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Cancers, Volume 16, Issue 4 (February-2 2024) – 163 articles

Cover Story (view full-size image): Epiregulin (EREG), a member of the EGF family, binds to the EGFR and ErbB4, and it stimulates EGFR-related downstream pathways. Increasing evidence indicates that EREG plays a pivotal role in the development of many human cancers, including non-small cell lung cancer. EREG overexpression is induced by activating mutations in the EGFR, KRAS, and BRAF and contributes to the aggressive phenotypes of non-small cell lung cancer with such oncogenic drivers. Recent studies have elucidated the roles of EREG in a tumor microenvironment, including the epithelial–mesenchymal transition, angiogenesis, immune evasion, and resistance to anticancer therapy. Here, we summarized the current understanding of EREG as an oncogene and discussed its oncogenic role in lung tumorigenesis and therapeutic resistance. View this paper
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14 pages, 1878 KiB  
Article
Predictive Markers of Treatment Response to Neoadjuvant Systemic Therapy with Dual HER2-Blockade
by Soong June Bae, Jee Hung Kim, Min Ji Lee, Seung Ho Baek, Yoonwon Kook, Sung Gwe Ahn, Yoon Jin Cha and Joon Jeong
Cancers 2024, 16(4), 842; https://doi.org/10.3390/cancers16040842 - 19 Feb 2024
Cited by 2 | Viewed by 711
Abstract
In patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer, achievement of pathologic complete response (pCR) is a known prognostic indicator after neoadjuvant systemic therapy (NAST). We investigated the clinicopathological factors associated with pCR in patients with HER2-positive breast cancer treated [...] Read more.
In patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer, achievement of pathologic complete response (pCR) is a known prognostic indicator after neoadjuvant systemic therapy (NAST). We investigated the clinicopathological factors associated with pCR in patients with HER2-positive breast cancer treated with dual HER2-blockade. In this retrospective study, 348 patients with HER2-positive breast cancer who received NAST with docetaxel and carboplatin, combined with trastuzumab and pertuzumab (TCHP), were included. Of the 348 patients with HER2 protein expression data, 278 (79.9%) had HER2 immunochemistry (IHC) 3+. Data on tumor-infiltrating lymphocyte (TIL) levels were available for 305 patients, showing a median TIL level of 20% (IQR 5–50), among which 121 (39.7%) had high TIL levels (≥30%). Estrogen receptor (ER) status (77.9% in ER-negative vs. 47.5% in ER-positive; p < 0.001), HER2 protein expression (71.6% in IHC 3+ vs. 34.3% in IHC 2+; p < 0.001), and TIL levels (71.9% in high vs. 57.6% in low; p = 0.011) were significantly associated with the pCR rate. In addition, we observed a significant link between numerical TIL levels (per 10% increment) and the pCR rate. After adjusting other clinicopathologic factors, ER status (low expression [defined as 1–9% expression] or negative), HER2 IHC 3+ and numerical TIL levels (per 10% increment), and high TIL levels (≥30%) were found to be independent predictors of pCR. Notably, in ER-negative breast cancer, the treatment response was excellent, irrespective of HER2 expression and TIL levels. Conversely, in ER-positive cases, low ER expression, HER2 IHC 3+, and numerical TIL levels or high TIL levels emerged as independent predictors of pCR. Our results suggest that ER expression, HER2 protein expression, and TIL levels serve as valuable predictors of the treatment response to neoadjuvant TCHP. Full article
(This article belongs to the Special Issue Neoadjuvant Therapy of Breast Cancer)
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11 pages, 2277 KiB  
Article
Impact of Complete Surgical Resection of Metastatic Lesions in Patients with Advanced Renal Cell Carcinoma in the Era of Tyrosine Kinase Inhibitors and Immune Checkpoint Inhibitors
by Takuto Shimizu, Makito Miyake, Nobutaka Nishimura, Takanori Yoshida, Yoshitaka Itami, Akira Tachibana, Chihiro Omori, Yuki Oda, Mikiko Kohashi, Mitsuru Tomizawa, Kenta Onishi, Shunta Hori, Yosuke Morizawa, Daisuke Dotoh, Yasushi Nakai, Kazumasa Torimoto, Nobumichi Tanaka and Kiyohide Fujimoto
Cancers 2024, 16(4), 841; https://doi.org/10.3390/cancers16040841 - 19 Feb 2024
Viewed by 672
Abstract
Complete metastasectomy (CM) in metastatic renal cell carcinoma (mRCC) has demonstrated efficacy in the cytokine era, but its effectiveness in the era of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) remains unclear. A multi-institutional database included clinicopathological data of 367 patients [...] Read more.
Complete metastasectomy (CM) in metastatic renal cell carcinoma (mRCC) has demonstrated efficacy in the cytokine era, but its effectiveness in the era of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) remains unclear. A multi-institutional database included clinicopathological data of 367 patients with mRCC. Patients were divided into two groups: the CM group and the non-CM group. These two groups were compared before and after propensity score matching (PSM). Cox proportional hazard models were used to detect factors associated with disease-free survival (DFS) and overall survival (OS) from mRCC diagnosis. The CM group showed a significant association with longer overall survival compared to the non-CM group in the PSM-unadjusted cohorts (p < 0.001, hazard ratio 0.49, 95% confidence interval 0.35–0.69), but no superiority was noted in the adjusted cohorts. The median DFS after CM was 24 months, with no significant differences based on relapse timing. Notably, the international metastatic RCC database consortium risk categories and metastatic burden were associated with DFS. This study supports the potential of CM in mRCC management during the TKI/ICI era, although limitations including sample size and selection bias need to be considered. Full article
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24 pages, 25063 KiB  
Article
Identifying PLAUR as a Pivotal Gene of Tumor Microenvironment and Regulating Mesenchymal Phenotype of Glioblastoma
by Zaixiang Fu, Zihang Chen, Jingya Ye, Jianxiong Ji, Weifang Ni, Weibo Lin, Haopu Lin, Liquan Lu, Ganggui Zhu, Qin Xie, Feng Yan, Gao Chen and Fuyi Liu
Cancers 2024, 16(4), 840; https://doi.org/10.3390/cancers16040840 - 19 Feb 2024
Viewed by 729
Abstract
The mesenchymal (MES) phenotype of glioblastoma (GBM) is the most aggressive and therapy-resistant subtype of GBM. The MES phenotype transition during tumor progression results from both tumor-intrinsic genetic alterations and tumor-extrinsic microenvironmental factors. In this study, we sought to identify genes that can [...] Read more.
The mesenchymal (MES) phenotype of glioblastoma (GBM) is the most aggressive and therapy-resistant subtype of GBM. The MES phenotype transition during tumor progression results from both tumor-intrinsic genetic alterations and tumor-extrinsic microenvironmental factors. In this study, we sought to identify genes that can modulate the MES phenotype via both mechanisms. By integrating weighted gene co-expression network analysis (WGCNA) and the differential expression analysis of hypoxia-immunosuppression-related genes, we identified the plasminogen activator, urokinase receptor (PLAUR) as the hub gene. Functional enrichment analysis and GSVA analysis demonstrated that PLAUR was associated with the MES phenotype of glioma and the hypoxia-immunosuppression-related microenvironmental components. Single-cell sequencing analysis revealed that PLAUR mediated the ligand–receptor interaction between tumor-associated macrophages (TAMs) and glioma cells. Functional experiments in vitro with cell lines or primary glioma cells and xenograft models using BALB/c nude mice confirmed the role of PLAUR in promoting the MES phenotype of GBM. Our findings indicate that PLAUR regulates both glioma cells and tumor cell-extrinsic factors that favor the MES phenotype and suggest that PLAUR might be a potential target for GBM therapy. Full article
(This article belongs to the Section Tumor Microenvironment)
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16 pages, 630 KiB  
Systematic Review
FAPi-Based Agents in Thyroid Cancer: A New Step towards Diagnosis and Therapy? A Systematic Review of the Literature
by Priscilla Guglielmo, Pierpaolo Alongi, Lucia Baratto, Miriam Conte, Elisabetta Maria Abenavoli, Ambra Buschiazzo, Greta Celesti, Francesco Dondi, Rossella Filice, Joana Gorica, Lorenzo Jonghi-Lavarini, Riccardo Laudicella, Maria Librando, Flavia Linguanti, Francesco Mattana, Alberto Miceli, Laura Olivari, Leandra Piscopo, Giulia Santo, Fabio Volpe and Laura Evangelistaadd Show full author list remove Hide full author list
Cancers 2024, 16(4), 839; https://doi.org/10.3390/cancers16040839 - 19 Feb 2024
Viewed by 914
Abstract
(1) Background: Thyroid cancer (TC) is often treated with surgery followed by iodine-131. Up to 50% of the instances of TC lose their avidity to 131I, becoming more aggressive. In this scenario, [18F]FDG PET/CT imaging is used for evaluating the [...] Read more.
