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Editor’s Choice Articles

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

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Article

11 pages, 7015 KiB  
Article
A Phase II Clinical Trial of Pembrolizumab Efficacy and Safety in Advanced Renal Medullary Carcinoma
by Chijioke Nze, Pavlos Msaouel, Mohamed H. Derbala, Bettzy Stephen, Abdulrahman Abonofal, Funda Meric-Bernstam, Nizar M. Tannir and Aung Naing
Cancers 2023, 15(15), 3806; https://doi.org/10.3390/cancers15153806 - 27 Jul 2023
Cited by 12 | Viewed by 3355
Abstract
Background. Renal medullary carcinoma (RMC) is one of most aggressive renal cell carcinomas and novel therapeutic strategies are therefore needed. Recent comprehensive molecular and immune profiling of RMC tissues revealed a highly inflamed phenotype, suggesting the potential therapeutic role for immune checkpoint therapies. [...] Read more.
Background. Renal medullary carcinoma (RMC) is one of most aggressive renal cell carcinomas and novel therapeutic strategies are therefore needed. Recent comprehensive molecular and immune profiling of RMC tissues revealed a highly inflamed phenotype, suggesting the potential therapeutic role for immune checkpoint therapies. We present the first prospective evaluation of an immune checkpoint inhibitor in a cohort of patients with RMC. Methods. A cohort of patients with locally advanced or metastatic RMC was treated with pembrolizumab 200 mg intravenously every 21 days in a phase II basket trial (ClinicalTrials.gov: NCT02721732). Responses were assessed by irRECIST. Tumor tissues were evaluated for PD-L1 expression and for tumor-infiltrating lymphocyte (TIL) levels. Somatic mutations were assessed by targeted next-generation sequencing. Results. A total of five patients were treated. All patients had advanced disease, with the majority of patients (60%) having metastatic disease at diagnosis. All patients had rapid disease progression despite pembrolizumab treatment, with a median time to progression of 8.7 weeks. One patient (patient 5) experienced sudden clinical progression immediately after treatment initiation and was thus taken off trial less than one week after receiving pembrolizumab. Conclusions. This prospective evaluation showed no evidence of clinical activity for pembrolizumab in patients with RMC, irrespective of PD-L1 or TIL levels. Full article
(This article belongs to the Special Issue Clinical and Translational Updates in Renal Cell Carcinoma)
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13 pages, 1190 KiB  
Article
Enhancing Triage Efficiency and Accuracy in Emergency Rooms for Patients with Metastatic Prostate Cancer: A Retrospective Analysis of Artificial Intelligence-Assisted Triage Using ChatGPT 4.0
by Georges Gebrael, Kamal Kant Sahu, Beverly Chigarira, Nishita Tripathi, Vinay Mathew Thomas, Nicolas Sayegh, Benjamin L. Maughan, Neeraj Agarwal, Umang Swami and Haoran Li
Cancers 2023, 15(14), 3717; https://doi.org/10.3390/cancers15143717 - 22 Jul 2023
Cited by 47 | Viewed by 6102
Abstract
Background: Accurate and efficient triage is crucial for prioritizing care and managing resources in emergency rooms. This study investigates the effectiveness of ChatGPT, an advanced artificial intelligence system, in assisting health providers with decision-making for patients presenting with metastatic prostate cancer, focusing on [...] Read more.
Background: Accurate and efficient triage is crucial for prioritizing care and managing resources in emergency rooms. This study investigates the effectiveness of ChatGPT, an advanced artificial intelligence system, in assisting health providers with decision-making for patients presenting with metastatic prostate cancer, focusing on the potential to improve both patient outcomes and resource allocation. Methods: Clinical data from patients with metastatic prostate cancer who presented to the emergency room between 1 May 2022 and 30 April 2023 were retrospectively collected. The primary outcome was the sensitivity and specificity of ChatGPT in determining whether a patient required admission or discharge. The secondary outcomes included the agreement between ChatGPT and emergency medicine physicians, the comprehensiveness of diagnoses, the accuracy of treatment plans proposed by both parties, and the length of medical decision making. Results: Of the 147 patients screened, 56 met the inclusion criteria. ChatGPT had a sensitivity of 95.7% in determining admission and a specificity of 18.2% in discharging patients. In 87.5% of cases, ChatGPT made the same primary diagnoses as physicians, with more accurate terminology use (42.9% vs. 21.4%, p = 0.02) and more comprehensive diagnostic lists (median number of diagnoses: 3 vs. 2, p < 0.001). Emergency Severity Index scores calculated by ChatGPT were not associated with admission (p = 0.12), hospital stay length (p = 0.91) or ICU admission (p = 0.54). Despite shorter mean word count (169 ± 66 vs. 272 ± 105, p < 0.001), ChatGPT was more likely to give additional treatment recommendations than physicians (94.3% vs. 73.5%, p < 0.001). Conclusions: Our hypothesis-generating data demonstrated that ChatGPT is associated with a high sensitivity in determining the admission of patients with metastatic prostate cancer in the emergency room. It also provides accurate and comprehensive diagnoses. These findings suggest that ChatGPT has the potential to assist health providers in improving patient triage in emergency settings, and may enhance both efficiency and quality of care provided by the physicians. Full article
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17 pages, 9854 KiB  
Article
The First Cold Atmospheric Plasma Phase I Clinical Trial for the Treatment of Advanced Solid Tumors: A Novel Treatment Arm for Cancer
by Jerome Canady, Saravana R. K. Murthy, Taisen Zhuang, Steven Gitelis, Aviram Nissan, Lawan Ly, Olivia Z. Jones, Xiaoqian Cheng, Mohammad Adileh, Alan T. Blank, Matthew W. Colman, Keith Millikan, Cristina O’Donoghue, Kerstin M. Stenson, Karen Ohara, Gal Schtrechman, Michael Keidar and Giacomo Basadonna
Cancers 2023, 15(14), 3688; https://doi.org/10.3390/cancers15143688 - 20 Jul 2023
Cited by 48 | Viewed by 7350
Abstract
Local regional recurrence (LRR) remains the primary cause of treatment failure in solid tumors despite advancements in cancer therapies. Canady Helios Cold Plasma (CHCP) is a novel Cold Atmospheric Plasma device that generates an Electromagnetic Field and Reactive Oxygen and Nitrogen Species to [...] Read more.
Local regional recurrence (LRR) remains the primary cause of treatment failure in solid tumors despite advancements in cancer therapies. Canady Helios Cold Plasma (CHCP) is a novel Cold Atmospheric Plasma device that generates an Electromagnetic Field and Reactive Oxygen and Nitrogen Species to induce cancer cell death. In the first FDA-approved Phase I trial (March 2020–April 2021), 20 patients with stage IV or recurrent solid tumors underwent surgical resection combined with intra-operative CHCP treatment. Safety was the primary endpoint; secondary endpoints were non-LRR, survival, cancer cell death, and the preservation of surrounding healthy tissue. CHCP did not impact intraoperative physiological data (p > 0.05) or cause any related adverse events. Overall response rates at 26 months for R0 and R0 with microscopic positive margin (R0-MPM) patients were 69% (95% CI, 19–40%) and 100% (95% CI, 100–100.0%), respectively. Survival rates for R0 (n = 7), R0-MPM (n = 5), R1 (n = 6), and R2 (n = 2) patients at 28 months were 86%, 40%, 67%, and 0%, respectively. The cumulative overall survival rate was 24% at 31 months (n = 20, 95% CI, 5.3–100.0). CHCP treatment combined with surgery is safe, selective towards cancer, and demonstrates exceptional LRR control in R0 and R0-MPM patients. (Clinical Trials identifier: NCT04267575). Full article
(This article belongs to the Section Clinical Research of Cancer)
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11 pages, 261 KiB  
Article
Effectiveness of Opioid Switching in Advanced Cancer Pain: A Prospective Observational Cohort Study
by Aaron K. Wong, Andrew A. Somogyi, Justin Rubio, Tien Dung Pham, Brian Le, Pal Klepstad and Jennifer Philip
Cancers 2023, 15(14), 3676; https://doi.org/10.3390/cancers15143676 - 19 Jul 2023
Cited by 4 | Viewed by 2285
Abstract
Opioid switching is a common practice of substituting one opioid for another to improve analgesia or adverse effects; however, it has limited evidence. This study aimed to examine the effectiveness of opioid switching in advanced cancer. This multi-center prospective cohort study recruited patients [...] Read more.
Opioid switching is a common practice of substituting one opioid for another to improve analgesia or adverse effects; however, it has limited evidence. This study aimed to examine the effectiveness of opioid switching in advanced cancer. This multi-center prospective cohort study recruited patients assessed to switch opioids (opioid switch group) or to continue ongoing opioid treatment (control group). Clinical data (demographics, opioids) and validated instruments (pain and adverse effects) were collected over two timepoints seven days apart. Descriptive analyses were utilized. Non-parametric tests were used to determine differences. Fifty-four participants were recruited (23 control group, 31 switch group). At the follow-up, opioid switching reduced pain (worst, average, and now) (p < 0.05), uncontrolled breakthrough pain (3-fold reduction, p = 0.008), and psychological distress (48% to 16%, p < 0.005). The switch group had a ≥25% reduction in the reported frequency of seven moderate-to-severe adverse effects (score ≥ 4), compared to a reduction in only one adverse effect in the control group. The control group experienced no significant pain differences at the follow-up. Opioid switching is effective at reducing pain, adverse effects, and psychological distress in a population with advanced cancer pain, to levels of satisfactory symptom control in most patients within 1 week. Full article
(This article belongs to the Special Issue Strategies for Cancer Pain Management)
18 pages, 7061 KiB  
Article
Validation of a Novel EUS-FNB-Derived Organoid Co-Culture System for Drug Screening in Patients with Pancreatic Cancer
by Simon Ezban Grützmeier, Bojan Kovacevic, Peter Vilmann, Charlotte Vestrup Rift, Linea Cecilie Melchior, Morten Orebo Holmström, Lene Brink, Hazem Hassan, John Gásdal Karstensen, Hanne Grossjohann, Deepthi Chiranth, Anders Toxværd, Carsten Palnæs Hansen, Estrid Høgdall, Jane Preuss Hasselby and Pia Klausen
Cancers 2023, 15(14), 3677; https://doi.org/10.3390/cancers15143677 - 19 Jul 2023
Cited by 6 | Viewed by 3528
Abstract
Cancer-associated fibroblasts (CAFs) have been shown to impact the chemosensitivity of patient-derived tumor organoids (PDTOs). However, the published literature comparing PDTO response to clinical outcome does not include CAFs in the models. Here, a co-culture model was created using PDTOs and CAFs derived [...] Read more.
Cancer-associated fibroblasts (CAFs) have been shown to impact the chemosensitivity of patient-derived tumor organoids (PDTOs). However, the published literature comparing PDTO response to clinical outcome does not include CAFs in the models. Here, a co-culture model was created using PDTOs and CAFs derived from endoscopic ultrasound-guided fine-needle biopsies (EUS-FNBs) for potential use in drug screening applications. Co-cultures were established, and growth was compared to monocultures using image metrics and a commercially available assay. We were able to establish and expand validated malignant PDTOs from 19.2% of adenocarcinomas from EUS-FNBs. CAFs could be established from 25% of the samples. The viability of PDTOs in the mixed cell co-culture could be isolated using image metrics. The addition of CAFs promoted PDTO growth in half of the established co-cultures. These results show that co-cultures can be established from tiny amounts of tissue provided by EUS-FNB. An increased growth of PDTOs was shown in co-cultures, suggesting that the present setup successfully models CAF–PDTO interaction. Furthermore, we demonstrated that standard validation techniques may be insufficient to detect contamination with normal cells in PDTO cultures established from primary tumor core biopsies. Full article
(This article belongs to the Special Issue Endoscopic Ultrasound in Gastrointestinal Cancers)
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15 pages, 1784 KiB  
Article
Incidence and Mortality of Malignant Brain Tumors after 20 Years of Mobile Use
by Mohy Uddin, Rozy Dhanta, Thejkiran Pitti, Diana Barsasella, Jeremiah Scholl, Wen-Shan Jian, Yu-Chuan (Jack) Li, Min-Huei Hsu and Shabbir Syed-Abdul
Cancers 2023, 15(13), 3492; https://doi.org/10.3390/cancers15133492 - 4 Jul 2023
Cited by 5 | Viewed by 5570
Abstract
(1) Objective: This population-based study was performed to examine the trends of incidence and deaths due to malignant neoplasm of the brain (MNB) in association with mobile phone usage for a period of 20 years (January 2000–December 2019) in Taiwan. (2) Methods: Pearson [...] Read more.
(1) Objective: This population-based study was performed to examine the trends of incidence and deaths due to malignant neoplasm of the brain (MNB) in association with mobile phone usage for a period of 20 years (January 2000–December 2019) in Taiwan. (2) Methods: Pearson correlation, regression analysis, and joinpoint regression analysis were used to examine the trends of incidence of MNB and deaths due to MNB in association with mobile phone usage. (3) Results: The findings indicate a trend of increase in the number of mobile phone users over the study period, accompanied by a slight rise in the incidence and death rates of MNB. The compound annual growth rates further support these observations, highlighting consistent growth in mobile phone users and a corresponding increase in MNB incidences and deaths. (4) Conclusions: The results suggest a weaker association between the growing number of mobile phone users and the rising rates of MNB, and no significant correlation was observed between MNB incidences and deaths and mobile phone usage. Ultimately, it is important to acknowledge that conclusive results cannot be drawn at this stage and further investigation is required by considering various other confounding factors and potential risks to obtain more definitive findings and a clearer picture. Full article
(This article belongs to the Special Issue Brain Tumor: Recent Advances and Challenges)
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17 pages, 4920 KiB  
Article
Vitamin D Receptor Antagonist MeTC7 Inhibits PD-L1
by Negar Khazan, Emily R. Quarato, Niloy A. Singh, Cameron W. A. Snyder, Taylor Moore, John P. Miller, Masato Yasui, Yuki Teramoto, Takuro Goto, Sabeeha Reshi, Jennifer Hong, Naixin Zhang, Diya Pandey, Priyanka Srivastava, Alexandra Morell, Hiroki Kawano, Yuko Kawano, Thomas Conley, Deepak M. Sahasrabudhe, Naohiro Yano, Hiroshi Miyamoto, Omar Aljitawi, Jane Liesveld, Michael W. Becker, Laura M. Calvi, Alexander S. Zhovmer, Erdem D. Tabdanov, Nikolay V. Dokholyan, David C. Linehan, Jeanne N. Hansen, Scott A. Gerber, Ashoke Sharon, Manoj K. Khera, Peter W. Jurutka, Natacha Rochel, Kyu Kwang Kim, Rachael B. Rowswell-Turner, Rakesh K. Singh and Richard G. Mooreadd Show full author list remove Hide full author list
Cancers 2023, 15(13), 3432; https://doi.org/10.3390/cancers15133432 - 30 Jun 2023
Cited by 7 | Viewed by 5916
Abstract
Small-molecule inhibitors of PD-L1 are postulated to control immune evasion in tumors similar to antibodies that target the PD-L1/PD-1 immune checkpoint axis. However, the identity of targetable PD-L1 inducers is required to develop small-molecule PD-L1 inhibitors. In this study, using chromatin immunoprecipitation (ChIP) [...] Read more.
