. Ola is superior to Bev as PSROC maintenance therapy, especially in Japanese and Asian populations. Full article
(This article belongs to the Special Issue Advances in Ovarian Cancer Research and Treatment)
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12 pages, 3115 KiB  
Article
Accurate Detection of Urothelial Bladder Cancer Using Targeted Deep Sequencing of Urine DNA
by Dongin Lee, Wookjae Lee, Hwang-Phill Kim, Myong Kim, Hyun Kyu Ahn, Duhee Bang and Kwang Hyun Kim
Cancers 2023, 15(10), 2868; https://doi.org/10.3390/cancers15102868 - 22 May 2023
Cited by 3 | Viewed by 1797
Abstract
Patients with hematuria are commonly given an invasive cystoscopy test to detect bladder cancer (BC). To avoid the risks associated with cystoscopy, several urine-based methods for BC detection have been developed, the most prominent of which is the deep sequencing of urine DNA. [...] Read more.
Patients with hematuria are commonly given an invasive cystoscopy test to detect bladder cancer (BC). To avoid the risks associated with cystoscopy, several urine-based methods for BC detection have been developed, the most prominent of which is the deep sequencing of urine DNA. However, the current methods for urine-based BC detection have significant levels of false-positive signals. In this study, we report on uAL100, a method to precisely detect BC tumor DNA in the urine without tumor samples. Using urine samples from 43 patients with BC and 21 healthy donors, uAL100 detected BC with 83.7% sensitivity and 100% specificity. The mutations identified in the urine DNA by uAL100 for BC detection were highly associated with BC tumorigenesis and progression. We suggest that uAL100 has improved accuracy compared to other urine-based methods for early BC detection and can reduce unnecessary cystoscopy tests for patients with hematuria. Full article
(This article belongs to the Special Issue Cell-Free DNA as Prognostic and Predictive Biomarker in Solid Cancers)
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17 pages, 3932 KiB  
Article
Serrate RNA Effector Molecule (SRRT) Is Associated with Prostate Cancer Progression and Is a Predictor of Poor Prognosis in Lethal Prostate Cancer
by Yaser Gamallat, Muhammad Choudhry, Qiaowang Li, Jon George Rokne, Reda Alhajj, Ramy Abdelsalam, Sunita Ghosh, Jaron Arbet, Paul C. Boutros and Tarek A. Bismar
Cancers 2023, 15(10), 2867; https://doi.org/10.3390/cancers15102867 - 22 May 2023
Viewed by 1525
Abstract
Arsenite-resistance protein 2, also known as serrate RNA effector molecule (ARS2/SRRT), is known to be involved in cellular proliferation and tumorigenicity. However, its role in prostate cancer (PCa) has not yet been established. We investigated the potential role of SRRT in 496 prostate [...] Read more.
Arsenite-resistance protein 2, also known as serrate RNA effector molecule (ARS2/SRRT), is known to be involved in cellular proliferation and tumorigenicity. However, its role in prostate cancer (PCa) has not yet been established. We investigated the potential role of SRRT in 496 prostate samples including benign, incidental, advanced, and castrate-resistant patients treated by androgen deprivation therapy (ADT). We also explored the association of SRRT with common genetic aberrations in lethal PCa using immunohistochemistry (IHC) and performed a detailed analysis of SRRT expression using The Cancer Genome Atlas (TCGA PRAD) by utilizing RNA-seq, clinical information (pathological T category and pathological Gleason score). Our findings indicated that high SRRT expression was significantly associated with poor overall survival (OS) and cause-specific survival (CSS). SRRT expression was also significantly associated with common genomic aberrations in lethal PCa such as PTEN loss, ERG gain, mutant TP53, or ATM. Furthermore, TCGA PRAD data revealed that high SRRT mRNA expression was significantly associated with higher Gleason scores, PSA levels, and T pathological categories. Gene set enrichment analysis (GSEA) of RNAseq data from the TCGA PRAD cohort indicated that SRRT may play a potential role in regulating the expression of genes involved in prostate cancer aggressiveness. Conclusion: The current data identify the SRRT’s potential role as a prognostic for lethal PCa, and further research is required to investigate its potential as a therapeutic target. Full article
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0 pages, 1320 KiB  
Review
Acute Myeloid Leukemia Stem Cells in Minimal/Measurable Residual Disease Detection
by Kritika Srinivasan Rajsri, Nainita Roy and Sohini Chakraborty
Cancers 2023, 15(10), 2866; https://doi.org/10.3390/cancers15102866 - 22 May 2023
Cited by 2 | Viewed by 1773 | Correction
Abstract
Acute myeloid leukemia (AML) is a hematological malignancy characterized by an abundance of incompletely matured or immature clonally derived hematopoietic precursors called leukemic blasts. Rare leukemia stem cells (LSCs) that can self-renew as well as give rise to leukemic progenitors comprising the bulk [...] Read more.
Acute myeloid leukemia (AML) is a hematological malignancy characterized by an abundance of incompletely matured or immature clonally derived hematopoietic precursors called leukemic blasts. Rare leukemia stem cells (LSCs) that can self-renew as well as give rise to leukemic progenitors comprising the bulk of leukemic blasts are considered the cellular reservoir of disease initiation and maintenance. LSCs are widely thought to be relatively resistant as well as adaptive to chemotherapy and can cause disease relapse. Therefore, it is imperative to understand the molecular bases of LSC forms and functions during different stages of disease progression, so we can more accurately identify these cells and design therapies to target them. Irrespective of the morphological, cytogenetic, and cellular heterogeneity of AML, the uniform, singularly important and independently significant prognosticator of disease response to therapy and patient outcome is measurable or minimal residual disease (MRD) detection, defined by residual disease detection below the morphology-based 5% blast threshold. The importance of LSC identification and frequency estimation during MRD detection, in order to make MRD more effective in predicting disease relapse and modifying therapeutic regimen is becoming increasingly apparent. This review focuses on summarizing functional and cellular composition-based LSC identification and linking those studies to current techniques of MRD detection to suggest LSC-inclusive MRD detection as well as outline outstanding questions that need to be addressed to improve the future of AML clinical management and treatment outcomes. Full article
(This article belongs to the Special Issue Acute Myeloid Leukemia: The Future Is Bright)
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17 pages, 3589 KiB  
Article
Nectin-4 as a Predictive Marker for Poor Prognosis of Endometrial Cancer with Mismatch Repair Impairment
by Ha Kyun Chang, Young Hoon Park, Jung-A Choi, Jeong Won Kim, Jisup Kim, Hyo Sun Kim, Hae Nam Lee, Hanbyoul Cho, Joon-Yong Chung and Jae-Hoon Kim
Cancers 2023, 15(10), 2865; https://doi.org/10.3390/cancers15102865 - 22 May 2023
Cited by 1 | Viewed by 1740
Abstract
The adhesion molecule Nectin-4 is a new potential therapeutic target for different types of cancer; however, little is known about its diagnosis significance in endometrial cancer (EC). We found that Nectin-4 expression was significantly higher in EC tissues than in nonadjacent normal tissue. [...] Read more.