(1) Background: Thyroid cancer (TC) is often treated with surgery followed by iodine-131. Up to 50% of the instances of TC lose their avidity to 131I, becoming more aggressive. In this scenario, [18F]FDG PET/CT imaging is used for evaluating the widespread nature of the disease, despite its low sensitivity and a false negative rate of 8–21.1%. A novel class of PET agents targeting the fibroblast activation protein inhibitor (FAPi) has emerged, studied particularly for their potential application to theranostics. (2) Methods: A search of the literature was performed by two independent authors (P.G. and L.E.) using the PubMed, Scopus, Web of Science, Cochrane Library, and EMBASE databases. The following terms were used: “FAP” or “FAPi” or “Fibroblast activating protein” and “thyroid” or “thyroid cancer”, in different combinations. The included papers were original articles, clinical studies, and case reports in the English language. No time limits were used. Editorials, conference papers, reviews, and preclinical studies were excluded. (3) Results: There were 31 papers that were selected. Some studies reported a low or absent FAPi uptake in TC lesions; others reported promising findings for the detection of metastases. (4) Conclusions: The preliminary results are encouraging. FAPI agents are an alternative to [18F]FDG and a promising theranostic tool. However, further studies with a larger population are needed. Full article
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18 pages, 1512 KiB  
Article
Outcome of Atezolizumab Plus Bevacizumab Combination Therapy in High-Risk Patients with Advanced Hepatocellular Carcinoma
by Sang Youn Hwang, Hyun Young Woo, Jeong Heo, Hyung Jun Kim, Young Joo Park, Ki Youn Yi, Yu Rim Lee, Soo Young Park, Woo Jin Chung, Byoung Kuk Jang and Won Young Tak
Cancers 2024, 16(4), 838; https://doi.org/10.3390/cancers16040838 - 19 Feb 2024
Viewed by 767
Abstract
Real-world data regarding treatment with atezolizumab plus bevacizumab in high-risk patients with advanced HCC are lacking. In this multicenter retrospective cohort study, a total of 215 patients with advanced HCC received atezolizumab plus bevacizumab treatment at four tertiary hospitals. High-risk patients were those [...] Read more.
Real-world data regarding treatment with atezolizumab plus bevacizumab in high-risk patients with advanced HCC are lacking. In this multicenter retrospective cohort study, a total of 215 patients with advanced HCC received atezolizumab plus bevacizumab treatment at four tertiary hospitals. High-risk patients were those with grade Vp4 portal vein thrombus, bile duct invasion, or more than 50% liver infiltration. In total, 98 (45.6%) were the high-risk population, 186 (86.5%) were considered to be Child–Pugh class A, and 128 (59.5%) had previously received neoadjuvant or concomitant radiation treatment. Median overall survival (OS) was 11.25 months (95% CI, 9.50–13.10), and the median progression-free survival (PFS) was 8.00 months (95% CI, 6.82–9.18). In the high-risk population, the median OS was 10 months (95% CI, 8.19–11.82) and the median PFS was 6.50 months (95% CI, 3.93–9.08). In the high-risk population, multivariate analysis indicated that radiation therapy and lower ALBI grade were associated with better OS and PFS. A total of 177 (82.3%) patients experienced adverse events of any grade, the most common being proteinuria (23.7%). Atezolizumab plus bevacizumab treatment showed consistent efficacy and tolerability in both the total and high-risk population. Radiation therapy combined with atezolizumab plus bevacizumab treatment might be helpful to improve PFS and OS in high-risk populations. Full article
(This article belongs to the Special Issue Advances in the Prevention and Treatment of Liver Cancer)
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11 pages, 1844 KiB  
Article
Atypical Ductal Hyperplasia and Lobular In Situ Neoplasm: High-Risk Lesions Challenging Breast Cancer Prevention
by Luca Nicosia, Luciano Mariano, Giuseppe Pellegrino, Federica Ferrari, Filippo Pesapane, Anna Carla Bozzini, Samuele Frassoni, Vincenzo Bagnardi, Davide Pupo, Giovanni Mazzarol, Elisa De Camilli, Claudia Sangalli, Massimo Venturini, Maria Pizzamiglio and Enrico Cassano
Cancers 2024, 16(4), 837; https://doi.org/10.3390/cancers16040837 - 19 Feb 2024
Viewed by 848
Abstract
This retrospective study investigates the histopathological outcomes, upgrade rates, and disease-free survival (DFS) of high-risk breast lesions, including atypical ductal hyperplasia (ADH or DIN1b) and lobular in situ neoplasms (LIN), following Vacuum-Assisted Breast Biopsy (VABB) and surgical excision. The study addresses the challenge [...] Read more.
This retrospective study investigates the histopathological outcomes, upgrade rates, and disease-free survival (DFS) of high-risk breast lesions, including atypical ductal hyperplasia (ADH or DIN1b) and lobular in situ neoplasms (LIN), following Vacuum-Assisted Breast Biopsy (VABB) and surgical excision. The study addresses the challenge posed by these lesions due to their association with synchronous or adjacent Breast Cancer (BC) and increased future BC risk. The research, comprising 320 patients who underwent stereotactic VABB, focuses on 246 individuals with a diagnosis of ADH (120) or LIN (126) observed at follow-up. Pathological assessments, categorized by the UK B-coding system, were conducted, and biopsy samples were compared with corresponding excision specimens to determine upgrade rates for in situ or invasive carcinoma. Surgical excision was consistently performed for diagnosed ADH or LIN. Finally, patient follow-ups were assessed and compared between LIN and ADH groups to identify recurrence signs, defined as histologically confirmed breast lesions on either the same or opposite side. The results reveal that 176 (71.5%) patients showed no upgrade post-surgery, with ADH exhibiting a higher upgrade rate to in situ pathology than LIN1 (Atypical Lobular Hyperplasia, ALH)/LIN2 (Low-Grade Lobular in situ Carcinoma, LCIS) (38% vs. 20%, respectively, p-value = 0.002). Considering only patients without upgrade, DFS at 10 years was 77%, 64%, and 72% for ADH, LIN1, and LIN2 patients, respectively (p-value = 0.92). The study underscores the importance of a multidisciplinary approach, recognizing the evolving role of VABB. It emphasizes the need for careful follow-up, particularly for lobular lesions, offering valuable insights for clinicians navigating the complex landscape of high-risk breast lesions. The findings advocate for heightened awareness and vigilance in managing these lesions, contributing to the ongoing refinement of clinical strategies in BC care. Full article
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25 pages, 1198 KiB  
Review
Role of Cyclins and Cytoskeletal Proteins in Endometriosis: Insights into Pathophysiology
by Marcin Szymański, Klaudia Bonowicz, Paulina Antosik, Dominika Jerka, Mariola Głowacka, Małgorzata Soroka, Kerstin Steinbrink, Konrad Kleszczyński and Maciej Gagat
Cancers 2024, 16(4), 836; https://doi.org/10.3390/cancers16040836 - 19 Feb 2024
Viewed by 785
Abstract
Endometriosis is a gynecological condition where endometrium-like tissue grows outside the uterus, posing challenges in understanding and treatment. This article delves into the deep cellular and molecular processes underlying endometriosis, with a focus on the crucial roles played by cyclins and cytoskeletal proteins [...] Read more.