Small-molecule inhibitors of PD-L1 are postulated to control immune evasion in tumors similar to antibodies that target the PD-L1/PD-1 immune checkpoint axis. However, the identity of targetable PD-L1 inducers is required to develop small-molecule PD-L1 inhibitors. In this study, using chromatin immunoprecipitation (ChIP) assay and siRNA, we demonstrate that vitamin D/VDR regulates PD-L1 expression in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) cells. We have examined whether a VDR antagonist, MeTC7, can inhibit PD-L1. To ensure that MeTC7 inhibits VDR/PD-L1 without off-target effects, we examined competitive inhibition of VDR by MeTC7, utilizing ligand-dependent dimerization of VDR-RXR, RXR-RXR, and VDR-coactivators in a mammalian 2-hybrid (M2H) assay. MeTC7 inhibits VDR selectively, suppresses PD-L1 expression sparing PD-L2, and inhibits the cell viability, clonogenicity, and xenograft growth of AML cells. MeTC7 blocks AML/mesenchymal stem cells (MSCs) adhesion and increases the efferocytotic efficiency of THP-1 AML cells. Additionally, utilizing a syngeneic colorectal cancer model in which VDR/PD-L1 co-upregulation occurs in vivo under radiation therapy (RT), MeTC7 inhibits PD-L1 and enhances intra-tumoral CD8+T cells expressing lymphoid activation antigen-CD69. Taken together, MeTC7 is a promising small-molecule inhibitor of PD-L1 with clinical potential. Full article
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15 pages, 1562 KiB  
Article
Assessing the Performance of a Novel Stool-Based Microbiome Test That Predicts Response to First Line Immune Checkpoint Inhibitors in Multiple Cancer Types
by Irina Robinson, Maximilian Johannes Hochmair, Manuela Schmidinger, Gudrun Absenger, Martin Pichler, Van Anh Nguyen, Erika Richtig, Barbara Margaretha Rainer, Leyla Ay, Christian Jansen, Cátia Pacífico, Alexander Knabl, Barbara Sladek, Nikolaus Gasche and Arschang Valipour
Cancers 2023, 15(13), 3268; https://doi.org/10.3390/cancers15133268 - 21 Jun 2023
Cited by 7 | Viewed by 4123
Abstract
The intestinal microbiome is by now an undebatable key player in the clinical outcome of ICI therapies. However, no microbiome profiling method to aid therapy decision is yet validated. We conducted a multi-centric study in patients with stage III/IV melanoma, NSCLC, or RCC [...] Read more.
The intestinal microbiome is by now an undebatable key player in the clinical outcome of ICI therapies. However, no microbiome profiling method to aid therapy decision is yet validated. We conducted a multi-centric study in patients with stage III/IV melanoma, NSCLC, or RCC receiving ICI treatment. The stool microbiome profile of 63 patients was analyzed with BiomeOne®, a microbiome-based algorithm that anticipates whether a patient will achieve clinical benefit with ICIs prior to therapy initiation. Classification of patient samples as Rs and NRs was achieved with a sensitivity of 81% and a specificity of 50% in this validation cohort. An ICI-favorable response was characterized by an intestinal microbiome rich in bacteria such as Oscillospira sp., Clostridia UCG-014, Lachnospiraceae UCG-010 sp., Prevotella copri, and a decrease in Sutterella sp., Lactobacillales, and Streptococcus sp. Patients who developed immune-related adverse events (irAEs) had an overall increased microbial diversity and richness, and a stool microbiome depleted in Agathobacter. When compared with the programmed death-ligand 1 (PD-L1) expression test in the subcohort of NSCLC patients (n = 38), BiomeOne® exhibited a numerically higher sensitivity (78.6%) in identifying responders when compared with the PD-L1 test (67.9%). This study provides an evaluation of BiomeOne®, the first microbiome-based test for prediction of ICI response, to achieve market authorization. Validation with further indications and expansion to other microbiome-based interventions will be essential to bring microbiome-based diagnostics into standard clinical practice. Full article
(This article belongs to the Special Issue Artificial Intelligence and Machine Learning in Precision Oncology)
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15 pages, 7002 KiB  
Article
Spatial Transcriptomics Identifies Expression Signatures Specific to Lacrimal Gland Adenoid Cystic Carcinoma Cells
by Acadia H. M. Moeyersoms, Ryan A. Gallo, Michelle G. Zhang, Vasileios Stathias, Michelle M. Maeng, Dawn Owens, Rayan Abou Khzam, Yoseph Sayegh, Cynthia Maza, Sander R. Dubovy, David T. Tse and Daniel Pelaez
Cancers 2023, 15(12), 3211; https://doi.org/10.3390/cancers15123211 - 16 Jun 2023
Cited by 8 | Viewed by 3699
Abstract
Although primary tumors of the lacrimal gland are rare, adenoid cystic carcinoma (ACC) is the most common and lethal epithelial lacrimal gland malignancy. Traditional management of lacrimal gland adenoid cystic carcinoma (LGACC) involves the removal of the eye and surrounding socket contents, followed [...] Read more.
Although primary tumors of the lacrimal gland are rare, adenoid cystic carcinoma (ACC) is the most common and lethal epithelial lacrimal gland malignancy. Traditional management of lacrimal gland adenoid cystic carcinoma (LGACC) involves the removal of the eye and surrounding socket contents, followed by chemoradiation. Even with this radical treatment, the 10-year survival rate for LGACC is 20% given the propensity for recurrence and metastasis. Due to the rarity of LGACC, its pathobiology is not well-understood, leading to difficulties in diagnosis, treatment, and effective management. Here, we integrate bulk RNA sequencing (RNA-seq) and spatial transcriptomics to identify a specific LGACC gene signature that can inform novel targeted therapies. Of the 3499 differentially expressed genes identified by bulk RNA-seq, the results of our spatial transcriptomic analysis reveal 15 upregulated and 12 downregulated genes that specifically arise from LGACC cells, whereas fibroblasts, reactive fibrotic tissue, and nervous and skeletal muscle account for the remaining bulk RNA-seq signature. In light of the analysis, we identified a transitional state cell or stem cell cluster. The results of the pathway analysis identified the upregulation of PI3K-Akt signaling, IL-17 signaling, and multiple other cancer pathways. This study provides insights into the molecular and cellular landscape of LGACC, which can inform new, targeted therapies to improve patient outcomes. Full article
(This article belongs to the Section Molecular Cancer Biology)
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16 pages, 4543 KiB  
Article
Immuno-PET Imaging of Tumour PD-L1 Expression in Glioblastoma
by Gitanjali Sharma, Marta C. Braga, Chiara Da Pieve, Wojciech Szopa, Tatjana Starzetz, Karl H. Plate, Wojciech Kaspera and Gabriela Kramer-Marek
Cancers 2023, 15(12), 3131; https://doi.org/10.3390/cancers15123131 - 9 Jun 2023
Cited by 8 | Viewed by 4784
Abstract
There is no established method to assess the PD-L1 expression in brain tumours. Therefore, we investigated the suitability of affibody molecule (ZPD-L1) radiolabelled with F-18 (Al18F) and Ga-68 to measure the expression of PD-L1 in xenograft mouse models of [...] Read more.
There is no established method to assess the PD-L1 expression in brain tumours. Therefore, we investigated the suitability of affibody molecule (ZPD-L1) radiolabelled with F-18 (Al18F) and Ga-68 to measure the expression of PD-L1 in xenograft mouse models of GBM. Mice bearing subcutaneous and orthotopic tumours were imaged 1 h post-radioconjugate administration. Ex vivo biodistribution studies and immunohistochemistry (IHC) staining were performed. Tumoural PD-L1 expression and CD4+/CD8+ tumour-infiltrating lymphocytes were evaluated in human GBM specimens. ZPD-L1 was radiolabelled with radiochemical yields of 32.2 ± 4.4% (F-18) and 73.3 ± 1.8% (Ga-68). The cell-associated radioactivity in vitro was consistent with PD-L1 expression levels assessed with flow cytometry. In vivo imaging demonstrated that 18F-AlF-NOTA-ZPD-L1 can distinguish between PD-L1 high-expressing tumours (U87-MGvIII) and PD-L1-negative ones (H292PD-L1Ko). The radioconjugate was quickly cleared from the blood and normal tissues, allowing for high-contrast images of brain tumours as early as 1 h post-injection. 68Ga-NOTA-ZPD-L1 showed heterogeneous and diffuse accumulation that corresponded to the extensively infiltrating GCGR-E55 tumours involving contiguous lobes of the brain. Lastly, 39% of analysed GBM patient samples showed PD-L1+ staining of tumour cells that was associated with elevated levels of CD4+ and CD8+ lymphocytes. Our results suggest that the investigated radioconjugates are very promising agents with the potential to facilitate the future design of treatment regimens for GBM patients. Full article
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13 pages, 3868 KiB  
Article
Comparing Oncologic Outcomes and Toxicity for Combined Modality Therapy vs. Carbon-Ion Radiotherapy for Previously Irradiated Locally Recurrent Rectal Cancer
by Elizabeth B. Jeans, Daniel K. Ebner, Hirotoshi Takiyama, Kaitlin Qualls, Danielle A. Cunningham, Mark R. Waddle, Krishan R. Jethwa, William S. Harmsen, Joleen M. Hubbard, Eric J. Dozois, Kellie L. Mathis, Hiroshi Tsuji, Kenneth W. Merrell, Christopher L. Hallemeier, Anita Mahajan, Shigeru Yamada, Robert L. Foote and Michael G. Haddock
Cancers 2023, 15(11), 3057; https://doi.org/10.3390/cancers15113057 - 5 Jun 2023
Cited by 10 | Viewed by 2204
Abstract
No standard treatment paradigm exists for previously irradiated locally recurrent rectal cancer (PILRRC). Carbon-ion radiotherapy (CIRT) may improve oncologic outcomes and reduce toxicity compared with combined modality therapy (CMT). Eighty-five patients treated at Institution A with CIRT alone (70.4 Gy/16 fx) and eighty-six [...] Read more.
No standard treatment paradigm exists for previously irradiated locally recurrent rectal cancer (PILRRC). Carbon-ion radiotherapy (CIRT) may improve oncologic outcomes and reduce toxicity compared with combined modality therapy (CMT). Eighty-five patients treated at Institution A with CIRT alone (70.4 Gy/16 fx) and eighty-six at Institution B with CMT (30 Gy/15 fx chemoradiation, resection, intraoperative electron radiotherapy (IOERT)) between 2006 and 2019 were retrospectively compared. Overall survival (OS), pelvic re-recurrence (PR), distant metastasis (DM), or any disease progression (DP) were analyzed with the Kaplan–Meier model, with outcomes compared using the Cox proportional hazards model. Acute and late toxicities were compared, as was the 2-year cost. The median time to follow-up or death was 6.5 years. Median OS in the CIRT and CMT cohorts were 4.5 and 2.6 years, respectively (p ≤ 0.01). No difference was seen in the cumulative incidence of PR (p = 0.17), DM (p = 0.39), or DP (p = 0.19). Lower acute grade ≥ 2 skin and GI/GU toxicity and lower late grade ≥ 2 GU toxicities were associated with CIRT. Higher 2-year cumulative costs were associated with CMT. Oncologic outcomes were similar for patients treated with CIRT or CMT, although patient morbidity and cost were lower with CIRT, and CIRT was associated with longer OS. Prospective comparative studies are needed. Full article
(This article belongs to the Section Cancer Therapy)
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17 pages, 5649 KiB  
Article
deepPERFECT: Novel Deep Learning CT Synthesis Method for Expeditious Pancreatic Cancer Radiotherapy
by Hamed Hooshangnejad, Quan Chen, Xue Feng, Rui Zhang and Kai Ding
Cancers 2023, 15(11), 3061; https://doi.org/10.3390/cancers15113061 - 5 Jun 2023
Cited by 16 | Viewed by 2767
Abstract
Major sources of delay in the standard of care RT workflow are the need for multiple appointments and separate image acquisition. In this work, we addressed the question of how we can expedite the workflow by synthesizing planning CT from diagnostic CT. This [...] Read more.
Major sources of delay in the standard of care RT workflow are the need for multiple appointments and separate image acquisition. In this work, we addressed the question of how we can expedite the workflow by synthesizing planning CT from diagnostic CT. This idea is based on the theory that diagnostic CT can be used for RT planning, but in practice, due to the differences in patient setup and acquisition techniques, separate planning CT is required. We developed a generative deep learning model, deepPERFECT, that is trained to capture these differences and generate deformation vector fields to transform diagnostic CT into preliminary planning CT. We performed detailed analysis both from an image quality and a dosimetric point of view, and showed that deepPERFECT enabled the preliminary RT planning to be used for preliminary and early plan dosimetric assessment and evaluation. Full article
(This article belongs to the Special Issue Radiation Therapy for Pancreatic Cancer)
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17 pages, 1467 KiB  
Article
Analysis of the Gut Microbiome and Dietary Habits in Metastatic Melanoma Patients with a Complete and Sustained Response to Immunotherapy
by Marin Golčić, Luka Simetić, Davorin Herceg, Krešimir Blažičević, Gordana Kenđel Jovanović, Ivan Dražić, Andrej Belančić, Nataša Skočibušić, Dora Palčevski, Igor Rubinić, Vera Vlahović-Palčevski, Tea Majnarić, Renata Dobrila-Dintinjana and Stjepko Pleština
Cancers 2023, 15(11), 3052; https://doi.org/10.3390/cancers15113052 - 4 Jun 2023
Cited by 10 | Viewed by 3204
Abstract
Immunotherapy has improved the prognosis of metastatic melanoma patients, although most patients do not achieve a complete response. While specific gut microbiome and dietary habits might influence treatment success, there is a lack of concordance between the studies, potentially due to dichotomizing patients [...] Read more.