The adhesion molecule Nectin-4 is a new potential therapeutic target for different types of cancer; however, little is known about its diagnosis significance in endometrial cancer (EC). We found that Nectin-4 expression was significantly higher in EC tissues than in nonadjacent normal tissue. The area under the receiver operating characteristic curve value of 0.922 indicated good diagnostic accuracy for Nectin-4 expression in EC. Furthermore, Nectin-4 expression was associated with DNA mismatch repair (MMR) protein deficiency. Notably, the high Nectin-4 expression group of patients with MSH2/6-deficient EC had shorter progression-free survival than that of the low Nectin-4 expression group. The number of lymphovascular space invasion-positive patients in groups with MMR deficiency and high Nectin-4 expression was also increased compared with that in the low Nectin-4 expression group. Bioinformatics analysis revealed that alteration in Nectin-4 and MMR genes is associated with Nectin-4 expression in EC. To the best of our knowledge, this is the first study to show that Nectin-4 expression may be a potential biomarker for EC diagnosis and that high Nectin-4 expression in MMR-deficient patients with EC can predict short progression-free survival, thus providing clues to identify patients for adjuvant therapy. Full article
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16 pages, 715 KiB  
Review
Pediatric Rhabdomyosarcomas of the Genitourinary Tract
by Jennifer T. Castle, Brittany E. Levy, Derek B. Allison, David A. Rodeberg and Eric J. Rellinger
Cancers 2023, 15(10), 2864; https://doi.org/10.3390/cancers15102864 - 22 May 2023
Cited by 1 | Viewed by 2364
Abstract
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in the pediatric and adolescent population, with 350 new cases diagnosed each year. While they can develop anywhere in the body, the genitourinary tract is the second most common primary location for an RMS [...] Read more.
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in the pediatric and adolescent population, with 350 new cases diagnosed each year. While they can develop anywhere in the body, the genitourinary tract is the second most common primary location for an RMS to develop. Overall survival has improved through the increased use of protocols and multidisciplinary approaches. However, the guidelines for management continue to change as systemic and radiation therapeutics advance. Given the relative rarity of this disease compared to other non-solid childhood malignancies, healthcare providers not directly managing RMS may not be familiar with their presentation and updated management. This review aims to provide foundational knowledge of the management of RMSs with an emphasis on specific management paradigms for those arising from the genitourinary tract. The genitourinary tract is the second most common location for an RMS to develop but varies greatly in symptomology and survival depending on the organ of origin. As the clinical understanding of these tumors advances, treatment paradigms have evolved. Herein, we describe the breadth of presentations for genitourinary RMSs with diagnostic and treatment management considerations, incorporating the most recently available guidelines and societal consensus recommendations. Full article
(This article belongs to the Special Issue Sarcomas of Extra-Mesenchymal Sites)
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22 pages, 1296 KiB  
Review
Crosstalk between Thyroid Carcinoma and Tumor-Correlated Immune Cells in the Tumor Microenvironment
by Mingyuan Song, Qi Liu, Wei Sun and Hao Zhang
Cancers 2023, 15(10), 2863; https://doi.org/10.3390/cancers15102863 - 22 May 2023
Cited by 1 | Viewed by 1705
Abstract
Thyroid cancer (TC) is the most common malignancy in the endocrine system. Although most TC can achieve a desirable prognosis, some refractory thyroid carcinomas, including radioiodine-refractory differentiated thyroid cancer, as well as anaplastic thyroid carcinoma, face a myriad of difficulties in clinical treatment. [...] Read more.
Thyroid cancer (TC) is the most common malignancy in the endocrine system. Although most TC can achieve a desirable prognosis, some refractory thyroid carcinomas, including radioiodine-refractory differentiated thyroid cancer, as well as anaplastic thyroid carcinoma, face a myriad of difficulties in clinical treatment. These types of tumors contribute to the majority of TC deaths due to limited initial therapy, recurrence, and metastasis of the tumor and tumor resistance to current clinically targeted drugs, which ultimately lead to treatment failure. At present, a growing number of studies have demonstrated crosstalk between TC and tumor-associated immune cells, which affects tumor deterioration and metastasis through distinct signal transduction or receptor activation. Current immunotherapy focuses primarily on cutting off the interaction between tumor cells and immune cells. Since the advent of immunotherapy, scholars have discovered targets for TC immunotherapy, which also provides new strategies for TC treatment. This review methodically and intensively summarizes the current understanding and mechanism of the crosstalk between distinct types of TC and immune cells, as well as potential immunotherapy strategies and clinical research results in the area of the tumor immune microenvironment. We aim to explore the current research advances to formulate better individualized treatment strategies for TC patients and to provide clues and references for the study of potential immune checkpoints and the development of immunotherapy technologies. Full article
(This article belongs to the Section Tumor Microenvironment)
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26 pages, 1198 KiB  
Review
Succinate-Directed Approaches for Warburg Effect-Targeted Cancer Management, an Alternative to Current Treatments?
by Adrian Casas-Benito, Sonia Martínez-Herrero and Alfredo Martínez
Cancers 2023, 15(10), 2862; https://doi.org/10.3390/cancers15102862 - 22 May 2023
Cited by 4 | Viewed by 2480
Abstract
Approximately a century ago, Otto Warburg discovered that cancer cells use a fermentative rather than oxidative metabolism even though the former is more inefficient in terms of energy production per molecule of glucose. Cancer cells increase the use of this fermentative metabolism even [...] Read more.
Approximately a century ago, Otto Warburg discovered that cancer cells use a fermentative rather than oxidative metabolism even though the former is more inefficient in terms of energy production per molecule of glucose. Cancer cells increase the use of this fermentative metabolism even in the presence of oxygen, and this process is called aerobic glycolysis or the Warburg effect. This alternative metabolism is mainly characterized by higher glycolytic rates, which allow cancer cells to obtain higher amounts of total ATP, and the production of lactate, but there are also an activation of protumoral signaling pathways and the generation of molecules that favor cancer progression. One of these molecules is succinate, a Krebs cycle intermediate whose concentration is increased in cancer and which is considered an oncometabolite. Several protumoral actions have been associated to succinate and its role in several cancer types has been already described. Despite playing a major role in metabolism and cancer, so far, the potential of succinate as a target in cancer prevention and treatment has remained mostly unexplored, as most previous Warburg-directed anticancer strategies have focused on other intermediates. In this review, we aim to summarize succinate’s protumoral functions and discuss the use of succinate expression regulators as a potential cancer therapy strategy. Full article
(This article belongs to the Special Issue Novel Metabolic Approaches Targeting Cancer Cells)
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15 pages, 6140 KiB  
Article
Partial Laryngectomy for pT4a Laryngeal Cancer: Outcomes and Limits in Selected Cases
by Giovanni Succo, Andy Bertolin, Izabela Costa Santos, Martina Tascone, Marco Lionello, Marco Fantini, Andressa Silva de Freitas, Ilaria Bertotto, Andrea Elio Sprio, Giuseppe Sanguineti, Fernando Luiz Dias, Giuseppe Rizzotto and Erika Crosetti
Cancers 2023, 15(10), 2861; https://doi.org/10.3390/cancers15102861 - 22 May 2023
Cited by 2 | Viewed by 1360
Abstract
A large multi-institutional case series of laryngeal cancer (LC) T4a was carried out, including 134 cases treated with open partial horizontal laryngectomies (OPHL) +/− post-operative radiation therapy (PORT). The goal was to understand better whether OPHL can be included among the viable options [...] Read more.