Endometriosis is a gynecological condition where endometrium-like tissue grows outside the uterus, posing challenges in understanding and treatment. This article delves into the deep cellular and molecular processes underlying endometriosis, with a focus on the crucial roles played by cyclins and cytoskeletal proteins in its pathogenesis, particularly in the context of Epithelial–Mesenchymal Transition (EMT). The investigation begins by examining the activities of cyclins, elucidating their diverse biological roles such as cell cycle control, proliferation, evasion of apoptosis, and angiogenesis among ectopic endometrial cells. A comprehensive analysis of cytoskeletal proteins follows, emphasizing their fundamental biological roles and their specific significance to endometriotic cell features. This review sheds light on the interconnected pathways through which cyclins and cytoskeletal proteins converge, contributing to the genesis and progression of endometriosis. Understanding these molecular complexities not only provides insight into the underlying causes of the disease but also holds promise for the development of specific therapeutic approaches, ushering in a new era in the management of this devastating disorder. Full article
(This article belongs to the Special Issue The Role of the Cytoskeleton in Tumor Progression)
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11 pages, 236 KiB  
Article
Safety and Diagnostic Efficacy of Image-Guided Biopsy of Small Renal Masses
by Muhamad Serhal, Sean Rangwani, Stephen M. Seedial, Bartley Thornburg, Ahsun Riaz, Albert A. Nemcek, Jr., Kent T. Sato, Kent T. Perry, Jr., Bonnie Choy, Robert J. Lewandowski and Andrew C. Gordon
Cancers 2024, 16(4), 835; https://doi.org/10.3390/cancers16040835 - 19 Feb 2024
Viewed by 617
Abstract
Introduction: Image-guided renal mass biopsy is gaining increased diagnostic acceptance, but there are limited data concerning the safety and diagnostic yield of biopsy for small renal masses (≤4 cm). This study evaluated the safety, diagnostic yield, and management after image-guided percutaneous biopsy for [...] Read more.
Introduction: Image-guided renal mass biopsy is gaining increased diagnostic acceptance, but there are limited data concerning the safety and diagnostic yield of biopsy for small renal masses (≤4 cm). This study evaluated the safety, diagnostic yield, and management after image-guided percutaneous biopsy for small renal masses. Methods: A retrospective IRB-approved study was conducted on patients who underwent renal mass biopsy for histopathologic diagnosis at a single center from 2015 to 2021. Patients with a prior history of malignancy or a renal mass >4 cm were excluded. Descriptive statistics were used to summarize patient demographics, tumor size, the imaging modality used for biopsy, procedure details, complications, pathological diagnosis, and post-biopsy management. A biopsy was considered successful when the specimen was sufficient for diagnosis without need for a repeat biopsy. Complications were graded according to the SIR classification of adverse events. A chi-squared test (significance level set at p ≤ 0.05) was used to compare the success rate of biopsies in different lesion size groups. Results: A total of 167 patients met the inclusion criteria. The median age was 65 years (range: 26–87) and 51% were male. The median renal mass size was 2.6 cm (range: one–four). Ultrasound was solely employed in 60% of procedures, CT in 33%, a combination of US/CT in 6%, and MRI in one case. With on-site cytopathology, the median number of specimens obtained per procedure was four (range: one–nine). The overall complication rate was 5%. Grade A complications were seen in 4% (n = 7), consisting of perinephric hematoma (n = 6) and retroperitoneal hematoma (n = 1). There was one grade B complication (0.5%; pain) and one grade D complication (0.5%; pyelonephritis). There was no patient mortality within 30 days post-biopsy. Biopsy was successful in 88% of cases. A sub-group analysis showed a success rate of 85% in tumors <3 cm and 93% in tumors ≥3 cm (p = 0.01). Pathological diagnoses included renal cell carcinoma (65%), oncocytoma (18%), clear cell papillary renal cell tumors (9%), angiomyolipoma (4%), xanthogranulomatous pyelonephritis (1%), lymphoma (1%), high-grade papillary urothelial carcinoma (1%), and metanephric adenoma (1%), revealing benign diagnosis in 30% of cases. The most common treatment was surgery (40%), followed by percutaneous cryoablation (22%). In total, 37% of patients were managed conservatively, and one patient received chemotherapy. Conclusion: This study demonstrates the safety and diagnostic efficacy of image-guided biopsy of small renal masses. The diagnostic yield was significantly higher for masses 3–4 cm in size compared to those <3 cm. The biopsy results showed a high percentage of benign diagnoses and informed treatment decisions in most patients. Full article
(This article belongs to the Collection Advances in Diagnostic and Interventional Radiology in Oncology)
22 pages, 3226 KiB  
Article
The Nitro Group Reshapes the Effects of Pyrido[3,4-g]quinazoline Derivatives on DYRK/CLK Activity and RNA Splicing in Glioblastoma Cells
by Sophia S. Borisevich, Tatiana E. Aksinina, Margarita G. Ilyina, Victoria O. Shender, Ksenia S. Anufrieva, Georgij P. Arapidi, Nadezhda V. Antipova, Fabrice Anizon, Yannick J. Esvan, Francis Giraud, Victor V. Tatarskiy, Pascale Moreau, Mikhail I. Shakhparonov, Marat S. Pavlyukov and Alexander A. Shtil
Cancers 2024, 16(4), 834; https://doi.org/10.3390/cancers16040834 - 19 Feb 2024
Viewed by 957
Abstract
Serine-threonine protein kinases of the DYRK and CLK families regulate a variety of vital cellular functions. In particular, these enzymes phosphorylate proteins involved in pre-mRNA splicing. Targeting splicing with pharmacological DYRK/CLK inhibitors emerged as a promising anticancer strategy. Investigation of the pyrido[3,4-g [...] Read more.
Serine-threonine protein kinases of the DYRK and CLK families regulate a variety of vital cellular functions. In particular, these enzymes phosphorylate proteins involved in pre-mRNA splicing. Targeting splicing with pharmacological DYRK/CLK inhibitors emerged as a promising anticancer strategy. Investigation of the pyrido[3,4-g]quinazoline scaffold led to the discovery of DYRK/CLK binders with differential potency against individual enzyme isoforms. Exploring the structure–activity relationship within this chemotype, we demonstrated that two structurally close compounds, pyrido[3,4-g]quinazoline-2,10-diamine 1 and 10-nitro pyrido[3,4-g]quinazoline-2-amine 2, differentially inhibited DYRK1-4 and CLK1-3 protein kinases in vitro. Unlike compound 1, compound 2 efficiently inhibited DYRK3 and CLK4 isoenzymes at nanomolar concentrations. Quantum chemical calculations, docking and molecular dynamic simulations of complexes of 1 and 2 with DYRK3 and CLK4 identified a dramatic difference in electron donor-acceptor properties critical for preferential interaction of 2 with these targets. Subsequent transcriptome and proteome analyses of patient-derived glioblastoma (GBM) neurospheres treated with 2 revealed that this compound impaired CLK4 interactions with spliceosomal proteins, thereby altering RNA splicing. Importantly, 2 affected the genes that perform critical functions for cancer cells including DNA damage response, p53 signaling and transcription. Altogether, these results provide a mechanistic basis for the therapeutic efficacy of 2 previously demonstrated in in vivo GBM models. Full article
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12 pages, 447 KiB  
Article
Preoperative Chronic Inflammation Is a Risk Factor for Postoperative Complications Independent of Body Composition in Gastric Cancer Patients Undergoing Radical Gastrectomy
by Ryota Matsui, Noriyuki Inaki, Toshikatsu Tsuji and Tetsu Fukunaga
Cancers 2024, 16(4), 833; https://doi.org/10.3390/cancers16040833 - 19 Feb 2024
Viewed by 605
Abstract
The purpose of this study was to investigate the association between preoperative inflammation and postoperative complications in gastric cancer patients having elective gastrectomy. Participants in this study were those who underwent radical gastrectomy between April 2008 and June 2018 and were diagnosed with [...] Read more.