Immunotherapy has improved the prognosis of metastatic melanoma patients, although most patients do not achieve a complete response. While specific gut microbiome and dietary habits might influence treatment success, there is a lack of concordance between the studies, potentially due to dichotomizing patients only into responders and non-responders. The aim of this study was to elucidate whether metastatic melanoma patients with complete and sustained response to immunotherapy exhibit differences in gut microbiome composition among themselves, and whether those differences were associated with specific dietary habits. Shotgun metagenomic sequencing revealed that patients who exhibited a complete response after more than 9 months of treatment (late responders) exhibited a significantly higher beta-diversity (p = 0.02), with a higher abundance of Coprococcus comes (LDA 3.548, p = 0.010), Bifidobacterium pseudocatenulatum (LDA 3.392, p = 0.024), and lower abundance of Prevotellaceae (p = 0.04) compared to early responders. Furthermore, late responders exhibited a different diet profile, with a significantly lower intake of proteins and sweets and a higher intake of flavones (p < 0.05). The research showed that metastatic melanoma patients with a complete and sustained response to immunotherapy were a heterogeneous group. Patients with a late complete response exhibited microbiome and dietary habits which were previously associated with an improved response to immunotherapy. Full article
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18 pages, 4551 KiB  
Article
Follicular Helper and Regulatory T Cells Drive the Development of Spontaneous Epstein–Barr Virus Lymphoproliferative Disorder
by Elshafa Hassan Ahmed, Mark Lustberg, Claire Hale, Shelby Sloan, Charlene Mao, Xiaoli Zhang, Hatice Gulcin Ozer, Sarah Schlotter, Porsha L. Smith, Frankie Jeney, Wing Keung Chan, Bonnie K. Harrington, Christoph Weigel, Eric Brooks, Haley L. Klimaszewski, Christopher C. Oakes, Tamrat Abebe, Muntaser E. Ibrahim, Lapo Alinari, Gregory K. Behbehani, Polina Shindiapina, Michael A. Caligiuri and Robert A. Baiocchiadd Show full author list remove Hide full author list
Cancers 2023, 15(11), 3046; https://doi.org/10.3390/cancers15113046 - 3 Jun 2023
Cited by 4 | Viewed by 3980
Abstract
Epstein–Barr virus (EBV) is a ubiquitous herpes virus associated with various cancers. EBV establishes latency with life-long persistence in memory B-cells and can reactivate lytic infection placing immunocompromised individuals at risk for EBV-driven lymphoproliferative disorders (EBV-LPD). Despite the ubiquity of EBV, only a [...] Read more.
Epstein–Barr virus (EBV) is a ubiquitous herpes virus associated with various cancers. EBV establishes latency with life-long persistence in memory B-cells and can reactivate lytic infection placing immunocompromised individuals at risk for EBV-driven lymphoproliferative disorders (EBV-LPD). Despite the ubiquity of EBV, only a small percentage of immunocompromised patients (~20%) develop EBV-LPD. Engraftment of immunodeficient mice with peripheral blood mononuclear cells (PBMCs) from healthy EBV-seropositive donors leads to spontaneous, malignant, human B-cell EBV-LPD. Only about 20% of EBV+ donors induce EBV-LPD in 100% of engrafted mice (High-Incidence, HI), while another 20% of donors never generate EBV-LPD (No-Incidence, NI). Here, we report HI donors to have significantly higher basal T follicular helper (Tfh) and regulatory T-cells (Treg), and depletion of these subsets prevents/delays EBV-LPD. Transcriptomic analysis of CD4+ T cells from ex vivo HI donor PBMC revealed amplified cytokine and inflammatory gene signatures. HI vs. NI donors showed a marked reduction in IFNγ production to EBV latent and lytic antigen stimulation. In addition, we observed abundant myeloid-derived suppressor cells in HI donor PBMC that decreased CTL proliferation in co-cultures with autologous EBV+ lymphoblasts. Our findings identify potential biomarkers that may identify individuals at risk for EBV-LPD and suggest possible strategies for prevention. Full article
(This article belongs to the Special Issue Epstein-Barr Virus-Associated Cancers: From Pathogenesis to Treatment)
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19 pages, 3798 KiB  
Article
An Aminosteroid Derivative Shows Higher In Vitro and In Vivo Potencies than Gold Standard Drugs in Androgen-Dependent Prostate Cancer Models
by Donald Poirier, Jenny Roy, René Maltais, Cindy Weidmann and Étienne Audet-Walsh
Cancers 2023, 15(11), 3033; https://doi.org/10.3390/cancers15113033 - 2 Jun 2023
Cited by 1 | Viewed by 5839
Abstract
The aminosteroid derivative RM-581 blocks with high potency the growth of androgen-dependent (AR+) prostate cancer VCaP, 22Rv1, and LAPC-4 cells. Notably, RM-581 demonstrated superior antiproliferative activity in LAPC-4 cells compared to enzalutamide and abiraterone, two drugs that exhibited a synergistic effect [...] Read more.
The aminosteroid derivative RM-581 blocks with high potency the growth of androgen-dependent (AR+) prostate cancer VCaP, 22Rv1, and LAPC-4 cells. Notably, RM-581 demonstrated superior antiproliferative activity in LAPC-4 cells compared to enzalutamide and abiraterone, two drugs that exhibited a synergistic effect in combination with RM-581. These findings suggest that RM-581 may have an action that is not directly associated with the hormonal pathway of androgens. Furthermore, RM-581 completely blocks tumor growth in LAPC-4 xenografts when given orally at 3, 10, and 30 mg/kg in non-castrated (intact) nude mice. During this study, an accumulation of RM-581 was observed in tumors compared to plasma (3.3–10 folds). Additionally, the level of fatty acids (FA) increased in the tumors and livers of mice treated with RM-581 but not in plasma. The increase was greater in unsaturated FA (21–28%) than in saturated FA (7–11%). The most affected FA were saturated palmitic acid (+16%), monounsaturated oleic acid (+34%), and di-unsaturated linoleic acid (+56%), i.e., the 3 most abundant FA, with a total of 55% of the 56 FA measured. For cholesterol levels, there was no significant difference in the tumor, liver, or plasma of mice treated or not with RM-581. Another important result was the innocuity of RM-581 in mice during a 28-day xenograft experiment and a 7-week dose-escalation study, suggesting a favorable safety window for this new promising drug candidate when given orally. Full article
(This article belongs to the Special Issue Novel Drugs for Prostate Cancer)
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16 pages, 1062 KiB  
Article
Cytogenetic Assessment and Risk Stratification in Myelofibrosis with Optical Genome Mapping
by Álvaro Díaz-González, Elvira Mora, Gayane Avetisyan, Santiago Furió, Rosalía De la Puerta, José Vicente Gil, Alessandro Liquori, Eva Villamón, Carmen García-Hernández, Marta Santiago, Cristian García-Ruiz, Marta Llop, Blanca Ferrer-Lores, Eva Barragán, Silvia García-Palomares, Empar Mayordomo, Irene Luna, Ana Vicente, Lourdes Cordón, Leonor Senent, Alberto Álvarez-Larrán, José Cervera, Javier De la Rubia, Juan Carlos Hernández-Boluda and Esperanza Suchadd Show full author list remove Hide full author list
Cancers 2023, 15(11), 3039; https://doi.org/10.3390/cancers15113039 - 2 Jun 2023
Cited by 3 | Viewed by 3140
Abstract
Cytogenetic assessment in myelofibrosis is essential for risk stratification and patient management. However, an informative karyotype is unavailable in a significant proportion of patients. Optical genome mapping (OGM) is a promising technique that allows for a high-resolution assessment of chromosomal aberrations (structural variants, [...] Read more.
Cytogenetic assessment in myelofibrosis is essential for risk stratification and patient management. However, an informative karyotype is unavailable in a significant proportion of patients. Optical genome mapping (OGM) is a promising technique that allows for a high-resolution assessment of chromosomal aberrations (structural variants, copy number variants, and loss of heterozygosity) in a single workflow. In this study, peripheral blood samples from a series of 21 myelofibrosis patients were analyzed via OGM. We assessed the clinical impact of the application of OGM for disease risk stratification using the DIPSS-plus, GIPSS, and MIPSS70+v2 prognostic scores compared with the standard-of-care approach. OGM, in combination with NGS, allowed for risk classification in all cases, compared to only 52% when conventional techniques were used. Cases with unsuccessful karyotypes (n = 10) using conventional techniques were fully characterized using OGM. In total, 19 additional cryptic aberrations were identified in 9 out of 21 patients (43%). No alterations were found via OGM in 4/21 patients with previously normal karyotypes. OGM upgraded the risk category for three patients with available karyotypes. This is the first study using OGM in myelofibrosis. Our data support that OGM is a valuable tool that can greatly contribute to improve disease risk stratification in myelofibrosis patients. Full article
(This article belongs to the Special Issue Diagnosis of Hematologic Malignancies)
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13 pages, 1789 KiB  
Article
Plasma Metabolomics Predicts Chemotherapy Response in Advanced Pancreatic Cancer
by Hayato Muranaka, Andrew Hendifar, Arsen Osipov, Natalie Moshayedi, Veronica Placencio-Hickok, Nicholas Tatonetti, Aleksandr Stotland, Sarah Parker, Jennifer Van Eyk, Stephen J. Pandol, Neil A. Bhowmick and Jun Gong
Cancers 2023, 15(11), 3020; https://doi.org/10.3390/cancers15113020 - 1 Jun 2023
Cited by 6 | Viewed by 2766
Abstract
Pancreatic cancer (PC) is one of the deadliest cancers. Developing biomarkers for chemotherapeutic response prediction is crucial for improving the dismal prognosis of advanced-PC patients (pts). To evaluate the potential of plasma metabolites as predictors of the response to chemotherapy for PC patients, [...] Read more.
Pancreatic cancer (PC) is one of the deadliest cancers. Developing biomarkers for chemotherapeutic response prediction is crucial for improving the dismal prognosis of advanced-PC patients (pts). To evaluate the potential of plasma metabolites as predictors of the response to chemotherapy for PC patients, we analyzed plasma metabolites using high-performance liquid chromatography–mass spectrometry from 31 cachectic, advanced-PC subjects enrolled into the PANCAX-1 (NCT02400398) prospective trial to receive a jejunal tube peptide-based diet for 12 weeks and who were planned for palliative chemotherapy. Overall, there were statistically significant differences in the levels of intermediates of multiple metabolic pathways in pts with a partial response (PR)/stable disease (SD) vs. progressive disease (PD) to chemotherapy. When stratified by the chemotherapy regimen, PD after 5-fluorouracil-based chemotherapy (e.g., FOLFIRINOX) was associated with decreased levels of amino acids (AAs). For gemcitabine-based chemotherapy (e.g., gemcitabine/nab-paclitaxel), PD was associated with increased levels of intermediates of glycolysis, the TCA cycle, nucleoside synthesis, and bile acid metabolism. These results demonstrate the feasibility of plasma metabolomics in a prospective cohort of advanced-PC patients for assessing the effect of enteral feeding as their primary source of nutrition. Metabolic signatures unique to FOLFIRINOX or gemcitabine/nab-paclitaxel may be predictive of a patient’s response and warrant further study. Full article
(This article belongs to the Special Issue Lipids and Small Metabolites in Cancer)
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14 pages, 1409 KiB  
Article
Efficacy of Tango Argentino for Cancer-Associated Fatigue and Quality of Life in Breast Cancer Survivors: A Randomized Controlled Trial
by Friedemann Schad, Thomas Rieser, Sarah Becker, Jessica Groß, Harald Matthes, Shiao Li Oei and Anja Thronicke
Cancers 2023, 15(11), 2920; https://doi.org/10.3390/cancers15112920 - 26 May 2023
Cited by 8 | Viewed by 4408
Abstract
Background: Persistent impairments of quality of life—in particular, cancer-associated fatigue—are a major limitation for breast cancer survivors. As physical activity and mindfulness interventions have been shown to be effective in reducing fatigue symptoms, we investigated the efficacy of a six-week Argentine tango program. [...] Read more.
Background: Persistent impairments of quality of life—in particular, cancer-associated fatigue—are a major limitation for breast cancer survivors. As physical activity and mindfulness interventions have been shown to be effective in reducing fatigue symptoms, we investigated the efficacy of a six-week Argentine tango program. Methods: A randomized controlled trial was conducted with 60 breast cancer survivors diagnosed with stage I-III tumors 12–48 months prior to study enrollment and who had increased symptoms of fatigue. The participants were randomly assigned with a 1:1 allocation to either the tango or the waiting group. The treatment consisted of six weeks of supervised weekly one-hour tango group-sessions. Self-reported fatigue and further quality of life parameters were assessed at baseline and six weeks post-baseline. Longitudinal changes, correlations, Cohen’s D (d) effect sizes, and association factors were also calculated. Results: Superiority of the tango intervention over the waiting list control was found in terms of improvement in fatigue (d = −0.64; 95%CI, −1.2 to −0.08; p = 0.03), especially cognitive fatigue. In addition, a superiority of the tango intervention over the waiting list was found in the improvement of diarrhea (d = −0.69; 95%CI, −1.25 to −0.13; p = 0.02). A pooled pre-post analysis of the 50 participants completing the six-week tango program revealed a close to 10% improvement of fatigue (p = 0.0003), insomnia (p = 0.008) and further quality of life outcomes. Adjusted multivariate linear regression analyses revealed the greatest improvements for participants who were more active in sports. In particular, survivors who received endocrine therapies, were obese, or had no prior dance experience seemed to especially benefit from the tango program. Conclusions: This randomized controlled trial demonstrated that a six-week Argentine tango program improves fatigue in breast cancer survivors. Further trials are warranted to determine whether such improvements lead to better long-term clinical outcomes. Trial registration: trial registration number DRKS00021601. Retrospectively registered on 21 August 2020. Full article
(This article belongs to the Special Issue Breast Cancer Survivors and Supportive Therapies)
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27 pages, 4387 KiB  
Article
Development and Validation of Blood-Based Predictive Biomarkers for Response to PD-1/PD-L1 Checkpoint Inhibitors: Evidence of a Universal Systemic Core of 3D Immunogenetic Profiling across Multiple Oncological Indications
by Ewan Hunter, Matthew Salter, Ryan Powell, Ann Dring, Tarun Naithani, Maria Eleni Chatziioannou, Abel Gebregzabhar, Mutaz Issa, Jayne Green, Serene Ng, Chun Ren Lim, Cheah Soon Keat, Ang Tick Suan, Rakesh Raman, Ho Kean Fatt, Fabian Lee Wei Luen, Heba Alshaker, Dmitri Pchejetski, Dave Blum, Thomas Guiel, Robert Heaton, Jr., Jedd Levine and Alexandre Akoulitchevadd Show full author list remove Hide full author list
Cancers 2023, 15(10), 2696; https://doi.org/10.3390/cancers15102696 - 10 May 2023
Cited by 9 | Viewed by 6341
Abstract
Background: Unprecedented advantages in cancer treatment with immune checkpoint inhibitors (ICIs) remain limited to only a subset of patients. Systemic analyses of the regulatory 3D genome architecture linked to individual epigenetic and immunogenetic controls associated with tumour immune evasion mechanisms and immune checkpoint [...] Read more.