A large multi-institutional case series of laryngeal cancer (LC) T4a was carried out, including 134 cases treated with open partial horizontal laryngectomies (OPHL) +/− post-operative radiation therapy (PORT). The goal was to understand better whether OPHL can be included among the viable options in selected pT4a LC patients who refuse a standard approach, represented by total laryngectomy (TL) + PORT. All 134 patients underwent OPHL type I (supraglottic), II (supracricoid), or III (supratracheal), according to the European Laryngological Society Classification. Comparing clinical and pathological stages showed pT up-staging in 105 cases (78.4%) and pN up-staging in 19 patients (11.4%). Five-year data on overall survival, disease-specific survival, disease-free survival, freedom from laryngectomy, and laryngo-esophageal dysfunction-free survival (rate of patients surviving without a local recurrence or requiring total laryngectomy and without a feeding tube or a tracheostomy) were, respectively, 82.1%, 89.8%, 75.7%, 89.7%, and 78.3%. Overall, complications were observed in 22 cases (16.4%). Sequelae were observed in 28 patients (20.9%). No patients died during the postoperative period. This large series highlights the good onco-functional results of low-volume pT4a laryngeal tumors, with minimal or absent cartilage destruction, treated with OPHLs. The level of standardization of the indication for OPHL should allow consideration of OPHL as a valid therapeutic option in cases where the patient refuses total laryngectomy or non-surgical protocols with concomitant chemo-radiotherapy. Full article
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13 pages, 5106 KiB  
Article
mRNA-Lipid Nanoparticle (LNP) Delivery of Humanized EpCAM-CD3 Bispecific Antibody Significantly Blocks Colorectal Cancer Tumor Growth
by Vita Golubovskaya, John Sienkiewicz, Jinying Sun, Yanwei Huang, Liang Hu, Hua Zhou, Hizkia Harto, Shirley Xu, Robert Berahovich, Walter Bodmer and Lijun Wu
Cancers 2023, 15(10), 2860; https://doi.org/10.3390/cancers15102860 - 22 May 2023
Cited by 9 | Viewed by 5689
Abstract
The epithelial cell adhesion molecule (EpCAM) is often overexpressed in many types of tumors, including colorectal cancer. We sequenced and humanized an EpCAM mouse antibody and used it to develop bispecific EpCAM-CD3 antibodies. Three different designs were used to generate bispecific antibodies such [...] Read more.
The epithelial cell adhesion molecule (EpCAM) is often overexpressed in many types of tumors, including colorectal cancer. We sequenced and humanized an EpCAM mouse antibody and used it to develop bispecific EpCAM-CD3 antibodies. Three different designs were used to generate bispecific antibodies such as EpCAM-CD3 CrossMab knob-in-hole, EpCAM ScFv-CD3 ScFv (BITE), and EpCAM ScFv-CD3 ScFv-human Fc designs. These antibody designs showed strong and specific binding to the EpCAM-positive Lovo cell line and T cells, specifically killed EpCAM-positive Lovo cells and not EpCAM-negative Colo741 cells in the presence of T cells, and increased T cells’ IFN-gamma secretion in a dose-dependent manner. In addition, transfection of HEK-293 cells with EpCAM ScFv-CD3 ScFv human Fc mRNA-LNPs resulted in antibody secretion that killed Lovo cells and did not kill EpCAM-negative Colo741 cells. The antibody increased IFN-gamma secretion against Lovo target cells and did not increase it against Colo741 target cells. EpCAM-CD3 hFc mRNA-LNP transfection of several cancer cell lines (A1847, C30, OVCAR-5) also demonstrated functional bispecific antibody secretion. In addition, intratumoral delivery of the EpCAM-CD3 human Fc mRNA-LNPs into OVCAR-5 tumor xenografts combined with intravenous injection of T cells significantly blocked xenograft tumor growth. Thus, EpCAM-CD3 hFc mRNA-LNP delivery to tumor cells shows strong potential for future clinical studies. Full article
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12 pages, 698 KiB  
Article
Benefit of Early Ruxolitinib Initiation Regardless of Fibrosis Grade in Patients with Primary Myelofibrosis: A Post Hoc Analysis of the Single-Arm Phase 3b JUMP Study
by Francesca Palandri, Haifa Kathrin Al-Ali, Paola Guglielmelli, Mike W. Zuurman, Rajendra Sarkar and Vikas Gupta
Cancers 2023, 15(10), 2859; https://doi.org/10.3390/cancers15102859 - 22 May 2023
Cited by 3 | Viewed by 1980
Abstract
Bone marrow fibrosis (BMF) is an adverse prognostic factor for myelofibrosis (MF). The single-arm, open-label, phase 3b JUMP trial (NCT01493414) assessed the safety and efficacy of the JAK1/JAK2 inhibitor ruxolitinib in patients with symptomatic MF. This post hoc analysis investigated the impact of [...] Read more.
Bone marrow fibrosis (BMF) is an adverse prognostic factor for myelofibrosis (MF). The single-arm, open-label, phase 3b JUMP trial (NCT01493414) assessed the safety and efficacy of the JAK1/JAK2 inhibitor ruxolitinib in patients with symptomatic MF. This post hoc analysis investigated the impact of BMF grade on response and outcomes in patients with primary MF (PMF) from the JUMP study. BMF was assessed by biopsy and graded from 0 to 3; grades 0–1 were considered low-grade fibrosis (LGF) and grades 2–3 were considered high-grade fibrosis (HGF). Patients with LGF (n = 268) had lower rates of cytopenias at baseline but showed comparable disease burden vs. patients with HGF (n = 852). The proportion of patients achieving a spleen response was greater in the LGF group vs. the HGF group at Week 24 and at any time during the study, while overall survival estimates were improved in patients with LGF vs. patients with HGF. Early initiation of ruxolitinib therapy (within 2 years of diagnosis) was associated with increased response rates in all patients. These results highlight the efficacy of ruxolitinib in symptomatic patients with PMF, with the greatest clinical improvements observed in patients with LGF and in patients who received early treatment. Full article
(This article belongs to the Section Cancer Therapy)
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20 pages, 711 KiB  
Review
Immune Checkpoint Inhibitors Combined with Targeted Therapy: The Recent Advances and Future Potentials
by Bin Li, Juan Jin, Duancheng Guo, Zhonghua Tao and Xichun Hu
Cancers 2023, 15(10), 2858; https://doi.org/10.3390/cancers15102858 - 22 May 2023
Cited by 20 | Viewed by 4874
Abstract
Immune checkpoint inhibitors (ICIs) have revolutionized the therapeutic landscape of cancer and have been widely approved for use in the treatment of diverse solid tumors. Targeted therapy has been an essential part of cancer treatment for decades, and in most cases, a special [...] Read more.
Immune checkpoint inhibitors (ICIs) have revolutionized the therapeutic landscape of cancer and have been widely approved for use in the treatment of diverse solid tumors. Targeted therapy has been an essential part of cancer treatment for decades, and in most cases, a special drug target is required. Numerous studies have confirmed the synergistic effect of combining ICIs with targeted therapy. For example, triple therapy of PD-L1 inhibitor atezolizumab plus BRAF inhibitor vemurafenib and MEK inhibitor cobimetinib has been approved as the first-line treatment in advanced melanoma patients with BRAFV600 mutations. However, not all combinations of ICIs and targeted therapy work. Combining ICIs with EGFR inhibitors in non-small-cell lung cancer (NSCLC) with EGFR mutations only triggered toxicities and did not improve efficacy. Therefore, the efficacies of combinations of ICIs and different targeted agents are distinct. This review firstly and comprehensively covered the current status of studies on the combination of ICIs mainly referring to PD-1 and PD-L1 inhibitors and targeted drugs, including angiogenesis inhibitors, EGFR/HER2 inhibitors, PARP inhibitors and MAPK/ERK signaling pathway inhibitors, in the treatment of solid tumors. We discussed the underlying mechanisms, clinical efficacies, side effects, and potential predictive biomarkers to give an integrated view of the combination strategy and provide perspectives for future directions in solid tumors. Full article
(This article belongs to the Special Issue Advances in Cancer Immunotherapy)
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11 pages, 1357 KiB  
Article
Carbon-Ion Radiotherapy Combined with Concurrent Chemotherapy for Locally Advanced Pancreatic Cancer: A Retrospective Case Series Analysis
by Masahiko Okamoto, Shintaro Shiba, Daijiro Kobayashi, Yuhei Miyasaka, Shohei Okazaki, Kei Shibuya and Tatsuya Ohno
Cancers 2023, 15(10), 2857; https://doi.org/10.3390/cancers15102857 - 22 May 2023
Cited by 1 | Viewed by 2167
Abstract
Systemic chemotherapy has significantly improved in recent years. In this study. the clinical impact of carbon-ion radiotherapy (CIRT) with concurrent chemotherapy for locally advanced unresectable pancreatic cancer (URPC) was evaluated. Methods: Patients with URPC who were treated with CIRT between January 2016 and [...] Read more.