The purpose of this study was to investigate the association between preoperative inflammation and postoperative complications in gastric cancer patients having elective gastrectomy. Participants in this study were those who underwent radical gastrectomy between April 2008 and June 2018 and were diagnosed with stage I–III primary gastric cancer. Preoperative CRP values were used to divide the patients into two groups: the inflammation group comprised individuals having a CRP level of ≥0.5 mg/dL; the other was the non-inflammation group. The primary outcome was overall complications of Clavien–Dindo grade II or higher after surgery. Using propensity score matching to adjust for background, we compared the postoperative outcomes of the groups and conducted a multivariate analysis to identify risk variables for complications. Of 951 patients, 852 (89.6%) were in the non-inflammation group and 99 (10.4%) were in the inflammation group. After matching, both groups included 99 patients, and no significant differences in patient characteristics were observed between both groups. The inflammation group had a significantly greater total number of postoperative complications (p = 0.019). The multivariate analysis revealed that a preoperative CRP level of ≥0.5 mg/dL was an independent risk factor for total postoperative complications in all patients (odds ratio: 2.310, 95% confidence interval: 1.430–3.730, p < 0.001). In conclusion, in patients undergoing curative resection for gastric cancer, preoperative inflammation has been found to be an independent risk factor for overall complications after surgery. Patients with chronic inflammation require preoperative treatment to reduce inflammation because chronic inflammation is the greatest risk factor for postoperative complications. Full article
(This article belongs to the Special Issue Developments in the Management of Gastrointestinal Malignancies)
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19 pages, 12313 KiB  
Article
The Combination of Anti-CD47 Antibody with CTLA4 Blockade Enhances Anti-Tumor Immunity in Non-Small Cell Lung Cancer via Normalization of Tumor Vasculature and Reprogramming of the Immune Microenvironment
by Zhan Zhuang, Jinglin Zhou, Minglian Qiu, Jiamian Li, Zhuangheng Lin, Huihan Yi, Xuerong Liu, Changyu Huang, Binghua Tang, Bo Liu and Xu Li
Cancers 2024, 16(4), 832; https://doi.org/10.3390/cancers16040832 - 19 Feb 2024
Viewed by 913
Abstract
In solid tumors, the formidable anti-tumor impact resulting from blocking the “don’t eat me” signal, arising from CD47–SIRPα interaction, is constrained, especially compared to its efficacy in hematopoietic malignancies. Activating macrophage anti-tumor activity not only necessitates the inhibition of the “don’t eat me” [...] Read more.
In solid tumors, the formidable anti-tumor impact resulting from blocking the “don’t eat me” signal, arising from CD47–SIRPα interaction, is constrained, especially compared to its efficacy in hematopoietic malignancies. Activating macrophage anti-tumor activity not only necessitates the inhibition of the “don’t eat me” signal, but also the activation of the “eat me” (pre-phagocyte) signal. Intriguingly, the cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibody (Ab) has been identified to stimulate Fc receptor-mediated active phagocytes in the tumor microenvironment, thereby generating “eat me” signals. This study postulates that concurrently targeting CD47 and CTLA4 could intensify the anti-tumor effects by simultaneously blocking the “don’t eat me” signal while triggering the “eat me” signal. The experimental data from this investigation confirm that the combined targeting of CD47 and CTLA4 enhances immunity against solid tumors in LLC cell-transplanted tumor-bearing mice. This effect is achieved by reducing myeloid-derived suppressor cell infiltration while increasing the presence of effector memory CD8+ T cells, NK1.1+ CD8+ T cells, and activated natural killer T cells. Meanwhile, combination therapy also alleviated anemia. Mechanistically, the anti-CD47 Ab is shown to upregulate CTLA4 levels in NSCLC cells by regulating Foxp1. Furthermore, targeting CD47 is demonstrated to promote tumor vascular normalization through the heightened infiltration of CD4+ T cells. These findings suggest that the dual targeting of CD47 and CTLA4 exerts anti-tumor effects by orchestrating the “eat me” and “don’t eat me” signals, reshaping the immune microenvironment, and fostering tumor vascular normalization. This combined therapeutic approach emerges as a potent strategy for effectively treating solid tumors. Full article
(This article belongs to the Special Issue Cancer Immunotherapy: Therapeutics and Mechanisms)
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15 pages, 286 KiB  
Review
Artificial Intelligence-Based Treatment Decisions: A New Era for NSCLC
by Oraianthi Fiste, Ioannis Gkiozos, Andriani Charpidou and Nikolaos K. Syrigos
Cancers 2024, 16(4), 831; https://doi.org/10.3390/cancers16040831 - 19 Feb 2024
Cited by 1 | Viewed by 1664
Abstract
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality among women and men, in developed countries, despite the public health interventions including tobacco-free campaigns, screening and early detection methods, recent therapeutic advances, and ongoing intense research on novel antineoplastic modalities. [...] Read more.
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality among women and men, in developed countries, despite the public health interventions including tobacco-free campaigns, screening and early detection methods, recent therapeutic advances, and ongoing intense research on novel antineoplastic modalities. Targeting oncogenic driver mutations and immune checkpoint inhibition has indeed revolutionized NSCLC treatment, yet there still remains the unmet need for robust and standardized predictive biomarkers to accurately inform clinical decisions. Artificial intelligence (AI) represents the computer-based science concerned with large datasets for complex problem-solving. Its concept has brought a paradigm shift in oncology considering its immense potential for improved diagnosis, treatment guidance, and prognosis. In this review, we present the current state of AI-driven applications on NSCLC management, with a particular focus on radiomics and pathomics, and critically discuss both the existing limitations and future directions in this field. The thoracic oncology community should not be discouraged by the likely long road of AI implementation into daily clinical practice, as its transformative impact on personalized treatment approaches is undeniable. Full article
(This article belongs to the Special Issue Recent Advances in Trachea, Bronchus and Lung Cancer Management)
13 pages, 1420 KiB  
Article
Knockdown of Antisense Noncoding Mitochondrial RNA Reduces Tumorigenicity of Patient-Derived Clear Cell Renal Carcinoma Cells in an Orthotopic Xenograft Mouse Model
by Mariela Araya, Francisca Sepúlveda, Jaime Villegas, Luis Alarcón, Luis O. Burzio, Verónica A. Burzio and Vincenzo Borgna
Cancers 2024, 16(4), 830; https://doi.org/10.3390/cancers16040830 - 19 Feb 2024
Viewed by 1007
Abstract
Clear cell renal cell carcinoma (ccRCC) is the most prevalent form of renal cancer and its treatment is hindered by a resistance to targeted therapies, immunotherapies and combinations of both. We have reported that the knockdown of the antisense noncoding mitochondrial RNAs (ASncmtRNAs) [...] Read more.