Background: Unprecedented advantages in cancer treatment with immune checkpoint inhibitors (ICIs) remain limited to only a subset of patients. Systemic analyses of the regulatory 3D genome architecture linked to individual epigenetic and immunogenetic controls associated with tumour immune evasion mechanisms and immune checkpoint pathways reveal a highly prevalent molecular profile predictive of response to PD-1/PD-L1 ICIs. A clinical blood test based on a set of eight (8) 3D genomic biomarkers has been developed and validated on the basis of an observational trial to predict response to ICI therapy. Methods: The predictive eight biomarker set is derived from prospective observational clinical trials, representing 280 treatments with Pembrolizumab, Atezolizumab, Durvalumab, Nivolumab, and Avelumab in a broad range of indications: melanoma, lung, hepatocellular, renal, breast, bladder, colon, head and neck, bone, brain, lymphoma, prostate, vulvar, and cervical cancers. Results: The 3D genomic eight biomarker panel for response to immune checkpoint therapy achieved a high accuracy of 85%, sensitivity of 93%, and specificity of 82%. Conclusions: This study demonstrates that a 3D genomic approach can be used to develop a predictive clinical assay for response to PD-1/PD-L1 checkpoint inhibition in cancer patients. Full article
(This article belongs to the Topic Biomarker Development and Application)
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14 pages, 3978 KiB  
Article
Pediatric Patients with Stage IV Rhabdomyosarcoma Significantly Benefit from Long-Term Maintenance Therapy: Results of the CWS-IV 2002 and the CWS DOK IV 2004-Trials
by Lars Tramsen, Konrad Bochennek, Monika Sparber-Sauer, Emilia Salzmann-Manrique, Monika Scheer, Tobias Dantonello, Arndt Borkhardt, Uta Dirksen, Anne Thorwarth, Jeanette Greiner, Martin Ebinger, Jadwiga Weclawek-Tompol, Ruth Ladenstein, Gustaf Ljungman, Erika Hallmen, Thomas Lehrnbecher, Ewa Koscielniak and Thomas Klingebiel
Cancers 2023, 15(7), 2050; https://doi.org/10.3390/cancers15072050 - 30 Mar 2023
Cited by 13 | Viewed by 4655
Abstract
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma (STS) in childhood. Whereas more than 90% of patients with localized low-risk RMS can be cured, metastatic RMS have a dismal outcome, with survival rates of less than 30%. The HD CWS-96 trial showed [...] Read more.
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma (STS) in childhood. Whereas more than 90% of patients with localized low-risk RMS can be cured, metastatic RMS have a dismal outcome, with survival rates of less than 30%. The HD CWS-96 trial showed an improved outcome for patients receiving maintenance therapy after completing intensive chemotherapy. Consequently, the international clinical trials CWS-IV 2002 and CWS DOK IV 2004 on metastatic disease of STS of the Cooperative Weichteilsarkom Studiengruppe (CWS) were designed in addition to the CWS-2002P trial for localized RMS disease. All patients received a multimodal intensive treatment regimen. To maintain remission, three options were compared: long-term maintenance therapy (LTMT) versus allogeneic hematopoietic stem cell transplantation (alloHSCT) versus high-dose chemotherapy (HDCT). A total of 176 pediatric patients with a histologically confirmed diagnosis of metastatic RMS or RMS-like tumor were included. A total of 89 patients receiving LTML showed a significantly better outcome, with an event-free survival (EFS) of 41% and an overall survival (OS) of 53%, than alloHSCT (n = 21, EFS 19%, p = 0.02, OS 24%, p = 0.002). The outcome of LTML was slightly improved compared to HDCT (n = 13, EFS 35%, OS 34%). In conclusion, our data suggest that in patients suffering from metastatic RMS, long-term maintenance therapy is a superior strategy in terms of EFS and OS compared to alloHSCT. EFS and OS of HDCT are similar in these strategies; however, the therapeutic burden of LTMT is much lower. Full article
(This article belongs to the Special Issue Rhabdomyosarcoma: Still Unresolved Questions but New Perspectives)
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20 pages, 576 KiB  
Article
Mathematical Model of Clonal Evolution Proposes a Personalised Multi-Modal Therapy for High-Risk Neuroblastoma
by Matteo Italia, Kenneth Y. Wertheim, Sabine Taschner-Mandl, Dawn Walker and Fabio Dercole
Cancers 2023, 15(7), 1986; https://doi.org/10.3390/cancers15071986 - 26 Mar 2023
Cited by 10 | Viewed by 3655
Abstract
Neuroblastoma is the most common extra-cranial solid tumour in children. Despite multi-modal therapy, over half of the high-risk patients will succumb. One contributing factor is the one-size-fits-all nature of multi-modal therapy. For example, during the first step (induction chemotherapy), the standard regimen (rapid [...] Read more.
Neuroblastoma is the most common extra-cranial solid tumour in children. Despite multi-modal therapy, over half of the high-risk patients will succumb. One contributing factor is the one-size-fits-all nature of multi-modal therapy. For example, during the first step (induction chemotherapy), the standard regimen (rapid COJEC) administers fixed doses of chemotherapeutic agents in eight two-week cycles. Perhaps because of differences in resistance, this standard regimen results in highly heterogeneous outcomes in different tumours. In this study, we formulated a mathematical model comprising ordinary differential equations. The equations describe the clonal evolution within a neuroblastoma tumour being treated with vincristine and cyclophosphamide, which are used in the rapid COJEC regimen, including genetically conferred and phenotypic drug resistance. The equations also describe the agents’ pharmacokinetics. We devised an optimisation algorithm to find the best chemotherapy schedules for tumours with different pre-treatment clonal compositions. The optimised chemotherapy schedules exploit the cytotoxic difference between the two drugs and intra-tumoural clonal competition to shrink the tumours as much as possible during induction chemotherapy and before surgical removal. They indicate that induction chemotherapy can be improved by finding and using personalised schedules. More broadly, we propose that the overall multi-modal therapy can be enhanced by employing targeted therapies against the mutations and oncogenic pathways enriched and activated by the chemotherapeutic agents. To translate the proposed personalised multi-modal therapy into clinical use, patient-specific model calibration and treatment optimisation are necessary. This entails a decision support system informed by emerging medical technologies such as multi-region sequencing and liquid biopsies. The results and tools presented in this paper could be the foundation of this decision support system. Full article
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15 pages, 2281 KiB  
Article
Immune Checkpoint and EMT-Related Molecules in Circulating Tumor Cells (CTCs) from Triple Negative Breast Cancer Patients and Their Clinical Impact
by Vasileios Vardas, Anastasios Tolios, Athina Christopoulou, Vassilis Georgoulias, Anastasia Xagara, Filippos Koinis, Athanasios Kotsakis and Galatea Kallergi
Cancers 2023, 15(7), 1974; https://doi.org/10.3390/cancers15071974 - 25 Mar 2023
Cited by 13 | Viewed by 2583
Abstract
Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype. There are few targeted therapies for these patients, leading to an unmet need for new biomarkers. The present study aimed to investigate the expression of PD-L1, CTLA-4, GLU, and VIM in [...] Read more.
Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype. There are few targeted therapies for these patients, leading to an unmet need for new biomarkers. The present study aimed to investigate the expression of PD-L1, CTLA-4, GLU, and VIM in CTCs of TNBC patients. Ninety-five patients were enrolled in this study: sixty-four TNBC and thirty-one luminal. Of these patients, 60 were in the early stage, while 35 had metastatic disease. Protein expression was identified by immunofluorescence staining experiments and VyCAP analysis. All the examined proteins were upregulated in TNBC patients. The expression of the GLU+VIM+CK+ phenotype was higher (50%) in metastatic TNBC compared to early TNBC patients (17%) (p = 0.005). Among all the BC patients, a significant correlation was found between PD-L1+CD45CK+ and CTLA-4+CD45CK+ phenotypes (Spearman test, p = 0.024), implying an important role of dual inhibition in BC. Finally, the phenotypes GLU+VIM+CK+ and PD-L1+CD45CK+ were associated with shorter OS in TNBC patients (OS: log-rank p = 0.048, HR = 2.9, OS: log-rank p < 0.001, HR = 8.7, respectively). Thus, PD-L1, CTLA-4, GLU, and VIM constitute significant biomarkers in TNBC associated with patients’ outcome, providing new therapeutic targets for this difficult breast cancer subtype. Full article
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21 pages, 5153 KiB  
Article
From Head and Neck Tumour and Lymph Node Segmentation to Survival Prediction on PET/CT: An End-to-End Framework Featuring Uncertainty, Fairness, and Multi-Region Multi-Modal Radiomics
by Zohaib Salahuddin, Yi Chen, Xian Zhong, Henry C. Woodruff, Nastaran Mohammadian Rad, Shruti Atul Mali and Philippe Lambin
Cancers 2023, 15(7), 1932; https://doi.org/10.3390/cancers15071932 - 23 Mar 2023
Cited by 13 | Viewed by 4031
Abstract
Automatic delineation and detection of the primary tumour (GTVp) and lymph nodes (GTVn) using PET and CT in head and neck cancer and recurrence-free survival prediction can be useful for diagnosis and patient risk stratification. We used data from nine different centres, with [...] Read more.
Automatic delineation and detection of the primary tumour (GTVp) and lymph nodes (GTVn) using PET and CT in head and neck cancer and recurrence-free survival prediction can be useful for diagnosis and patient risk stratification. We used data from nine different centres, with 524 and 359 cases used for training and testing, respectively. We utilised posterior sampling of the weight space in the proposed segmentation model to estimate the uncertainty for false positive reduction. We explored the prognostic potential of radiomics features extracted from the predicted GTVp and GTVn in PET and CT for recurrence-free survival prediction and used SHAP analysis for explainability. We evaluated the bias of models with respect to age, gender, chemotherapy, HPV status, and lesion size. We achieved an aggregate Dice score of 0.774 and 0.760 on the test set for GTVp and GTVn, respectively. We observed a per image false positive reduction of 19.5% and 7.14% using the uncertainty threshold for GTVp and GTVn, respectively. Radiomics features extracted from GTVn in PET and from both GTVp and GTVn in CT are the most prognostic, and our model achieves a C-index of 0.672 on the test set. Our framework incorporates uncertainty estimation, fairness, and explainability, demonstrating the potential for accurate detection and risk stratification. Full article
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14 pages, 1976 KiB  
Article
Exact Probability Distribution for the ROC Area under Curve
by Joakim Ekström, Jim Åkerrén Ögren and Tobias Sjöblom
Cancers 2023, 15(6), 1788; https://doi.org/10.3390/cancers15061788 - 15 Mar 2023
Cited by 15 | Viewed by 2455
Abstract
The Receiver Operating Characteristic (ROC) is a de facto standard for determining the accuracy of in vitro diagnostic (IVD) medical devices, and thus the exactness in its probability distribution is crucial toward accurate statistical inference. We show the exact probability distribution of the [...] Read more.
The Receiver Operating Characteristic (ROC) is a de facto standard for determining the accuracy of in vitro diagnostic (IVD) medical devices, and thus the exactness in its probability distribution is crucial toward accurate statistical inference. We show the exact probability distribution of the ROC AUC-value, hence exact critical values and p-values are readily obtained. Because the exact calculations are computationally intense, we demonstrate a method of geometric interpolation, which is exact in a special case but generally an approximation, vastly increasing computational speeds. The method is illustrated through open access data, demonstrating superiority of 26 composite biomarkers relative to a predicate device. Especially under correction for testing of multiple hypotheses, traditional asymptotic approximations are encumbered by considerable imprecision, adversely affecting IVD device development. The ability to obtain exact p-values will allow more efficient IVD device development. Full article
(This article belongs to the Section Cancer Informatics and Big Data)
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8 pages, 2264 KiB  
Article
Radical Prostatectomy without Prior Biopsy in Patients with High Suspicion of Prostate Cancer Based on Multiparametric Magnetic Resonance Imaging and Prostate-Specific Membrane Antigen Positron Emission Tomography: A Prospective Cohort Study
by Michael Chaloupka, Maria Apfelbeck, Nikolaos Pyrgidis, Julian Marcon, Philipp Weinhold and Christian G. Stief
Cancers 2023, 15(4), 1266; https://doi.org/10.3390/cancers15041266 - 16 Feb 2023
Cited by 16 | Viewed by 2635
Abstract
Modern risk stratification of prostate cancer (PCa) allows for prediction of advanced disease with a high level of certainty. We aimed to evaluate a prospective series of patients undergoing radical prostatectomy without prior biopsy based solely on clinical criteria and imaging results. The [...] Read more.
Modern risk stratification of prostate cancer (PCa) allows for prediction of advanced disease with a high level of certainty. We aimed to evaluate a prospective series of patients undergoing radical prostatectomy without prior biopsy based solely on clinical criteria and imaging results. The patients were divided into three groups. Group 1 included 27 patients with: (i) suspicious digital rectal examination, (ii) PSA ≥ 10 ng/mL, (iii) PI-RADS 4/5 on mpMRI, and (iv) high suspicion of PCa on PSMA-PET. Group 2 included six patients who fulfilled criteria i, ii, and iii but did not undergo PSMA-PET imaging. Group 3 included 17 patients with at least one clinical (i or ii) and one imaging (iii or iv) criterion. All of the patients were diagnosed with PCa. Comparison of Group 1 and 2 versus Group 3 showed a significantly higher ratio of locally advanced PCa for Groups 1 and 2 compared to Group 3 (60.6% versus 11.8%, p = 0.005, respectively). Similarly, these patients displayed a significantly higher ratio of aggressive PCa (ISUP grade > 2: 66.7% versus 23.5%, p = 0.027, respectively) and tumor infiltration (median tumor infiltration: 32.5% vs. 15%, p = 0.001, respectively) in the final specimen compared to Group 3. In conclusion, we have shown that radical prostatectomy without prior biopsy is safe in terms of the diagnosis of clinically significant PCa when proper preoperative risk stratification involving mpMRI and PSMA-PET imaging is applied. Full article
(This article belongs to the Section Cancer Therapy)
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13 pages, 1717 KiB  
Article
Circulating Chromosome Conformation Signatures Significantly Enhance PSA Positive Predicting Value and Overall Accuracy for Prostate Cancer Detection
by Dmitri Pchejetski, Ewan Hunter, Mehrnoush Dezfouli, Matthew Salter, Ryan Powell, Jayne Green, Tarun Naithani, Christina Koutsothanasi, Heba Alshaker, Jiten Jaipuria, Martin J. Connor, David Eldred-Evans, Francesca Fiorentino, Hashim Ahmed, Alexandre Akoulitchev and Mathias Winkler
Cancers 2023, 15(3), 821; https://doi.org/10.3390/cancers15030821 - 29 Jan 2023
Cited by 9 | Viewed by 23343
Abstract
Background: Prostate cancer (PCa) has a high lifetime prevalence (one out of six men), but currently there is no widely accepted screening programme. Widely used prostate specific antigen (PSA) test at cut-off of 3.0 ng/mL does not have sufficient accuracy for detection of [...] Read more.