Systemic chemotherapy has significantly improved in recent years. In this study. the clinical impact of carbon-ion radiotherapy (CIRT) with concurrent chemotherapy for locally advanced unresectable pancreatic cancer (URPC) was evaluated. Methods: Patients with URPC who were treated with CIRT between January 2016 and December 2020 were prospectively registered and analyzed. The major criteria for registration were (1) diagnosed as URPC on imaging; (2) pathologically diagnosed adenocarcinoma; (3) no distant metastasis; (4) Eastern Cooperative Oncology Group performance status of 0–2; (5) tumors without gastrointestinal tract invasion; and (6) available for concurrent chemotherapy. Patients who received neoadjuvant chemotherapy (NAC) for more than one year prior to CIRT were excluded. Results: Forty-four patients met the inclusion criteria, and thirty-seven received NAC before CIRT. The median follow-up period of living patients was 26.0 (6.0–68.6) months after CIRT. The estimated two-year overall survival, local control, and progression-free survival rates after CIRT were 56.6%, 76.1%, and 29.0%, respectively. The median survival time of all patients was 29.6 months after CIRT and 34.5 months after the initial NAC. Conclusion: CIRT showed survival benefits for URPC even in the multiagent chemotherapy era. Full article
(This article belongs to the Special Issue Particle Therapy: State-of-the-Art and Future Prospects)
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25 pages, 2048 KiB  
Review
Interdependencies of the Neuronal, Immune and Tumor Microenvironment in Gliomas
by Alexander Yuile, Joe Q. Wei, Aditya A. Mohan, Kelly M. Hotchkiss and Mustafa Khasraw
Cancers 2023, 15(10), 2856; https://doi.org/10.3390/cancers15102856 - 21 May 2023
Cited by 1 | Viewed by 2843
Abstract
Gliomas are the most common primary brain malignancy and are universally fatal. Despite significant breakthrough in understanding tumor biology, treatment breakthroughs have been limited. There is a growing appreciation that major limitations on effective treatment are related to the unique and highly complex [...] Read more.
Gliomas are the most common primary brain malignancy and are universally fatal. Despite significant breakthrough in understanding tumor biology, treatment breakthroughs have been limited. There is a growing appreciation that major limitations on effective treatment are related to the unique and highly complex glioma tumor microenvironment (TME). The TME consists of multiple different cell types, broadly categorized into tumoral, immune and non-tumoral, non-immune cells. Each group provides significant influence on the others, generating a pro-tumor dynamic with significant immunosuppression. In addition, glioma cells are highly heterogenous with various molecular distinctions on the cellular level. These variations, in turn, lead to their own unique influence on the TME. To develop future treatments, an understanding of this complex TME interplay is needed. To this end, we describe the TME in adult gliomas through interactions between its various components and through various glioma molecular phenotypes. 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 8 | Viewed by 3555
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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14 pages, 2577 KiB  
Article
Midterm Results of High-Dose-Rate Intraoperative Brachytherapy in the Treatment of Soft Tissue Sarcomas
by Dietmar Dammerer, Johannes Neugebauer, Matthias Braito, Moritz Wagner, Markus Neubauer, Lukas Moser, Markus Süß, Michael Liebensteiner and David Putzer
Cancers 2023, 15(10), 2854; https://doi.org/10.3390/cancers15102854 - 21 May 2023
Cited by 1 | Viewed by 1238
Abstract
Introduction: According to the literature only sparse data are available on the use of high-dose-rate intraoperative brachytherapy (IOHDR-BT) as a boost to external-beam irradiation (EBRT) in combination with a wide resection in patients with high-grade soft tissue sarcomas (STS). Materials and Methods: Applying [...] Read more.
Introduction: According to the literature only sparse data are available on the use of high-dose-rate intraoperative brachytherapy (IOHDR-BT) as a boost to external-beam irradiation (EBRT) in combination with a wide resection in patients with high-grade soft tissue sarcomas (STS). Materials and Methods: Applying a retrospective study design, we investigated all patients who between 2010 and 2016 underwent marginal resection of a high-grade STS and intraoperative radiotherapy, followed by EBRT. We included only patients with a traceable follow-up time of at least two years. Of 89 patients, 35 met our inclusion criteria and showed an average follow-up of four years. Results: We found an overall 2-year local control rate of 94.3%. The local recurrence rate for R0 resections was 6%, whereas recurrences occurred in 13% of R1 resections and in 100% of R2 resections. One affected patient received only intraoperative radiotherapy. The recurrence rate by tumour entity was 36% for LPS, 11% for myxofibrosarcoma and 17% for undifferentiated pleomorphic sarcoma. Conclusion: The treatment regimen consisting of limb-preserving surgery, IORT and pre- or postoperative radiotherapy consistently shows excellent local control rates. Full article
(This article belongs to the Special Issue Advances in Bone Tumor and Sarcoma)
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13 pages, 1139 KiB  
Article
Pretreatment Proteinuria Predicts the Prognosis of Patients Receiving Systemic Therapy for Unresectable Hepatocellular Carcinoma
by Kazuyuki Mizuno, Norihiro Imai, Takafumi Yamamoto, Shinya Yokoyama, Kenta Yamamoto, Takanori Ito, Yoji Ishizu, Takashi Honda, Teiji Kuzuya, Masatoshi Ishigami and Hiroki Kawashima
Cancers 2023, 15(10), 2853; https://doi.org/10.3390/cancers15102853 - 21 May 2023
Cited by 1 | Viewed by 1495
Abstract
Background: Proteinuria is a common adverse event in systemic therapy for hepatocellular carcinoma (HCC). However, whether the presence of pretreatment proteinuria affects the clinical course is still unclear. Method: From 2011 to 2022, 321 patients with unresectable HCC who were treated with systemic [...] Read more.
Background: Proteinuria is a common adverse event in systemic therapy for hepatocellular carcinoma (HCC). However, whether the presence of pretreatment proteinuria affects the clinical course is still unclear. Method: From 2011 to 2022, 321 patients with unresectable HCC who were treated with systemic therapy as first-line treatment were enrolled in this study. We retrospectively analyzed the presence of pretreatment proteinuria and the treatment course of systemic therapy. Results: In the cohort, 190 patients were tested for proteinuria qualitatively within 3 months before systemic therapy; 75 were treated with sorafenib, 72 were treated with lenvatinib, and 43 were treated with atezolizumab plus bevacizumab. Overall survival tended to be longer for patients treated with lenvatinib and significantly longer with atezolizumab plus bevacizumab in patients without pretreatment proteinuria but not for those treated with sorafenib. Further analysis was performed in 111 patients treated with lenvatinib or atezolizumab plus bevacizumab who had proteinuria measured quantitatively. Multivariate analysis including proteinuria, liver function, and HCC stage revealed that the severity of proteinuria was an independent predictor of prognosis. Conclusion: Pretreatment proteinuria predicts a poorer prognosis in patients with unresectable HCC treated with lenvatinib or atezolizumab plus bevacizumab but not in those treated with sorafenib. Full article
(This article belongs to the Special Issue Systemic Therapy for Hepatocellular Carcinoma)
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16 pages, 339 KiB  
Review
Hepatitis C Virus (HCV)-Ribonucleic Acid (RNA) As a Biomarker for Lymphoid Malignancy with HCV Infection
by Yutaka Tsutsumi, Shinichi Ito, Souichi Shiratori and Takanori Teshima
Cancers 2023, 15(10), 2852; https://doi.org/10.3390/cancers15102852 - 21 May 2023
Viewed by 1535
Abstract
The hepatitis C virus (HCV) is potentially associated with liver cancer, and advances in various drugs have led to progress in the treatment of hepatitis C and attempts to prevent its transition to liver cancer. Furthermore, reactivation of HCV has been observed in [...] Read more.