Clear cell renal cell carcinoma (ccRCC) is the most prevalent form of renal cancer and its treatment is hindered by a resistance to targeted therapies, immunotherapies and combinations of both. We have reported that the knockdown of the antisense noncoding mitochondrial RNAs (ASncmtRNAs) with chemically modified antisense oligonucleotides induces proliferative arrest and apoptotic death in tumor cells from many human and mouse cancer types. These studies have been mostly performed in vitro and in vivo on commercially available cancer cell lines and have shown that in mouse models tumor growth is stunted by the treatment. The present work was performed on cells derived from primary and metastatic ccRCC tumors. We established primary cultures from primary and metastatic ccRCC tumors, which were subjected to knockdown of ASncmtRNAs in vitro and in vivo in an orthotopic xenograft model in NOD/SCID mice. We found that these primary ccRCC cells are affected in the same way as tumor cell lines and in the orthotopic model tumor growth was significantly reduced by the treatment. This study on patient-derived ccRCC tumor cells represents a model closer to actual patient ccRCC tumors and shows that knockdown of ASncmtRNAs poses a potential treatment option for these patients. Full article
(This article belongs to the Special Issue Mitochondria as Targets for Cancer Therapy)
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5 pages, 210 KiB  
Editorial
Clear Cell Renal Cell Carcinoma: A Test Bench for Investigating Tumor Complexity
by Claudia Manini, Estíbaliz López-Fernández, Gorka Larrinaga and José I. López
Cancers 2024, 16(4), 829; https://doi.org/10.3390/cancers16040829 - 19 Feb 2024
Viewed by 699
Abstract
Clear cell renal cell carcinoma (CCRCC), by far the most common renal cancer subtype, is an aggressive tumor variant, serving in recent years as a prolific test bench in cancer research [...] Full article
(This article belongs to the Special Issue Clear Cell Renal Cell Carcinoma 2022–2023)
14 pages, 2284 KiB  
Article
Prognostic Value of Inflammatory Burden Index in Advanced Gastric Cancer Patients Undergoing Multimodal Treatment
by Zuzanna Pelc, Katarzyna Sędłak, Radosław Mlak, Magdalena Leśniewska, Katarzyna Mielniczek, Piotr Rola, Jacek Januszewski, Olena Zhaldak, Anna Rekowska, Katarzyna Gęca, Magdalena Skórzewska, Wojciech P. Polkowski, Timothy M. Pawlik and Karol Rawicz-Pruszyński
Cancers 2024, 16(4), 828; https://doi.org/10.3390/cancers16040828 - 18 Feb 2024
Viewed by 731
Abstract
Since increasing evidence underlines the prominent role of systemic inflammation in carcinogenesis, the inflammation burden index (IBI) has emerged as a promising biomarker to estimate survival outcomes among cancer patients. The IBI has only been validated in Eastern gastric cancer (GC) patients; therefore, [...] Read more.
Since increasing evidence underlines the prominent role of systemic inflammation in carcinogenesis, the inflammation burden index (IBI) has emerged as a promising biomarker to estimate survival outcomes among cancer patients. The IBI has only been validated in Eastern gastric cancer (GC) patients; therefore, the aim of this study was to evaluate the IBI as a prognostic biomarker in Central European GC patients undergoing multimodal treatment. Ninety-three patients with histologically confirmed GC who underwent multimodal treatment between 2013 and 2021 were included. Patient recruitment started with the standardization of neoadjuvant chemotherapy (NAC). Blood samples were obtained one day prior to surgical treatment. The textbook outcome (TO) served as the measure of surgical quality, and tumor responses to NAC were evaluated according to Becker’s system tumor regression grade (TRG). A high IBI was associated with an increased risk of postoperative complications (OR 2.95, 95% CI 1.13–7.72). In multivariate analysis, a high IBI (HR = 2.56, 95% CI 1.28–5.13) and a high neutrophil-to-lymphocyte ratio (NLR, HR = 2.55, 95% CI 1.32–4.94) were associated with an increased risk of death, while NAC administration (HR = 0.40, 95% CI 0.18–0.90) and TO achievement (HR = 0.42, 95% CI 0.22–0.81) were associated with a lower risk of death. The IBI was associated with postoperative complications and mortality among GC patients undergoing multimodal treatment. Full article
(This article belongs to the Special Issue Gastric Cancer Surgery: Gastrectomy, Risk, and Related Prognosis)
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26 pages, 2045 KiB  
Review
Innovations in Antibody-Drug Conjugate (ADC) in the Treatment of Lymphoma
by Ali Al Sbihi, Maryam Alasfour and Georgios Pongas
Cancers 2024, 16(4), 827; https://doi.org/10.3390/cancers16040827 - 18 Feb 2024
Viewed by 1367
Abstract
Chemoimmunotherapy and cellular therapy are the mainstay of the treatment of relapsed/refractory (R/R) lymphomas. Development of resistance and commonly encountered toxicities of these treatments limit their role in achieving desired response rates and durable remissions. The Antibody–Drug Conjugate (ADC) is a novel class [...] Read more.
Chemoimmunotherapy and cellular therapy are the mainstay of the treatment of relapsed/refractory (R/R) lymphomas. Development of resistance and commonly encountered toxicities of these treatments limit their role in achieving desired response rates and durable remissions. The Antibody–Drug Conjugate (ADC) is a novel class of targeted therapy that has demonstrated significant efficacy in treating various cancers, including lymphomas. To date, three ADC agents have been approved for different lymphomas, marking a significant advancement in the field. In this article, we aim to review the concept of ADCs and their application in lymphoma treatment, provide an analysis of currently approved agents, and discuss the ongoing advancements of ADC development. Full article
(This article belongs to the Special Issue Innovation in Antibody-Drug Conjugates (ADCs))
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15 pages, 3397 KiB  
Article
Baseline IgM Amounts Can Identify Patients with Poor Outcomes: Results from a Real-Life Single-Center Study on Classical Hodgkin Lymphoma
by Andrea Duminuco, Gabriella Santuccio, Annalisa Chiarenza, Amalia Figuera, Giovanna Motta, Anastasia Laura Caruso, Alessandro Petronaci, Massimo Ippolito, Claudio Cerchione, Francesco Di Raimondo and Alessandra Romano
Cancers 2024, 16(4), 826; https://doi.org/10.3390/cancers16040826 - 18 Feb 2024
Viewed by 640
Abstract
Hodgkin Lymphoma (HL) is characterized by an inflammatory background in which the reactive myeloid cells may exert an immune-suppressive effect related to the progression of the disease. Immunoglobulin M is the first antibody isotype produced during an immune response, which also plays an [...] Read more.
Hodgkin Lymphoma (HL) is characterized by an inflammatory background in which the reactive myeloid cells may exert an immune-suppressive effect related to the progression of the disease. Immunoglobulin M is the first antibody isotype produced during an immune response, which also plays an immunoregulatory role. Therefore, we investigated if, as a surrogate of defective B cell function, it could have any clinical impact on prognosis. In this retrospective, observational, single–center study, we evaluated 212 newly diagnosed HL patients, including 132 advanced-stage. A 50 mg/dL level of IgM at baseline resulted in 84.1% sensitivity and 45.5% specificity for predicting a complete response in the whole cohort (area under curve (AUC) = 0.62, p = 0.013). In multivariate analysis, baseline IgM ≤ 50 mg/dL and the presence of a large nodal mass (<7 cm) were independent variables able to predict the clinical outcome, while, after two cycles of treatment, IgM ≤ 50 mg/dL at baseline and PET-2 status were independent predictors of PFS. The amount of IgM at diagnosis is a valuable prognostic factor much earlier than PET-2, and it can also provide information for PET-2-negative patients. This can help to identify different HL classes at risk of treatment failure at baseline. Full article
(This article belongs to the Section Cancer Pathophysiology)
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21 pages, 5626 KiB  
Article
ncRNAs Orchestrate Chemosensitivity Induction by Neddylation Blockades
by Andrea Pérez-González, Ivonne Ramírez-Díaz, Josué Guzmán-Linares, Pouya Sarvari, Pourya Sarvari and Karla Rubio
Cancers 2024, 16(4), 825; https://doi.org/10.3390/cancers16040825 - 18 Feb 2024
Viewed by 1219
Abstract
We performed an integrative transcriptomic in silico analysis using lung adenocarcinoma A549 cells treated with the neddylation inhibitor MLN4924 and the gefitinib-resistant PC9 cell line (PC9GR). We focused on the transcriptional effects of the top differentially expressed ncRNA biotypes and their correlating stemness [...] Read more.