Background: Prostate cancer (PCa) has a high lifetime prevalence (one out of six men), but currently there is no widely accepted screening programme. Widely used prostate specific antigen (PSA) test at cut-off of 3.0 ng/mL does not have sufficient accuracy for detection of any prostate cancer, resulting in numerous unnecessary prostate biopsies in men with benign disease and false reassurance in some men with PCa. We have recently identified circulating chromosome conformation signatures (CCSs, Episwitch® PCa test) allowing PCa detection and risk stratification in line with standards of clinical PCa staging. The purpose of this study was to determine whether combining the Episwitch PCa test with the PSA test will increase its diagnostic accuracy. Methods: n = 109 whole blood samples of men enrolled in the PROSTAGRAM screening pilot study and n = 38 samples of patients with established PCa diagnosis and cancer-negative controls from Imperial College NHS Trust were used. Samples were tested for PSA, and the presence of CCSs in the loci encoding for of DAPK1, HSD3B2, SRD5A3, MMP1, and miRNA98 associated with high-risk PCa identified in our previous work. Results: PSA > 3 ng/mL alone showed a low positive predicted value (PPV) of 0.14 and a high negative predicted value (NPV) of 0.93. EpiSwitch alone showed a PPV of 0.91 and a NPV of 0.32. Combining PSA and Episwitch tests has significantly increased the PPV to 0.81 although reducing the NPV to 0.78. Furthermore, integrating PSA, as a continuous variable (rather than a dichotomised 3 ng/mL cut-off), with EpiSwitch in a new multivariant stratification model, Prostate Screening EpiSwitch (PSE) test, has yielded a remarkable combined PPV of 0.93 and NPV of 0.95 when tested on the independent combined cohort. Conclusions: Our results demonstrate that combining the standard PSA readout with circulating chromosome conformations (PSE test) allows for significantly enhanced PSA PPV and overall accuracy for PCa detection. The PSE test is accurate, rapid, minimally invasive, and inexpensive, suggesting significant screening diagnostic potential to minimise unnecessary referrals for expensive and invasive MRI and/or biopsy testing. Further extended prospective blinded validation of the new combined signature in a screening cohort with low cancer prevalence would be the recommended step for PSE adoption in PCa screening. Full article
(This article belongs to the Section Cancer Causes, Screening and Diagnosis)
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17 pages, 920 KiB  
Article
Safety and Feasibility of Radiation Therapy Combined with CDK 4/6 Inhibitors in the Management of Advanced Breast Cancer
by Marcin Kubeczko, Dorota Gabryś, Marzena Gawkowska, Anna Polakiewicz-Gilowska, Alexander J. Cortez, Aleksandra Krzywon, Grzegorz Woźniak, Tomasz Latusek, Aleksandra Leśniak, Katarzyna Świderska, Marta Mianowska-Malec, Barbara Łanoszka, Konstanty Chomik, Mateusz Gajek, Anna Michalik, Elżbieta Nowicka, Rafał Tarnawski, Tomasz Rutkowski and Michał Jarząb
Cancers 2023, 15(3), 690; https://doi.org/10.3390/cancers15030690 - 22 Jan 2023
Cited by 15 | Viewed by 5640
Abstract
The addition of CDK4/6 inhibitors to endocrine therapy in advanced hormone receptor-positive HER2-negative breast cancer has led to practice-changing improvements in overall survival. However, data concerning the safety of CDK4/6i combination with radiotherapy (RT) are conflicting. A retrospective evaluation of 288 advanced breast [...] Read more.
The addition of CDK4/6 inhibitors to endocrine therapy in advanced hormone receptor-positive HER2-negative breast cancer has led to practice-changing improvements in overall survival. However, data concerning the safety of CDK4/6i combination with radiotherapy (RT) are conflicting. A retrospective evaluation of 288 advanced breast cancer patients (pts) treated with CDK4/6i was performed, and 100 pts also received RT. Forty-six pts received 63 RT courses concurrently and fifty-four sequentially before CDK4/6i initiation (76 RT courses). Neutropenia was common (79%) and more frequent during and after concurrent RT than sequential RT (86% vs. 76%); however, CDK4/6i dose reduction rates were similar. In patients treated with CDK4/6i alone, the dose reduction rate was 42% (79 pts) versus 38% with combined therapy, and 5% discontinued treatment due to toxicity in the combined group. The risk of CDK4/6i dose reduction was correlated with neutropenia grade, RT performed within the first two CDK4/6i cycles, and more than one concurrent RT; a tendency was observed in concurrent bone irradiation. However, on multivariate regression analysis, only ECOG 1 performance status and severe neutropenia at the beginning of the second cycle were found to be associated with a higher risk of CDK4/6i dose reduction. This largest single-center experience published to date confirmed the acceptable safety profile of the CDK4/6i and RT combination without a significantly increased toxicity compared with CDK4/6i alone. However, one might delay RT for the first two CDK4/6i cycles, when myelotoxic AE are most common. Full article
(This article belongs to the Special Issue Radiation Therapy for Breast Cancer: Recent Advances and Challenges)
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21 pages, 5981 KiB  
Article
Single-Cell Transcriptomic Profiles of Lung Pre-Metastatic Niche Reveal Neutrophil and Lymphatic Endothelial Cell Roles in Breast Cancer
by Yung-Chi Huang, Chao-Yuan Chang, Yu-Yuan Wu, Kuan-Li Wu, Ying-Ming Tsai, Hsiao-Chen Lee, Eing-Mei Tsai and Ya-Ling Hsu
Cancers 2023, 15(1), 176; https://doi.org/10.3390/cancers15010176 - 28 Dec 2022
Cited by 8 | Viewed by 5675
Abstract
The establishment of a pre-metastatic niche (PMN) is critical for cancer metastasis. However, it remains unclear as to which phenotypes induce changes in the PMN. Single-cell transcriptomic profiling of all cells of the lung in cancer-bearing MMTV-PyVT mice revealed an increased infiltration of [...] Read more.
The establishment of a pre-metastatic niche (PMN) is critical for cancer metastasis. However, it remains unclear as to which phenotypes induce changes in the PMN. Single-cell transcriptomic profiling of all cells of the lung in cancer-bearing MMTV-PyVT mice revealed an increased infiltration of N2-type neutrophils and classical monocytes associated with chronic inflammation; notably, lung neutrophils isolated from mice with primary cancer exhibited similar N2-type phenotypes and expressed high levels of inflammatory and angiogenic factors. We also discovered a new cluster of Ki67-upregulated lymphatic endothelial cells (ECs) that activated several cell division-related pathways. Receptor–ligand interactions within the lung potentially mediated PMN formation; these were exemplified by the cross talk of lymphatic EC–N2-type neutrophil via S100A6. In vitro study revealed S100A6 impaired EC tight junction and increased the transendothelial migration of neutrophils. Our results highlight the molecular mechanisms that shape lung PMN and inspire preventive strategies for lung metastasis in breast cancer. Full article
(This article belongs to the Section Molecular Cancer Biology)
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19 pages, 3444 KiB  
Article
BRAF and MEK Inhibitors and Their Toxicities: A Meta-Analysis
by Mattia Garutti, Melissa Bergnach, Jerry Polesel, Lorenza Palmero, Maria Antonietta Pizzichetta and Fabio Puglisi
Cancers 2023, 15(1), 141; https://doi.org/10.3390/cancers15010141 - 26 Dec 2022
Cited by 43 | Viewed by 5426
Abstract
Purpose: This meta-analysis summarizes the incidence of treatment-related adverse events (AE) of BRAFi and MEKi. Methods: A systematic search of Medline/PubMed was conducted to identify suitable articles published in English up to 31 December 2021. The primary outcomes were profiles for all-grade and [...] Read more.
Purpose: This meta-analysis summarizes the incidence of treatment-related adverse events (AE) of BRAFi and MEKi. Methods: A systematic search of Medline/PubMed was conducted to identify suitable articles published in English up to 31 December 2021. The primary outcomes were profiles for all-grade and grade 3 or higher treatment-related AEs, and the analysis of single side effects belonging to both categories. Results: The overall incidence of treatment-related all-grade Aes was 99% for Encorafenib (95% CI: 0.97–1.00) and 97% for Trametinib (95% CI: 0.92–0.99; I2 = 66%) and Binimetinib (95% CI: 0.94–0.99; I2 = 0%). In combined therapies, the rate was 98% for both Vemurafenib + Cobimetinib (95% CI: 0.96–0.99; I2 = 77%) and Encorafenib + Binimetinib (95% CI: 0.96–1.00). Grade 3 or higher adverse events were reported in 69% of cases for Binimetinib (95% CI: 0.50–0.84; I2 = 71%), 68% for Encorafenib (95% CI: 0.61–0.74), and 72% for Vemurafenib + Cobimetinib (95% CI: 0.65–0.79; I2 = 84%). The most common grade 1–2 AEs were pyrexia (43%) and fatigue (28%) for Dabrafenib + Trametinib and diarrhea for both Vemurafenib + Cobimetinib (52%) and Encorafenib + Binimetinib (34%). The most common AEs of grade 3 or higher were pyrexia, rash, and hypertension for Dabrafenib + Trametinib (6%), rash and hypertension for Encorafenib + Binimetinib (6%), and increased AST and ALT for Vemurafenib + Cobimetinib (10%). Conclusions: Our study provides comprehensive data on treatment-related adverse events of BRAFi and MEKi combination therapies, showing related toxicity profiles to offer a helpful tool for clinicians in the choice of therapy. Full article
(This article belongs to the Special Issue Side Effects of Anticancer Therapy: Prevention and Management)
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32 pages, 3691 KiB  
Article
Targets, Mechanisms and Cytotoxicity of Half-Sandwich Ir(III) Complexes Are Modulated by Structural Modifications on the Benzazole Ancillary Ligand
by M. Isabel Acuña, Ana R. Rubio, Marta Martínez-Alonso, Natalia Busto, Ana María Rodríguez, Nerea Davila-Ferreira, Carl Smythe, Gustavo Espino, Begoña García and Fernando Domínguez
Cancers 2023, 15(1), 107; https://doi.org/10.3390/cancers15010107 - 24 Dec 2022
Cited by 7 | Viewed by 4573
Abstract
Cancers are driven by multiple genetic mutations but evolve to evade treatments targeting specific mutations. Nonetheless, cancers cannot evade a treatment that targets mitochondria, which are essential for tumor progression. Iridium complexes have shown anticancer properties, but they lack specificity for their intracellular [...] Read more.
Cancers are driven by multiple genetic mutations but evolve to evade treatments targeting specific mutations. Nonetheless, cancers cannot evade a treatment that targets mitochondria, which are essential for tumor progression. Iridium complexes have shown anticancer properties, but they lack specificity for their intracellular targets, leading to undesirable side effects. Herein we present a systematic study on structure-activity relationships of eight arylbenzazole-based Iridium(III) complexes of type [IrCl(Cp*)], that have revealed the role of each atom of the ancillary ligand in the physical chemistry properties, cytotoxicity and mechanism of biological action. Neutral complexes, especially those bearing phenylbenzimidazole (HL1 and HL2), restrict the binding to DNA and albumin. One of them, complex 1[C,NH-Cl], is the most selective one, does not bind DNA, targets exclusively the mitochondria, disturbs the mitochondria membrane permeability inducing proton leak and increases ROS levels, triggering the molecular machinery of regulated cell death. In mice with orthotopic lung tumors, the administration of complex 1[C,NH-Cl] reduced the tumor burden. Cancers are more vulnerable than normal tissues to a treatment that harnesses mitochondrial dysfunction. Thus, complex 1[C,NH-Cl] characterization opens the way to the development of new compounds to exploit this vulnerability. Full article
(This article belongs to the Special Issue Advances in Anticancer Drugs and Pharmacotherapy of Cancer)
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12 pages, 1091 KiB  
Article
Low-Energy X-Ray Intraoperative Radiation Therapy (Lex-IORT) for Resected Brain Metastases: A Single-Institution Experience
by Christian D. Diehl, Steffi U. Pigorsch, Jens Gempt, Sandro M. Krieg, Silvia Reitz, Maria Waltenberger, Melanie Barz, Hanno S. Meyer, Arthur Wagner, Jan Wilkens, Benedikt Wiestler, Claus Zimmer, Bernhard Meyer and Stephanie E. Combs
Cancers 2023, 15(1), 14; https://doi.org/10.3390/cancers15010014 - 20 Dec 2022
Cited by 18 | Viewed by 2533
Abstract
Background: Resection followed by local radiation therapy (RT) is the standard of care for symptomatic brain metastases. However, the optimal technique, fractionation scheme and dose are still being debated. Lately, low-energy X-ray intraoperative RT (lex-IORT) has been of increasing interest. Method: Eighteen consecutive [...] Read more.
Background: Resection followed by local radiation therapy (RT) is the standard of care for symptomatic brain metastases. However, the optimal technique, fractionation scheme and dose are still being debated. Lately, low-energy X-ray intraoperative RT (lex-IORT) has been of increasing interest. Method: Eighteen consecutive patients undergoing BM resection followed by immediate lex-IORT with 16–30 Gy applied to the spherical applicator were retrospectively analyzed. Demographic, RT-specific, radiographic and clinical data were reviewed to evaluate the effectiveness and safety of IORT for BM. Descriptive statistics and Kaplan–Meyer analysis were applied. Results: The mean follow-up time was 10.8 months (range, 0–39 months). The estimated local control (LC), distant brain control (DBC) and overall survival (OS) at 12 months post IORT were 92.9% (95%-CI 79.3–100%), 71.4% (95%-CI 50.2–92.6%) and 58.0% (95%-CI 34.1–81.9%), respectively. Two patients developed radiation necrosis (11.1%) and wound infection (CTCAE grade III); both had additional adjuvant treatment after IORT. For five patients (27.8%), the time to the start or continuation of systemic treatment was ≤15 days and hence shorter than wound healing and adjuvant RT would have required. Conclusion: In accordance with previous series, this study demonstrates the effectiveness and safety of IORT in the management of brain metastases despite the small cohort and the retrospective characteristic of this analysis. Full article
(This article belongs to the Special Issue Advances in Modern Radiation Oncology)
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17 pages, 2313 KiB  
Article
TP53 Co-Mutation Status Association with Clinical Outcomes in Patients with EGFR-Mutant Non-Small Cell Lung Cancer
by Xiuning Le, Cliff Molife, Mark S. Leusch, Maria Teresa Rizzo, Patrick M. Peterson, Nicola Caria, Yongmei Chen, Elena Gonzalez Gugel and Carla Visseren-Grul
Cancers 2022, 14(24), 6127; https://doi.org/10.3390/cancers14246127 - 12 Dec 2022
Cited by 14 | Viewed by 3562
Abstract
TP53 co-mutations have shown association with poor prognosis in various solid tumors. For EGFR-mutated advanced non-small cell lung cancer (aNSCLC), conflicting results exist regarding its impact on survival. Clinical outcomes and genomic data were obtained retrospectively from the real-world (rw) de-identified clinicogenomic [...] Read more.