The hepatitis C virus (HCV) is potentially associated with liver cancer, and advances in various drugs have led to progress in the treatment of hepatitis C and attempts to prevent its transition to liver cancer. Furthermore, reactivation of HCV has been observed in the treatment of lymphoma, during which the immortalization and proliferation of lymphocytes occur, which leads to the possibility of further stimulating cytokines and the like and possibly to the development of lymphoid malignancy. There are also cases in which the disappearance of lymphoid malignancy has been observed by treating HCV and suppressing HCV-Ribonucleic acid (RNA), as well as cases of recurrence with an increase in HCV-RNA. While HCV-associated lymphoma has a poor prognosis, improving the prognosis with Direct Acting Antivirals (DAA) has recently been reported. The reduction and eradication of HCV-RNA by means of DAA is thus important for the treatment of lymphoid malignancy associated with HCV infection, and HCV-RNA can presumably play a role as a biomarker. This review provides an overview of what is currently known about HCV-associated lymphoma, its epidemiology, the mechanisms underlying the progression to lymphoma, its treatment, the potential and limits of HCV-RNA as a therapeutic biomarker, and biomarkers that are expected now that DAA therapy has been developed. Full article
12 pages, 900 KiB  
Article
Laparoscopic Right Hemihepatectomy after Future Liver Remnant Modulation: A Single Surgeon’s Experience
by Tijs J. Hoogteijling, Jasper P. Sijberden, John N. Primrose, Victoria Morrison-Jones, Sachin Modi, Giuseppe Zimmitti, Marco Garatti, Claudio Sallemi, Mario Morone and Mohammad Abu Hilal
Cancers 2023, 15(10), 2851; https://doi.org/10.3390/cancers15102851 - 21 May 2023
Viewed by 1580
Abstract
Background: Laparoscopic right hemihepatectomy (L-RHH) is still considered a technically complex procedure, which should only be performed by experienced surgeons in specialized centers. Future liver remnant modulation (FLRM) strategies, including portal vein embolization (PVE), and associating liver partition and portal vein ligation for [...] Read more.
Background: Laparoscopic right hemihepatectomy (L-RHH) is still considered a technically complex procedure, which should only be performed by experienced surgeons in specialized centers. Future liver remnant modulation (FLRM) strategies, including portal vein embolization (PVE), and associating liver partition and portal vein ligation for staged hepatectomy (ALPPS), might increase the surgical difficulty of L-RHH, due to the distortion of hepatic anatomy, periportal inflammation, and fibrosis. Therefore, this study aims to evaluate the safety and feasibility of L-RHH after FLRM, when compared with ex novo L-RHH. Methods: All consecutive right hemihepatectomies performed by a single surgeon in the period between October 2007 and March 2023 were retrospectively analyzed. The patient characteristics and perioperative outcomes of L-RHH after FLRM and ex novo L-RHH were compared. Results: A total of 59 patients were included in the analysis, of whom 33 underwent FLRM. Patients undergoing FLRM prior to L-RHH were most often male (93.9% vs. 42.3%, p < 0.001), had an ASA-score >2 (45.5% vs. 9.5%, p = 0.006), and underwent a two-stage hepatectomy (45.5% vs. 3.8% p < 0.001). L-RHH after FLRM was associated with longer operative time (median 360 vs. 300 min, p = 0.008) and Pringle duration (31 vs. 24 min, p = 0.011). Intraoperative blood loss, unfavorable intraoperative incidents, and conversion rates were similar in both groups. There were no significant differences in length of hospital stay and 30-day overall and severe morbidity rates. Radical resection margin (R0) and textbook outcome rates were equal. One patient who underwent an extended RHH in the FLRM group deceased within 90 days of surgery, due to post-hepatectomy liver failure. Conclusion: L-RHH after FLRM is more technically complex than L-RHH ex novo, as objectified by longer operative time and Pringle duration. Nevertheless, this procedure appears safe and feasible in experienced hands. Full article
(This article belongs to the Special Issue Advances in Minimally Invasive Liver Resection for Cancer Therapies)
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13 pages, 1873 KiB  
Article
Transfer-Learning Deep Radiomics and Hand-Crafted Radiomics for Classifying Lymph Nodes from Contrast-Enhanced Computed Tomography in Lung Cancer
by Fabian Christopher Laqua, Piotr Woznicki, Thorsten A. Bley, Mirjam Schöneck, Miriam Rinneburger, Mathilda Weisthoff, Matthias Schmidt, Thorsten Persigehl, Andra-Iza Iuga and Bettina Baeßler
Cancers 2023, 15(10), 2850; https://doi.org/10.3390/cancers15102850 - 21 May 2023
Cited by 3 | Viewed by 1598
Abstract
Objectives: Positron emission tomography (PET) is currently considered the non-invasive reference standard for lymph node (N-)staging in lung cancer. However, not all patients can undergo this diagnostic procedure due to high costs, limited availability, and additional radiation exposure. The purpose of this study [...] Read more.
Objectives: Positron emission tomography (PET) is currently considered the non-invasive reference standard for lymph node (N-)staging in lung cancer. However, not all patients can undergo this diagnostic procedure due to high costs, limited availability, and additional radiation exposure. The purpose of this study was to predict the PET result from traditional contrast-enhanced computed tomography (CT) and to test different feature extraction strategies. Methods: In this study, 100 lung cancer patients underwent a contrast-enhanced 18F-fluorodeoxyglucose (FDG) PET/CT scan between August 2012 and December 2019. We trained machine learning models to predict FDG uptake in the subsequent PET scan. Model inputs were composed of (i) traditional “hand-crafted” radiomics features from the segmented lymph nodes, (ii) deep features derived from a pretrained EfficientNet-CNN, and (iii) a hybrid approach combining (i) and (ii). Results: In total, 2734 lymph nodes [555 (20.3%) PET-positive] from 100 patients [49% female; mean age 65, SD: 14] with lung cancer (60% adenocarcinoma, 21% plate epithelial carcinoma, 8% small-cell lung cancer) were included in this study. The area under the receiver operating characteristic curve (AUC) ranged from 0.79 to 0.87, and the scaled Brier score (SBS) ranged from 16 to 36%. The random forest model (iii) yielded the best results [AUC 0.871 (0.865–0.878), SBS 35.8 (34.2–37.2)] and had significantly higher model performance than both approaches alone (AUC: p < 0.001, z = 8.8 and z = 22.4; SBS: p < 0.001, z = 11.4 and z = 26.6, against (i) and (ii), respectively). Conclusion: Both traditional radiomics features and transfer-learning deep radiomics features provide relevant and complementary information for non-invasive N-staging in lung cancer. Full article
(This article belongs to the Special Issue Imaging and Molecular Biology as Biomarkers for Lung Cancer)
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22 pages, 4757 KiB  
Article
A Reconstructed Human Melanoma-in-Skin Model to Study Immune Modulatory and Angiogenic Mechanisms Facilitating Initial Melanoma Growth and Invasion
by Elisabetta Michielon, Marta López González, Dorian A. Stolk, Joeke G. C. Stolwijk, Sanne Roffel, Taco Waaijman, Sinéad M. Lougheed, Tanja D. de Gruijl and Susan Gibbs
Cancers 2023, 15(10), 2849; https://doi.org/10.3390/cancers15102849 - 20 May 2023
Cited by 4 | Viewed by 1905
Abstract
Invasion, immune modulation, and angiogenesis are crucial in melanoma progression. Studies based on animals or two-dimensional cultures poorly recapitulate the tumor-microenvironmental cross-talk found in humans. This highlights a need for more physiological human models to better study melanoma features. Here, six melanoma cell [...] Read more.