We performed an integrative transcriptomic in silico analysis using lung adenocarcinoma A549 cells treated with the neddylation inhibitor MLN4924 and the gefitinib-resistant PC9 cell line (PC9GR). We focused on the transcriptional effects of the top differentially expressed ncRNA biotypes and their correlating stemness factors. Interestingly, MLN4924-treated cells showed a significant upregulation of mRNAs involved in carcinogenesis, cell attachment, and differentiation pathways, as well as a parallel downregulation of stemness maintenance and survival signaling pathways, an effect that was inversely observed in PC9GR cells. Moreover, we found that stemness factor expression could be contrasted by selected up-regulated ncRNAs upon MLN4924 treatment in a dose and time-independent manner. Furthermore, upregulated miRNAs and lncRNA-targeted mRNAs showed an evident enrichment of proliferation, differentiation, and apoptosis pathways, while downregulated ncRNA-targeted mRNAs were implicated in stem cell maintenance. Finally, our results proved that stemness (KLF4 and FGFR2) and epithelial–mesenchymal transition (ZEB2, TWIST2, SNAI2, CDH2, and VIM) factors, which are highly expressed in PC9GR cells compared to gefitinib-sensitive PC9 cells, could be abrogated with the neddylation inhibitor MLN4924 mainly through activation of epithelial differentiation pathways, thus exerting a protective role in lung cancer cells and chemosensitivity against lung tumorigenic transformation. Full article
(This article belongs to the Special Issue Functional and Structural Insights of Non-coding RNA in Cancer)
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21 pages, 3530 KiB  
Article
Identification of Tissue miRNA Signatures for Pancreatic Ductal Adenocarcinoma
by Carlo Caputo, Michela Falco, Anna Grimaldi, Angela Lombardi, Chiara Carmen Miceli, Mariateresa Cocule, Marco Montella, Luca Pompella, Giuseppe Tirino, Severo Campione, Chiara Tammaro, Antonio Cossu, Grazia Fenu Pintori, Margherita Maioli, Donatella Coradduzza, Giovanni Savarese, Antonio Fico, Alessandro Ottaiano, Giovanni Conzo, Madhura S. Tathode, Fortunato Ciardiello, Michele Caraglia, Ferdinando De Vita and Gabriella Missoadd Show full author list remove Hide full author list
Cancers 2024, 16(4), 824; https://doi.org/10.3390/cancers16040824 - 18 Feb 2024
Cited by 1 | Viewed by 957
Abstract
Pancreatic ductal adenocarcinoma (PDAC), a neoplasm of the gastrointestinal tract, is the most common pancreatic malignancy (90%) and the fourth highest cause of cancer mortality worldwide. Surgery intervention is currently the only strategy able to offer an advantage in terms of overall survival, [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC), a neoplasm of the gastrointestinal tract, is the most common pancreatic malignancy (90%) and the fourth highest cause of cancer mortality worldwide. Surgery intervention is currently the only strategy able to offer an advantage in terms of overall survival, but prognosis remains poor even for operated patients. Therefore, the development of robust biomarkers for early diagnosis and prognostic stratification in clinical practice is urgently needed. In this work, we investigated deregulated microRNAs (miRNAs) in tissues from PDAC patients with high (G3) or low (G2) histological grade and with (N+) or without (N−) lymph node metastases. miRNA expression profiling was performed by a comprehensive PCR array and subsequent validation by RT-qPCR. The results showed a significant increase in miR-1-3p, miR-31-5p, and miR-205-5p expression in G3 compared to G2 patients (** p < 0.01; *** p < 0.001; *** p < 0.001). miR-518d-3p upregulation and miR-215-5p downregulation were observed in N+ compared to N− patients. A statistical analysis performed using OncomiR program showed the significant involvement (p < 0.05) of two miRNAs (miR-31 and miR-205) in the histological grade of PDAC patients. Also, an expression analysis in PDAC patients showed that miR-31 and miR-205 had the highest expression at grade 3 compared with normal and other tumor grades. Overall, survival plots confirmed that the overexpression of miR-31 and miR-205 was significantly correlated with decreased survival in TCGA PDAC clinical samples. A KEGG pathway analysis showed that all three miRNAs are involved in the regulation of multiple pathways, including the Hippo signaling, adherens junction and microRNAs in cancer, along with several target genes. Based on in silico analysis and experimental validation, our study suggests the potential role of miR-1-3p, miR-31-5p, and miR-205-5p as useful clinical biomarkers and putative therapeutic targets in PDAC, which should be further investigated to determine the specific molecular processes affected by their aberrant expression. Full article
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24 pages, 4039 KiB  
Review
Exosomes in Glioma: Unraveling Their Roles in Progression, Diagnosis, and Therapy
by Song Yang, Yumeng Sun, Wei Liu, Yi Zhang, Guozhu Sun, Bai Xiang and Jiankai Yang
Cancers 2024, 16(4), 823; https://doi.org/10.3390/cancers16040823 - 18 Feb 2024
Cited by 1 | Viewed by 1084
Abstract
Gliomas, the most prevalent primary malignant brain tumors, present a challenging prognosis even after undergoing surgery, radiation, and chemotherapy. Exosomes, nano-sized extracellular vesicles secreted by various cells, play a pivotal role in glioma progression and contribute to resistance against chemotherapy and radiotherapy by [...] Read more.
Gliomas, the most prevalent primary malignant brain tumors, present a challenging prognosis even after undergoing surgery, radiation, and chemotherapy. Exosomes, nano-sized extracellular vesicles secreted by various cells, play a pivotal role in glioma progression and contribute to resistance against chemotherapy and radiotherapy by facilitating the transportation of biological molecules and promoting intercellular communication within the tumor microenvironment. Moreover, exosomes exhibit the remarkable ability to traverse the blood–brain barrier, positioning them as potent carriers for therapeutic delivery. These attributes hold promise for enhancing glioma diagnosis, prognosis, and treatment. Recent years have witnessed significant advancements in exosome research within the realm of tumors. In this article, we primarily focus on elucidating the role of exosomes in glioma development, highlighting the latest breakthroughs in therapeutic and diagnostic approaches, and outlining prospective directions for future research. Full article
(This article belongs to the Special Issue Novel Diagnostic and Therapeutic Approaches in Diffuse Gliomas)
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16 pages, 2070 KiB  
Review
The Rise of Hypothesis-Driven Artificial Intelligence in Oncology
by Zilin Xianyu, Cristina Correia, Choong Yong Ung, Shizhen Zhu, Daniel D. Billadeau and Hu Li
Cancers 2024, 16(4), 822; https://doi.org/10.3390/cancers16040822 - 18 Feb 2024
Viewed by 2763
Abstract
Cancer is a complex disease involving the deregulation of intricate cellular systems beyond genetic aberrations and, as such, requires sophisticated computational approaches and high-dimensional data for optimal interpretation. While conventional artificial intelligence (AI) models excel in many prediction tasks, they often lack interpretability [...] Read more.
Cancer is a complex disease involving the deregulation of intricate cellular systems beyond genetic aberrations and, as such, requires sophisticated computational approaches and high-dimensional data for optimal interpretation. While conventional artificial intelligence (AI) models excel in many prediction tasks, they often lack interpretability and are blind to the scientific hypotheses generated by researchers to enable cancer discoveries. Here we propose that hypothesis-driven AI, a new emerging class of AI algorithm, is an innovative approach to uncovering the complex etiology of cancer from big omics data. This review exemplifies how hypothesis-driven AI is different from conventional AI by citing its application in various areas of oncology including tumor classification, patient stratification, cancer gene discovery, drug response prediction, and tumor spatial organization. Our aim is to stress the feasibility of incorporating domain knowledge and scientific hypotheses to craft the design of new AI algorithms. We showcase the power of hypothesis-driven AI in making novel cancer discoveries that can be overlooked by conventional AI methods. Since hypothesis-driven AI is still in its infancy, open questions such as how to better incorporate new knowledge and biological perspectives to ameliorate bias and improve interpretability in the design of AI algorithms still need to be addressed. In conclusion, hypothesis-driven AI holds great promise in the discovery of new mechanistic and functional insights that explain the complexity of cancer etiology and potentially chart a new roadmap to improve treatment regimens for individual patients. Full article
(This article belongs to the Collection Artificial Intelligence in Oncology)
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17 pages, 2113 KiB  
Review
Malignant Acute Colonic Obstruction: Multidisciplinary Approach for Endoscopic Management
by Aurelio Mauro, Davide Scalvini, Sabrina Borgetto, Paola Fugazzola, Stefano Mazza, Ilaria Perretti, Anna Gallotti, Anna Pagani, Luca Ansaloni and Andrea Anderloni
Cancers 2024, 16(4), 821; https://doi.org/10.3390/cancers16040821 - 18 Feb 2024
Viewed by 633
Abstract
Patients presenting with acute colonic obstruction are usually evaluated in the emergency department and multiple specialties are involved in the patients’ management. Pre-treatment evaluation is essential in order to establish the correct endoscopic indication for stent implantation. Contrast-enhanced imaging could allow the exclusion [...] Read more.