TP53 co-mutations have shown association with poor prognosis in various solid tumors. For EGFR-mutated advanced non-small cell lung cancer (aNSCLC), conflicting results exist regarding its impact on survival. Clinical outcomes and genomic data were obtained retrospectively from the real-world (rw) de-identified clinicogenomic database. Patients who initiated therapy for EGFR-mutated aNSCLC between January 2014 and December 2020 were identified. Clinical outcomes were evaluated by TP53-mutational status. In 356 eligible EGFR-mutated aNSCLC patients (median age 68 years), 210 (59.0%) had TP53 co-mutation and 146 (41.0%) had TP53 wild-type tumor. Unadjusted analysis showed significantly shorter survival in patients with TP53 co-mutation versus TP53 wild-type (rw progression-free survival [rwPFS]: HR = 1.4, 95% CI 1.1–1.9, p = 0.0196; overall survival [OS]: HR = 1.6, 95% CI 1.1–2.2, p = 0.0088). Multivariable analysis confirmed independent association between TP53 co-mutation and worse rwPFS (HR = 1.4, 95% CI 1.0–0.9, p = 0.0280) and OS (HR = 1.4, 95% CI 1.0–2.0, p = 0.0345). Directionally consistent findings were observed for response rates, and subgroups by EGFR-activating mutation and first-line (1 L) therapy, with more pronounced negative effect in 1 L EGFR-TKI subgroup. TP53 co-mutations negatively affected survival in patients with EGFR-mutated aNSCLC receiving standard 1 L therapy in real-world practice. Full article
(This article belongs to the Special Issue Actionable Mutations in Lung Cancer)
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16 pages, 1610 KiB  
Article
Dual NGS Comparative Analysis of Liquid Biopsy (LB) and Formalin-Fixed Paraffin-Embedded (FFPE) Samples of Non-Small Cell Lung Carcinoma (NSCLC)
by Laura Buburuzan, Maria-Anca Zamfir (Irofei), Carmen Maria Ardeleanu, Alin Horatiu Muresan, Florina Vasilescu, Ariana Hudita, Marieta Costache, Bianca Galateanu, Alexandra Puscasu, Alexandru Filippi and Natalia Motas
Cancers 2022, 14(24), 6084; https://doi.org/10.3390/cancers14246084 - 10 Dec 2022
Cited by 2 | Viewed by 4048
Abstract
Lung cancer ranks second worldwide after breast cancer and third in Europe after breast and colorectal cancers when both sexes and all ages are considered. In this context, the aim of this study was to emphasize the power of dual analysis of the [...] Read more.
Lung cancer ranks second worldwide after breast cancer and third in Europe after breast and colorectal cancers when both sexes and all ages are considered. In this context, the aim of this study was to emphasize the power of dual analysis of the molecular profile both in tumor tissue and plasma by NGS assay as a liquid biopsy approach with impact on prognosis and therapy modulation in NSCLC patients. NGS analysis was performed both from tissue biopsies and from cfNAs isolated from peripheral blood samples. Out of all 29 different mutations detectable by both NGS panels (plasma and tumor tissue), seven different variants (24.13%; EGFR L858R in two patients, KRAS G13D and Q61H and TP53 G244D, V197M, R213P, and R273H) were detected only in plasma and not in the tumor itself. These mutations were detected in seven different patients, two of them having known distant organ metastasis. Our data show that NGS analysis of cfDNA could identify actionable mutations in advanced NSCLC and, therefore, this analysis could be used to monitor the disease progression and the treatment response and even to modulate the therapy in real time. Full article
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39 pages, 8167 KiB  
Article
Integrating Pharmacogenomics Data-Driven Computational Drug Prediction with Single-Cell RNAseq to Demonstrate the Efficacy of a NAMPT Inhibitor against Aggressive, Taxane-Resistant, and Stem-like Cells in Lethal Prostate Cancer
by Suman Mazumder, Taraswi Mitra Ghosh, Ujjal K. Mukherjee, Sayak Chakravarti, Farshad Amiri, Razan S. Waliagha, Farnaz Hemmati, Panagiotis Mistriotis, Salsabil Ahmed, Isra Elhussin, Ahmad-Bin Salam, Windy Dean-Colomb, Clayton Yates, Robert D. Arnold and Amit K. Mitra
Cancers 2022, 14(23), 6009; https://doi.org/10.3390/cancers14236009 - 6 Dec 2022
Cited by 9 | Viewed by 5404
Abstract
Metastatic prostate cancer/PCa is the second leading cause of cancer deaths in US men. Most early-stage PCa are dependent on overexpression of the androgen receptor (AR) and, therefore, androgen deprivation therapies/ADT-sensitive. However, eventual resistance to standard medical castration (AR-inhibitors) and secondary chemotherapies (taxanes) [...] Read more.
Metastatic prostate cancer/PCa is the second leading cause of cancer deaths in US men. Most early-stage PCa are dependent on overexpression of the androgen receptor (AR) and, therefore, androgen deprivation therapies/ADT-sensitive. However, eventual resistance to standard medical castration (AR-inhibitors) and secondary chemotherapies (taxanes) is nearly universal. Further, the presence of cancer stem-like cells (EMT/epithelial-to-mesenchymal transdifferentiation) and neuroendocrine PCa (NEPC) subtypes significantly contribute to aggressive/lethal/advanced variants of PCa (AVPC). In this study, we introduced a pharmacogenomics data-driven optimization-regularization-based computational prediction algorithm (“secDrugs”) to predict novel drugs against lethal PCa. Integrating secDrug with single-cell RNA-sequencing/scRNAseq as a ‘Double-Hit’ drug screening tool, we demonstrated that single-cells representing drug-resistant and stem-cell-like cells showed high expression of the NAMPT pathway genes, indicating potential efficacy of the secDrug FK866 which targets NAMPT. Next, using several cell-based assays, we showed substantial impact of FK866 on clinically advanced PCa as a single agent and in combination with taxanes or AR-inhibitors. Bulk-RNAseq and scRNAseq revealed that, in addition to NAMPT inhibition, FK866 regulates tumor metastasis, cell migration, invasion, DNA repair machinery, redox homeostasis, autophagy, as well as cancer stemness–related genes, HES1 and CD44. Further, we combined a microfluidic chip-based cell migration assay with a traditional cell migration/‘scratch’ assay and demonstrated that FK866 reduces cancer cell invasion and motility, indicating abrogation of metastasis. Finally, using PCa patient datasets, we showed that FK866 is potentially capable of reversing the expression of several genes associated with biochemical recurrence, including IFITM3 and LTB4R. Thus, using FK866 as a proof-of-concept candidate for drug repurposing, we introduced a novel, universally applicable preclinical drug development pipeline to circumvent subclonal aggressiveness, drug resistance, and stemness in lethal PCa. Full article
(This article belongs to the Collection Prostate Cancer: Pathophysiology, Pathology and Therapy)
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15 pages, 4023 KiB  
Article
Regression of Lung Cancer in Mice by Intranasal Administration of SARS-CoV-2 Spike S1
by Monica Sheinin, Brian Jeong, Ramesh K. Paidi and Kalipada Pahan
Cancers 2022, 14(22), 5648; https://doi.org/10.3390/cancers14225648 - 17 Nov 2022
Cited by 19 | Viewed by 9839
Abstract
This study underlines the importance of SARS-CoV-2 spike S1 in prompting death in cultured non-small cell lung cancer (NSCLC) cells and in vivo in lung tumors in mice. Interestingly, we found that recombinant spike S1 treatment at very low doses led to death [...] Read more.
This study underlines the importance of SARS-CoV-2 spike S1 in prompting death in cultured non-small cell lung cancer (NSCLC) cells and in vivo in lung tumors in mice. Interestingly, we found that recombinant spike S1 treatment at very low doses led to death of human A549 NSCLC cells. On the other hand, boiled recombinant SARS-CoV-2 spike S1 remained unable to induce death, suggesting that the induction of cell death in A549 cells was due to native SARS-CoV-2 spike S1 protein. SARS-CoV-2 spike S1-induced A549 cell death was also inhibited by neutralizing antibodies against spike S1 and ACE2. Moreover, our newly designed wild type ACE2-interacting domain of SARS-CoV-2 (wtAIDS), but not mAIDS, peptide also attenuated SARS-CoV-2 spike S1-induced cell death, suggesting that SARS-CoV-2 spike S1-induced death in A549 NSCLC cells depends on its interaction with ACE2 receptor. Similarly, recombinant spike S1 treatment also led to death of human H1299 and H358 NSCLC cells. Finally, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) intoxication led to the formation tumors in lungs of A/J mice and alternate day intranasal treatment with low dose of recombinant SARS-CoV-2 spike S1 from 22-weeks of NNK insult (late stage) induced apoptosis and tumor regression in the lungs. These studies indicate that SARS-CoV-2 spike S1 may have implications for lung cancer treatment. Full article
(This article belongs to the Section Cancer Therapy)
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19 pages, 4696 KiB  
Article
Gambogic Acid Induces Pyroptosis of Colorectal Cancer Cells through the GSDME-Dependent Pathway and Elicits an Antitumor Immune Response
by Hanjie Xu, Danya Zhang, Rui Wei, Ying Zhou, Geyang Dai, Jie Li, Yue Sun, Fei Li and Ling Xi
Cancers 2022, 14(22), 5505; https://doi.org/10.3390/cancers14225505 - 9 Nov 2022
Cited by 39 | Viewed by 3665
Abstract
Pyroptosis is a recently identified form of programmed cell death (PCD) that exerts a vital influence on the antitumor immune response. GA, a xanthone structure isolated from gamboge resin, is a naturally occurring bioactive ingredient with several anticancer activities, such as activities that [...] Read more.
Pyroptosis is a recently identified form of programmed cell death (PCD) that exerts a vital influence on the antitumor immune response. GA, a xanthone structure isolated from gamboge resin, is a naturally occurring bioactive ingredient with several anticancer activities, such as activities that affect cell cycle arrest, apoptosis, and autophagy. Here, we found that GA decreased the viability of the CRC cell lines, HCT116 and CT26, in a dose- and time-dependent manner, and multiple pores and large bubbles in the membranes, which are morphological characteristics of pyroptosis, were observed by light microscopy and transmission electron microscopy (TEM). Furthermore, the cleavage of gasdermin E (GSDME) was observed after exposure to GA, along with concomitant activation of caspase-3. Additionally, GSDME-dependent pyroptosis triggered by GA could be attenuated by siRNA-mediated knockdown of GSDME and treatment with the caspase-3 inhibitor. Moreover, we found that GA induced pyroptosis and significantly inhibited tumor growth in CT26 tumor-bearing mice. Strikingly, significantly increased proportions of CD3+ T cells, cytotoxic T lymphocytes (CTLs), and dendritic cells (DCs) were observed in the tumor microenvironment in the GA-treated groups. Moreover, significantly increased proportions of CTLs and effector memory T cells (TEM) (CD8+ CD44+ CD62L) were also detected in the spleens of the GA-treated groups, suggesting that the pyroptosis-induced immune response generated a robust memory response that mediated protective immunity. In this study, we revealed a previously unrecognized mechanism by which GA induces GSDME-dependent pyroptosis and enhances the anticancer immune response. Based on this mechanism, GA is a promising antitumor drug for CRC treatment that induces caspase-3-GSDME-dependent pyroptosis. This study provides novel insight into cancer chemoimmunotherapy. Full article
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10 pages, 514 KiB  
Article
Global Association of COVID-19 Pandemic Measures with Cancer Treatment: A Systematic Review and Meta-Analysis
by Federica Teglia, Marco Angelini, Giulia Casolari, Laura Astolfi and Paolo Boffetta
Cancers 2022, 14(22), 5490; https://doi.org/10.3390/cancers14225490 - 8 Nov 2022
Cited by 13 | Viewed by 2131
Abstract
Importance: The COVID-19 pandemic has put a serious strain on health services, including cancer treatment. Objective: This study aimed to investigate the changes in cancer treatment worldwide during the first phase of the SARS-CoV-2 outbreak. Data Sources: Pubmed, Proquest, and Scopus databases were [...] Read more.
Importance: The COVID-19 pandemic has put a serious strain on health services, including cancer treatment. Objective: This study aimed to investigate the changes in cancer treatment worldwide during the first phase of the SARS-CoV-2 outbreak. Data Sources: Pubmed, Proquest, and Scopus databases were searched comprehensively for articles published between 1 January 2020 and 12 December 2021, in order to perform a systematic review and meta-analysis conducted following the PRISMA statement. Study Selection: Studies and articles that reported data on the number of or variation in cancer treatments between the pandemic and pre-pandemic periods, comprising oncological surgery, radiotherapy, and systemic therapies, were included. Data Extraction and Synthesis: Data were extracted from two pairs of independent reviewers. The weighted average of the percentage variation was calculated between the two periods to assess the change in the number of cancer treatments performed during the pandemic. Stratified analyses were performed by type of treatment, geographic area, time period, study setting, and type of cancer. Results: Among the 47 articles retained, we found an overall reduction of −18.7% (95% CI, −24.1 to −13.3) in the total number of cancer treatments administered during the COVID-19 pandemic compared to the previous periods. Surgical treatment had a larger decrease compared to medical treatment (−33.9% versus −12.6%). For all three types of treatments, we identified a U-shaped temporal trend during the entire period January–October 2020. Significant decreases were also identified for different types of cancer, in particular for skin cancer (−34.7% [95% CI, −46.8 to −22.5]) and for all geographic areas, in particular, Asia (−42.1% [95% CI, −49.6 to −34.7]). Conclusions and Relevance: The interruption, delay, and modifications to cancer treatment due to the COVID-19 pandemic are expected to alter the quality of care and patient outcomes. Full article
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18 pages, 1880 KiB  
Article
An Effective Method for Lung Cancer Diagnosis from CT Scan Using Deep Learning-Based Support Vector Network
by Imran Shafi, Sadia Din, Asim Khan, Isabel De La Torre Díez, Ramón del Jesús Palí Casanova, Kilian Tutusaus Pifarre and Imran Ashraf
Cancers 2022, 14(21), 5457; https://doi.org/10.3390/cancers14215457 - 6 Nov 2022
Cited by 89 | Viewed by 17039
Abstract
The diagnosis of early-stage lung cancer is challenging due to its asymptomatic nature, especially given the repeated radiation exposure and high cost of computed tomography(CT). Examining the lung CT images to detect pulmonary nodules, especially the cell lung cancer lesions, is also tedious [...] Read more.
The diagnosis of early-stage lung cancer is challenging due to its asymptomatic nature, especially given the repeated radiation exposure and high cost of computed tomography(CT). Examining the lung CT images to detect pulmonary nodules, especially the cell lung cancer lesions, is also tedious and prone to errors even by a specialist. This study proposes a cancer diagnostic model based on a deep learning-enabled support vector machine (SVM). The proposed computer-aided design (CAD) model identifies the physiological and pathological changes in the soft tissues of the cross-section in lung cancer lesions. The model is first trained to recognize lung cancer by measuring and comparing the selected profile values in CT images obtained from patients and control patients at their diagnosis. Then, the model is tested and validated using the CT scans of both patients and control patients that are not shown in the training phase. The study investigates 888 annotated CT scans from the publicly available LIDC/IDRI database. The proposed deep learning-assisted SVM-based model yields 94% accuracy for pulmonary nodule detection representing early-stage lung cancer. It is found superior to other existing methods including complex deep learning, simple machine learning, and the hybrid techniques used on lung CT images for nodule detection. Experimental results demonstrate that the proposed approach can greatly assist radiologists in detecting early lung cancer and facilitating the timely management of patients. Full article
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12 pages, 2080 KiB  
Article
Predicting Malignant Lymph Nodes Using a Novel Scoring System Based on Multi-Endobronchial Ultrasound Features
by Momoko Morishita, Keigo Uchimura, Hideaki Furuse, Tatsuya Imabayashi, Takaaki Tsuchida and Yuji Matsumoto
Cancers 2022, 14(21), 5355; https://doi.org/10.3390/cancers14215355 - 30 Oct 2022
Cited by 8 | Viewed by 13960
Abstract
Endobronchial ultrasound (EBUS) features with B-, power/color Doppler, and elastography modes help differentiate between benign and malignant lymph nodes (MLNs) during transbronchial needle aspiration (TBNA); however, only few studies have assessed them simultaneously. We evaluated the diagnostic accuracy of each EBUS feature and [...] Read more.