Invasion, immune modulation, and angiogenesis are crucial in melanoma progression. Studies based on animals or two-dimensional cultures poorly recapitulate the tumor-microenvironmental cross-talk found in humans. This highlights a need for more physiological human models to better study melanoma features. Here, six melanoma cell lines (A375, COLO829, G361, MeWo, RPMI-7951, and SK-MEL-28) were used to generate an in vitro three-dimensional human melanoma-in-skin (Mel-RhS) model and were compared in terms of dermal invasion and immune modulatory and pro-angiogenic capabilities. A375 displayed the most invasive phenotype by clearly expanding into the dermal compartment, whereas COLO829, G361, MeWo, and SK-MEL-28 recapitulated to different extent the initial stages of melanoma invasion. No nest formation was observed for RPMI-7951. Notably, the integration of A375 and SK-MEL-28 cells into the model resulted in an increased secretion of immune modulatory factors (e.g., M-CSF, IL-10, and TGFβ) and pro-angiogenic factors (e.g., Flt-1 and VEGF). Mel-RhS-derived supernatants induced endothelial cell sprouting in vitro. In addition, observed A375-RhS tissue contraction was correlated to increased TGFβ release and α-SMA expression, all indicative of differentiation of fibroblasts into cancer-associated fibroblast-like cells and reminiscent of epithelial-to-mesenchymal transition, consistent with A375′s most prominent invasive behavior. In conclusion, we successfully generated several Mel-RhS models mimicking different stages of melanoma progression, which can be further tailored for future studies to investigate individual aspects of the disease and serve as three-dimensional models to assess efficacy of therapeutic strategies. Full article
(This article belongs to the Section Cancer Immunology and Immunotherapy)
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17 pages, 6336 KiB  
Article
Evaluation of the Elements of Short Hairpin RNAs in Developing shRNA-Containing CAR T Cells
by Ryan Urak, Brenna Gittins, Citradewi Soemardy, Nicole Grepo, Lior Goldberg, Madeleine Maker, Galina Shevchenko, Alicia Davis, Shirley Li, Tristan Scott, Kevin V. Morris, Stephen J. Forman and Xiuli Wang
Cancers 2023, 15(10), 2848; https://doi.org/10.3390/cancers15102848 - 20 May 2023
Viewed by 1873
Abstract
Short hairpin RNAs (shRNAs) have emerged as a powerful tool for gene knockdown in various cellular systems, including chimeric antigen receptor (CAR) T cells. However, the elements of shRNAs that are crucial for their efficacy in developing shRNA-containing CAR T cells remain unclear. [...] Read more.
Short hairpin RNAs (shRNAs) have emerged as a powerful tool for gene knockdown in various cellular systems, including chimeric antigen receptor (CAR) T cells. However, the elements of shRNAs that are crucial for their efficacy in developing shRNA-containing CAR T cells remain unclear. In this study, we evaluated the impact of different shRNA elements, including promoter strength, orientation, multiple shRNAs, self-targeting, and sense and antisense sequence composition on the knockdown efficiency of the target gene in CAR T cells. Our findings highlight the importance of considering multiple shRNAs and their orientation to achieve effective knockdown. Moreover, we demonstrate that using a strong promoter and avoiding self-targeting can enhance CAR T cell functionality. These results provide a framework for the rational design of CAR T cells with shRNA-mediated knockdown capabilities, which could improve the therapeutic efficacy of CAR T cell-based immunotherapy. Full article
(This article belongs to the Special Issue CAR T Cell Therapy for Cancers)
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10 pages, 1736 KiB  
Article
Practical Utility of Liquid Biopsies for Evaluating Genomic Alterations in Castration-Resistant Prostate Cancer
by Seung-Hwan Jeong, Dongsoo Kyung, Hyeong Dong Yuk, Chang Wook Jeong, Wookjae Lee, Jung-Ki Yoon, Hwang-Phill Kim, Duhee Bang, Tae-You Kim, Yoojoo Lim and Cheol Kwak
Cancers 2023, 15(10), 2847; https://doi.org/10.3390/cancers15102847 - 20 May 2023
Cited by 2 | Viewed by 1766
Abstract
Traditional tissue-based assessments of genomic alterations in castration-resistant prostate cancer (CRPC) can be challenging. To evaluate the real-world clinical utility of liquid biopsies for the evaluation of genomic alterations in CRPC, we preemptively collected available plasma samples and archival tissue samples from patients [...] Read more.
Traditional tissue-based assessments of genomic alterations in castration-resistant prostate cancer (CRPC) can be challenging. To evaluate the real-world clinical utility of liquid biopsies for the evaluation of genomic alterations in CRPC, we preemptively collected available plasma samples and archival tissue samples from patients that were being treated for clinically confirmed CRPC. The cell-free DNA (cfDNA) and tumor tissue DNA were analyzed using the AlphaLiquid®100-HRR panel. Plasma samples from a total of 87 patients were included in this study. Somatic mutations from cfDNA were detected in 78 (89.7%) patients, regardless of the presence of overt metastasis or concomitant treatment given at the time of plasma sample collection. Twenty-three patients were found to have known deleterious somatic or germline mutations in HRR genes from their cfDNA. Archival tissue samples from 33 (37.9%) patients were available for comparative analysis. Tissue sequencing was able to yield an NGS result in only 51.5% of the tissue samples. The general sensitivity of cfDNA for detecting somatic mutations in tissues was 71.8%, but important somatic/germline mutations in HRR genes were found to have a higher concordance (100%). Liquid biopsies can be a reasonable substitute for tissue biopsies in CRPC patients when evaluating genomic alterations. Full article
(This article belongs to the Special Issue Cell-Free DNA as Prognostic and Predictive Biomarker in Solid Cancers)
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14 pages, 1604 KiB  
Article
Clinical Meaning of Stromal Tumor Infiltrating Lymphocytes (sTIL) in Early Luminal B Breast Cancer
by Esmeralda García-Torralba, Miguel Pérez Ramos, Alejandra Ivars Rubio, Esther Navarro-Manzano, Noel Blaya Boluda, Pilar de la Morena Barrio, Elisa García-Garre, Francisco Martínez Díaz, Asunción Chaves-Benito, Elena García-Martínez and Francisco Ayala de la Peña
Cancers 2023, 15(10), 2846; https://doi.org/10.3390/cancers15102846 - 20 May 2023
Cited by 1 | Viewed by 1442
Abstract
Luminal breast cancer (BC) is associated with less immune activation, and the significance of stromal lymphocytic infiltration (sTIL) is more uncertain than in other BC subtypes. The aim of this study was to investigate the predictive and prognostic value of sTIL in early [...] Read more.