Patients presenting with acute colonic obstruction are usually evaluated in the emergency department and multiple specialties are involved in the patients’ management. Pre-treatment evaluation is essential in order to establish the correct endoscopic indication for stent implantation. Contrast-enhanced imaging could allow the exclusion of benign causes of colonic obstruction and evaluation of the length of malignant stricture. Endoscopic stenting is the gold standard of treatment for palliative indications whereas there are still concerns about its use as a bridge to surgery. Different meta-analyses showed that stenting as a bridge to surgery improves short-term surgical outcomes but has no role in improving long-term outcomes. Multidisciplinary evaluation is also essential in patients that may be started on or are currently receiving antiangiogenic agents because endoscopic stenting may increase the risk of perforation. Evidence in the literature is weak and based on retrospective data. Here we report on how to correctly evaluate a patient with acute colonic malignant obstruction in collaboration with other essential specialists including a radiologist, surgeon and oncologist, and how to optimize the technique of endoscopic stenting. Full article
(This article belongs to the Special Issue The Application of Endoscopy in Gastrointestinal Cancers)
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19 pages, 6932 KiB  
Article
Inhibitory Effects of Alpha-Connexin Carboxyl-Terminal Peptide on Canine Mammary Epithelial Cells: A Study on Benign and Malignant Phenotypes
by Ivone Izabel Mackowiak da Fonseca, Marcia Kazumi Nagamine, Ayami Sato, Carlos Alberto Rossatto-Jr, Elizabeth Shinmay Yeh and Maria Lucia Zaidan Dagli
Cancers 2024, 16(4), 820; https://doi.org/10.3390/cancers16040820 - 18 Feb 2024
Viewed by 783
Abstract
Mammary cancer is highly prevalent in non-castrated female dogs. Cell-to-cell communication is an important mechanism to maintain homeostasis, and connexins are proteins that assemble to form the communicating gap junctions. In many cancers, communication capacity is reduced; several approaches are being tested in [...] Read more.
Mammary cancer is highly prevalent in non-castrated female dogs. Cell-to-cell communication is an important mechanism to maintain homeostasis, and connexins are proteins that assemble to form the communicating gap junctions. In many cancers, communication capacity is reduced; several approaches are being tested in order to increase the communication capacity in cancer cells and, therefore, alter their viability. This study analyzed the effects of the alpha-connexin carboxyl-terminal peptide (αCT1) on canine mammary non-neoplastic and neoplastic epithelial cells. Seven canine epithelial mammary cell lines were used. Among these, one was a normal canine epithelial mammary cell line (LOEC-NMG), two canine mammary adenomas (LOEC-MAd1 and LOEC-MAd2), and four canine mammary adenocarcinomas (LOEC-MCA1, LOEC-MCA2, LOEC-MCA3 and CF41). The αCT1 corresponds to a short Cx43 C-terminal sequence linked to an internalization sequence called the antennapedia. After 24 h of incubation, the medium containing different αCT1 peptide concentrations was added to the cells, and only the culture medium was used for control. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test was used to quantify cell viability before treatment and 48, 72, and 96 h after the treatment. Results showed that the normal mammary epithelial cell line (LOEC-NMG) was resistant to treatment with αCT1, which is consistent with a previous study on human mammary cell lines. One of the adenoma cell lines (LOEC-MAd2) was also resistant to treatment with αCT1, although the other (LOEC-MAd1) was susceptible to treatment, mostly at 72 h after treatment. Regarding the four canine adenocarcinoma cell lines, they differ regarding the susceptibility to the treatment with αCT1. Three cell lines, canine mixed adenocarcinoma (LOEC-MCA1), canine complex adenocarcinoma (LOEC-MCA2), and commercial canine mammary adenocarcinoma cell line CF41, were susceptible to treatment with αCT1, while one canine mammary adenocarcinoma cell line (LOEC-MCA3) was resistant to treatment. In most αCT1 treated cell lines, Cx43 was strongly detected in cell membranes by immunofluorescence. We propose that αCT1 restored the cell-to-cell communication capacity of neoplastic cells and induced inhibitory effects on cell viability. Full article
(This article belongs to the Special Issue Cellular Communication, Carcinogenesis and Targeted Interventions)
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11 pages, 943 KiB  
Review
Saving Lives in Thoracic Surgery: Balancing Oncological Radicality and Functional Preservation, Transitioning from Standard Pneumonectomy to Targeted Sublobar Resection
by Takashi Eguchi, Hirotaka Kumeda, Kentaro Miura, Kazutoshi Hamanaka and Kimihiro Shimizu
Cancers 2024, 16(4), 819; https://doi.org/10.3390/cancers16040819 - 18 Feb 2024
Viewed by 600
Abstract
This review chronicles the evolution of thoracic surgical interventions, from the standardized pneumonectomy to the precise approach of sublobar resections. It discusses the emergence and acceptance of minimally invasive and robot-assisted surgical techniques, highlighting their impact on improving outcomes beyond cancer and their [...] Read more.
This review chronicles the evolution of thoracic surgical interventions, from the standardized pneumonectomy to the precise approach of sublobar resections. It discusses the emergence and acceptance of minimally invasive and robot-assisted surgical techniques, highlighting their impact on improving outcomes beyond cancer and their influence on the surgical management of early-stage lung cancer. Evaluating historical developments alongside present methodologies, this review underscores the critical need for meticulous surgical planning and execution to optimize both oncological radicality and functional preservation. This evolution portrayed not only technical advancements but also a shift in the clinical approach towards tailored, organ-preserving methodologies, culminating in a contemporary framework promoting sublobar resections as the standard for specific patient profiles, signifying a new era of precision in thoracic surgery. Full article
(This article belongs to the Section Cancer Therapy)
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0 pages, 203 KiB  
Editorial
Chronic Viral Infections and Cancer, Openings for Therapies and Vaccines
by Maria G. Isaguliants, Alexander V. Ivanov and Franco M. Buonaguro
Cancers 2024, 16(4), 818; https://doi.org/10.3390/cancers16040818 - 18 Feb 2024
Viewed by 728
Abstract
Infections are responsible for approximately one out of six cases of cancer worldwide [...] Full article
18 pages, 826 KiB  
Review
The Role of Pelvic Exenteration in Cervical Cancer: A Review of the Literature
by Ana Carla Franco Ubinha, Priscila Grecca Pedrão, Aline Cássia Tadini, Ronaldo Luis Schmidt, Marcelo Henrique dos Santos, Carlos Eduardo Mattos da Cunha Andrade, Adhemar Longatto Filho and Ricardo dos Reis
Cancers 2024, 16(4), 817; https://doi.org/10.3390/cancers16040817 - 18 Feb 2024
Cited by 1 | Viewed by 898
Abstract
Pelvic exenteration represents a radical procedure aimed at achieving complete tumor resection with negative margins. Although it is the only therapeutic option for some cases of advanced tumors, it is associated with several perioperative complications. We believe that careful patient selection is related [...] Read more.
Pelvic exenteration represents a radical procedure aimed at achieving complete tumor resection with negative margins. Although it is the only therapeutic option for some cases of advanced tumors, it is associated with several perioperative complications. We believe that careful patient selection is related to better oncologic outcomes and lower complication rates. The objectives of this review are to identify the most current indications for this intervention, suggest criteria for case selection, evaluate recommendations for perioperative care, and review oncologic outcomes and potential associated complications. To this end, an analysis of English language articles in PubMed was performed, searching for topics such as the indication for pelvic exenteration for recurrent gynecologic neoplasms selection of oncologic cases, the impact of tumor size and extent on oncologic outcomes, preoperative and postoperative surgical management, surgical complications, and outcomes of overall survival and recurrence-free survival. Full article
(This article belongs to the Special Issue Management of Locally Advanced Cervical Cancer)
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24 pages, 1041 KiB  
Review
Circulating Tumor Cells: How Far Have We Come with Mining These Seeds of Metastasis?
by Vijay Radhakrishnan, Jussuf T. Kaifi and Kanve N. Suvilesh
Cancers 2024, 16(4), 816; https://doi.org/10.3390/cancers16040816 - 17 Feb 2024
Viewed by 1166
Abstract
Circulating tumor cells (CTCs) are cancer cells that slough off from the tumor and circulate in the peripheral blood and lymphatic system as micro metastases that eventually results in macro metastases. Through a simple blood draw, sensitive CTC detection from clinical samples has [...] Read more.