Endobronchial ultrasound (EBUS) features with B-, power/color Doppler, and elastography modes help differentiate between benign and malignant lymph nodes (MLNs) during transbronchial needle aspiration (TBNA); however, only few studies have assessed them simultaneously. We evaluated the diagnostic accuracy of each EBUS feature and aimed to establish a scoring system to predict MLNs. EBUS features of consecutive patients and final diagnosis per lymph node (LN) were examined retrospectively. In total, 594 LNs from 301 patients were analyzed. Univariable analyses revealed that EBUS features, except for round shape, could differentiate MLNs from benign LNs. Multivariable analysis revealed that short axis (>1 cm), heterogeneous echogenicity, absence of central hilar structure, presence of coagulation necrosis sign, and blue-dominant elastographic images were independent predictors of MLNs. At three or more EBUS features predicting MLNs, our scoring system had high sensitivity (77.9%) and specificity (91.8%). The area under the receiver operating curve (AUC) was 0.894 (95% confidence interval (CI): 0.868–0.920), which was higher than that of B-mode features alone (AUC: 0.840 (95% CI: 0.807–0.873)). The novel scoring system could predict MLNs more accurately than B-mode features alone. Multi-EBUS features may increase EBUS-TBNA efficiency for LN evaluation. Full article
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30 pages, 36396 KiB  
Article
A Soft Label Deep Learning to Assist Breast Cancer Target Therapy and Thyroid Cancer Diagnosis
by Ching-Wei Wang, Kuan-Yu Lin, Yi-Jia Lin, Muhammad-Adil Khalil, Kai-Lin Chu and Tai-Kuang Chao
Cancers 2022, 14(21), 5312; https://doi.org/10.3390/cancers14215312 - 28 Oct 2022
Cited by 15 | Viewed by 3475
Abstract
According to the World Health Organization Report 2022, cancer is the most common cause of death contributing to nearly one out of six deaths worldwide. Early cancer diagnosis and prognosis have become essential in reducing the mortality rate. On the other hand, cancer [...] Read more.
According to the World Health Organization Report 2022, cancer is the most common cause of death contributing to nearly one out of six deaths worldwide. Early cancer diagnosis and prognosis have become essential in reducing the mortality rate. On the other hand, cancer detection is a challenging task in cancer pathology. Trained pathologists can detect cancer, but their decisions are subjective to high intra- and inter-observer variability, which can lead to poor patient care owing to false-positive and false-negative results. In this study, we present a soft label fully convolutional network (SL-FCN) to assist in breast cancer target therapy and thyroid cancer diagnosis, using four datasets. To aid in breast cancer target therapy, the proposed method automatically segments human epidermal growth factor receptor 2 (HER2) amplification in fluorescence in situ hybridization (FISH) and dual in situ hybridization (DISH) images. To help in thyroid cancer diagnosis, the proposed method automatically segments papillary thyroid carcinoma (PTC) on Papanicolaou-stained fine needle aspiration and thin prep whole slide images (WSIs). In the evaluation of segmentation of HER2 amplification in FISH and DISH images, we compare the proposed method with thirteen deep learning approaches, including U-Net, U-Net with InceptionV5, Ensemble of U-Net with Inception-v4, Inception-Resnet-v2 encoder, and ResNet-34 encoder, SegNet, FCN, modified FCN, YOLOv5, CPN, SOLOv2, BCNet, and DeepLabv3+ with three different backbones, including MobileNet, ResNet, and Xception, on three clinical datasets, including two DISH datasets on two different magnification levels and a FISH dataset. The result on DISH breast dataset 1 shows that the proposed method achieves high accuracy of 87.77 ± 14.97%, recall of 91.20 ± 7.72%, and F1-score of 81.67 ± 17.76%, while, on DISH breast dataset 2, the proposed method achieves high accuracy of 94.64 ± 2.23%, recall of 83.78 ± 6.42%, and F1-score of 85.14 ± 6.61% and, on the FISH breast dataset, the proposed method achieves high accuracy of 93.54 ± 5.24%, recall of 83.52 ± 13.15%, and F1-score of 86.98 ± 9.85%, respectively. Furthermore, the proposed method outperforms most of the benchmark approaches by a significant margin (p <0.001). In evaluation of segmentation of PTC on Papanicolaou-stained WSIs, the proposed method is compared with three deep learning methods, including Modified FCN, U-Net, and SegNet. The experimental result demonstrates that the proposed method achieves high accuracy of 99.99 ± 0.01%, precision of 92.02 ± 16.6%, recall of 90.90 ± 14.25%, and F1-score of 89.82 ± 14.92% and significantly outperforms the baseline methods, including U-Net and FCN (p <0.001). With the high degree of accuracy, precision, and recall, the results show that the proposed method could be used in assisting breast cancer target therapy and thyroid cancer diagnosis with faster evaluation and minimizing human judgment errors. Full article
(This article belongs to the Special Issue Clinical Perspective and Translational Oncology of Liquid Biopsy)
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34 pages, 4145 KiB  
Article
Involvement of HHV-4 (Epstein–Barr Virus) and HHV-5 (Cytomegalovirus) in Inflammatory Bowel Disease and Colorectal Cancer: A Meta-Analysis
by Luigi Marongiu, Sascha Venturelli and Heike Allgayer
Cancers 2022, 14(20), 5085; https://doi.org/10.3390/cancers14205085 - 17 Oct 2022
Cited by 4 | Viewed by 3679
Abstract
Gastrointestinal diseases (GDs) include colorectal cancer (CRC), gastric cancer (GC), and inflammatory bowel disease (IBD). CRC and GC are typically diagnosed at later stages of development, reducing patients’ chances of survival. IBD is characterized by chronic intestinal inflammation and is a significant risk [...] Read more.
Gastrointestinal diseases (GDs) include colorectal cancer (CRC), gastric cancer (GC), and inflammatory bowel disease (IBD). CRC and GC are typically diagnosed at later stages of development, reducing patients’ chances of survival. IBD is characterized by chronic intestinal inflammation and is a significant risk factor for the development of CRC. Chronic bacterial infections have been shown to promote some GDs, but the role of viruses in the etiology of these diseases is less clear. The present meta-analysis retrieved literature on the viral prevalence in GD patients, measuring the GD risk in odd ratios. By quantifying the study heterogeneity, the literature bias was fundamentally included in the analysis. The analysis also included 11 metagenomic studies. Our meta-analysis retrieved 11,413 studies, with 196 suitable for analysis. HHV-4 (Epstein–Barr virus) was identified as a significant risk factor for the development of IBD, and HHV-5 (cytomegalovirus) as a risk factor for both CRC and IBD. Polyomaviruses and the Hepatitis B virus were also, less strongly, involved in the risk of CRC and IBD. No relations withstanding the literature bias were identified for GC. The study discusses these findings, as well as the role of other viruses in the etiology of CRC and IBD. Full article
(This article belongs to the Special Issue Biomarker in Metastatic Colorectal Cancer)
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24 pages, 11851 KiB  
Article
Development of a High-Affinity Antibody against the Tumor-Specific and Hyperactive 611-p95HER2 Isoform
by Esmaeil Dorraji, Elin Borgen, Dario Segura-Peña, Puneet Rawat, Eva Smorodina, Claire Dunn, Victor Greiff, Nikolina Sekulić, Hege Russnes and Jon Amund Kyte
Cancers 2022, 14(19), 4859; https://doi.org/10.3390/cancers14194859 - 5 Oct 2022
Cited by 2 | Viewed by 5240
Abstract
The expression of human epidermal growth factor receptor 2 (HER2) is a key classification factor in breast cancer. Many breast cancers express isoforms of HER2 with truncated carboxy-terminal fragments (CTF), collectively known as p95HER2. A common p95HER2 isoform, 611-CTF, is a biomarker for [...] Read more.
The expression of human epidermal growth factor receptor 2 (HER2) is a key classification factor in breast cancer. Many breast cancers express isoforms of HER2 with truncated carboxy-terminal fragments (CTF), collectively known as p95HER2. A common p95HER2 isoform, 611-CTF, is a biomarker for aggressive disease and confers resistance to therapy. Contrary to full-length HER2, 611-p95HER2 has negligible normal tissue expression. There is currently no approved diagnostic assay to identify this subgroup and no therapy targeting this mechanism of tumor escape. The purpose of this study was to develop a monoclonal antibody (mAb) against 611-CTF-p95HER2. Hybridomas were generated from rats immunized with cells expressing 611-CTF. A hybridoma producing a highly specific Ab was identified and cloned further as a mAb. This mAb, called Oslo-2, gave strong staining for 611-CTF and no binding to full-length HER2, as assessed in cell lines and tissues by flow cytometry, immunohistochemistry and immunofluorescence. No cross-reactivity against HER2 negative controls was detected. Surface plasmon resonance analysis demonstrated a high binding affinity (equilibrium dissociation constant 2 nM). The target epitope was identified at the N-terminal end, using experimental alanine scanning. Further, the mAb paratope was identified and characterized with hydrogen-deuterium-exchange, and a molecular model for the (Oslo-2 mAb:611-CTF-p95HER2) complex was generated by an experimental-information-driven docking approach. We conclude that the Oslo-2 mAb has a high affinity and is highly specific for 611-CTF-p95HER2. The Ab may be used to develop potent and safe therapies, overcoming p95HER2-mediated tumor escape, as well as for developing diagnostic assays. Full article
(This article belongs to the Section Methods and Technologies Development)
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22 pages, 2945 KiB  
Article
Factors Predicting Surgical Effort Using Explainable Artificial Intelligence in Advanced Stage Epithelial Ovarian Cancer
by Alexandros Laios, Evangelos Kalampokis, Racheal Johnson, Sarika Munot, Amudha Thangavelu, Richard Hutson, Tim Broadhead, Georgios Theophilou, Chris Leach, David Nugent and Diederick De Jong
Cancers 2022, 14(14), 3447; https://doi.org/10.3390/cancers14143447 - 15 Jul 2022
Cited by 26 | Viewed by 5221
Abstract
(1) Background: Surgical cytoreduction for epithelial ovarian cancer (EOC) is a complex procedure. Encompassed within the performance skills to achieve surgical precision, intra-operative surgical decision-making remains a core feature. The use of eXplainable Artificial Intelligence (XAI) could potentially interpret the influence of human [...] Read more.
(1) Background: Surgical cytoreduction for epithelial ovarian cancer (EOC) is a complex procedure. Encompassed within the performance skills to achieve surgical precision, intra-operative surgical decision-making remains a core feature. The use of eXplainable Artificial Intelligence (XAI) could potentially interpret the influence of human factors on the surgical effort for the cytoreductive outcome in question; (2) Methods: The retrospective cohort study evaluated 560 consecutive EOC patients who underwent cytoreductive surgery between January 2014 and December 2019 in a single public institution. The eXtreme Gradient Boosting (XGBoost) and Deep Neural Network (DNN) algorithms were employed to develop the predictive model, including patient- and operation-specific features, and novel features reflecting human factors in surgical heuristics. The precision, recall, F1 score, and area under curve (AUC) were compared between both training algorithms. The SHapley Additive exPlanations (SHAP) framework was used to provide global and local explainability for the predictive model; (3) Results: A surgical complexity score (SCS) cut-off value of five was calculated using a Receiver Operator Characteristic (ROC) curve, above which the probability of incomplete cytoreduction was more likely (area under the curve [AUC] = 0.644; 95% confidence interval [CI] = 0.598–0.69; sensitivity and specificity 34.1%, 86.5%, respectively; p = 0.000). The XGBoost outperformed the DNN assessment for the prediction of the above threshold surgical effort outcome (AUC = 0.77; 95% [CI] 0.69–0.85; p < 0.05 vs. AUC 0.739; 95% [CI] 0.655–0.823; p < 0.95). We identified “turning points” that demonstrated a clear preference towards above the given cut-off level of surgical effort; in consultant surgeons with <12 years of experience, age <53 years old, who, when attempting primary cytoreductive surgery, recorded the presence of ascites, an Intraoperative Mapping of Ovarian Cancer score >4, and a Peritoneal Carcinomatosis Index >7, in a surgical environment with the optimization of infrastructural support. (4) Conclusions: Using XAI, we explain how intra-operative decisions may consider human factors during EOC cytoreduction alongside factual knowledge, to maximize the magnitude of the selected trade-off in effort. XAI techniques are critical for a better understanding of Artificial Intelligence frameworks, and to enhance their incorporation in medical applications. Full article
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14 pages, 900 KiB  
Article
Accurate Screening for Early-Stage Breast Cancer by Detection and Profiling of Circulating Tumor Cells
by Timothy Crook, Robert Leonard, Kefah Mokbel, Alastair Thompson, Michael Michell, Raymond Page, Ashok Vaid, Ravi Mehrotra, Anantbhushan Ranade, Sewanti Limaye, Darshana Patil, Dadasaheb Akolkar, Vineet Datta, Pradip Fulmali, Sachin Apurwa, Stefan Schuster, Ajay Srinivasan and Rajan Datar
Cancers 2022, 14(14), 3341; https://doi.org/10.3390/cancers14143341 - 9 Jul 2022
Cited by 31 | Viewed by 12335
Abstract
Background: The early detection of breast cancer (BrC) is associated with improved survival. We describe a blood-based breast cancer detection test based on functional enrichment of breast-adenocarcinoma-associated circulating tumor cells (BrAD-CTCs) and their identification via multiplexed fluorescence immunocytochemistry (ICC) profiling for GCDFP15, GATA3, [...] Read more.