Luminal breast cancer (BC) is associated with less immune activation, and the significance of stromal lymphocytic infiltration (sTIL) is more uncertain than in other BC subtypes. The aim of this study was to investigate the predictive and prognostic value of sTIL in early luminal BC. The study was performed with an observational design in a prospective cohort of 345 patients with predominantly high-risk luminal (hormone receptor positive, HER2 negative) BC and with luminal B features (n = 286), in which the presence of sTIL was analyzed with validated methods. Median sTIL infiltration was 5% (Q1–Q3 range (IQR), 0–10). We found that sTIL were associated with characteristics of higher biological and clinical aggressiveness (tumor and lymph node proliferation and stage, among others) and that the percentage of sTIL was predictive of pathologic complete response in patients treated with neoadjuvant chemotherapy (OR: 1.05, 95%CI 1.02–1.09, p < 0.001). The inclusion of sTIL (any level of lymphocytic infiltration: sTIL > 0%) in Cox regression multivariable prognostic models was associated with a shorter relapse-free interval (HR: 4.85, 95%CI 1.33–17.65, p = 0.016) and significantly improved its performance. The prognostic impact of sTIL was independent of other clinical and pathological variables and was mainly driven by its relevance in luminal B BC. Full article
(This article belongs to the Special Issue New Insights in Tumor-Infiltrating Lymphocytes)
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28 pages, 819 KiB  
Review
Role of Estrogen Receptor β, G-Protein Coupled Estrogen Receptor and Estrogen-Related Receptors in Endometrial and Ovarian Cancer
by Susanne Schüler-Toprak, Maciej Skrzypczak, Carsten Gründker, Olaf Ortmann and Oliver Treeck
Cancers 2023, 15(10), 2845; https://doi.org/10.3390/cancers15102845 - 20 May 2023
Cited by 6 | Viewed by 1616
Abstract
Ovarian and endometrial cancers are affected by estrogens and their receptors. It has been long known that in different types of cancers, estrogens activate tumor cell proliferation via estrogen receptor α (ERα). In contrast, the role of ERs discovered later, including ERβ and [...] Read more.
Ovarian and endometrial cancers are affected by estrogens and their receptors. It has been long known that in different types of cancers, estrogens activate tumor cell proliferation via estrogen receptor α (ERα). In contrast, the role of ERs discovered later, including ERβ and G-protein-coupled ER (GPER1), in cancer is less well understood, but the current state of knowledge indicates them to have a considerable impact on both cancer development and progression. Moreover, estrogen related receptors (ERRs) have been reported to affect pathobiology of many tumor types. This article provides a summary and update of the current findings on the role of ERβ, GPER1, and ERRs in ovarian and endometrial cancer. For this purpose, original research articles on the role of ERβ, GPER1, and ERRs in ovarian and endometrial cancers listed in the PubMed database have been reviewed. Full article
(This article belongs to the Special Issue Molecular Alterations of Endometrial Cancer)
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11 pages, 658 KiB  
Article
Antithrombotic Therapy Increases the Risk of Bleeding after Endoscopic Submucosal Dissection for Early Gastric Cancer: A Propensity Score-Matched Analysis
by Tae-Se Kim, Byung-Hoon Min, Sun-Young Baek, Kyunga Kim, Yang-Won Min, Hyuk Lee, Jun-Haeng Lee, Poong-Lyul Rhee and Jae J. Kim
Cancers 2023, 15(10), 2844; https://doi.org/10.3390/cancers15102844 - 19 May 2023
Viewed by 1074
Abstract
Whether antithrombotic agent (ATA) usage increases the risk of gastric post-endoscopic submucosal dissection (ESD) bleeding remains controversial. The aim of this study was to elucidate the effects of usage, type, and cessation timing of ATA on post-ESD bleeding. A total of 4775 early [...] Read more.
Whether antithrombotic agent (ATA) usage increases the risk of gastric post-endoscopic submucosal dissection (ESD) bleeding remains controversial. The aim of this study was to elucidate the effects of usage, type, and cessation timing of ATA on post-ESD bleeding. A total of 4775 early gastric cancer patients undergoing ESD were analyzed; 1:3 propensity score matching between ATA and non-ATA groups resulted in 318 and 767 matched patients in each group, respectively. Outcomes were compared between the two groups using a generalized estimating equation method. After matching, post-ESD bleeding rates in ATA users and non-users were 9.1% and 4.2%, respectively (p = 0.001). In multivariable analysis, ATA usage was independently associated with an increased risk of post-ESD bleeding (adjusted odds ratio: 2.28, 95% confidence interval: 1.34–3.86). Both the continued or insufficient cessation groups and the sufficient cessation group had an increased incidence of post-ESD bleeding compared to their matched controls (12.5% versus 5.2%, p = 0.048; 8.1% versus 3.9%, p = 0.014). Post-ESD bleeding rates in antiplatelet agent users were significantly higher than those of their matched controls (8.3% versus 4.2%, p = 0.010). ATA usage increased the risk of post-ESD bleeding even after its sufficient cessation. Careful observation after ESD is required regardless of the cessation status of ATA. Full article
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11 pages, 1865 KiB  
Article
The Prognostic Relevance of MRI Characteristics in Myxofibrosarcoma Patients Treated with Neoadjuvant Radiotherapy
by Stefan G. van Ravensteijn, Maikel J. L. Nederkoorn, Tom C. P. Wal, Yvonne M. H. Versleijen-Jonkers, Pètra M. Braam, Uta E. Flucke, Johannes J. Bonenkamp, Bart H. W. Schreuder, Carla M. L. van Herpen, Johannes H. W. de Wilt, Ingrid M. E. Desar and Jacky W. J. de Rooy
Cancers 2023, 15(10), 2843; https://doi.org/10.3390/cancers15102843 - 19 May 2023
Cited by 3 | Viewed by 2161
Abstract
To improve local control, neoadjuvant radiotherapy (nRT) followed by surgery is the standard of care in myxofibrosarcoma (MFS) because of its infiltrative growth pattern. Nevertheless, local recurrence rates are high. Data on prognostic factors for poor clinical outcomes are lacking. This retrospective study [...] Read more.
To improve local control, neoadjuvant radiotherapy (nRT) followed by surgery is the standard of care in myxofibrosarcoma (MFS) because of its infiltrative growth pattern. Nevertheless, local recurrence rates are high. Data on prognostic factors for poor clinical outcomes are lacking. This retrospective study thus investigates the prognostic relevance of magnetic resonance imaging (MRI) characteristics before and after nRT in 40 MFS patients, as well as their association with disease-free survival (DFS) and overall survival (OS). A vascular pedicle, defined as extra-tumoral vessels at the tumor periphery, was observed in 12 patients (30.0%) pre-nRT and remained present post-nRT in all cases. Patients with a vascular pedicle had worse DFS (HR 5.85; 95% CI 1.56–21.90; p = 0.009) and OS (HR 9.58; 95% CI 1.91–48.00; p = 0.006). An infiltrative growth pattern, referred to as a tail sign, was observed in 22 patients (55.0%) pre-nRT and in 19 patients (47.5%) post-nRT, and was associated with worse DFS post-nRT (HR 6.99; 95% CI 1.39–35.35; p = 0.019). The percentage of tumor necrosis estimated by MRI was increased post-nRT, but was not associated with survival outcomes. The presence of a tail sign or vascular pedicle on MRI could support the identification of patients at risk for poor clinical outcomes after nRT. Full article
(This article belongs to the Special Issue Personalized Therapy of Sarcomas)
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18 pages, 4731 KiB  
Article
Mass Spectrometry Imaging Reveals Abnormalities in Cardiolipin Composition and Distribution in Astrocytoma Tumor Tissues
by Anna C. Krieger, Luis A. Macias, J. Clay Goodman, Jennifer S. Brodbelt and Livia S. Eberlin
Cancers 2023, 15(10), 2842; https://doi.org/10.3390/cancers15102842 - 19 May 2023
Cited by 1 | Viewed by 1472
Abstract
Cardiolipin (CL) is a mitochondrial lipid with diverse roles in cellular respiration, signaling, and organelle membrane structure. CL content and composition are essential for proper mitochondrial function. Deranged mitochondrial energy production and signaling are key components of glial cell cancers and altered CL [...] Read more.