Circulating tumor cells (CTCs) are cancer cells that slough off from the tumor and circulate in the peripheral blood and lymphatic system as micro metastases that eventually results in macro metastases. Through a simple blood draw, sensitive CTC detection from clinical samples has proven to be a useful tool for determining the prognosis of cancer. Recent technological developments now make it possible to detect CTCs reliably and repeatedly from a simple and straightforward blood test. Multicenter trials to assess the clinical value of CTCs have demonstrated the prognostic value of these cancer cells. Studies on CTCs have filled huge knowledge gap in understanding the process of metastasis since their identification in the late 19th century. However, these rare cancer cells have not been regularly used to tailor precision medicine and or identify novel druggable targets. In this review, we have attempted to summarize the milestones of CTC-based research from the time of identification to molecular characterization. Additionally, the need for a paradigm shift in dissecting these seeds of metastasis and the possible future avenues to improve CTC-based discoveries are also discussed. Full article
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0 pages, 1052 KiB  
Article
Relationship between the Expression of CHK2 and p53 in Tumor Tissue and the Course of Papillary Thyroid Cancer in Patients with CHEK2 Germline Mutations
by Danuta Gąsior-Perczak, Artur Kowalik, Janusz Kopczyński, Paweł Macek, Kornelia Niemyska, Agnieszka Walczyk, Krzysztof Gruszczyński, Monika Siołek, Tomasz Dróżdż, Marcin Kosowski, Iwona Pałyga, Piotr Przybycień, Olga Wabik, Stanisław Góźdź and Aldona Kowalska
Cancers 2024, 16(4), 815; https://doi.org/10.3390/cancers16040815 - 17 Feb 2024
Viewed by 718
Abstract
The aim of this study was to determine whether the expression of CHK2 and p53 in tumor tissue in carriers of germline CHEK2 mutations can serve as a prognostic marker for PTC, and whether CHEK2 and TP53 copy numbers correlates with the course [...] Read more.
The aim of this study was to determine whether the expression of CHK2 and p53 in tumor tissue in carriers of germline CHEK2 mutations can serve as a prognostic marker for PTC, and whether CHEK2 and TP53 copy numbers correlates with the course of PTC disease. This study included 156 PTC patients previously tested for the presence of CHEK2. Clinicopathological features, treatment response, disease outcome, and germline mutation status of the CHEK2 gene were assessed with respect to CHK2 and p53 expression, and CHEK2 and TP53 gene copy statuses. In patients with and without a germline mutation in CHEK2 and with higher CHK2 expression, the chances of an excellent treatment response and no evidence of disease were lower than in patients without or with lower CHK2 expression. TP53 deletion was associated with angioinvasion. In patients with a truncating mutation, the chance of a CHEK2 deletion was higher than in patients with WT CHEK2 alone or those with WT CHEK2 and with the missense I157T mutation. Higher CHK2 expression was associated with poorer treatment responses and disease outcomes. Higher CHK2 expression and positive p53 together with a TP53 deletion could be a prognostic marker of unfavorable disease outcomes in patients with germline truncating mutations in CHEK2. Full article
(This article belongs to the Special Issue Thyroid Cancer: Diagnosis, Prognosis and Treatment)
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23 pages, 5097 KiB  
Article
Transduction Efficiency of Zika Virus E Protein Pseudotyped HIV-1gfp and Its Oncolytic Activity Tested in Primary Glioblastoma Cell Cultures
by Jan Patrick Formanski, Hai Dang Ngo, Vivien Grunwald, Celine Pöhlking, Jana Sue Jonas, Dominik Wohlers, Birco Schwalbe and Michael Schreiber
Cancers 2024, 16(4), 814; https://doi.org/10.3390/cancers16040814 - 17 Feb 2024
Viewed by 808
Abstract
The development of new tools against glioblastoma multiforme (GBM), the most aggressive and common cancer originating in the brain, remains of utmost importance. Lentiviral vectors (LVs) are among the tools of future concepts, and pseudotyping offers the possibility of tailoring LVs to efficiently [...] Read more.
The development of new tools against glioblastoma multiforme (GBM), the most aggressive and common cancer originating in the brain, remains of utmost importance. Lentiviral vectors (LVs) are among the tools of future concepts, and pseudotyping offers the possibility of tailoring LVs to efficiently transduce and inactivate GBM tumor cells. Zika virus (ZIKV) has a specificity for GBM cells, leaving healthy brain cells unharmed, which makes it a prime candidate for the development of LVs with a ZIKV coat. Here, primary GBM cell cultures were transduced with different LVs encased with ZIKV envelope variants. LVs were generated by using the pNLgfpAM plasmid, which produces the lentiviral, HIV-1-based, core particle with GFP (green fluorescent protein) as a reporter (HIVgfp). Using five different GBM primary cell cultures and three laboratory-adapted GBM cell lines, we showed that ZIKV/HIVgfp achieved a 4–6 times higher transduction efficiency compared to the commonly used VSV/HIVgfp. Transduced GBM cell cultures were monitored over a period of 9 days to identify GFP+ cells to study the oncolytic effect due to ZIKV/HIVgfp entry. Tests of GBM tumor specificity by transduction of GBM tumor and normal brain cells showed a high specificity for GBM cells. Full article
(This article belongs to the Special Issue Feature Papers in Section "Methods and Technologies Development")
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12 pages, 2341 KiB  
Article
Cost–Utility Analysis of Tenofovir Alafenamide and Entecavir in Chronic Hepatitis B Patients: A Markov Decision Model
by Chun-Huang Lai, Hon-Yi Shi, Cheng-En Tsai, Yuan-Chieh Yang and Si-Un Frank Chiu
Cancers 2024, 16(4), 813; https://doi.org/10.3390/cancers16040813 - 17 Feb 2024
Viewed by 585
Abstract
From the perspective of health economics, the evaluation of drug-related cost effectiveness and clinical utility is crucial. We conducted a cost–utility analysis of two first-line drugs, tenofovir alafenamide (TAF) and entecavir (ETV), in the treatment of chronic hepatitis B (CHB) patients. We performed [...] Read more.
From the perspective of health economics, the evaluation of drug-related cost effectiveness and clinical utility is crucial. We conducted a cost–utility analysis of two first-line drugs, tenofovir alafenamide (TAF) and entecavir (ETV), in the treatment of chronic hepatitis B (CHB) patients. We performed inverse probability of treatment weighting (IPTW) to match the independent variables between the two treatment groups. The incremental cost effectiveness ratio (ICER) of the two treatment groups was simulated using a decision tree with the Markov annual-cycle model. A total of 54 patients treated with TAF and 98 with ETV from January 2016 to December 2020 were enrolled. The total medical cost in the TAF group was NT$76,098 less than that in the ETV group, and TAF demonstrated more effectiveness than ETV by 3.19 quality-adjusted life years (QALYs). When the time horizon was set at 30 years, the ICER of the TAF group compared with the ETV group was −NT$23,878 per QALY, suggesting more cost savings for TAF. Additionally, with the application of TAF, over NT$366 million (approximately US$12 million) can be saved annually. TAF demonstrates cheaper medical costs and more favorable clinical QALYs than ETV. To balance health insurance benefits and cost effectiveness, TAF is the optimal treatment for CHB. Full article
(This article belongs to the Section Cancer Survivorship and Quality of Life)
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