Background: The early detection of breast cancer (BrC) is associated with improved survival. We describe a blood-based breast cancer detection test based on functional enrichment of breast-adenocarcinoma-associated circulating tumor cells (BrAD-CTCs) and their identification via multiplexed fluorescence immunocytochemistry (ICC) profiling for GCDFP15, GATA3, EpCAM, PanCK, and CD45 status. Methods: The ability of the test to differentiate BrC cases (N = 548) from healthy women (N = 9632) was evaluated in a case–control clinical study. The ability of the test to differentiate BrC cases from those with benign breast conditions was evaluated in a prospective clinical study of women (N = 141) suspected of BrC. Results: The test accurately detects BrAD-CTCs in breast cancers, irrespective of age, ethnicity, disease stage, grade, or hormone receptor status. Analytical validation established the high accuracy and reliability of the test under intended use conditions. The test detects and differentiates BrC cases from healthy women with 100% specificity and 92.07% overall sensitivity in a case–control study. In a prospective clinical study, the test shows 93.1% specificity and 94.64% overall sensitivity in differentiating breast cancer cases (N = 112) from benign breast conditions (N = 29). Conclusion: The findings reported in this manuscript support the clinical potential of this test for blood-based BrC detection. Full article
(This article belongs to the Special Issue Breast Development and Cancer)
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15 pages, 2997 KiB  
Article
Brain Functional Connectivity in Low- and High-Grade Gliomas: Differences in Network Dynamics Associated with Tumor Grade and Location
by Luca Pasquini, Mehrnaz Jenabi, Onur Yildirim, Patrick Silveira, Kyung K. Peck and Andrei I. Holodny
Cancers 2022, 14(14), 3327; https://doi.org/10.3390/cancers14143327 - 8 Jul 2022
Cited by 27 | Viewed by 5133
Abstract
Brain tumors lead to modifications of brain networks. Graph theory plays an important role in clarifying the principles of brain connectivity. Our objective was to investigate network modifications related to tumor grade and location using resting-state functional magnetic resonance imaging (fMRI) and graph [...] Read more.
Brain tumors lead to modifications of brain networks. Graph theory plays an important role in clarifying the principles of brain connectivity. Our objective was to investigate network modifications related to tumor grade and location using resting-state functional magnetic resonance imaging (fMRI) and graph theory. We retrospectively studied 30 low-grade (LGG), 30 high-grade (HGG) left-hemispheric glioma patients and 20 healthy controls (HC) with rs-fMRI. Tumor location was labeled as: frontal, temporal, parietal, insular or occipital. We collected patients’ clinical data from records. We analyzed whole-brain and hemispheric networks in all patients and HC. Subsequently, we studied lobar networks in subgroups of patients divided by tumor location. Seven graph-theoretical metrics were calculated (FDR p < 0.05). Connectograms were computed for significant nodes. The two-tailed Student t-test or Mann–Whitney U-test (p < 0.05) were used to compare graph metrics and clinical data. The hemispheric network analysis showed increased ipsilateral connectivity for LGG (global efficiency p = 0.03) and decreased contralateral connectivity for HGG (degree/cost p = 0.028). Frontal and temporal tumors showed bilateral modifications; parietal and insular tumors showed only local effects. Temporal tumors led to a bilateral decrease in all graph metrics. Tumor grade and location influence the pattern of network reorganization. LGG may show more favorable network changes than HGG, reflecting fewer clinical deficits. Full article
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16 pages, 1829 KiB  
Article
Urine CA125 and HE4 for the Triage of Symptomatic Women with Suspected Endometrial Cancer
by Kelechi Njoku, Chloe E. Barr, Caroline J. J. Sutton and Emma J. Crosbie
Cancers 2022, 14(14), 3306; https://doi.org/10.3390/cancers14143306 - 6 Jul 2022
Cited by 13 | Viewed by 4555
Abstract
A simple, noninvasive and accurate detection tool that can triage women with suspected endometrial cancer for definitive testing will transform patient care. The aim of this study was to evaluate urine CA125 and HE4 levels for the detection of endometrial cancer in symptomatic [...] Read more.
A simple, noninvasive and accurate detection tool that can triage women with suspected endometrial cancer for definitive testing will transform patient care. The aim of this study was to evaluate urine CA125 and HE4 levels for the detection of endometrial cancer in symptomatic women. This was a cross-sectional diagnostic accuracy study of 153 symptomatic women who underwent urgent diagnostic investigations for suspected endometrial cancer at a large gynecological cancer center. Urine samples were collected prior to routine clinical procedures. Urine CA125 and HE4 levels were determined using automated chemiluminescent enzyme immunoassays. Univariate and multivariable receiver operating characteristic (ROC) curve analyses were performed. Urine CA125 and HE4 were discovered to be significantly elevated in women with endometrial cancer, compared to controls (p < 0.001 and p = 0.01, respectively). Urine CA125 and HE4 detected endometrial cancer with an area under the ROC curve (AUC) of 0.89 (0.81, 0.98) and 0.69 (0.55, 0.83), respectively. CA125 exhibited good discriminatory potential for Type I and early-stage tumors (AUC 0.93 and 0.90, respectively). A diagnostic model that combined urine CA125 and transvaginal ultrasound-measured endometrial thickness predicted endometrial cancer with an AUC of 0.96 (0.91, 1.00). Urine CA125 displays potential as a diagnostic tool for symptomatic women with suspected endometrial cancer. When combined with transvaginal ultrasound-measured endometrial thickness, this patient-friendly, urine-based test could help triage women for invasive diagnostics or safe reassurance, reducing costs and improving patient experience. Full article
(This article belongs to the Special Issue Cancer Detection in Primary Care)
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16 pages, 3171 KiB  
Article
Prognostic and Predictive Role of Body Composition in Metastatic Neuroendocrine Tumor Patients Treated with Everolimus: A Real-World Data Analysis
by Nicoletta Ranallo, Andrea Prochoswski Iamurri, Flavia Foca, Chiara Liverani, Alessandro De Vita, Laura Mercatali, Chiara Calabrese, Chiara Spadazzi, Carlo Fabbri, Davide Cavaliere, Riccardo Galassi, Stefano Severi, Maddalena Sansovini, Andreas Tartaglia, Federica Pieri, Laura Crudi, David Bianchini, Domenico Barone, Giovanni Martinelli, Giovanni Luca Frassineti, Toni Ibrahim, Luana Calabrò, Rossana Berardi and Alberto Bongiovanniadd Show full author list remove Hide full author list
Cancers 2022, 14(13), 3231; https://doi.org/10.3390/cancers14133231 - 30 Jun 2022
Cited by 9 | Viewed by 2908
Abstract
Neuroendocrine tumors (NETs) are rare neoplasms frequently characterized by an upregulation of the mammalian rapamycin targeting (mTOR) pathway resulting in uncontrolled cell proliferation. The mTOR pathway is also involved in skeletal muscle protein synthesis and in adipose tissue metabolism. Everolimus inhibits the mTOR [...] Read more.
Neuroendocrine tumors (NETs) are rare neoplasms frequently characterized by an upregulation of the mammalian rapamycin targeting (mTOR) pathway resulting in uncontrolled cell proliferation. The mTOR pathway is also involved in skeletal muscle protein synthesis and in adipose tissue metabolism. Everolimus inhibits the mTOR pathway, resulting in blockade of cell growth and tumor progression. The aim of this study is to investigate the role of body composition indexes in patients with metastatic NETs treated with everolimus. The study population included 30 patients with well-differentiated (G1-G2), metastatic NETs treated with everolimus at the IRCCS Romagnolo Institute for the Study of Tumors (IRST) “Dino Amadori”, Meldola (FC), Italy. The body composition indexes (skeletal muscle index [SMI] and adipose tissue indexes) were assessed by measuring on a computed tomography (CT) scan the cross-sectional area at L3 at baseline and at the first radiological assessment after the start of treatment. The body mass index (BMI) was assessed at baseline. The median progression-free survival (PFS) was 8.9 months (95% confidence interval [CI]: 3.4–13.7 months). The PFS stratified by tertiles was 3.2 months (95% CI: 0.9–10.1 months) in patients with low SMI (tertile 1), 14.2 months (95% CI: 2.3 months-not estimable [NE]) in patients with intermediate SMI (tertile 2), and 9.1 months (95% CI: 2.7 months-NE) in patients with high SMI (tertile 3) (p = 0.039). Similarly, the other body composition indexes also showed a statistically significant difference in the three groups on the basis of tertiles. The median PFS was 3.2 months (95% CI: 0.9–6.7 months) in underweight patients (BMI ≤ 18.49 kg/m2) and 10.1 months (95% CI: 3.7–28.4 months) in normal-weight patients (p = 0.011). There were no significant differences in terms of overall survival. The study showed a correlation between PFS and the body composition indexes in patients with NETs treated with everolimus, underlining the role of adipose and muscle tissue in these patients. Full article
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17 pages, 3161 KiB  
Article
Targeting Immunosuppressive Tumor-Associated Macrophages Using Innate T Cells for Enhanced Antitumor Reactivity
by Yan-Ruide Li, James Brown, Yanqi Yu, Derek Lee, Kuangyi Zhou, Zachary Spencer Dunn, Ryan Hon, Matthew Wilson, Adam Kramer, Yichen Zhu, Ying Fang and Lili Yang
Cancers 2022, 14(11), 2749; https://doi.org/10.3390/cancers14112749 - 1 Jun 2022
Cited by 46 | Viewed by 6375
Abstract
The field of T cell-based and chimeric antigen receptor (CAR)-engineered T (CAR-T) cell-based antitumor immunotherapy has seen substantial developments in the past decade; however, considerable issues, such as graft-versus-host disease (GvHD) and tumor-associated immunosuppression, have proven to be substantial roadblocks to widespread adoption [...] Read more.
The field of T cell-based and chimeric antigen receptor (CAR)-engineered T (CAR-T) cell-based antitumor immunotherapy has seen substantial developments in the past decade; however, considerable issues, such as graft-versus-host disease (GvHD) and tumor-associated immunosuppression, have proven to be substantial roadblocks to widespread adoption and implementation. Recent developments in innate immune cell-based CAR therapy have opened several doors for the expansion of this therapy, especially as it relates to allogeneic cell sources and solid tumor infiltration. This study establishes in vitro killing assays to examine the TAM-targeting efficacy of MAIT, iNKT, and γδT cells. This study also assesses the antitumor ability of CAR-engineered innate T cells, evaluating their potential adoption for clinical therapies. The in vitro trials presented in this study demonstrate the considerable TAM-killing abilities of all three innate T cell types, and confirm the enhanced antitumor abilities of CAR-engineered innate T cells. The tumor- and TAM-targeting capacity of these innate T cells suggest their potential for antitumor therapy that supplements cytotoxicity with remediation of tumor microenvironment (TME)-immunosuppression. Full article
(This article belongs to the Special Issue Engineering the Tumor Immune Microenvironment)
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19 pages, 2247 KiB  
Article
Gallic Acid: A Natural Phenolic Compound Exerting Antitumoral Activities in Colorectal Cancer via Interaction with G-Quadruplexes
by Victoria Sanchez-Martin, María del Carmen Plaza-Calonge, Ana Soriano-Lerma, Matilde Ortiz-Gonzalez, Angel Linde-Rodriguez, Virginia Perez-Carrasco, Inmaculada Ramirez-Macias, Marta Cuadros, Jose Gutierrez-Fernandez, Javier Murciano-Calles, Juan Carlos Rodríguez-Manzaneque, Miguel Soriano and Jose Antonio Garcia-Salcedo
Cancers 2022, 14(11), 2648; https://doi.org/10.3390/cancers14112648 - 26 May 2022
Cited by 29 | Viewed by 3633
Abstract
Natural phenolic compounds have gained momentum for the prevention and treatment of cancer, but their antitumoral mechanism of action is not yet well understood. In the present study, we screened the antitumoral potential of several phenolic compounds in a cellular model of colorectal [...] Read more.
Natural phenolic compounds have gained momentum for the prevention and treatment of cancer, but their antitumoral mechanism of action is not yet well understood. In the present study, we screened the antitumoral potential of several phenolic compounds in a cellular model of colorectal cancer (CRC). We selected gallic acid (GA) as a candidate in terms of potency and selectivity and extensively evaluated its biological activity. We report on the role of GA as a ligand of DNA G-quadruplexes (G4s), explaining several of its antitumoral effects, including the transcriptional inhibition of ribosomal and CMYC genes. In addition, GA shared with other established G4 ligands some effects such as cell cycle arrest, nucleolar stress, and induction of DNA damage. We further confirmed the antitumoral and G4-stabilizing properties of GA using a xenograft model of CRC. Finally, we succinctly demonstrate that GA could be explored as a therapeutic agent in a patient cohort with CRC. Our work reveals that GA, a natural bioactive compound present in the diet, affects gene expression by interaction with G4s both in vitro and in vivo and paves the way towards G4s targeting with phenolic compounds. Full article
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12 pages, 1890 KiB  
Article
Sex Differences in the Prevalence of Head and Neck Cancers: A 10-Year Follow-Up Study of 10 Million Healthy People
by Jun-Ook Park, Inn-Chul Nam, Choung-Soo Kim, Sung-Joon Park, Dong-Hyun Lee, Hyun-Bum Kim, Kyung-Do Han and Young-Hoon Joo
Cancers 2022, 14(10), 2521; https://doi.org/10.3390/cancers14102521 - 20 May 2022
Cited by 67 | Viewed by 4863
Abstract
Background: Descriptive epidemiologists have repeatedly reported that males are more susceptible to head and neck cancers. However, most published data are those of cross-sectional studies, and no population-based cohort study has yet been published. The aim of this study was to compare the [...] Read more.
Background: Descriptive epidemiologists have repeatedly reported that males are more susceptible to head and neck cancers. However, most published data are those of cross-sectional studies, and no population-based cohort study has yet been published. The aim of this study was to compare the prevalence of head and neck cancers in healthy males with females. Methods: A retrospective cohort study using the Korean National Health Insurance Service database on 9,598,085 individuals who underwent regular health checkups from 1 January to 31 December 2009. We sought head and neck cancers developed during the 10-year follow-up. Results: A total of 10,732 (incidence rate (IR) per 1000 person-years 0.25) individuals were newly diagnosed with head and neck cancer among the 9,598,085 individuals during the 10-year follow-up. The IR was 0.19 in males (8500 affected) and 0.06 in females (2232 affected). Notably, the male–female ratio increased with age below 70 years but decreased thereafter. The male–female difference was most apparent for laryngeal cancer; the male IR was 11-fold higher in the 40 s and 20-fold higher in the 60 s, followed by hypopharyngeal cancer (6.8- and 24.2-fold). Males smoked more and drank more alcohol than females (p < 0.0001 *, p < 0.0001 *). When never-smokers/-drinkers (only) were compared, males remained at a 2.9-fold higher risk of head and neck cancer than females. The hazard ratios for head and neck cancers in males tended to increase in the lower part of the upper aerodigestive tract: larynx (13.9) > hypopharynx (10.9) > oropharynx (4.4) > nasopharynx (2.9) > sinonasal region (1.8) > oral (1.6). Only the salivary gland cancer incidence did not differ between the sexes; the gland is not in the upper aerodigestive tract. Conclusion: Males are much more susceptible to head and neck cancers than females regardless of whether they drink alcohol or smoke tobacco. Sex differences in the incidence of head and neck cancer are most evident in the 60 s in the lower part of the upper aerodigestive tract, such as the larynx and hypopharynx. Full article
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