Cardiolipin (CL) is a mitochondrial lipid with diverse roles in cellular respiration, signaling, and organelle membrane structure. CL content and composition are essential for proper mitochondrial function. Deranged mitochondrial energy production and signaling are key components of glial cell cancers and altered CL molecular species have been observed in mouse brain glial cell xenograft tumors. The objective of this study was to describe CL structural diversity trends in human astrocytoma tumors of varying grades and correlate these trends with histological regions within the heterogeneous astrocytoma microenvironment. To this aim, we applied desorption electrospray ionization coupled with high field asymmetric ion mobility mass spectrometry (DESI-FAIMS-MS) to map CL molecular species in human normal cortex (N = 29), lower-grade astrocytoma (N = 19), and glioblastoma (N = 28) tissues. With this platform, we detected 46 CL species and 12 monolysocardiolipin species from normal cortex samples. CL profiles detected from glioblastoma tissues lacked diversity and abundance of longer chain polyunsaturated fatty acid containing CL species when compared to CL detected from normal and lower-grade tumors. CL profiles correlated with trends in tumor viability and tumor infiltration. Structural characterization of the CL species by tandem MS experiments revealed differences in fatty acid and double bond isomer composition among astrocytoma tissues compared with normal cortex and glioblastoma tissues. The GlioVis platform was used to analyze astrocytoma gene expression data from the CGGA dataset. Decreased expression of several mitochondrial respiratory enzyme encoding-genes was observed for higher-grade versus lower-grade tumors, however no significant difference was observed for cardiolipin synthesis enzyme CRLS1. Full article
(This article belongs to the Special Issue Metabolic Hallmarks of Malignant Cells)
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20 pages, 3158 KiB  
Article
Effects of Co-Culture EBV-miR-BART1-3p on Proliferation and Invasion of Gastric Cancer Cells Based on Exosomes
by Mengyao Lin, Shun Hu, Tianyi Zhang, Jiezhen Li, Feng Gao, Zhenzhen Zhang, Ke Zheng, Guoping Li, Caihong Ren, Xiangna Chen, Fang Guo and Sheng Zhang
Cancers 2023, 15(10), 2841; https://doi.org/10.3390/cancers15102841 - 19 May 2023
Cited by 2 | Viewed by 1882
Abstract
Aim: EBV encodes at least 44 miRNAs involved in immune regulation and disease progression. Exosomes can be used as carriers of EBV-miRNA-BART intercellular transmission and affect the biological behavior of cells. We characterized exosomes and established a co-culture experiment of exosomes to explore [...] Read more.
Aim: EBV encodes at least 44 miRNAs involved in immune regulation and disease progression. Exosomes can be used as carriers of EBV-miRNA-BART intercellular transmission and affect the biological behavior of cells. We characterized exosomes and established a co-culture experiment of exosomes to explore the mechanism of miR-BART1-3p transmission through the exosome pathway and its influence on tumor cell proliferation and invasion. Materials and methods: Exosomes of EBV-positive and EBV-negative gastric cancer cells were characterized by transmission electron microscopy. NanoSight and Western blotting, and miRNA expression profiles in exosomes were sequenced with high throughput. Exosomes with high or low expression of miR-BART1-3p were co-cultured with AGS cells to study the effects on proliferation, invasion, and migration of gastric cancer cells. The target genes of EBV-miR-BART1-3p were screened and predicted by PITA, miRanda, RNAhybrid, virBase, and DIANA-TarBase v.8 databases, and the expression of the target genes after co-culture was detected by qPCR. Results: The exosomes secreted by EBV-positive and negative gastric cancer cells range in diameter from 30 nm to 150 nm and express the exosomal signature proteins CD9 and CD63. Small RNA sequencing showed that exosomes expressed some human miRNAs, among which hsa-miR-23b-3p, hsa-miR-320a-3p, and hsa-miR-4521 were highly expressed in AGS-exo; hsa-miR-21-5p, hsa-miR-148a-3p, and hsa-miR-7-5p were highly expressed in SNU-719-exo. All EBV miRNAs were expressed in SNU-719 cells and their exosomes, among which EBV-miR-BART1-5p, EBV-miR-BART22, and EBV-miR-BART16 were the highest in SNU-719 cells; EBV-miR-BART1-5p, EBV-miR-BART10-3p, and EBV-miR-BART16 were the highest in SNU-719-exo. After miR-BART1-3p silencing in gastric cancer cells, the proliferation, healing, migration, and invasion of tumor cells were significantly improved. Laser confocal microscopy showed that exosomes could carry miRNA into recipient cells. After co-culture with miR-BART1-3p silenced exosomes, the proliferation, healing, migration, and invasion of gastric cancer cells were significantly improved. The target gene of miR-BART1-3p was FAM168A, MACC1, CPEB3, ANKRD28, and USP37 after screening by a targeted database. CPEB3 was not expressed in all exosome co-cultured cells, while ANKRD28, USP37, MACC1, and FAM168A were all expressed to varying degrees. USP37 and MACC1 were down-regulated after up-regulation of miR-BART1-3p, which may be the key target genes for miR-BART1-3p to regulate the proliferation of gastric cancer cells through exosomes. Conclusions: miR-BART1-3p can affect the growth of tumor cells through the exosome pathway. The proliferation, healing, migration, and invasion of gastric cancer cells were significantly improved after co-culture with exosomes of miR-BART1-3p silenced expression. USP37 and MACC1 may be potential target genes of miR-BART1-3p in regulating cell proliferation. Full article
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11 pages, 1865 KiB  
Article
Impact of Postoperative Changes in Brain Anatomy on Target Volume Delineation for High-Grade Glioma
by Cas Stefaan Dejonckheere, Anja Thelen, Birgit Simon, Susanne Greschus, Mümtaz Ali Köksal, Leonard Christopher Schmeel, Timo Wilhelm-Buchstab and Christina Leitzen
Cancers 2023, 15(10), 2840; https://doi.org/10.3390/cancers15102840 - 19 May 2023
Cited by 1 | Viewed by 1578
Abstract
High-grade glioma has a poor prognosis, and radiation therapy plays a crucial role in its management. Every step of treatment planning should thus be optimised to maximise survival chances and minimise radiation-induced toxicity. Here, we compare structures needed for target volume delineation between [...] Read more.
High-grade glioma has a poor prognosis, and radiation therapy plays a crucial role in its management. Every step of treatment planning should thus be optimised to maximise survival chances and minimise radiation-induced toxicity. Here, we compare structures needed for target volume delineation between an immediate postoperative magnetic resonance imaging (MRI) and a radiation treatment planning MRI to establish the need for the latter. Twenty-eight patients were included, with a median interval between MRIs (range) of 19.5 (8–50) days. There was a mean change in resection cavity position (range) of 3.04 ± 3.90 (0–22.1) mm, with greater positional changes in skull-distant (>25 mm) resection cavity borders when compared to skull-near (≤25 mm) counterparts (p < 0.001). The mean differences in resection cavity and surrounding oedema and FLAIR hyperintensity volumes were −32.0 ± 29.6% and −38.0 ± 25.0%, respectively, whereas the mean difference in midline shift (range) was −2.64 ± 2.73 (0–11) mm. These data indicate marked short-term volumetric changes and support the role of an MRI to aid in target volume delineation as close to radiation treatment start as possible. Planning adapted to the actual anatomy at the time of radiation limits the risk of geographic miss and might thus improve outcomes in patients undergoing adjuvant radiation for high-grade glioma. Full article
(This article belongs to the Special Issue Brain Cancer: Imaging and Radiotherapy)
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